Radiographic Imaging

In the United States, radiographs (radiogram s, x-rays) are negative im ages. Thus, air produces a totally black area (no stopping of x-rays) and lead produces a totally w hite area (total stopping of x-rays). Various body structures have different abilities to stop the passage of x-rays so that, for exam ple, bones are dense and relatively light gray while the lungs are mostly filled with air and are relatively dark gray. Radiopaque agents are usually organic chem ical molecules that contain iodine in their structures. The iodine is the radiopaque portion of the m olecule. Barium sulfate (BaSO 4) is a radiopaque agent, that does not contain iodine. Radiopaque agents stop passage of x-rays and produce a white im age on the x-ray. Radiopharm aceuticals are various types of chemicals containing som e radioactive isotope as part of their structure or form ulation. Radiopharm aceuticals emit radioactive particles and create a black image on the x-ray. Organ im aged with a Radiopaque Agent Organ im aged with a Radiopharm aceutical Agent Im age of liver visualized with a radiopharm aceutical and indicating (white spot) area of poor blood flow where the lesion would be located. Tissue around the organ is gray and the organ is black (filled with the radiopharm aceutical agent). The usual truth, in both radiopaque agents and radiopharm aceuticals, is varying shades of gray rather than an absolute black and white. Image of stomach and upper ileum using Barium Sulfate or other radiopaque agent. Tissue around the organ is black and the organ is white (filled with the radiopaque agent). Radiopharm aceuticals Used in Nuclear M edicine Radionuclide Dosage Form Uses Carbon Carbon Cardiac: Blood volum e measurement C-11 m onoxide Carbon C-11 Carbon C-11 Carbon C-11 Carbon C-11 Carbon C-14 Chromium Cr-51 Flum azenil Injection Methionine Injection Raclopride Injection Brain: Benzodiazepine receptor im aging Adult Dose 60-100m Ci (m illicuries) 20-30 m Ci Route Inhalation

IV

Evaluation of neoplastic disease in the brain

10-20 m Ci

IV

Brain: Dopam ine D2 receptor im aging

10-15 m Ci

IV

Sodium Cardiac: Marker of oxidative m etabolism acetate Injection Urea Diagnosis of Helicobacter pylori infection

12-40 m Ci

IV

1 Ci (m icrocuries)

PO

Sodium chrom ate Injection

Labeling red blood cells (RBCs) for m easuring 10-80 Ci RBC volume, survival and splenic sequestration

IV

Page 1

Radionuclide Dosage Form Cobalt Co-57

Uses

Adult Dose 1 Ci

Route PO

Cyanocobalam in Diagnosis of pernicious anemia and Capsules defects of intestinal absorption Glucose utilization in brain, cardiac and neoplastic disease Dopam ine neuronal decarboxylase activity in brain Bone im aging

Fluorine Fludeoxyglucose F-18 Injection Fluorine F-18 Fluorine F-18 Gallium Ga-67 Indium In-111 Indium In-111 Indium In-111 Indium In-111 Fluorodopa Injection Sodium fluoride Injection Gallium citrate Injection Caprom ab pencletide Inj Indium chloride sterile solution Indium oxine sterile solution Pentetate Injection

10-15 m Ci

IV

4-6 m Ci

IV

10 m Ci

IV

Hodgkin's disease, lym phom a Acute inflam m atory lesions Metastatic imaging in patients with biopsy-proven prostate cancer Radiolabeling various
111

8-10 m Ci 5 m Ci 5 m Ci

IV IV IV

In radiopharm aceuticals

Various

Labeling autologous leukocytes

500 Ci

IV

Cisternography a diagnostic procedure 500 Ci that involves injecting a drug into the cistern of spinal fluid at the base of the brain Neuroendocrine tumors

Intrathecal

Indium In-111 Indium In-111

Pentetreotide Injection Ibritum om ab tiuxetan

3 m Ci (planar) 6 m Ci (SPECT) 5 m Ci IV

IV

Biodistribution im aging prior to therapeutic dosing with 90Y Zevalin (Biogen Idec) in the treatm ent of non-Hodgkin's lym phoma Thyroid gland im aging Thyroid m etastasis (total body) Pheochrom ocytom a, carcinoid tum ors nonsecreting paragangliom as, neuroblastom a Plasma volum e determ ination

Iodine I-123 Iodine I-123

Sodium iodide caps and solution Iobenguane Injection

400-600 Ci 2 m Ci

PO PO IV

0.14 m Ci/kg (child) 10 m Ci (adult)

Iodine I-125 Iodine I-125 Iodine I-131

Album in Injection

5-10 Ci

IV

lothalam ate Glomerular filtration rate (GFR) Sodium Injection determ ination Sodium iodide capsules and solution Thyroid function Thyroid im aging (neck) Thyroid imaging (substernal) Thyroid m etastases (total body) Hyperthyroidism Carcinom a

30 Ci

IV

5-10 Ci 50-100 Ci 100 Ci 2 m Ci 5-33 m Ci 150-200 m Ci

PO

Page 2

Radionuclide Dosage Form Iodine I-131 Iodine I-131 Iodine I-131 Iobenguane Injection Iodohippurate sodium injection Tositumom ab

Uses

Adult Dose

Route IV

Pheochrom ocytom a, carcinoid tum ors, 0.5 m Ci/l.7m 2 nonsecreting paragangliomas, neuroblastoma Recoverable renal function 200 Ci (2 kidneys) 75 Ci (1 kidney)

IV

Treatment of refractory low-grade non-Hodgkin's lym phoma

Patient-specific IV dosing; not >75 cGy (centigray) whole body 10-20 m Ci IV

Nitrogen N-13 Oxygen O-15

Am m onia Injection W ater Injection

Myocardial perfusion studies

Cardiac perfusion

30-100 m Ci

IV

Phosphorus Chromic P-32 phosphate suspension Phosphorus Sod phosphate P-32 Injection Rubidium Rb-82 Samarium Sm -153 Strontium Sr-89

Peritoneal and pleural effusions

10-20 m Ci No IV use intraperitoneal or intrapleural 1-8 m Ci IV

Polycythem ia

Rubidium Myocardial perfusion studies chloride Injection Lexidronam Injection Strontium chloride Inj Bone pain palliation in confirm ed osteoblastic m etastatic bone lesions Bone pain palliation in confirm ed osteoblastic m etastatic bone lesions Heart blood pool im aging

30-60 m Ci

IV

1.0 m Ci/kg

IV

4 m Ci

IV

Technetium Album in Tc-99m Injection

20 m Ci

IV

Technetium Albumin Perfusion lung im aging Tc-99m aggregated Injection Technetium Arcitumom ab Tc-99m Technetium Bicisate Tc-99m Injection Technetium Disofenin Tc-99m Injection Technetium Exam etazim e Tc-99m Injection Recurrent or m etastatic colorectal carcinom a Adjunct to CT`/MRId in patients with confirmed stroke Hepatobiliary im aging

3 m Ci

IV

20 m Ci

IV

20 m Ci

IV

5 m Ci

IV

W ith or without m ethylene blue for 20 m Ci regional cerebral perfusion in stroke W ithout methylene blue for leukocyte labeling 10 m Ci Brain im aging Renal perfusion im aging 20 m Ci 10 m Ci

IV IV IV IV

Technetium Gluceptate Tc-99m Injection

Page 3

Radionuclide Dosage Form Technetium Mebrofenin Tc-99m Injection Technetium Medronate Tc-99m Injection Technetium Mertiatide Tc-99m Injection

Uses Hepatobiliary im aging

Adult Dose 5 m Ci

Route IV

Bone imaging

20-30 m Ci

IV

Kidney im aging Renogram renal transplant Renogram captopril Bone imaging

5 m Ci 1-3 m Ci 1-3 m Ci 20-30 m Ci

IV IV IV IV

Technetium Oxidronate Tc-99m Injection Technetium Pentetate Tc-99m Injection

GFR glom erular filtration rate (quantitative) Renogram (diuretic) Renal perfusion im aging Infarct-avid scan

3 m Ci 3 m Ci 10 m Ci 15 m Ci

IV IV IV IV

Technetium Pyrophosphate Tc-99m Injection Technetium Red blood cells Tc-99m Injection Technetium Sestam ibi Tc-99m Injection

GI bleed (interm ittent)

15 m Ci

IV

Myocardial perfusion and function, parathyroid im aging Brain im aging Thyroid im aging Radionuclide ventriculogram Radionuclide cystography Dacryocystography Meckel's diverticulum Renal scan differential renal function Renal scan cortical anatom y Liver and/or spleen scan Lym phoscintigraphy (breast) Lym phoscintigraphy (m elanoma) Gastric em ptying (scrambled egg) GI bleed (acute) Lung aspiration Gastroesophageal reflux Myocardial perfusion and function

8-40 m Ci

IV

Technetium Sodium Tc-99m pertechnetate Injection

20 m Ci 10 m Ci 20 m Ci 1 mCi 0.1 m Ci 5 m Ci 5 m Ci 5 m Ci

IV IV IV Urethral Eye drops IV IV IV

Technetium Succim er Tc-99m Injection Technetium Sulfur colloid Tc-99m Injection

5 m Ci IV 0.4-0.6 m Ci Interstitial 0.5-0.8 m Ci Intradermal 1 mCi PO 10 m Ci IV 5 m Ci PO 0.2 m Ci PO 8-40 m Ci IV

Technetium Tetrofosm in Tc-99m Injection Thallium TI-201 Thallous chloride Injection Xenon

Myocardial perfusion im aging Parathyroid im aging Lung ventilation im aging Treatment of refractory low-grade non-Hodgkin's lym phom a

3-4 m Ci 2 m Ci 10-20 m Ci 0.3-0.4 m Ci/kg

IV IV Inhaled IV

Xenon Xe-133 Yttrium Y-90

Ibritum om ab tiuxetan

Page 4

m Ci = m illicuries; Ci = m icrocuries; IV = intravenous; PO = oral; SPECT = single-photon emission computed tomography; CT = computed tomography; MRI = m agnetic resonance Chem ical and Physical Form s of Radiopharm aceuticals Form Exam ples Elem ental Xenon 133, krypton 81m Simple ions Labeled sm all m olecules 131 I - (iodide), 99m TcO 4 (pertechnetate) 131 IMIBG (covalently bonded) 99m Tc-DTPA (chelation com pound) 125 I-hum an serum album in (protein) 111 In-caprom ab pendetide (antibody) 99 Tc-sulfur colloid 99 Tc-m acroaggregated albumin 51 Cr- or 99 Tc-erythrocytes 111 In- or 99m Tc-leukocytes

Labeled macrom olecules

Labeled particles

Labeled cells

Vitamins
Vitam ins are "organic substances required to prom ote one or m ore essential biochem ical reactions within living cells." They are required in daily am ounts ranging from microgram s to milligram s to provide for norm al growth, developm ent and m aintenance of the hum an biological system. The 13 vitam ins are Nine water-soluble vitamins Vitam in B-1 (thiam ine) Vit B-5 (pantothenic acid) Vit B-2 (riboflavin) Vit B-6 (pyridoxine) Vit B-3 (niacin or nicotinic acid) Vit B-12 (cyanocobalam in) Four fat-soluble vitamins Vitam in A (carotenoids, retinoids) Vitam in E (tocopherol)

Folic acid (folacin) Biotin Vit C (ascorbic acid)

Vitam in D (calciferol) Vitam in K (phytonadione)

Three anti-oxidant vitam ins (included above) Vitam in A (carotenoids, retinoids) Vitamin C (ascrobic acid) Vitam in E (tocopherol) The bioflavanoids, rutin and hesperidin (the so-called vitam in P factors) are not vitam ins and there is no objective evidence that these substances are effective in preventing or treating any m edical disorder. Choline, inositol and para-am inobenzoic acid are not required by m an but are metabolized in vivo as nutrients. Vitam in F is an inaccurate nam e sometim es applied to a mixture of unsaturated fatty acids such as linolenic and linoleic acids. These fatty acids are the precursors for the formation of prostaglandins and thromboxanes (cyclooxygenase pathway) and the leukotrienes (lipoxygenase pathway). Evening Prim rose Oil (EPO) is a nutraceutical used for its content of these fatty acids. It is im portant to understand the difference between vitam in use as prophylactic supplem ents to prevent a deficiency and therapeutic use to treat a deficiency. In m ost cases, the average Am erican diet does not require vitam in supplem entation. Healthy individuals consuming a balanced diet can expect no physiological benefit from additional vitamins. The position of the AMA Council on Food and Nutrition is that "vitam ins are essential nutrients that have food as their usual source; all the nutrients essential for maintaining health in the 'norm al' individual can be supplied by an adequate diet." The difficulty can occur in m aking purveyors of vitam ins for treatm ent of certain m edical conditions prove that the vitam ins are truly effective.

Page 5

Certain vitamin supplem ents are useful during periods of increased dem and such as: 1. Pregnancy 2. Lactation 3. Acute or chronic illness of hyperm etabolic or catabolic nature (bum s, m ajor traum a, cancer, chronic infection) 4. Rapid growth phase of adolescence 5. Malabsorption 6. Regular, strenuous physical activity 7. Neglect of diet (elderly, food faddists, crash diet, emotional upset, poverty, alcoholism, teens) 8. Chronic drug ingestion which may increase vitam in requirem ents (e.g., folic acid with folic acid antagonists, phenytoin or oral contraceptives; B-6 with hydralazine, INH or cycloserine) 9. Breast fed infants 10. Prem ature infants 11. Vegetarian children 12. Children receiving non-fortified skim m ilk Recom mended Daily Intake (RDI) of vitam ins, as determ ined by the Food and Nutrient Board of the National Academ y of Science/National Research Council (NAS/NRC), is adequate to m eet the known nutritional needs of practically all healthy individuals. Allowances are established by age, weight, sex, pregnancy and lactation. The RDI may not cover special needs associated with increased dem and such as those listed above. The new term is Dietary Reference Intakes (DRIs). Vitam in Myths? Vitam ins are often m isused. They are not harm less chemical entities. Distortion of facts by uninform ed or unethical sales personnel has led to a proliferation of high cost products from alfalfa to zinc, bee pollen, garlic, selenium , glucom annan, and overpriced m ultivitam ins. These are claimed to prevent or treat everything from falling hair to fallen arches, rheum atoid arthritis, cancer, m uscular dystrophy, heart attack, aging, varicose veins, ulcers, kidney stones, hangover, thyroid conditions, colds and sexual dysfunction. Approximately 75% of the public believe vitam ins will provide extra energy. No vitam in will produce a rapid burst of energy. Many sales outlets encourage the use of vitam ins to reduce stress. One national health food and nutrition chain encourages the use of vitam ins to "com bat stress associated with traffic jam s, arguments, m eeting deadlines, and deciding what to wear to a party." Regular athletic or occupational physical stress m ay warrant vitam in supplementation to maintain norm al body physiology, but there is no evidence of stress relief. Vitam ins A, C and E are the antioxidant vitam ins. There are indications that taking reasonable supplements of these agents may reduce the rate of certain cancers and som e degenerative diseases. Research to date has generally been favorable but there have also been unfavorable outcomes. The problem lies in this data being population based as opposed to cause-and-effect in a single individual. Most current studies attribute the greatest benefit to Vitam in E. Vitam in C com es in second, as long as doses exceed 200 mg per day. Vitam in A has failed to dem onstrate any consistent benefit to date. Megavitam in therapy is strongly advocated so vitam ins can "crash through the physiological dam," an apparently unseen barrier, and so be effective in treating neuroses, psychoses, angina, arthritic conditions, derm al ulcers, arteriosclerotic conditions and phlebitis. Serious attem pts to objectively dem onstrate the value of megavitam in therapy have not been successful. The very real risk of hypervitaminosis cannot be ignored. Linus Pauling (Nobel Prizes in Chemistry and in Peace) advocated m assive doses of vitam in C and did live into his 90s. The natural vs synthetic vitam in controversy continues to rage. Getting "back to nature" can be an expensive trip. One comparison of prices showed that a typical "natural" version was 4 to 5 times more expensive than the "synthetic" form of the sam e vitam in. For exam ple, vitam in C from rose hips, acerola cherries or other natural sources costs at least 5 tim es more than the synthetic form . Form ulations of "natural vitamins" contain synthetically derived fillers, binders, preservatives, dyes and other form ulation factors to make the dosage form stable and aesthetic. Finally, the body cannot tell the difference between a natural source molecule and one that was synthesized; they are physiologically identical.

Page 6

Many "diet aids" m ake claim s of value and efficacy that are vague and misleading. Som e contain glucomannin, described as a plant fiber which form s a gel around food particles and reduces their absorption. Many diet aids contain Ephedra (source for ephedrine), which m ust be used with great caution and m ay be contraindicated in persons with cardiac rhythm disturbances, angina or hypertension. Many fraudulent claim s of efficacy exist for vitamins. Furthermore, toxicity and the drug interaction potential of vitam ins must be recognized. The Fat Soluble Vitamins Vitam ins A, D, E, and K. are the fat-soluble vitam ins. They are chemically unrelated organic compounds essential for the maintenance of various norm al m etabolic finictions. Profound deficiency states are rare in developed countries, but certain people m ay ingest inadequate am ounts of various vitam ins due to a health condition or neglect of diet. Vitam in A refers to several biologically active com pounds. Retinol is the m aj or naturally occurring form. Good dietary sources of vitam in A (retinol) include fish, butter, m ilk, eggs, cream and organ m eats (esp liver). Dietary sources of carotenoids (provitam in A) are carrots, squash and dark, leafy vegetables. Vitam in A is essential; it prom otes good vision, resistance to infection, gluconeogenesis, mucopolysaccharide synthesis, m aintenance of healthy epithelium, myelin, cartilage and bone, adrenal cortex and steroid hormone synthesis, and a healthy reproductive system . Early sym ptom s of deficiency are night blindness and a dry, scratchy conjunctiva. They may progress to photophobia, corneal distortion, permanent vision loss, skin drying and hyperkeratinization, corneal or skin infection, neurological lesions and increased intracranial pressure. High dose therapy requires close m edical supervision. Vitamin A is stored prim arily in the liver. Reserves can prevent signs of deficiency for 3 to 6 months of significant deprivation. Causes of deficiency include severe catabolic illness (e.g.. cancer, tuberculosis, pneumonia), fat malabsorption (e.g., sprue, obstructive jaundice, cystic fibrosis, liver cirrhosis), m alnutrition and drug induced malabsorption (by oral neom ycin or cholestryamine). Vitam in A m ay be quite toxic if taken inappropriately. There is no evidence that it is effective, as claim ed by some, in treating colds, kidney stones, hyperthyroidism, sunburn, pressure sores or other derm al ulcerations, or degenerative conditions of the central nervous system . Retinoids, the active form s of vitamin A, have been modified to produce medications that are effective in the management of some skin conditions. Hypervitaminosis A is more likely to occur than hypovitam inosis A due to overzealous ingestion by nutritional enthusiasts and the ability of the vitam in to be stored in the body. Toxic sym ptoms include fatigue, m alaise, lethargy, abdom inal distress, bone and joint pain, headache due to increased intracranial pressure, insom nia, exophthalm os, rough skin, loss of body hair, brittle nails, menstrual irregularity, emotional lability and double vision. Supplemental vitam in A in doses of 15,000 to 25,000 IU per day for 1 to 3 m onths m ay cause hypervitam inosis A. If the supplement is stopped, sym ptom s of toxicity usually begin to subside within one week. Vitam in D refers to several chem icals and their metabolites. Cholecalciferol (D-3), the natural form, is synthesized in skin from cholesterol intake or ultraviolet light exposure. Ergocalciferol (D- 2) is obtained m ostly in the diet (e.g.. m ilk, eggs, liver, fish). Ergocalciferol and cholecalciferol are equipotent. Vitamin D must be converted to active metabolites by liver and kidneys. The prim ary functions of vitam in D are to stim ulate calcium and phosphorus absorption from the small intestine, m obilize bone calcium and contribute to calcium hom eostasis by involvem ent with parathyroid horm one and calcitonin biochem istry. Deficiency states may be caused by short bowel syndrom e, hypoparathyroidism, renal or liver disease, hypophosphatem ia and inadequate intake. Clinical m anifestations generally arereflectedin calcium abnorm alities (e.g.. bone demineralization, tetany, osteom alacia, inadequate epiphyseal plate closure in children). Vitam in D is the m ost likely vitam in to cause toxicity in small m ultiples of RDI. Hypervitam inosis D may occur in only a few weeks to months at supplemental doses of 1000 to 3000 IU/day. Sym ptoms include hypercalcemia, ectopic soft tissue calcification (e.g.. heart, blood vessels, kidneys), anorexia, nausea,

Page 7

vomiting, headache, fatigue, weakness, general aches, polyuria, constipation, azotemia and renal damage (rare). The FDA has attem pted to place all vitam in D supplem ents containing > 400 IU per dosage unit on prescription-only status. The m argin of safety between the therapeutic and toxic dose appears narrower than form erly thought. Vitamin E refers to a group of eight com pounds, Alpha-tocopherol is m ost active and is used to calculate vitamin E content. Vitam in E is essential in norm al developm ent of musculature, nervous and circulatory system s. Quantities are usually adequate in the typical diet. Sources include m argarine, green vegetables and whole grains. As noted earlier, vitam in E is the m ost effective of the antioxidant vitam ins. This effect is achieved with norm al doses and does not require the ingestion of excess am ounts. Premature infants may be deficient in vitam in E; supplementation has had a positive effect on edema, hem olytic anem ia, reticulocytosis and throm bocytosis. Patients with conditions that m ay lead to low absorption (biliary disease, cystic fibrosis) m ay require supplem entation. Vitam in E is rem arkably safe. Megadoses of 800 IU per day for 5 m onths in one m an produced no toxicity. Muscle weakness, fatigue, nausea and diarrhea have occurred in persons on 800 to 3200 IU per day. Doses greater than 1000 IU per day antagonize vitam in K and enhance risk of an exaggerated response from oral anticoagulants. The RDI is 30 IU per day for the typical adult. Although risk from m egadoses may be minimal, value is also m inimal. Vitamin E (alpha tocopherol) is reputed to have m ore "indications" than any other vitam in. The RDI for this essential nutrient is only 30 IU per day. The absence of vitam in E deficiency in the general public suggests that adequate quantities are present in the usual diet. It is com m on for doses of 400 to 3200 IU of Vitamin E per day to be consum ed to "treat" rheum atoid arthritis, burns, cancer, muscular dystrophy, peptic ulcers, varicose veins, hem orrhoids, hangovers and fibrocystic breast disease. Further, it m ay be taken to prom ote physical endurance, slow the aging process, protect the lungs against air pollution and prevent heart attacks. It also has the spurious reputation of enhancing sexual prowess and having antisterility properties. W hile relatively safe in itself, inappropriate use m ay lead to costly delays in seeking medical attention. The primary dietary source of Vitam in K is leafy green vegetables; however, its chief source is the normal intestinal bacterial flora. Vitam in K synthesized in the intestine is optim ally absorbed in the presence of bile salts and pancreatic lipase. Newborn infants are given 1 m g of Vitam in K until they are capable of forming it on their own. Vitam in K, thought to be a prosthetic group for enzym es essential in prothrombin synthesis, has no established RDI. The anticoagulant drug warfarin exerts its action by serving as a vitam in K antagonist in the synthesis of clotting factors. Vitam in K deficiencies are rare in the US. The following m ay require supplem entation: decreased bile production or secretion, m ajor bowel resections, malabsorption syndrom es, chronic use of drugs that m ay decrease vitam in K absorption (e.g., cholestyram ine, mineral oil), liver disease resulting in decreased prothrom bin levels, chronic broad spectrum anti-infective use (decreases gut flora and vitamin K synthesis), use of certain parenteral 3 rd generation cephalosporins, and hemorrhage. Deficiencies which m anifest them selves clinically usually result in hem orrhage. Most vitam in K used to correct a bleeding disorder is synthetic (e.g.. phytonadione or K 1, m enadione) and is injected subQ, IM or IV to rapidly correct hypoprothrom binem ia. Major hemorrhage m ay require 20 mg parenteral synthetic vitamin K 1. Minor bleeding disorders may respond to 1 to 5 m g parenteral vitam in K 1. The W ater Soluble Vitamins The water-soluble vitam ins consist of vitam in C (ascorbic acid) and eight B-com plex vitam ins, including thiam ine, riboflavin, niacin, pyridoxine, folacin, cyanocobalam in, biotin and pantothenic acid. Profound deficiency states are rare in developed countries. However, supplem entation m ay be required in num erous health or dietary situations. Ascorbic Acid (Vitam in C) cannot be synthesized by the hum an body; it m ust be provided exogenously. It is essential to form ation of connective tissue, wound healing, norm al tissue growth and development, and iron and folic acid m etabolism . Patients with severe physical traum a, bum s and infections benefit

Page 8

significantly from vitam in C. The value of m egadoses of C in preventing or treating the com m on cold and in prolonging life in cancer victim is not supported by clinical trials. Vitam in C is of no value in gum bleeding caused by periodontal disease. Scurvy is the clinical m anifestation of severe, prolonged vitam in C deprivation. Sym ptom s may develop 3 to 5 m onths after cessation of intake. The few cases reported each year in the US are generally associated with neglect of health and diet. Only 10 rag C per day is required to prevent scurvy; a normal diet contains several tim es this am ount. Com m on sym ptom s of early deficiency are prom inent hair follicles, rough skin, anorexia, irritability, weight loss, weakness, and joint and m uscle pain. Symptoms of severe deficiency include bleeding abnorm alities. W ound healing m ay be m arkedly impaired. Vitam in C excess may contribute to form ation of renal stones, possible destruction of vitamin B-12, diarrhea and drug interactions. If C is given in doses adequate to acidify urine (> 12 gm /day), acidic drugs may be reabsorbed more readily from renal tubules and basic drugs m ay be excreted more rapidly; C m ay potentiate coum arin anticoagulants, chelate iron and convert m ethenam ine to form aldehyde in the urine. Large quantities of C in the urine m ay lead to a false- negative urine glucose test with TesTape and Clinistix glucose oxidase test m ethod) and a false-positive urine glucose test with Clinitest (copper reduction method). Ascorbic acid may produce false-negative tests for blood in the stool (occult blood). Objective, placebo-controlled clinical trials have shown no evidence that large doses of ascorbic acid prevent colds or shorten their duration. Other difficult to prove claim s are that large doses of vitamin C prolong survival tim e in cancer, increase appetite, protect against heart disease, promote relief from vertebral disc lesions, foster the healing of fractures, increase mental alertness and decrease nausea and vomiting from cancer chem otherapy. Thiam ine (Vitamin B-1) is essential for proper carbohydrate m etabolism ; requirements may increase when carbohydrate is consum ed in large quantities or in alcoholism, pregnancy, high fever and untreated hyperthyroidism . Deficiency m ay be evident 2 or 3 weeks after withdrawal. Cardiovascular symptoms include edem a, tachycardia, ECG abnorm alities, precordial or epigastric pain and cardiac failure. Neurological m anifestations include paresthesia of extrem ities, weakness, fatigue, m ental confusion, ataxia and muscle atrophy. Severe deficiency (beriberi) is rare in developed countries. Heart failure due to profound B-1 deficiency requires a thiam ine dose of 5 to 10 mg, 3 tim es daily for several days. Neurological symptoms are more refractory, requiring parenteral thiam ine (30 to 100 m g/day) for several days or until an oral diet can be started. The extreme alcoholic is a special problem because of the likelihood of nutritional neglect and alcohol's ability to im pair thiam ine transport across the intestine. Prom pt and aggressive B-1 treatm ent (parenteral if necessary) is indicated to prevent or minimize the severe neurological manifestations of W ernicke's encephalopathy and Korsakoffs psychosis. Oral thiam ine as an insect repellant has been advocated. The odor of the raw chem ical is certainly offensive. Insect repellant effects at oral doses of 300 mg/day are not been confirmed. Riboflavin (Vitam in B-2) is essential since cellular growth cannot occur without it. Need increases during periods of increased cell growth, particularly during pregnancy and wound healing. Vegetarians, alcoholics and others with inadequate diets m ay have lower levels. Early m anifestations of B-2 deficiency are cheilosis, stomatitis, glossitis, vascularization of the cornea (resulting in photophobia, itching, burning and visual im pairm ent), and nonspecific genital derm atitis. More severe deficiency m ay result in seborrheic derm atitis of nose, face and scrotum . In deficiency, 10 m g/day is adequate. Larger doses are not harm ful but provide no added benefit. Niacin (nicotinic acid) form erly called vitamin B-3 and PP (pellagra preventive), is not to be confused with niacinam ide (nicotinam ide). They are equipotent as vitam ins, however, and can be substituted. Because niacin produces a substantial degree of discom forting vasodilation (especially in the blush area), niacinam ide is generally preferred as the oral drug to treat or prevent deficiencies. Niacinam ide cannot be used instead of niacin for lowering cholesterol.

Page 9

Niacin and niacinam ide contribute to form ation of two essential coenzym es, NAD and NADP. High niacin doses apparently have a positive effect on lipid m etabolism and m ay lower plasm a cholesterol, triglycerides and free fatty acids. Niacinam ide does not have this effect. Niacin deficiency usually involves the nervous system, skin and GI tract. A subclinical pellagra may produce mild symptoms such as indigestion, headache, insom nia or nervousness. Severe deficiency is characterized by dementia, dermatitis and diarrhea. Use high doses of niacin with caution; they m ay stim ulate release of histam ine, thus producing or aggravating preexisting gastritis, peptic ulcer disease or asthm a. Doses > 1 gm /day m ay im pair liver function, produce cholestatic jaundice, disturb glucose tolerance and produce hyperuricem ia. Avoid m egadose niacin therapy over a prolonged period, but short bursts of high dose therapy to treat profound deficiency (300- 500 mg/day in divided doses) m ay be appropriate. Pyridoxine (Vitam in B-6) is involved in protein and am ino acid m etabolism, particularly tryptophan m etabolism. Vitam in B-6 deficiencies are rare. Infants with severe deficiency experience irritability and, rarely, convulsive disorders. Adult vitamin B-6 deficiency appears sim ilar to niacin and riboflavin deficiencies. Pyridoxine requirem ents are increased in pregnancy and lactation. Vitam in B-6 is depleted or antagonized by isoniazid, cycloserine, hydralazine, estrogen, phenytoin and folic acid. Supplemental doses of pyridoxine are indicated in patients receiving therapeutic doses of isoniazid. A depressive syndrom e seen in som e wom en on estrogen-containing oral contraceptives m ay respond to pyridoxine (20 to 100 mg/day). Penicillam ine may cause pyridoxine responsive neurotoxicity, Pyridoxine in doses up to 100 mg 3 tim es/day relieved paresthesias and pain in hands of patients with carpal tunnel syndrom e. Pyridoxine is not effective in nausea and vom iting in pregnancy. Persons with Parkinson's Disease should avoid supplemental pyridoxine due to its serving as a cofactor for dopa decarboxylase, the enzym e that inactivates levodopa in the peripheral circulation. Pyridoxine antagonizes the therapeutic action of levodopa, as it facilitates levodopa conversion to dopam ine outside the CNS. Patients receiving Sinem et or other form s of carbidopa + levodopa can take standard doses of pyridoxine. Concurrent B-6 does not adversely effect the levodopa + carbidopa combination, as carbidopa is a peripheral dopa decarboxylase inhibitor. High daily pyridoxine doses (200 to 600 mg) may inhibit prolactin. Sensory neuropathy has been reported in wom en taking up to l gm /day to treat PMS. Vitamin B-6 (pyridoxine) in doses 1000% to 7500% of the RDI has been recom m ended as a primary drug in weight control program s, and for treatm ent of m ental disorders, carpal tunnel syndrome and premenstrual tension. Folacin (folic acid or pteroylglutam ic acid): Folate is reduced in the body to tetrahydrofolic acid, which functions in the biosynthesis of purine, pyrim idine, serine, m ethionine and choline. B-12 is necessary for m etabolism of folates, and folate deficiency m ay result from B-12 deficiency. Folic acid deficiency is usually caused by poor diet or alcoholism ; m egaloblastic anemia is a m ost com m on feature. Other symptoms include sore throat, diarrhea, irritability and forgetfulness. Daily dietary folic acid intake is 0.5 m g/day. Folates are heat labile. Canning, long exposure to heat and extensive refining may destroy 50% to 100% of folates in food. Folic acid requirem ents increase in pregnancy, infections, hem olytic anem ia, blood loss, hyperthyroidism , rheum atoid arthritis and certain hematopoietic malignancies. Phenytoin, oral contraceptive therapy, trim ethoprim and methotrexate may increase folic acid requirem ents. Conversely, folic acid may lower phenytoin levels and the convulsive threshold and com plicate managem ent of seizures. The therapeutic dose of folic acid to correct a deficiency is usually 1 m g/day, and therapy > 1 to 3 m onths is seldom needed. Folic acid has little toxicity; doses up to 15 mg/day m ay be well tolerated, though rarely necessary. In chronic malabsorption, folic acid m ay be continuous and given by inj ection. Folic acid m ay mask sym ptoms of pernicious anemia; products containing > 0. 8 mg/oral dosage form are available by prescription only. Cyanocobalam in (Vitam in B-12) deficiencies do not m anifest themselves clinically for m any weeks to m onths. Vitamin B-12 is involved in num erous hum an biochemical processes. It is essential for normal

Page 10

growth, m etabolism of lipids, maintenance of myelin throughout the CNS and norm al hematopoiesis. Pernicious anemia (a macrocytic anem ia) occurs with B-12 deficiency due to inadequate intake or lack of intrinsic factor (essential for absorption). Other manifestations include paresthesias of hands and feet, weakness, m ental confusion, bizarre behavior, hallucinations, optic atrophy, weight loss and shortness of breath. An accurate diagnosis of a suspected anemia is critical, especially with folic acid and vitam in B-12. Folic acid, given in pernicious anemia, corrects the hematological abnorm ality (anemia) but not its neurological m anifestations. In fact, folic acid used to treat pernicious anemia m ay accelerate the neurological damage caused by B-12 deficiency. If deficiency is due to inadequate dietary intake, an oral supplem ent of 1 to 3 m cg/day is generally effective. If deficiency is due to im paired absorption, inject B-12 usually 100 mcg per m onth. Larger doses offer no advantage. Biotin and Pantothenic Acid: Biotin, once called vitamin H, is important in the m etabolism of carbohydrates, proteins and fats. Deficiency states are rare. Sym ptoms may include mild skin disorders, sleeplessness, m uscle pain, depression and anemia. Pantothenic acid, once called vitam in B-5, is a precursor to coenzym e A and is involved in many biological reactions. It is not an effective antistress drug and does not prevent graying of hair. Deficiency states are rare and difficult to detect. Sym ptoms may include abdominal cram ps, nausea, vomiting, headache, fatigue, insom nia, weakness and paresthesia. Toxicity is m inim al; up to 20 m g produces no side effects except diarrhea. A Little Com m on Sense on Herbal M edications Herbal medicines are drugs. The vast m ajority are plants that have been in use in various societies for hundreds or even thousands of years. Properly collected and prepared they can provide effective products for drug therapy. M ost natural products fell into disuse in the m odern era due to som e of the problems inherent in the use of natural products, such as: 1. Source of the Drug . Plants growing under different conditions produce different chemicals. The opium poppy that produces opiate narcotics w hen cultivated in the Far East and Middle East will not produce opiates when grown in the United States. 2. Accuracy of Collection . Many plants look alike and grow in the sam e general localities. The person collecting a natural product m ust be sure they are gathering the correct plant. 3. Part of the Plant Collected . In one plant, the drug m ay only be found in the flowers, while in others it may only be in the leaves or the roots. If the entire plant is collected, drug content will be reduced or if the wrong part is collected, there m ay be no drug in the resulting herbal product. 4. Time of Collection . If the active ingredient is predom inantly in the flowers, then the drug can only be properly obtained when the plant is in flower. This means that the entire supply of a drug may need to be collected in a very short tim e period. 5. Preparation of the Product . M ost of the drug chemicals in plants are large and very complicated m olecules subject to dam age or degradation if not properly handled during the process of preparing dosage form s. False claims for natural products are rare. W hat is comm on, however, are extension of facts to make statements that m ay not necessarily be true. Sharks allegedly do not get cancer but does that mean shark m eat or shark cartilage will prevent it in humans? (Actually, sharks DO get cancer.) Chickens don't get m alaria, but plenty of people who eat chicken parts still get m alaria. Danger in contam ination of natural products is always an issue. This can range from including a second drug in with the one desired right on up through m icrobial contam ination of products. Hum an growth hormone was originally obtained from cadaver pituitary glands. Its use was banned after som e patients developed incurable viral infections sim ilar to m ad cow disease. Legalization of the current herbal therapy m arket occurred with the Dietary Supplem ent Health and Education Act of 1994. This act defined m ost natural products as dietary supplements and said they were not foods, food additives or drugs. This definition changing m eans that the FDA cannot require the m arketer of a product to prove either safety or efficacy. The FDA m ust prove danger to the public to have a product removed from the market. There are lim its on the m edical claim s that can be m ade for a

Page 11

dietary supplem ent. Som e of the USP-NF herbs listed below are included because proper processing to rem ove poisons is required before the drugs can be used. Herbs to use with caution: Chaparral Comfrey Germ ander Ma huang (Ephedra) Yohim be Alfalfa Liver toxicity Liver toxicity (banned in parts of Europe) Liver toxicty Stroke Kidney failure Throm bocytopenia

NAPLEX says questions about nutraceuticals and herbal products will be a part of the exam . Questions will be limited to efficacies, adverse effects, toxicities and drug interactions. The USP-NF will be the standard for dietary supplem ent specifications and professional journals will be used for clinically significant efficacy, adverse reactions, toxicities and drug interactions. The USP-NF counts vitamins and m inerals as nutraceuticals. Listed below are the herbals that are currently official or are being developed for inclusion in the USP along with inform ation about each agent. These are the herbs you need to concentrate on for study. Botanical Product BLACK COHOSH Snake root USP Standards Developm ent Status Rhizom e with roots of Actaea racem osa (L.) Nutt. Also known as Cim icifuga racem osa Fam . Ranunculaceae Black Cohosh Previews July - Aug 2001

The main uses are for premenstrual and m enstrual discomfort or pain and m enopause related nervousness. Cim icifuga means bug repellant and so black cohosh has been used for that purpose as well. It has also been tried for respiratory problem s. The m ost com m on side effect is GI discom fort. Miscarriages are a possibility, especially when large am ounts (~ 5 gram s) are ingested. Any circumstance in which estrogens should be avoided would apply to black cohosh. Efficacy level 4 on a scale of 1 (ineffective) to 5 (effective). CAT'S CLAW Una de gato; Peru vine Vine and other parts of Uncaria tom entosa (W ild.) DC Fam . Rubiaceae; Cat's Claw Draft under Developm ent

Cats Claw is m ost often used in com bination with AZT by AIDS patients because of purported immune system stimulation but benefits are questionable. It is also used for peptic ulcers, gastritis and hem orrhoids. The drug appears safe but patients who cannot have their im mune system stimulated (organ transplant patients) should not use the drug. Efficacy 3 out of 5. CHAMOMILE Flower heads of Matricaria recutita L. Fam . Asteraceae Cham omile Official in USP 25-NF 20

This agent has been tried for virtually every hum an and anim al com plaint known. Its active ingredients include bisabolol, a recognized antispasmodic. Thus, cham om ile is used to calm the GI tract, as a mild sedative, to reduce fever, to ease peptic ulcers, and to control m uscle and m enstrual cram ps. Externally it is used to heal m inor skin irritations and wounds and to treat eczem a and hem orrhoids. Chamomile is also used in m any sham poos and body lotions and as a flavoring agent in foods and soft drinks. Cham omile is not likely to be toxic or product drug interactions. It is botanically related to ragweed, so possible cross allergenicity must be considered. Efficacy 4 out of 5. CHASTE TREE BERRY Monks pepper, Vitex Berries of Vitex agnus-castus L. Fam . Verbenaceae Chaste tree Previews Jan - Feb 2002

This herb has been used for centuries in Europe to handle virtually every female reproductive system complaint ranging from m enstrual cram ps to reducing the sex drive of young females. It is given postpartum to aid in discharge of the placenta. The m ain adverse effect is GI upset and som e patients develop an urticarial rash. Pregnant wom en should avoid the drug and its safety in children is questionable. Efficacy 4 out of 5.

Page 12

CRANBERRY

Juice from the fruit of Vaccinium oxycoccos L.; Vaccinium m acrocarpon; Fam . Ericaceae; Cranberry Official in USP 25-NF 20

Cranberry juice has been used for two centuries as a urinary tract antiseptic. It is more likely that cranberry juice will help prevent urinary tract infections than it is that it would cure an already established infection. Cranberry juice has not, however, convinced all its doubters of its efficacy. Some well controlled studies have dem onstrated that 500 m ls of cranberry juice a day will reduce the ability of bacteria to adhere to the walls of the urinary tract as well as reduce the pH of the urine to levels so acidic as to be detrim ental to bacterial growth. Cranberry juice also reduces urine odor. The bottom line on cranberry juice would be to use it and then treat any infections that were not prevented. The only likely side effects would com e from sim ple ingestion of excessive volum es that could cause diarrhea. Patients who clearly have a urinary tract infection should not depend on cranberry juice to treat the infection. Efficacy 5 out of 5. ECHINACEA ANGUSTIFOLIA Purple coneflower Rhizom e with roots of Echinacea angustifolia DC Fam . Asteraceae Echinacea angustifolia, Official in USP 26;

The angustifolia form of Echinacea cannot be confused with other varieties. Often, studies have not clarified the form of echinacea used and this has com plicated assessm ents of the drugs benefits and side effects. Early native am ericans used the drug topically for every type of skin injury or bite and drank a tea to boost the im m une system when treating colds and arthritis. Patent m edicine formulations advocated echinacea for virtually every disease state. Most modern users are seeking enhancement of the im mune system in fighting off a m yriad of bacterial and infections, including HIV. Studies to show the efficacy of echinacea in treating infectious diseases provide confusing data. In vitro studies have been m ore effective at demonstrating echinaceas antim icrobiological effects that have hum an based clinical trials. Echinacea appears safe but not because of toxicity studies; rather, few users have reported side effects. Persons suffering from im m une system m ediated diseases should use echinacea with caution. Efficacy 4 out of 5 ECHINACEA PALLIDA See above ECHINACEA PURPUREA See above Rhizom e with roots of Echinacea pallida (Nutt.) Fam . Asteraceae Echinacea pallida, Official in USP 26

Rhizom e with Roots and Leaves with Flowers of Echinacea purpurea (L.) Moench; Fam . Asteraceae; Official in USP 26

FEVERFEW Altam isa; Santa Maria W ild chamomile

Leaves of Tanacetum parthenium (L.) Schultz-Bip.; sometim es referred to as Chrysanthemum or Matricaria; Official in USP 25-NF 20

Early users of feverfew were seeking a solution to various aches and pains ranging from m enstrual disorders to an antidote for excessive opium use. The nam e of the plant indicates the respect it had as a reducer of fevers (possibly undeserved). Feverfew is also used as an air purifier and insect repellant based on its odor. The use of feverfew for m igraines dates only back into the 1970s and this benefit is apparently based in ingredients term ed parthenolides which m ust be present at a concentration of about 0.2% which provides a dose of 250 m cg of the ingredient. Studies are needed on the long term safety of feverfew. In studies that have been done, about 10% of patients develop m outh ulcers, particularly if they choose to chew the leaves to get the drug vs taking comm ercially prepared dosage form s. Feverfew may be som ewhat habit forming as some patients undergo withdrawal when stopping the drug. Feverfew probably acts by inhibiting blood clotting, so individuals taking antiplatelet drugs or anticoagulants should not take feverfew. Pregnant women should not take the drug because it appears to increase uterine blood flow during menstruation. Efficacy 4 out of 5.

Page 13

GARLIC

Bulbs of Allium sativum L. Fam . Liliaceae Garlic Official in USP 25-NF 20

Garlic has been used by hum ans for at least 5000 years. The Egyptians ate garlic daily to ward of a host of diseases. Garlic was also believed capable of warding of vam pires, witches and other dem ons of the past. Louis Pasteur referred to antiseptic properties of garlic, Schweitzer treated am oebic dysentery with garlic and it was term ed Russian penicillin during W orld W ar II. Garlic juice has been applied to wounds to fight infection. Garlic contains an odorless am ino acid derivative called alliin that is readily converted to odoriferous allicin. More recently garlic has gained attention due to its ability to reduce cholesterol levels (by about 10% ) and reduce GI upset. Garlic will reduce cholesterol while increasing levels of HDL and reducing levels of LDL. It takes 5 cloves of garlic a day to achieve these results. Garlics side effects are mostly associated with GI upset. Garlic has drug interactions with hypoglycem ics, anticoagulants and aspirin (antagonist to their action). Garlic has been used as an abortifacient in some cultures and so should not be taken, in large doses, by pregnant wom en. Enteric coated tablets have the advantage of getting the acid labile active ingredient, allicin, through the stom ach while reducing the odor associated with oral ingestion of the drug. Efficacy 5 out of 5. GINGER Rhizom e of Zingiber officinale, Roscoe; Fam . Zingiberaceae Ginger Official in USP 25-NF 20

Gingers prime use through the centuries has been as a digestive aid. Antiinflam m atory agents have been identified in ginger which support its use in arthritis but this use has not been supported by clinical studies. Likewise, its activity in cardiovascular disease by som e effect in slowing blood clotting cannot be supported with definitive clinical evidence. Nausea and vom iting seem to be am enable to treatment with ginger. It takes 1000 m g of ginger to provide the sam e antinauseant effect as 100 m g of dimenhydrinate or 50 m g of diphenhydram ine. The fact that ginger does inhibit blood coagulation limit recom mendations to use the agent in either pregnancy or post-operative nausea and vom iting. Ginger works by inhibiting throm boxane synthetase in a dose dependent fashion. Based on lim ited data, it seem s to take m ore than 2 gram s of ginger a day to product an effect on throm boxane synthetase; 5 gram s a day definitely produces an effect. Throm boxane synthetase can block proper developm ent of the CNS in a fetus and this is another reason for pregnant wom en to use the drug with extrem e caution and in lim ited am ounts. Ginger should not be used to treat the pain of gallstones because it can increase m uscle activity in the gall bladder and sphincter of Oddi. Drug interactions can occur with drugs for diabetes, anticoagulants and other heart m edications. Efficacy for GI problems 5 out of 5, but watch for side effects. AM ERICAN GINSENG W estern ginseng Roots of Panax quinquefolius L.; Fam . Araliaceae Am erican Ginseng In-Process Revision, Mar - Apr 2001 See Asian Ginseng for uses and cautions Roots of Panax ginseng C.A. Meyer; Fam . Araliaceae Asian Ginseng Official in USP 25-NF 20

ASIAN GINSENG Ren shen (man root)

Panax m eans all healing and this herbal root that looks like a hum an form has been advocated for virtually every hum an illness. Active principles in ginseng include ginsenosides that are steroid-like saponins in their structures and therefore can produce steroid effects. Som e agents produce opposite effects of others. There are no definitive, proven uses for ginseng. It is used as a tonic to invigorate those who use it and to improve the spirits of those w ho need a lift. Just as there have been no studies to demonstrate efficacy, neither have any demonstrated side effects except, possibly, mild mental stimulation. Ginseng can be tried for everything but not work for anything. Efficacy rating 3 out of 5. ELEUTHEROCOCCUS (Siberian Ginseng) Rhizom e with roots of Eleutherococcus senticosus (Rupr. & Maxim .); Maxim Fam . Araliaceae; Official in USP 26

The active principles of this herb are compounds known as eleutherosides, of which at least 7 have been identified. Russian scientists considered Siberian ginseng to be an adaptogen which means it is innocuous but has a normalizing effect on the body. Russian studies have show n the drug to have a

Page 14

slight benefit in im proving perform ance, particularly in stressful work environm ents. Eleutherococcus cannot be shown to have hypotensive properties, but patients with hypertension felt better when taking the drug. The sam e is true for other chronic diseases. Im m une system stim ulation can be demonstrated in tests, but this has not translated to benefits in diseases. Efficacy rating 3 or 4 out of 5. GINKGO Maidenhair or kew tree Leaves of Ginkgo biloba L.; Fam . Ginkgoaceae Ginkgo Official in USP 25-NF 20

Talk about tough, Ginkgo biloba has survived both the Ice Age and the atom ic bom b. Because it has been around so long, ginkgo is advocated for alm ost every health problem. Uses include heart disease, vertigo, tinnitus, asthm a, im potence, circulatory insufficiency, peripheral vascular disease, neuralgia, eye problem s, im provem ent of short term m em ory, dem entia and other m ental changes associated with aging. Most of the good clinical studies have used a standardized GBE or gingko biloba extract. Most diseases amenable to im provem ent with a greater blood flow to tissues show som e level of im provement in patients using ginger. Studies on improved mental function, from any cause, are also generally positive. Ginkgo is rem arkably free of side effects as long as single doses of GBE are < 600 m g. The blood clotting inhibition m eans that ginkgo should be used cautiously by m any patients. Efficacy 5 out of 5. GOLDENSEAL Hydrastis Rhizom e with roots of Hydrastis canadensis L.; Fam . Ranunculaceae; Goldenseal In Process, official in USP 26

Goldenseal has two primary active ingredients, hydrastine (2 to 4% ) and berberine (0.5 to 6% ). Both agents have astringent and antiseptic properties and this has lead to their use in mouthwashes and eyewashes. The astringent properties cause contraction of peripheral blood vessels leading to use of the drug in stopping bleeding from m inor cuts and scratches. Claim s for use of goldenseal, or either alkaloid, in pregnancy and the postpartum period have been proven baseless. Similarly, astringent properties have lead to use of the drug in diarrhea and related GI problems, again without defined benefit. Goldenseal is also advocated as a m eans of covering up illicit drugs in urine samples, especially marijuana, but properly done analytical tests will not be altered in their outcom e. Efficacy rating 3 out of 5 HAWTHORN Leaves with Flowers of Crataegus m onogyna Jacq. em end Lindm an; Crataegus laevigata (Poir) DC; Fam . Rosaceae Hawthorn Leaf with Flower, Official in USP 26

Rem ember that digitalis (source of digoxin) is also a herb used for heart disease that m ust be carefully m onitored. The sam e is true for hawthorn. Standardized extracts (not the whole herb) have been shown to dilate coronary arteries and im prove circulation in other blood vessels, leading to a drop in blood pressure. The drug also appears to have a inotropic effect as well. Digitalis is about five times more potent than hawthorn. Basically, hawthorn is a weaker herbal m edicine than digitalis and all the same precautions should be followed. Efficacy 5 out of 5. HORSE CHESTNUT Seeds of Aesculus hippocastanum L.; Fam . Hippocastanaceae Horse Chestnut In Process, May - June 2002

Another circulation im proving herb used to relieve hemorrhoids, phlebitis and varicose veins. The active saponin principle is aescin or escin. Because it can be dem onstrated to im prove blood flow, it has also been advocated for cardiovascular conditions ranging from angina to hypertension. Germans also use the drug as an anticoagulant, especially to prevent venous stasis clots associated with surgery or prolonged bed rest. Horse chestnut products that have not been properly prepared to remove the chemical aesculin may cause fatal poisoning. It is essential to determ ine the processing of horse chestnut products before they are used. For this reason, this is a drug to use carefully or not at all. It should never be given to children. Efficacy rating 5 out of 5, with the toxicity warning.

Page 15

KAVA Kava kava

Rhizom e of Piper m ethysticum G. Forst.; Fam . Piperaceae Kava In Process, May - June 2002

This is a pepper variety used to produce sedation or sleep based on the actice of kavalactones found in the plants roots. The drugs action is somewhat like that of beverage alcohol in that people believe they are more sociable and happy when using kava. There m ay also be som e sm ooth m uscle relaxing benefit and a local anesthetic effect occurs when the drug is chewed. Like all plant drugs of abuse, kava is not without risks. Heavy use for extended periods of tim e can cause severe skin rashes, weight loss and blood dyscrasias. Use in combination with other sedative agents (alcohol, benzodiazepines) can cause deep com a and som e deaths have been reported. Apparently, the drug is not addictive but it m ay be habit form ing. Efficacy rating 4 out of 5 as a sedative or calm ative, but watch out for abuse by prolonged or heavy use. LICORICE Glycyrrhiza Rhizom e, stolons and roots of Glycyrrhiza uralensis Fisch. ex DC. Glycyrrhiza glabra L.; Fam . Fabaceae

Licorice has been used to flavor candy, chewing tobacco and drug products for centuries. Most of the licorice sold in the US is actually candy flavored with anise oil. Licorice has been advocated for use as a cough suppressant, expectorant, antiseptic, and to treat peptic ulcers. Many of the active principles of licorice are steroids and are the cause of most of its side effects. The small am ounts used to flavor candy are not likely to cause any problems but one would do well to lim it intake of glycyrrhizin to 100 m g a day or less. Due to the m ineralocorticoid action of its ingredients, licorice will cause pseudoaldosteronism with elevated blood pressure, hypokalemia, hypernatrem ia and edem a. These side effects caused licorice to be withdrawn as a potential treatm ent for peptic and gastric ulcers. Anyone contem plating the use of licorice for any reason should inform their physician in the event side effects develop. Efficacy 4 out of 5 for cough. M ARITIME PINE French m aritim e pine Bark of Pinus pinaster Aiton (Pinus maritim a Poir.); Fam . Pinaceae Maritim e Pine Draft under developm ent

Pine bark products have been used for years as cough suppressants and dem ulcents. They contain terpenes which do have antiseptic properties and can be used to prepare inhalants. Maritim e pine, on the other hand, is a source of pycnogenol. Pycnogenol from pine trees is not as potent as that obtained from grape seed extract. Both drugs contain procyanidins which are antioxidants claim ed to have some benefit against cancer. No human tests have ever proved any defined benefit but its antioxidant properties are equivalent to those of vitamin A. No toxicity studies have been perform ed. Efficacy 3 out of 5; it m ight work but it has not been proven. M ILK THISTLE Mary thistle Ripe fruit of Silybum m arianum (L.) Gaertner; Fam . Asteraceae Milk Thistle Official, Official in USP 26

Extracts of milk thistle produce silym arin and this is the substance that has been studied for most purposes. Prim ary indications for silym arin or m ilk thistle include liver disease, digestive problems and excess m enstrual flow. The ability of silym arin to protect the liver has been well docum ented in both laboratory and clinical studies. It is essential to use lipophilic preparations of the whole herb in order to receive adequate am ounts of silym arin. Best is to just get the silym arin itself and take about 500 mg a day in 3 or 4 divided doses. The m ain side effect seem s to be diarrhea. Hepatic disease is no laughing m atter and any patient planning to use m ilk thistle should have the diagnosis confirmed by a physician and inform the physician of the use of the drug. Efficacy rating for liver disease 5 out of 5. NETTLES Stinging nettle Rhizome with roots of Urtica dioica L. ssp. Dioica Urtica urens; Fam . Urticaceae, Official in USP 26

Nettle has a mild diuretic action and increases urine output to a level that m ight benefit in premenstrual edema but is not likely to be potent enough for use in renal or heart failure. Som e diet aids contain nettle in an effort to rem ove water weight. Evidence for the use of nettle in benign prostatic hypertrophy is less than Saw Palm etto. Nettle is also advocated for reduction of hay fever but the two studies that have been

Page 16

done failed to dem onstrate any superiority over placebo. Nettle will not lower blood sugar and may, in fact, elevate it. Neither will nettle grow hair in m ale pattern baldness. Nettle toxicity appears m inimal but users should drink adequate fluids to insure renal function when taking the drug and pregnant women should avoid it because of a potential to cause uterine contractions. Efficacy rating 3 out of 5 PYGEUM AFRICANUM African bark Bark of Prunus africana (Hook f.) Kalkm . (Pygeum africanum Hook) Rosaceae.; Pygeum africanum Draft under preparation

Another benign prostatic hypertrophy agent but this one has good clinical trials to support its use. It acts by reducing the am ount of cholesterol in the prostate and is also, by som e users, advocated to reduce serum cholesterol (but data is lacking). The drug contains a host of chemicals, including som e steroids, but toxicity appears minimal. Efficacy 5 out of 5 RED CLOVER Meadow clover Flowers of Trifolium pratense L.; Fam . Fabaceae Red Clover In Process, May - June 2002

This plant has been tried for several uses through the years, largely without success. Because it contains coum arins and estrogenic substances, som e have advocated its use in m enopausal problems. Cows that overeat red clover develop a swollen uterus and changes in the milk bladder which indicate the drug could be toxic with heavy or prolonged use. Harry Hoxey em ployed red clover in his discredited herbal anticancer form ula, so some still cling to this disproven use. Oils that can be extracted from red clover do contain m ethyl salicylate so topical action of this agent m ay give the drug a lim ited benefit. It is likely harm less in lim ited use. Efficacy rating 2 out of 5; not likely to work but not likely to hurt. SAW PALMETTO Dwarf palm tree Ripe fruit of Serenoa repens (Bartram) Sm all; Fam . Arecaceae Saw Palm etto Official in USP 25-NF 20

Recent studies have failed to dem onstrate any benefit for saw palm etto in the treatm ent of either benign prostatic hypertropy or prostate cancer.

ST. JOHN'S W ORT (HYPERICUM) VALERIAN

Flowers or aerial parts of Hypericum perforatum L.; Fam . Hyperaceae St. John's Wort Official in USP 25-NF 20 Rhizome, stolons and roots of Valeriana officinalis L.; Fam . Valerianaceae; Valerian Official in USP 25-NF 20 Am ericas Top Twelve Herbs in 2005 (based on sales)

Herb Nam e Ginkgo biloba

Com m on Use(s) Maintain mental functions, vertigo, tinnitus; standardized extract, 40 m g 3-4 tim es a day Mild to moderate depression; skin disorders

Useful Inform ation Avoid in pregnancy; probably works through reduced platelet aggregation with som e antioxidant activity probable type B MAOI, SSRI activity; com bination use should be avoided; avoid in pregnancy; can cause skin problem s, increases recovery time from opiate anesthesia 1-2 gm per day for NMT 3 m onths; watch out for insom nia, nervousness, hypertension, stim ulants, diabetics; m ay decrease effect of Lasix and increase effect of CNS drugs

St Johns W ort

Ginseng; Siberian version is called Eleutherococcus

Panax = all healing; relieve stress or fatigue; im prove athletic activity

Page 17

Garlic

Cardiovascular diseases, cancer prevention, bacterial infections, 2-4 gm fresh garlic (or equivalent) daily

Inhibits platelet aggregation (means watch warfarin); GI irritation; avoid in pregnancy and lactation; m ay lower blood glucose; transplant patients should avoid Im m unity stim ulated, antiviral, antibacterial, antiinflam m atory; liver toxicity with long term use; any allergy to daisy flower fam ily; watch INR in warfarin patients Inhibits 5-alpha reductase conversion of testosterone (same as Proscar); dose not alter PSA tst, may cause headache; failed recent efficacy studies so use with caution. W orks like lidocaine on GABA receptors; probably dopam ine antagonist; causes skin problems; dependency possible; enhances effects of CNS drugs, esp depressants W atch with anticoagulants

Echinacea or Goldenseal

Colds, flu, URI, UTI, yeast infections; 1 gram TID; contraindicated in AIDS, HIV, autoim m une diseases

Saw Palm etto

Benign prostatic hypertropy (but not prostate cancer); 180 m g BID

Kava kava

Muscle relaxant and anxiolytic

Pycnogenol or Grape Seed Extract Cranberry Juice

Antioxidant and improve circulation; 50-100 m g per day, up to 300 m g

Urinary tract infections, take onehalf cup of juice per day

Bacteria m ust adhere to tissue to do dam age, this reduces their ability to take hold; also acidifies urine W orks on GABA receptors; has om ega-3 fatty acids; caution with other CNS m eds, avoid in pregnancy; lim it use to 3 m os 3-6 gm s per day; contains essential fatty acids; m ay cause abdominal discomfort, nausea, headache; may increase action or ADRs of NSAIDs; increased seizures Antioxidants m ay be m echanism; increases glutathione levels; questionable ability to cause liver recovery; safe to use; takes m onths to have an effect

Valerian root

Insomnia, mild anxiety; decreases blood pressure; antiinflam m atory

Evening prim rose oil

Atopic eczema, diabetic neuropathy, prem enstrual syndrom e, m astalgia

Milk thistle

Liver protectant; jaundice; m enstrual problems; 280-420 mg/day

And Som e Non-Herbal Alternative M edications in Com m on Use M elatonin Sleep, dose is 1 to 5 m g (usually 3) Norm al body chemical Osteoarthritis and other traumatic joint conditions Questionable effectiveness in clinical trials but m ay have good placebo effect; science basis is logical Efficacy equivalent to low dose NSAIDs for short duration; sulfate best form ; chondroitin probably not needed. Recent studies failed to demonstrate any effect good or bad.

Glucosamine +/Chondroitin

Page 18

SAMe S-A denosyl M e thionine Chromium picolinate

Natural body chemical used as donor of methyl groups in wide instances Chromium is a cofactor for insulin, therefore will do everything related

May be useful in osteoarthritis, wide dose range; efficacy as antidepressant less clear

Advocated for weight loss, diabetes, m uscle building, increased levels of growth hormone

Docum ented Natural Product Drug Interactions Natural Product Dong quai inhibits platelet adhesion Ephedra has additive adrenergic effects Ginkgo biloba inhibits platelet adhesion and inhibits CYP2C9 Ginseng induces CYP2C9 Effects Observed Increased INR with warfarin Drugs to W atch For Other antiplatelet adhesion drugs Antihypertensives, other cardiac drugs Tolbutam ide, phenytoin, any antiplatelet adhesion drug, CYP2C9 substrates Tolbutam ide, phenytoin, any antiplatelet adhesion drug, CYP2C9 substrates Hypoglycem ic drugs and insulin (do not combine) Caffeine, clozapine and other CYP1A2 substrates Benzodiazepines and other sedatives

Toxicity when com bined with caffeine & other stimulants Increased INR with warfarin Bleeding with aspirin Toxicity with trazodone Increased INR with warfarin

Glucosam ine increased insulin resistance Ipriflavone CYP1A2 inhibition Kava kava additive effects with benzodiazipines

Decreased glucose tolerance

Increased theophylline levels

Toxicity when com bined with alprazolam (com a)

Natural Products That M ay Interact with Drugs Natural Product Cats Claw Interaction M echanism Inhibition of Cyp3A4 Drugs to be M onitored HIV protease inhibitors, cyclosporine, and others HIV protease inhibitors, cyclosporine, and others HIV protease inhibitors, cyclosporine, and others Anticoagulants and antiplatelet aggregation drugs HIV protease inhibitors, cyclosporine, and others Digoxin

Cham omile

Inhibition of Cyp3A4

Echinacea

Inhibition of Cyp3A4

Garlic

Inhibition of platelet aggregation Inhibition of Cyp3A4

Goldenseal

Siberian ginseng, or Eleutherococcus Melatonin

Product alteration

Additive cardiovascular effect

Nifedipine

Page 19

HOM E DIAGNOSTIC KITS The developm ent of home diagnostic kits has m ade possible patient assessment of certain diseases states (e.g., diabetes m ellitus) and determ ination of the presence or absence of certain conditions (e.g., pregnancy, cancer, HIV infection). The following are exam ples of som e types of kits available with comm ents on their use. The listing of brand nam e products does notinclude every product available. Urine Ketone Test Kits Ketones (usually as acetoacetic acid, acetone and beta-hydroxybutyric acid) result from incomplete fat m etabolism. If diabetics are not properly m etabolizing dextrose through the citric acid cycle, then ketone bodies will be form ed. Ketone bodies can also occur in non-diabetics who are on low carbohydrate diets (ketogenic diets). Ketones prove that fats are being burned as a source of energy. Test Kit Nam e Ketostix Unique Features Uses sodium nitroprusside as the test reagent Stick is dipped into urine and changes color (see Diastix above) Drop of urine is placed on the tablet and color change occurs. The sam e tablet can also be used for ketones in whole blood or plasma. Blood Glucose Test Kits This is perhaps the m ost comm only sold and routinely used hom e diagnostic test for the purpose of m onitoring disease therapy. Virtually every system requires a stick to the side of a finger and putting a drop of blood onto a test strip. The test strip is inserted into the m onitor and the blood sugar is reported after 30 to 60 seconds (depending on specific device). Each test strip costs the patient between 50 and 75 cents. All system s come with a m ethod of standardizing and calibration of the instrum ent to insure accuracy. The degradation of glucose by glucose oxidase is the usual m ethod of perform ing the assay. Test Kit Nam e Chem strip bG Unique Features Read visually or use AccuChek, AccuChek-II, IIm or III blood glucose (bG) m eters Read visually or use BetaScan m eter or Trendsmeter to read strip Read visually or use AccuChek, AccuChek-II bG or Tracer bG m eters

Acetest Tablets

BetaScan Trend Strips Tracer bG

Diascan-S Reagent Strips Read visually or use a Glucom eter Dextrostix Glucostix Kyodix Reagent Strips Visidex-II Glucofilm ExacTech Precision QID Advantage Easy Test Strips Accu-Check Complete Read visually or use a Glucom eter Read visually or use a Glucom eter-II Read visually or use a Glucom eter Read visually Requires an ExacTech m onitor Used for Precision QID, Com panion-2 and MediSense bG m onitors For use with the AccuChek Advantage m onitor For use with the AccuChek Easy m onitor This hand-held glucose m onitor utilizes laptop com puter technologies, and its information can be transferred into a com puter using software provided by the manufacturer. The com pany plans to offer a m odem that can transmit information directly to the patient's health care provider.

Page 20

Urine Glucose Test Kits Test Kit Nam e Clinitest Tabs Test Method Copper sulfate Com m ents Urine and water m ixed in test tube, add reduction m ethod tablet, wait for reaction to end, see resulting color on chart Dip stick into urine and wait for color to develop, then read on chart

Chem strip-uG Clinistix Diastix TesTape

Glucose oxidase

Glucose oxidase Dip stick in urine read color change on chart; dextrose only Glucose oxidase Dip stick in urine read color change on chart; dextrose and ketones

Glucose oxidase Dip stick in urine read color change on chart; dextrose only

The copper sulfate m ethod is better quantitatively but is subject to m ore interferences (false positives). The glucose oxidase method is less subject to interferences but is less accurate. Urinary Tract Infection Test Kits Unique Features Read visually; detects protein which will increase in a patient with a urinary tract infection (from bacteria and cells sloughed off due to dam age) Read visually; detects leukocytes (W BCs, PMNs) Read visually; detects glucose and protein Read visually; detects glucose, protein, pH, urobilinogen, and specific gravity, ketones, bilirubin and blood Dip stick test where a treated sensor pad is placed in the urine with results appearing in less than one m inute Dip stick test where a treated sensor pad is placed in the urine with results appearing in less than one m inute Pregnancy Test Kits for Hom e Use These tests measure a rise in the level of chorionic gonadotropin (HCG, CG) that begins with the second week of pregnancy and peaks at about 8 weeks. Delay refers to num ber of days after a m issed menstrual cycle before the test is effective. Tim e (m inutes) is the tim e required for the color change (or other sign) to develop in a positive test. Kit Nam e Advance Assay Type Monoclonal Antibody Hem agglutination Hem agglutination Monoclonal Antibody M. antibody M. antibody Delay 1 Tim e 30 Unique Features No drug interference; color change on strip; not a fluid Sensitive to vibration Contains 2 tests; vibration sensitive Portable one-step test No drug interference Sensitive to vibration No drug interference

Test Kit Nam e Microstix Nitrite Chem strip-LN N-Uristix N-Multistix

UTI Hom e Screening Kit Health Check Uri-Test

Answer Daisy-2 e.p.t. Plus FACT FIRST RESPONSE

9 3 1

60 45 10

3 1

45 20

Page 21

Kit Nam e Predictor Q-TEST One Step Clear Blue Easy

Assay Type Delay Hem agglutination 9 M. antibody M. antibody Monoclonal Antibody 1 3 1

Tim e 60 16 3 5

Unique Features Sensitive to vibration Error control pad to verify test results

Ovulation Prediction Test Kits These tests determ ine a rise in leutinizing horm one (LH) as an indicator or ovulation. Sim ilarities exist between the names of ovulation and pregnancy test kits, Be sure of what you are being asked about before jumping to the answer. Test Kit Nam e First Response Ovutim e Q-Test Unique Features Six days of kits; refills for additional 3 days available Available in kits of 6 or 9 tests per kit Available in kits with 5 days of tests

W arfarin Therapy Monitoring Kit Test Kit Nam e ProTim e Microcoagulation System Unique Features Finger stick test that determ ines prothrom bin tim e. Test reported on basis of INR and device indicates low or high based on program m ing

Cholesterol Tests Test Kit Nam e Advanced Care Cholesterol Test Unique Features Cassette for blood test. In kits containing test cassette, result chart, lancet, gauze pad, adhesive bandage, instruction booklet and question and answer booklet Patient pricks finger to get enough blood to fill sam ple well on device. Produces color bar that is "test device reading". U se test result card to convert device reading to cholesterol in m g/dl. H I V Infection Test Kits Test Kit Nam e Confide Unique Features The patient pricks a finger, places a few drops of blood on a card, then mails it to the laboratory for analysis. Patients first call Hom e Access Health to answer a few questions and speak to a counselor (optional). Results are obtained in three days via telephoneusing an anonym ous pin num ber. Trained counselors are available 24/7. Reagent kit for oral fluid tests. In kit containing collection pad, vial and reagent for 1 test.

CholesTrak Home Test Kit

Home Access

OraSure

Page 22

Hepatitis C Hom e Diagnostic Test Kit Test Kit Nam e Hepatitis C Check Service Unique Features Clients testing with the Hepatitis C Check Service use a safety lancet to draw a few blood drops from a fingertip. The drops are placed on special sam ple paper. The sam ple is placed in a pre-paid envelope and shipped to a certified laboratory. Results are available within 10 business days. Colorectal Cancer Test Kits Test Kit Nam e ColoCare Hemoccult Home Test Detecatest Early Detector Colo-Screen Self-Test Unique Features Kit for fecal specim ens in kits containing 3 tests User collects sam ple of stool on slide User collects sample of stool on slide W ipe stool on to tissue and spray with test spray; flush after use Drop test pad in toilet bowl; not affected by iron, peroxidases or vegetables; toilet bowl cleaners m ay give false positive result. Drop test pad in toilet bowl; reagent is chrom agen Tetram ethylbenzidine Collection kit for fecal specim ens containing sample collection card, applicator, self-sealing sam ple bag and instructions. For use with the Hem eSelect Reagent Kit.

EZ - Detect HemeSelect

Acquired Im m une Deficiency Syndrom e (AIDS) Infection with the HIV (human im m unodeficiency virus) and resulting developm ent of a host of infectious disease sym ptom s. Norm al im m une system . The normal im m une system guards against infection by a host of invaders bacteria, viruses, fungi, allergens, toxins, cancer and others. Im m une cells arise from stem cells in the bone m arrow and a variety of white blood cells. Som e cells (lym phocytes) m igrate to the thym us gland (located in the upper chest) where they are converted to three different subtypes of cells. The three types are T-helpers , which recognize that an invasion has occurred, T-killer cells, which respond to the T-helper cells and attack the invader, and the T-suppressor cells which call off the T-killer cells once the invader has been destroyed. The T-suppressor cells are probably necessary to m odulate all immune reactions to prevent excessive and inappropriate responses. Outside the thym us gland, B-Lym phocytes (the B comes from an organ in chickens where this occurs; the bursa) are program m ed and m ature into plasm a cells. Plasm a cells and B-Lym phocytes produce the antibodies used in attacking a wide variety of foreign cells, including bacteria and viruses. B cells and plasm a cells are involved in the production of antibodies which are often necessary in both the recognition and destruction of invading cells. In AIDS, a virus, known as HIV (hum an im m unodeficiency virus), attacks the T-Helper cells and prevents them from alerting the imm une system to the presence of an invader. The infection requires the HIV particle to fuse its m em brane to that of the T-helper cell. Once fused, the retroviral RNA is injected into the lym phocyte and reproduction can begin. The infected T-Helper cells spread HIV both within the host person and into the environm ent. After clinical AIDS infection has developed, the patient cannot fight off infections. The HIV itself rarely kills the patient. Instead, its victim s die of other diseases the body is no longer able to ward off; especially infectious diseases such as pneum onia. Current therapies allow patients to live for years after acquiring the virus.

Page 23

The AIDS virus, designated HIV-1 or HIV-2, attaches to cells with a CD4 antigen receptor such as T-helper cells, glial cells in the brain and m onocytes (m acrophages). After attachm ent, the HIV invades T-helper cells and blocks their ability to warn the T-killers of invading foreign cells. The HIV virus is a retrovirus which means that it carries its genetic code as RNA rather than the normal viral m ethod of using DNA. Retroviruses contain an enzym e called reverse transcriptase that can convert retroviral RNA in the cytoplasm into DNA that m igrates to the cell nucleus. (The usual course of events is formation of RNA in the cytoplasm from DNA in the cell nucleus. Retroviruses reverse this normal process.) Infected T-helper cells produce even m ore AIDS virus which then infects more T-helper cells. The HIV virus rarely kills an infected person directly. Rather, it prevents the im m une system from doing its job and preventing invasion by all of the various pathogenic microorganism and other factors that can produce disease in hum ans. Of the two major types, HIV-1 is m ore toxic than HIV-2 and causes about 90% of all infections. Most long term survivors that are fully evaluated have an HIV-2 infection. Other groups of retroviruses (simeon im munoviruses, or SIVs) can affect hum ans and all have a rem arkable affinity for lym phocytes, especially the T-4 helper lym phocytes. The T-kilIer and T-suppressor lym phocytes are designated T-8 lym phocytes. The T-4 and T-8 nomenclature is based on the "cluster of differentiation" [CD] antigens they produce. CD4, the antigen produced by the T-helper cells, has been isolated and reproduced. As m entioned earlier, the CD4 antigen is the initial point of attachm ent for the HIV. The HIV-1 and HIV-2 are associated with certain lymphom as or leukem ias in hum ans. The virus can also infect nerve cells and m ost AIDS patients have neurological complications, especially in the latter stages of the disease. Transmission of HIV from an infected person to a uninfected individual requires the exchange of body fluids, especially blood, plasma, sem en, or vaginal secretions. Transmission by clothing, bedding, saliva, tears or air has not been dem onstrated. Living with an HIV infected person has not been shown to result in HIV transm ission unless there is sharing of body fluids through sexual contact or IV drug abuse. Initially, the disease predom inated in hom osexual and bisexual m ales and in IV drug users. The biggest other group was persons who have received the virus through adm inistration of blood or blood products (transfusions, hemophiliacs). Another subgroup is children born to mothers with AIDS. Heterosexual transmission occurs with greater frequency and no social group is im m une from the disease. Good statistics are com plicated by the long delay between presence of the HIV virus or its antibodies in an individual and the frank expression of AIDS in that sam e individual. AIDS Diagnostic Tests (Also See Above in Hom e Diagnostic Kits) Indication Detects HIV antibodies, indication of exposure to HIV Antigen test determines if patient has responded to HIV presence

Test Name Elisa HTLV3-EIA Envacor

Detect antibodies to core antigen P24 and the envelope antigen P41; conclusively dem onstrates response to HIV infection W estern Blot Kit Confirm s results of positive ELISA test that antibodies are due to presence of HIV OraQuick 20-minute HIV test; to use OraQuick, a health worker pricks a person's finger, puts a spot of blood into a vial containing a developing solution, and then dips in the sticklike testing device. A single reddish line on the OraQuick dipstick m eans no HIV. Two reddish lines means the person may be infected and needs a confirmatory test to be sure. The test detects antibodies to HIV, and scientific studies show it provides results with 99.6% accuracy.

If a definite date of infection can be established, HIV infection results in a nonspecific viral syndrome some 2 to 4 w eeks later and seroconversion (form ation of detectable anti-HIV antibodies) in 1 to 3 m onths. Most patients are then relatively symptom free for som e 2 to 5 years. It is during this time that they are m ost likely to transm it the virus to other individuals. A condition known as AIDS related complex (ARC) usually occurs next. During this tim e the HIV infected individual suffers a serious of gradually w orsening episodes of viral-like illnesses. Actual developm ent of clinical AIDS m ay require years. The Centers for Disease Control has established a list of opportunistic diseases whose occurrence

Page 24

is considered to be diagnostic of AIDS. This list has been supplem ented by the acceptance of using CD4 cell and viral particle counts as a means of establishing that a person has AIDS and should receive anti-HIV m edications. Opportunistic Diseases Associated with AIDS Pneumocystis carinii pneum onia Toxoplasma gondii dissem inated or encephalitic infection Cryptosporidium enteritis for > 1 month Chronic (> 30 days) mucocutaneous, herpes sim plex Cytom egaloviral infection of other than liver or lym ph node Progressive m ultifocal leukoencephalopathy Candida esophagitis Cryptococcal dissem inated or encephalitic infection Dissem inated bacterial infections Mycobacterium avium intracellular Kaposi's sarcom a (in som eone < 60 years of age) A prim ary brain lym phom a, lim ited to the brain The AIDS related com plex (ARC) is a collection of chronic signs and sym ptom s in patients who belong to a group associated w ith a high incidence of AIDS. Persons with ARC will not, however, manifest the opportunistic infections or Kaposi's sarcom a that are characteristic of the full blown disease state. If the ARC can be considered to be an early form of AIDS, then the sym ptoms listed below can be considered as early signs of AIDS, at least in som e patient groups.

There is no defined data to state that ARC will always m ature into AIDS. However, patients with ARC should be considered to be AIDS positive and be prepared for a full blown case of AIDS. ARC sufferers who develop the wasting syndrom e (lose >15% of body weight) are m ore likely to develop AIDS than are others. Other than those already discussed, the prim ary diagnostic features of AIDS are associated w ith im m unologic abnorm alities, especially deficiency states. AIDS patients tend to be anergic and do not respond to ordinary skin tests. It is possible to do direct counts of T4 cells and these are dim inished as is the overall population of all T cells. Once diagnosed, an AIDS patient is in for a continuing roller coaster of infections and other im m unological insults until an infectious episode cannot be fought off, even with vigorous m edical support. Signs and Sym ptom s of AIDS related com plex (ARC) Generalized lym phadenopathy W eight loss Chronic diarrhea Lym phopenia Rectal condylom ata (warts) Leukopenia Oral candidiasis (thrush) W asting syndrom e Idiopathic thrombocytopenia Intermittent fever Malaise and lethargy Anem ia W hen HIV infection first occurred it was not recognized as a viral infection but the disease burst into the m edical literature as Gay Related Im m unodeficiency (GRID, because all the first patients were gay males), and later Acquired Im m une Deficiency Syndrom e (AIDS). The causative agent was identified as the hum an imm unodeficiency virus (HIV) in 1985. The virus was found to weaken the im m une system by destroying the T-helper cells, also called CD4 cells. This weakening of the im m une system led to the developm ent of opportunistic infections. Opportunistic pathogens rarely cause infections in healthy people. Exam ples include Pneumocystis carinii pneum onia; candidiasis in the mouth or esophagus; toxoplasm osis in the brain; Cytomegalovirus retinitis; Mycobacterium avium com plex related infections in the bone marrow, GI tract or lungs, and others. Often, these infections attack m ultiple organ system s. In 2006, with over 1 m illion people infected in North Am erica and over 45 million infected worldwide, there are m ore than 20 distinct m edical products approved by the Food and Drug Adm inistration (FDA) to treat HIV infection. This includes four classes of m edications (NRTI's, NNRTI's, Protease Inhibitors and fusion inhibitors), several products with m ultiple dosage forms, and many com bination products. Most people who initiate therapy for HIV infection today will start with at least three active m edications. Current Department of Health and Hum an Services (DHHS) guidelines for the treatment of HIV infection in adults and adolescents recomm end lopinavir/ritonavir with lam ivudine and either zidovudine or stavudine as initial PI-based therapy in treatment nave patients; or efavirenz with lam ivudine and either zidovudine, tenofovir DF, or stavudine as NNRTI-based therapy (except in pregnant fem ales, due to the teratogenic potential of efavirenz).

Page 25

Once daily approved AIDS M edications Didanosine 250m g and 400m g Lam ivudine 300m g Tenofovir DF 300m g Am prenavir/ritonavir 1200mg/200m g Abacavir 600m g Saquinavir/ritonavir 1600mg/100m g Lopinavir/ritonavir 800m g/200m g

Em tricitabine 200m g Stavudine (Zerit XR) 75m g and 100m g Efavirenz 600m g Atazanavir (w/ritonavir) 400mg (or 300mg/100m g) Nevirapine 400m g Indinavir/ritonavir 1600mg/100 m g

Treatm ent of Patients with AIDS Reverse Transcriptase Inhibitors. Reverse transcriptase is the enzym e required to read RNA and produce DNA in order for synthesis of m ore viral RNA and other necessary proteins to occur. By inhibiting reverse transcriptase, one can prevent (to som e degree) viral reproduction. NRTI is the abbreviation for nucleoside reverse transcriptase inhibitors and refers to drugs that m im ic the structures of the nucleosides of RNA and DNA. A nucleoside is a com bination of a purine or pyrimidine base with a pentose sugar (ribose or deoxyribose). The NRTI agents are incorporated into the synthetic chain of DNA and effect the formation of useless DNA or cause breaks in the chain. Non-nuclesoside reverse transcriptase inhibitors (NNRTIs) do not m im ic the structure of nucleosides and are selective for the reverse transcriptase in HIV-1. The virus tends to very rapidly develop resistance to these drugs, so they m ust be used in com bination. Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Most of the recomm ended doses for these drugs have decreased from earlier recomm endations, largely due to the use of com bination therapy. When combined with protease inhibitors, it is usually possible to decrease the dose of the NRTI agents by at least one-third. Nucleoside Reverse Transcriptase Inhibitors (NRTI) Abacavir - Ziagen Guanosine analog Stavudine - Zerit Thym idine analog Adefovir - Hepsera nucleoside Zalcitabine - Hivid Cytosine analog Didanosine - Videx; Videx-EC Adenosine analog Zidovudine - Retrovir Thym idine analog Em tricitabine - Em triva Cytosine analog Zidovudine + Lam ivudine Com bivir Lam ivudine - Epivir; Epivir-HBC Cytosine analog Abacavir + Lam ivudine + Zidovudine Trizivir Highly Active AntiRetroviral Therapy (HAART) M edications Nucleoside and Nucleotide Reverse Transcriptase Inhibitors Side effects as a class: lactic acidosis, severe hepatomegaly with steatosis, including som e fatal cases M edication Ziagen, ABC Abacavir Videx, ddI Didanosine Adult dosage 300 m g BID or 600 m g daily >60 kg: 200 mg BID or 400 m g daily; if with tenofovir, 250 mg/daily Side effects, com m ents and toxicities Severe hypersensitivity reaction (can be fatal do not rechallenge); nausea and vom iting; no food restriction Pancreatitis; nausea, diarrhea; and peripheral neuropathy; take on an empty stom ach

<60 kg: 125 mg BID or 250 m g daily; if with tenofovir, dose not established. Do not use with stavudine (d4T, Zerit) due to increased risk and severity of lactic acidosis; avoid Videx + Zerit during pregnancy; avoid ddl/d4T com bination in general because of increased risk for adverse events (e.g., neuropathy, pancreatitis, and hyperlactem ia); Em triva, FTC Em tricitabine 200 mg daily Minimal toxicity; lactic acidosis; and hepatic steatosis, a rare but possibly life-threatening event; no food restrictions

Page 26

M edication Epivir, 3TC Lam ivudine Zerit, d4T Stavudine

Adult dosage 150 mg BID or 300 mg daily >60 kg: 40 mg BID <60 kg: 30 mg BID

Side effects, com m ents and toxicities Minimal toxicity; lactic acidosis and hepatic steatosis; a rare but possibly life-threatening event; no food restrictions Pancreatitis; peripheral neuropathy; rapidly progressive ascending neurom uscular weakness (rare); antagonizes action of zidovidine, do not use in com bination; no food restrictions

Do not use with didanosine (ddi, Videx) during pregnancy; avoid ddl/d4T combination in general because of increased risk for adverse events (e.g., neuropathy, pancreatitis, and hyperlactatemia) Viread Tenofovir 300 m g daily Nausea, vom iting, diarrhea; headache; asthenia; flatulence and renal im pairm ent; see above for dosage adjustment if taken with Videx; decreases levels of protease inhibitor atazanavir (Reyataz); take with food; a nucleotide RTI Gastrointestinal intolerance; bone marrow suppression (anem ia, n eutr openia); insom nia; headache; asthenia; and m yopathy; no food restrictions

Retrovir, AZT Zidovudine

200 m g TID or 300 m g BID

Non-nucleoside reverse transcriptase inhibitors Side effects as a class: Stevens-Johnson syndrom e Rescriptor Delavirdine Sustiva Efavirenz 400 mg TID Headaches; inhibits Cyt P-450; no food issues; do not use as m onotherapy (true for all); avoid in pregnancy Do not use during known or possible pregnancy; rash; central nervous system sym ptom s (e.g., dizziness, im paired concentration, insom nia (dream s), abnorm al transam inase elevation and false positive cannabinoid test; do not take after high fat m eal due to increased peak concentration

600 mg daily at HS

Viram une Nevirapine

200 mg daily for Inducer of Cyt P-450; no food issues; hepatitis; rash; 2 weeks, then Stevens-Johnson syndrom e most likely here 200 mg BID or 400 mg daily Fusion Inhibitor

Fuzeon 90 mg BID Enfuvirtide, T-20 subQ

Injection site reaction; bacterial pneumonia; HIV negative persons should not use as may cause a false positive test for HIV presence

Protease Inhibitors Side effects as a class: gastrointestinal intolerance, hyperlipidemia, hyperglycem ia, diabetes, fat redistribution, and possible increased bleeding in hemophiliacs Reyata Atazanavir 400 m g once daily; if adm inistered with tenofovir + ritonavir, 300 mg once daily 1,400 mg BID Indirect hyperbilinibinemia; prolonged PR interval (use caution in patients with underlying cardiac conduction defects or on concom itant medications that can cause PR prolongation) Gastrointestinal intolerance, nausea, vomiting, diarrhea. rash; elevated transam inases; and headache Gastrointestinal intolerance; nausea, vom iting, diarrhea paresthesias; hepatitis; pancreatitis; asthenia, taste perversion; m any drug interactions

Lexiva Fosamprenavir Norvir Ritonavir

See doses used in com bination with other specific protease inhibitors; full dose is

Page 27

up to 600 mg BID Crixivan Indinavir 800 m g q 8 hrs W ith ritonavir (might increase risk for renal adverse events), dose is 800 mg indinavir and 100 m g ritonavir q 12 hrs - or 800 mg indinavir and 200 m g ritonavir q 12 hrs 750 m g TID or 1,250 mg BID Gastrointestinal intolerance, nausea; asthenia; headache; nephrolithiasis; blurred vision; metallic taste; indirect hyperbilirubinem ia (inconsequential); throm bocytopenia; and hem olytic anem ia

Viracept Neffinavir Invirase Saquinavir (hard-gel caps)

Diarrhea; and elevated transam inases

W ith ritonavir: Gastrointestinal intolerance; nausea, diarrhea; 400 m g saquinavir and headache; and elevated transarninases 400 mg ritonavir BID - or 1,000 mg saquinavir and 100 mg ritonavir BID W ith Ritonavir: Gastrointestinal intolerance; diarrhea; nausea, 400 mg saquinavir and abdominal pain; dyspepsia; headache; and 400 m g ritonavir BID elevated transam inases - or 1,000 mg saquinavir and 100 mg ritonavir BID Com bination Products of Antiretroviral Agents

Fortavase Saquinavir (soft-gel caps)

Kaletra 400 m g lopinavir 100 m g ritonavir

3 tabs BID

Diarrhea, nausea, vom iting; asthenia; elevated transam inases; hyperglycem ia; fat redistribution; lipid abnorm alities; possible increased bleeding in persons with hem ophilia; and pancreatitis See above individual m edications

Combivir 300 m g zidovudine l 50 mg lam ivudine Trizivir 300 m g zidovudine 150 m g lamivudine 300 m g abacavir Epzicom 300 m g lamivudine 600 m g abacavir

1 tab BID

1 tab BID

See above individual m edications

1 tab daily

See above individual m edications

Truvada 1 tab daily 200 m g emtricitabine 300 m g tenofovir

See above individual m edications

On March 19th, 1987, the FDA approved AZT for the treatm ent of HIV infection. Clinically, AZT (a Nucleoside Reverse Transcriptase Inhibitor, NRTI) was found to marginally increase CD4 cells (50-100

Page 28

cells) and to have short-lived effects (6-12 m onths). At the tim e HIV viral load testing was not available, so its direct, in vivo effects against the virus could not be tested clinically. Additionally, at doses of 300 m g five times a day, the drug was poorly tolerated (prim arily due to nausea and vom iting), often toxic, and sometim es life threatening (both due to bone m arrow toxicity). Over tim e, the pharm acodynamic effects of the drug became better known. The dosing recom m endation changed to 200 m g three tim es a day and then 300 m g twice a day. At a total daily dose of 600 m g, AZT has become a better tolerated and safer (relative to daily doses of 1,500 m g daily) m edication. In fact, today it is still one of the most comm only used HIV medications either as Retrovir or as part of Com bivir or Trizivir. Zidovudine (ZDV, AZT, Retrovir) is the standard drug of first choice for m ost AIDS patients. A newly diagnosed AIDS patient should receive 600 m g per day. Som e physicians prefer to dose the drug in higher dosages (up to 1200 m g per day) during the first phase of therapy. A patient with CD4 counts as high as 500 can use the drug. Zidovudine alone can extend the lives of patients with AIDS in virtually all patient groups. Whether or not it can prevent the developm ent of AIDS in a person exposed to fluids from an AIDS patient (as in a needle stick) has not been fully resolved. Studies have dem onstrated that treatment of an HIV infected pregnant wom an with zidovudine can reduce the rate of transm ission of the HIV virus to the fetus. The drug is, however, toxic to the bone m arrow and is carcinogenic, in rats, at doses equivalent to those used in hum ans. Patients receiving AZT m ust be carefully m onitored for signs of intolerable bone marrow depression and for signs of m alignancies not generally associated with the disease. Patients with AIDS are at a greater risk by not receiving AZT than from any potential cancers associated with use of the drug. Other concerns with the use of AZT are the potential for the AIDS virus to develop resistance to the drug and the long term effects of taking zidovudine, especially in pregnant wom en and children. The second anti-HIV drug m arketed, in 1991, was didanosine (ddI, Videx). The m ain role of didanosine is in patients who can no longer tolerate zidovudine due to its toxicities. Didanosine does not have the bone marrow toxicity associated with zidovudine and can be an alternative for patients with significant anemia. The main adverse reactions of didanosine involve the nervous system and pancreas. The usual dosage of didanosine is 200 mg every 12 hours and it must be given on an em pty stom ach . The drug has very poor bioavailability and the tablets are quite large (about like two 25-cent pieces stuck together. The tablets also contain pH elevating buffers that can interfere with the absorption of drugs such as dapsone, protease inhibitors, ketoconazole and quinolone antiinfectives in which low stom ach pH is needed. Doses of Videx and one of these other drugs should be separated by two hours. Alcohol can exacerbate didanosine toxicity. Hivid (ddC, zalcitabine) was approved in 1992 and was initially lim ited to use only in com bination with zidovudine. It has been found to have benefit when used alone, however, and is given to patients who have not adequately responded to zidovudine or who are otherwise not candidates for the drug. The usual dose is 0.75 mg every 8 hours. Its side effect profile is sim ilar to that of didanosine, so these two agents cannot be used in com bination. Magnesium and aluminum containing antacids can reduce the oral absorption of zalcitabine if the antacid is taken at about the sam e time as the Hivid. Stavudine (d4T, Zerit) m ay be more effective than zidovudine in som e patients. Zerit (stavudine) was m arketed in 1994. It does not cause bone m arrow depression but does cause significant peripheral neuropathy. Fortunately, the neuropathy does usually reverse if the drug is discontinued or the dose is reduced. The usual dose of stavudine is 40 mg q 12 hours. Stavudine and Zidovidine are mutual antagonists and cannot be given together. Lam ivudine (3-TC, Epivir) is given at a dose of 150 mg q 12 hours. Main side effects are a mild rash, headache, diarrhea and hair loss. Epivir works in the sam e m anner as previously approved drugs and should be used in combination with zidovudine. Concom itant therapy with TMP/SMX elevates lam ivudine levels but there is no clear im plication for use or avoidance of the two drugs. Com bivir is a combination of 150 m g of lam ivudine and 300 m g of zidovidine. One tablet is taken twice daily. Like m ost combination drug products, this facilitates patient compliance but complicates dosage adjustments. Epivir (lam ivudine) was marketed in 1995.

Page 29

Abacavir (Ziagen) is a prodrug converted by cellular enzym es to carbovir triphosphate, the active form of the drug. This is a conversion sim ilar to that for antiviral agents used against herpes infections (acyclovir, etc). Abacavir should always be used in com bination with other anti-H IV drugs. It is particularly useful when combined with a NNRTI and a protease inhibitor due to different binding sites on reverse transcriptase and different enzyme targets, respectively. The m ost im portant side effect for Ziagen is a potentially fatal hypersensitivity reaction that can occur in up to 5% of both adults and children receiving the drug. If a rash occurs in a patient, the patient should not receive any further doses and a rechallenge can be fatal. The drug should be stopped at the first sign of a rash or other indication of hypersensitivity. Nausea (50% ), vom iting (16% )and sleep disorders (7% ) are the m ajor adverse effects that occur in adults. Children are m ore prone to these side effects. The usual dose of Ziagen is 300 mg BID in com bination with other anti-HIV agents. Taking the drug less often during the day m ay im prove compliance when compared to som e other NRTI agents. Kaletra is a com bination of two HIV protease inhibitors, lopinavir and ritonavir. The ritonavir blocks the m etabolism of the of the lopinavir resulting in higher blood levels of that drug. Fourteen years after the first HIV cases were reported, there were now m ultiple m edications available to treat HIV infection. However, the standard of care for a long tim e was to use one m edication at a tim e. There was not enough evidence to support combining m edications for increased effects, and there was a significant concern of increased toxicity. Around 1993, HIV specialists began using com binations of m edications, two at a time typically, to see what effects could be garnered, while keeping a close eye on toxicity. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). In June of 1996, the first nonnucleoside reverse transcriptase inhibitors (NNRTI's), was approved. Viram une (nevirapine) m arked the beginning of a new era in the treatment of patients with AIDS and HIV infection. The NNRTI's offered m ore efficacious therapy that was m ore reliable, particularly when combined with protease inhibitors. That is, they resulted in greater decreases in viral loads, greater increases in CD4 counts, and these effects lasted longer. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Delavirdine - Rescrriptor Efavirenz - Sustiva Nevirapine - Viram une These m edications m arked the beginning of a significant event in the treatm ent of new patients with AIDS and HIV infection. Not just because of these new classes and new treatment options, but because concurrent, with these m edications becom ing available, m ore was being learned about combination therapy and the possibility of combining the older m edications with the options presented in the two new classes. Additionally, the tools to monitor viral response to therapy (by m easuring HIV viral loads) and to detect resistance to the HIV medications (with genotype and phenotype tests) were also becoming clinically available at this time. Following the release of protease inhibitors and NNRTI's, deaths due to AIDS decreased m arkedly. New cases of AIDS also decreased during this tim e. Anecdotally, many hospital w ards that were being m aintained only for patients with AIDS were finding that they could either close these wards, or use them for other patients. Since then, the incidence of new cases of AIDS and deaths due to AIDS has leveled off, while the rate of new HIV infections has continued to increase. However, m any patients whose lives were saved with the new m edications are now in a tenuous position with their HIV care. Early history of sequential m onotherapy with the NRTI's led to resistance to these m edications. Without the full benefit of these medications in their therapy, the other classes of antiretrovirals often lose their effectiveness as resistance develops. Nevirapine (NVP, Viramune) is a non-nucleoside reverse transcriptase inhibitor specific for HIV-1. Chem ically, nevirapine is a dipyrido-diazepinone derivative, structurally sim ilar to the benzodiazepines. Nevirapine selectively inhibits reverse transcriptase activity. The inhibitory mechanism is noncompetitive for both the nucleoside and tem plate prim er; binding sites on HIV-1 reverse transcriptase appear to be the conserved tyrosines (Tyr-181 m id Tyr-188) on the p66 subunit. Nevirapine has no activity against reverse transcriptase from other retroviruses, including HIV-2, and is inactive against all four human DNA polym erases.

Page 30

Unlike nucleoside analogues (NRTIs), nevirapine does not require intracellular phosphorylation for antiviral activity. Nevirapine dem onstrated in vitro activity against zidovudine-resistant strains of HIV-1, and synergistic antiviral activity (without enhanced cytotoxicity) when combined with zidovudine. HIV-1 resistance to nevirapine has occurred within days or weeks and nevirapine resistant strains are cross resistant to other NNRTIs. Cross resistance does not occur between NNRTIs and NRTIs. Cross resistance between protease inhibitors and reverse transcriptase inhibitors, is unlikely since different targeted enzymes are involved. In the treatm ent of HIV, oral nevirapine is dosed at 200 m g daily for 14 days, then increased to 200 mg twice daily, in com bination with a nucleoside analogue reverse transcriptase inhibitor. Nevirapine is rapidly absorbed, with high plasm a levels sustained for approxim ately 24 hours after oral doses. Nevirapine is m etabolized in the liver. The elim ination half-life of oral nevirapine exceeds 20 hours. The primary adverse effects are skin rash, fever, nausea, headache, and abnorm al liver function tests. It is the need to develop tolerance to the rash that requires starting at a low dose and then increasing once the patient has dem onstrated ability to tolerate the drug. The plasm a protein binding of nevirapine is 50 to 60% and the hepatic m etabolism of nevirapine occurs primarily via hydroxylation. Nevirapine induces hepatic enzym es, (cytochrom e P450 isoenzymes) and enhances its own m etabolism . The elim ination half-life of nevirapine following single doses ranges from 22 to 84 hours. Skin reactions have occurred when using nevirapine, including Stevens-Johnson syndrome, which m ay warrant discontinuation of therapy. Liver disease represents a potential need for dose adjustments and patients w ith central nervous system disorders m ay voice additional com plaints. Significant adverse hematologic abnorm alities have not been reported during nevirapine therapy in prelim inary studies, but periodic m onitoring of blood counts during therapy is suggested to detect throm bocytopenia. Somnolence, fatigue and headache are com m on adverse effects of nevirapine, the first two suggestive of sedative activity of the drug. Infrequent adverse CNS effects include irritability and confusion. Somnolence and/or fatigue occurred in 63% of patients receiving nevirapine 12.5 to 200 mg daily as m onotherapy. Headache was observed in 33% of patients. Rash is the major clinical toxicity with nevirapine therapy, and usually occurs within the first 4 to 6 weeks of treatment. The incidence of rash is approxim ately 17% with 7% requiring discontinuation of the drug. The incidence of rash also increases in com bination therapy with other antiviral agents. The incidence of rash is not dose-related, but a higher incidence occurs in patients taking higher doses. Fever has been associated with oral nevirapine m onotherapy in up to 40% of patients, with no apparent dose relationship. Co-adm inistered cim etidine may cause m odest increases in nevirapine serum concentrations. Cim etidine is known to inhibit cytochrom e P450, IIIA, the subfam ily of enzym es thought to be m ost responsible for nevirapine m etabolism and clearance. Interaction with the cytochrome P450-3A system has becom e a significant problem with antiretroviral m edications. Some of the drugs likely to be used by AIDS patients and their effect on nevirapine blood levels are listed below. Clarithrom ycin increases Dirithromycin increases Ketoconazole increases Rifabutin decreases Erythrom ycin increases Rifam pin decreases

Combining protease inhibitors and nevirapine results in reduced serum concentrations of the protease inhibitor. Reduced zidovudine serum concentrations and possibly reduced zidovudine efficacy may occur when nevirapine and zidovudine are given in combination with didanosine. Delavirdine (DLV, Rescriptor) is another NNRTI specific for HIV-1. It binds directly to reverse transcriptase and blocks RNA-dependent and DNA-dependent DNA polym erase activities. Delaviridine does not compete with template; prim er or deoxyribonucleoside triphosphates. HV-2RT and hum an cellular DNA polym erases are not inhibited by delaviridine. In addition, HIV-I group O, a group of highly divergent strains that are uncomm on in North Am erica, may not be inhibited by delaviridine.

Page 31

Delaviridine, com bined with zidovudine, didanosine, zalcitabine, lam ivudine, interferon alpha, and protease inhibitors has resulted in additive synergistic anti-HIV-1 activity in in vitro studies. Delaviridine m ay confer cross-resistance to other non-nucleoside reverse transcriptase inhibitors if used alone or in combination. The potential for cross-resistance betw een delaviridine and protease inhibitors is low because of the different enzym e targets involved. The potential for cross- resistance between NNRTIs and nucleoside analog RTIs is low because of different binding sites on the viral RT and distinct m echanisms of action. In the treatm ent of HIV-1 infection, the recom m ended dosage is 400 m g orally (four 100 mg tabs) three tim es daily. Use delaviridine in com bination with appropriate other antiretroviral therapy. Adm inister delaviridine with or without food. Delaviridine is rapidly absorbed following oral adm inistration with peak plasm a concentrations occurring at approxim ately one hour. Delaviridine is m etabolized in the liver prim arily by cytochrom e P450-3A. The elim ination half life is from 2-11 hours. Delaviridine is extensively bound (about 98% ) to plasm a proteins. The primary adverse effects of delaviridine are skin rash, headache, fatigue, nausea/vomiting, diarrhea, and increased liver enzymes. There are m any other adverse affects, but they only occur in less that 2% of the patients. The major toxicity is rash, and patients should be advised to see a physician promptly if rash is noted especially when accom panied by fever, blistering, oral lesions, swelling or m uscle and joint aches. Drugs likely to be used by AIDS patients and their effect on nevirapine levels are listed below: Anticonvulsants decrease Delavifidine decreases Fluoxetine increases Antacids decrease Clarithrom ycin increases Didanosine decreases Antim ycobacterial agents decrease Ketoconazole increases

Coadm inistration of delaviridine with the som e drugs m ay result in potentially serious or life threatening adverse events because of the inhibitory effect of delaviridine on CYP3A and CYP2C9 hepatic m etabolism: Antihistamines (e.g., Astemizole) Benzodiazepines Antim icrobial agents (e.g.. Clarithrom ycin, Dapsone, Rifabutin) Cisapride Dihydropyridine Calcium Channel Blockers (e.g., Nifedipine) Ergot derivatives Quinidine W arfarin Protease inhibitors (e.g., Indinavir, Saquinavir) (May prove clinically useful) Efavirenz (Sustiva) was the third NNRTI to be marketed. The im portance of Sustiva is its long period of action to perm it once daily dosing. Like other NNRTIs, it must be used in com bination with one or more anti-HIV drugs. Cross resistance with NRTIs, NNRTIs and protease inhibitors is not likely to be of concern. Again, allergic skin rashes (30% ) are the most comm on side effects. Other side effects that com m only occur include CNS and psychiatric sym ptom s (52% ), diarrhea (39% ), fever (25% ), cough (26% ) and nausea or vom iting (16% ). Often, patients develop tolerance to these problem s or can restart the drug with fewer problem s after stopping it for two or m ore weeks. The drug m etabolism interactions are about the sam e as for other NNRTIs. One peculiar occurrence has been false positive urine tests for m arijuana on only one specific test method. Retesting with another method is used to confirm or deny m arijuana use. The usual dose for Sustiva is 600 mg (3 capsules) once a day. Nucleotide Reverse Transcriptase Inhibitors. A nucleotide is a structure that com bines the purine or pyrimidine base plus the pentose sugar (nuclesoside) and the phosphoric acid. Nucleotides do not require phosphorylation to be activated (as do the nucleoside agents). Tenofovir - Viread is a nucleotide (already phosphorylated) reverse transcriptase inhibitor. Protease Inhibitors. In Decem ber 1995, the first of a new class of antiretrovirals, protease inhibitors (PI's), Invirase (saquinavir) was approved. In March of the next year, the second and third protease inhibitors, Norvir (ritonavir) and Crixivan (indinavir) becam e available, although indinavir's initial distribution was lim ited to only one pharm acy in the U.S.

Page 32

Am prenavir Agenerase Fosamprenavir Lexiva Ritonavir - Norvir

Protease Inhibitors Indinavir Crixivan Saquinavir Fortovase or Invirase Atazanavir Reyataz Nelfinavir Viracept Atazanavir Reyataz Lopinavir and Ritonavir Kaletra

A virus is transm itted from an infected cell to an uninfected cell with the DNA (or RNA in the case of HIV) protected inside a protein coating. In order for the viral DNA to take over the reproductive processes of the newly infected cell, this protein coat, and other pre-protein products within the virus, must be dissolved by proteases carried inside the viral protein coat. By inactivating these proteases, one may prevent uncoating of the virus, prevent release of needed reproductive enzymes and stop any further viral reproduction. HIV-1 encodes an aspartate protease with two sym m etric subunits. This enzyme is required for cleavage of polypeptides that generate the structural proteins and enzym es of the virus. These include reverse transcriptase, integrase and the protease enzym e itself. Protease inhibitors are effective in both acutely and chronically infected cells. Resistance can develop over several months and this is the reason that a drug "cocktair' is required for most effective therapy. Alm ost all have relatively poor bioavailability and are inactivated by the cytochrome P450 system, leading to a host of drug interactions. For saquinavir (SQV, Fortovase) the dose is 1200 m g q 8 hours, preferably with a high fat m eal. M ost comm on side effects are headache and nausea. Rifam pin stim ulates m etabolism while ketoconazole and tetraconazole decrease metabolism . The drug can cause photosensitivity and is m etabolized by the cytochrom e P-450 oxidase system . Poor bioavailability lim its its use. W ith indinavir (Crixivan, IDV) the dose is 800 m g q 8 hours one hour before or two hours after a meal. The m ain side effects are increases in indirect bilirubm , kidney stones, hematuria, GI upset, fatigue, headache and nausea. Patients should drink at least 1.5 liters of fluid a day to minim ize the renal com plications. The GI side effects seem to lessen with prolonged use. Indinavir has the sam e set of cytochrome P450 interactions as described above. Ritonavir (Norvir, RTV) has a dose of 600 m g every 12 hours with food. The usual starting dose is 300 m g every 12 hours for the first 7 to 10 days and the dose is increased once the patient has developed tolerance to the drug. It has the m ost drug interactions. Its main side effects involve the GI tract and paresthesias. However, it can also have severe interactions with psychoactive drugs and this often requires stopping one of the two drugs. The capsules m ust be refrigerated. The nelfinavir (Viracept, AG-1343, NFV) dosage for adults is 750 m g q 8 hours, with food. Children receive 20-25 m g/Kg every 8 hours. This agent is better tolerated orally, causing only m ild diarrhea. W hile it shares m ost of the cytochrom e P450 issues of other protease inhibitors, it is not affected by either ketoconazole or clarithrom ycin. Amprenavir (Agenerase), in com bination with other antiretroviral agents, is indicated for the treatment of HIV-1 infection. Am prenavir is an inhibitor of hum an im m unodeficiency virus (HIV)-1 protease. Am prenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors, resulting in the form ation of im m ature noninfectious viral particles. Am prenavir m ay be taken with or without food; however, a high-fat m eal decreases the absorption of am prenavir and should be avoided. Advise adult and pediatric patients not to take supplem ental vitamin E since the vitam in E content of am prenavir capsules and oral solution exceeds the Reference Daily Intake (adults, 30 IU; pediatrics, 10 IU). Am prenavir capsules and oral solution are not interchangeable on a m g per m g basis. The dose of am prenavir capsules, for adults and adolescents (13-16 years), the recom m ended dose is 1200 m g (eight 150 mg caps) twice daily in com bination with other antiretroviral agents. For patients between 4 and 12 years of age or for patients 13-16 years of age with weight of < 50 kg, the recomm ended dose is 20 mg/kg twice daily or 15 m g/kg 3 tim es daily (to a m axim um daily dose of 2400 m g) in combination with other antiretroviral agents.

Page 33

Dosing is different when using the oral solution. Am prenavir oral solution was 14% less bioavailable compared to the capsules. The recom m ended dose for patients between 4 and 12 years of age or for patients 13 to 16 years of age with weight < 50 kg is 22.5 m g/kg (1.5 m l/kg) twice daily or 17 m g/kg (1.1 m l/kg) 3 tim es daily (to a maxim um daily dose of 2800 m g) in com bination with other antiretroviral agents. Use with caution in patients with m oderate or severe hepatic im pairm ent. Am prenavir is m etabolized in the liver by the cytochrom e CYP3A4 enzyme system. The 2 m ajor m etabolites result from oxidation of the tetrahydrofuran and aniline m oieties. Glucuronide conjugates of oxidized m etabolites have been identified as m inor metabolites in urine and feces. Lexiva (fosam prenavir) is a phosphate ester prodrug of am prenavir. Fosam prenavir is quickly hydrolyzed to am prenavir in the gut wall, and distributed in the blood as am prenavir. The post-absorption pharm acokinetics are identical to am prenavir. However, fosam prenavir has a better absorption and tolerability profile com pared to am prenavir, and has sm aller and fewer pills to take (2-4 fosamprenavir versus 6-12 am prenavir). It can still be dosed once daily (when boosted with ritonavir) or BID (with or without boosting), as with am prenavir. Fosam prenavir is supported by three Phase 3 clinical trials. The SOLO Study com pared boosted fosam prenavir once daily and nelfinavir BID in 649 treatment nave patients (~30% female) from diverse countries and of diverse ethnic backgrounds. These patients had lower CD4 counts than seen in most studies (166 cells/m L in the fosam prenavir arm and 177 in the nelfinavir arm ), and 42-44% of subjects had HIV RNA viral loads >100,000 copies/m L. Overall, fosam prenavir and nelfinavir perform ed equally, although fosam prenavir appeared to do better than nelfinavir in patients with viral loads >500,000 copies/mL and CD4 counts <50 cells/mL. The NEAT Study com pared unboosted fosam prenavir BID and nelfinavir BID in 249 treatm ent nave subjects from the U.S., Panama, Puerto Rico, and South Africa. Ethnic backgrounds were well distributed, and ~30% were fem ale. Viral loads were sim ilar to the SOLO Study, but CD4 counts were slightly higher (212-214 cells/m L). W hile CD4+ cell count increases were similar in both groups, a higher proportion of fosamprenavir subjects achieved viral load <50 copies/mL, including a significantly greater proportion of subjects with high baseline viral loads (55% vs. 24% ). Lastly, the studies supporting the use of fosam prenavir in nave patients used a group that was m ore diverse (by ethnicity and gender) and sicker than seen in m ost Phase 3 studies of other HIV m edications. This may make the results more generalizable to a greater num ber of patients. The Context Study compared boosted fosam prenavir (once daily and twice daily) to lopinavir/ritonavir in 315 PI experienced patients. Subjects were enrolled from many sites across the globe, with 13-17% of subjects being female and 57-73% of subjects being Caucasian. The data from boosted fosam prenavir once daily shows a 50% response rate (as com pared to 61% and 58% for lopinavir/ritonavir and boosted fosam prenavir). Because of this data, once daily boosted fosamprenavir is not recom m ended in PI experienced patients. Boosted fosam prenavir BID appeared to perform similar to lopinavir/ritonavir. However, the sample size was not large enough to m ake definitive conclusions about comparing the two products. Of note, the SOLO Study showed that subjects who failed boosted fosam prenavir once daily did not develop PI resistance. Instead they typically failed with NRTI resistance or no resistant m utations at all (reflecting poor adherence to the medications). Among persons experiencing failure of boosted fosamprenavir, there were no m utations in the protease gene that resulted in resistance changes. This corroborates with the finding that treatment nave patients experience failure of other boosted PI's such as lopinavir/ritonavir, indinavir/ritonavir and saquinavir/ritonavir. The developm ent of resistance in nave subjects who received unboosted fosam prenavir and in subjects with PI experience were sim ilar to what has historically been seen with am prenavir. W hile fosam prenavir appears to be better tolerated than am prenavir, the addition of ritonavir limits its use in som e patients. The occurrence of other side effects (i.e. hyperlipidem ia, lipoaccumulation, and others) was sim ilar to am prenavir. Amprenavir appears to cause less of an increase in cholesterol and triglycerides, but the difference is not clinically significant in m any patients. Drug interactions seen with fosamprenavir are sim ilar to am prenavir (both are m ixed inducers/inhibitors of the CYP 3A4 enzymes). Food does not affect its absorption.

Page 34

Atazanavir is also supported by three Phase 3 studies. BMS-034 com pared unboosted atazanavir with efavirenz in ~270 treatm ent nave patients (35% female, 33% Caucasian). CD4 counts were near 320 cells/m L and viral loads averaged ~63,000 copies/m L. Unboosted atazanavir perform ed as well as efavirenz. BMS-043 compared unboosted atazanavir with lopinavir/ritonavir and BMS-045 com pared boosted atazanavir with lopinavir/ritonavir in PI experienced patients (229 and 243 patients, respectively). Both studies included ~20% wom en, while BMS-043 had more ethnic minorities than BMS045 (~40% vs. ~60% Caucasian, respectively). Lopinavir/ritonavir outperform ed unboosted atazanavir, but was com parable to boosted atazanavir. A third arm in BMS-045 included atazanavir and saquinavir together, but it perform ed much worse than either the lopinavir/ritonavir arm or the boosted atazanavir arm . However, this m ay be a result of the pharm acokinetic interaction between atazanavir and tenofovir DF which was not known at that tim e. Atazanavir has som e drug interactions that were not expected. Videx tablets will decrease atazanavir absorption, presum ably because atazanavir absorption is dependent on a low pH. As such, there is presumed to be an interaction with proton pum p inhibitors and H2-blockers. Current package inform ation data suggests adm inistering these products 12 hours away from the dose of atazanavir. Studies to confirm these interactions and form ulate concrete recomm endations are ongoing. Additionally, tenofovir DF has been shown to decrease the levels of atazanavir (a m echanism for this interaction has not yet been reported). Bristol- Myers Squibb recom m ends using boosted atazanavir when given with tenofovir DF. Efavirenz (and probably nevirapine) will also decrease atazanavir blood levels, therefore, boosting is recom m ended. Drug interaction studies with other PI's are ongoing, but current data recom mends not combining atazanavir with lopinavir/ritonavir. Atazanavir is better tolerated than m ost other PI's. It has a lower incidence of diarrhea, a lower propensity for causing lipoaccum ulation, and a much lower incidence of hyperlipidem ia. However, hyperbilirubinem ia is a com m on side effect of atazanavir. Atazanavir inhibits the enzym e uridine diphosphate 5'-glucuronyl transferase (UGT 1A1). This enzym e is responsible for converting unconjugated bilirubin to conjugated bilirubin. As such, there is an increased level of indirect bilirubin. This hyperbilirubinem ia, which is sim ilar to the hyperbilirubinem ia that has been seen with indinavir is neither a cause of physiologic harm , nor is it a reflection of any physiologic dam age. It is essentially an asymptomatic laboratory abnorm ality. A sm all proportion of patients on atazanavir m ay become jaundiced or develop scleral icteris. However, anecdotal reports state that this often passes while still on atazanavir, and m ay recur periodically. Unlike lopinavir/ritonavir, efavirenz, and m any of the other antiretrovirals that are dosed BID, these newer, sim pler therapies do not have as m uch supporting data. However, data does support their effectiveness in treating HIV infection in treatm ent nave and experienced patients. Additionally, they are often better tolerated and better accepted by m any patients. As such, they offer a viable option in the treatm ent of HIV infection. Some currently recom m ended anti-HIV regimens are: Zidovudine + Lam ivudine + a protease inhibitor Stavudine + Lam ivudine + a protease inhibitor Zidovudine + Didanosine + a protease inhibitor Zidovudine + Zalcitabine + a protease inhibitor Ritonavir + Saquinavir each in a dose of 400 m g BID drug interaction works to result in lower dose of both drugs and causes fewer adverse reactions As the therapeutic m anagem ent of HIV infection grew to include m ultiple m edications, so did the complexity of the regim ens. As the effectiveness of the regim ens grew, the incidence of OI's decreased and treatment goals changed from short-term to long-term. The new regim ens, while saving lives, were very complicated. They often involved numerous large sized pills, which had to be taken 2-4 tim es a day. The ability of patients to take these m edications properly was quickly seen to be a m ajor concern. Poor adherence led to drug failure and/or drug resistance. The need for sim pler therapies quickly became evident. The first m ove toward sim pler therapies began with Com bivir, which com bined zidovudine and lam ivudine. These two medications were manufactured by the sam e company and data showed that they worked well together, so it was a natural starting place. Today, Com bivir is still considered one of the cornerstones of HIV therapy.

Page 35

A year after Combivir became available the first once daily medication for HIV was introduced. Sustiva (efavirenz) has a 55-hour term inal half-life, m aking it ideal for once daily regim ens. Since then, efavirenz has becom e the preferred NNRTI with treatment nave patients. The problem, however, was that a once daily regimen containing three drugs could not be constructed if only one of the agents supported once daily use. Didanosine was the first NRTI to receive approval as a once daily agent, and in October of 2000, the enteric coated form ulation was approved. Videx EC capsules replaced a form ulation that was previously available as chewable tablets that tasted like bitter antacid, and offered the sam e m edication as one capsule once daily (on an empty stomach). Additionally, the use of ritonavir in low doses was found to inhibit the m etabolism of certain other m edications and act as a pharmacokinetic "boosting" agent for other PI's. This discovery has allowed for the reduction in total number of pills and, often, the frequency of adm inistration. Fusion inhibitors. In March 2003, Fuzeon (enfuvirtide), the first medication in a fourth class of antiretroviral m edications called fusion inhibitors was approved in the U .S. It is also the first antiretroviral m edication that is only available as a subcutaneous injection (zidovudine is available as oral and injectable formulations). Its twice daily dosing, reconstitution considerations, and cost are factors that have influenced the prescribing of the m edication. However, for m any patients, this m edication has helped them regain their im m une system and health, as we saw with the PI's and NNRTI's. Fusion inhibitors prevent the HIV virus from being able to fuse with the CD4 cells, thus preventing entry and infection. The first drug in this class is Fuzeon (enfuvirtide), and is available only as a subcutaneous injectable form ulation. Enfuvirtide is indicated for treatm ent experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy. Initially, the distribution of the product was limited due to com plexities of producing the drug. It is anticipated that there will be wider availability of Fuzeon in the near future. The HIV virus has two proteins that are instrumental in the process of fusing the virus to the host cell. The GP120 protein acts to "attract" the virus to the cell. The GP41 protein acts as a "harpoon" and crank arm , and pulls the virus into the host cell. Enfuvirtide blocks the process at the GP41 site, thus preventing fusion. Enfuvirtide is a huge m olecule; a 36 am ino acid, synthetic peptide. Due to its size, it is not absorbed through the skin and because of its structure, it is not stable in the acidic environment of the stomach. Early in developm ent, the use of continuous subcutaneous infusion pum ps, as are used with insulin in some diabetes patients, was tested. However, these pum ps often becam e clogged, they had poor pharm acokinetic profiles, and often resulted in painful nodules at the site of infusion. Therefore, it is currently adm inistered subcutaneously. Subcutaneous injection sites should be rotated, allow for more predictable pharm acokinetics, and are better tolerated in the injection site reactions. Enfuvirtide was supported primarily by two Phase three studies, TORO-1 and TORO- 2. TORO-1 included 491 subjects who had to have at least six m onths of prior antiretrovirals, resistance or treatment with all three classes of antiretrovirals (including at least two PI's), and a HIV-RNA viral load of >5,000 copies/m L. TORO- 2 included 504 subjects with sim ilar antiretroviral histories, except they only needed to have three months of prior treatment, and did not need to have a history of two PI's. Both studies included m ostly men (92% in TORO-1 and 87% in TORO-2) and mostly Caucasians (~82% in TORO-1 and 95% in TORO-2), with an average age of 42. All patients had a median of seven years of prior HIV treatm ent, a median of 12 antiretroviral agents, median viral load of ~130,000 160,000 copies/m L, and a m edian CD4 count of 75 87 cells/m L. Patients with AIDS should not wait until all other antiretrovirals are useless before utilizing enfuvirtide. Helping patients accept enfuvirtide as a necessary part of therapy at the appropriate tim e is an important part of patient counseling, by their m edical provider, nurse and pharm acist. Enfuvirtide has also been studied in a pediatric population. Enfuvirtide was found to be effective in children ages 6 to 16 years-old when added to a stable, failing HIV regimen. Injection site reactions were com m on and generally well tolerated. Enfuvirtide is approved for use in children at a dose of ~2m g/kg (see the package insert for a full dosing table). Though Fuzeon is anticipated to be m ore widely available in the near future, some third party payers have been slow to cover the m edication due in large part to the estim ated per patient cost of ~$21,000 a year. However, this was also the case with other HIV treatm ent breakthrough m edications but eventually, as these agents became the standard of care, they began to be covered by

Page 36

insurance. According to the package insert, enfuvirtide m ay lead to the developm ent of antibodies to the drug, which could potentially cross react with the HIV ELIZA antibody test, resulting in a false positive. However, a confirm atory Western Blot test should rem ain negative. Use of enfuvirtide in HIV negative subjects, including as prophylaxis, has not been studied as of yet. Treatment in both studies included enfuvirtide with an "Optim ized Background Regim en" (OBR), which included an average of four other antiretrovirals, or an OBR alone. The optim ized background regimen was determined with the use of phenotype and genotype sensitivity scores. These scores were derived from their respective resistance tests. Patients were random ized in a 2:1 ratio to receive enfuvirtide plus the OBR, or the OBR alone. At 24 weeks, data from TORO-1 showed a decrease in viral load of 1.696 log10 copies/m L from baseline in the enfuvirtide group, versus a decline of 0.764 log10 in the OBR only group ( p < 0.001). The enfuvirtide group also showed a greater increase in CD4 cells as com pared to the OBR only group (76 vs. 32 cells/m L, respectively; p < 0.001). TORO-2 showed sim ilar results at 24 weeks, favoring the subjects on enfuvirtide (1.429 vs. 0.648 log10 copies/m L viral load, p < 0.001, and 65.5 vs. 38 cells/m L CD4 count; p < 0.02). Data from both trials at 48 weeks was sim ilar to week 24 results supporting the durability of enfuvirtide. For patients who are starting therapy with enfuvirtide, instructions from the pharmacist are essential to ensure the proper preparation and adm inistration of the medication. Reconstitution of enfuvirtide m ust be performed with the sam e care as w ith other proteins. Reconstitution is done using 1.1 m L of sterile water diluent with 90 m g vials of enfuvirtide. Vigorous injection of the diluent, or shaking of the vial, will likely cause the drug to foam, and may dam age the protein, resulting in less active drug. To reconstitute the drug, the required am ount of diluent should be added slowly, the vial should be tapped for 10 seconds and gently rolled between the hands. Additionally, the time it takes for the drug to dissolve is norm ally 30-45 m inutes. To m ake tim e m anagement easier, two vials may be reconstituted at the sam e tim e, with the second vial stored in the refrigerator until the next dose is due. Enfuvirtide m ust be injected by the patient subcutaneously twice daily. Adm inistration is perform ed with a small gauge needle being injected into an accessible, preferably fatty, area of the body (although it may be difficult to find a fatty area in patients with advanced disease). The upper arm , abdom en, or anterior thigh, are recom m ended injection sites. To som e patients, the steps required to adm inister the m edication m ay seem daunting, however, few subjects from the TORO trials experienced significant problem s. Subcutaneous adm inistration often results in an injection site reaction. This reaction will vary from patient to patient and often from one injection to the next. W ays to minim ize these reactions include: rotate the injection site, rub the injection site after the drug has been adm inistered, inject into a fatty area and try different angles of injection. Severe injection site reactions have occurred when enfuvirtide was injected repeatedly in the sam e area. Since these reactions typically take 5-10 days to resolve, patients should utilize several different potential injection sites. Despite these considerations, only three percent of subjects in research studies discontinued enfuvirtide because of injection site reactions. Additionally, since these reactions are the only prom inent side effect of enfuvirtide, it is actually better tolerated than m any of the other available antiretroviral agents. Resistance to enfuvirtide has been seen. In patients with a large am ount of viral resistance to other antiretrovirals, enfuvirtide can offer some help, but resistance is likely to develop if there are not enough other active m edications being used. As such, m any question where to appropriately position Fuzeon in therapy. Much has happened in the treatment of HIV infection since AZT first becam e available in 1987. Efforts are now split between finding new treatment options for patients with few options left, and exploring optim ization of current treatm ents. No longer are drugs that save lives enough. Now, they need to be dosed as few tim es a day as possible, with as few pills as possible, and with as few side effects as possible. The fusion inhibitors represent a new class of HIV m edications, and three additions to existing antiretroviral m edications that are well tolerated and can be dosed once daily have recently become available. W ith com bination products of currently available medications being the next weapons awaiting approval, this trend will likely continue.

Page 37

M onitoring Param eters and General Patient Instructions with anti-HIV m edications Laboratory Param eters. CD4+ cell and viral particle counts, serum p24 antigen, HIV RNA, and beta-2 m icroglobulin periodically during therapy. Liver function tests, renal function tests, routine blood chem istry, and com plete blood counts periodically during therapy. Physical Exam ination. Body weight, temperature, com plete physical exam ination, and chest X-rays periodically during therapy. Question in regard to physical activity, energy levels, and appetite. If You Miss a Dose: Take a m issed dose as soon as possible. Skip a m issed dose if it is alm ost time for your next regular dose. Do not take two doses at the sam e tim e. Be sure your doctor knows if you stop taking the m edicine for 7 days or m ore. You m ay need to take less of the medicine for 2 weeks and then build up to your regular dose. Inform ation about FDA approved clinical trials of anti-AIDS drugs can be obtained by calling 1-800-TRIALSA (9 AM-7 PM ET, M-F). Additional inform ation can be obtained by accessing the National Library of Medicines com puterized databases AIDSTRIALS and AIDSDRUGS. AIDS has, unfortunately, spawned an industry directing at giving hope to AIDS patients by having treatm ents the governm ent "refuses to release". The FDA has been placed in the perfect no-win situation. If they insist on determ ining the toxicity of a new drug before m aking it available, they are denying patients a potentially helpful m edication. But, if they m ake the drug quickly available and it proves to have intolerable toxicities, then they are trying to kill off the AIDS patients with toxic compounds. A fast track m ethod for approval of anti-AIDS drugs has been developed. A host of natural and synthetic compounds are being studied in an effort to uncover a com pound that kills the virus (reverse transcriptase and protease inhibitors and only stop further reproduction) without producing the toxicities seen with current agents. Vaccines have been developed that m ay prevent one from acquiring HIV infection and early clinical trials are underway in some countries. Treatm ent of AIDS Complications As mentioned earlier, it is not the infection of the AIDS virus that is the usual cause of death but rather some com plication of a loss of the im m une system . Toxicities of antiviral drugs, especially the bone m arrow depression, could also contribute to death from an infection. The rem ainder of this section will concentrate on how to manage the complications of AIDS that do occur. Generally, the therapy of first choice is listed first and alternative therapies follow. Toxoplasm osis produces a protozoal brain lesion (m ass) and other sites of infection in immuno comprom ised patients to a degree not usually seen in ordinary victim s. After P. carinii , toxoplasma encephalitis is the leading cause of death am ong AIDS patients. Drugs and Doses Route(s) Pyrimethamine, 100All 200 m g once, then PO 50-100 m g/day + Folinic Acid, 10 mg q d + Sulfadiazine 4 to 8 Gm/day (25 mg/Kg q 6 hrs) Duration 6 weeks Com m on Side Effects Fever, rash, neurotoxicity, blood dyscrasias, bone m arrow depression Crystalluria

6 weeks

Pyrimetham ine, 100PO 6 weeks 200 m g once, then 50100 m g/day + Folinic Acid, PO 10 m g q d + Clindam ycin, 900-1200 mg IV or 300-450 mg q 6 hrs PO

Fever, rash, neurotoxicity, blood dyscrasias, bone m arrow depression

Pneum ocystis carinii pneum onia is, caused by a protozoan parasite that apparently can only exist in an im munologically com prom ised m am malian host. There is no single consistent sign, other than im paired pulm onary function with diffuse infiltration of the lung. Once the disease occurs, it tends to reoccur in 20-50 percent of patients. AIDS patients rarely survive 3 episodes.

Page 38

Drug and Dose Route(s) Co-Trimoxazole IV, PO (SMX/TMP) 15-20 mg/kg/day (based on trim ethoprim ) Co-Trimoxazole PO 160 m g BID for prophylaxis Pentamidine 4 m g/kg/day 4 m g/kg biweekly for prophylaxis Atovaquone (Mepron) 750 m g TID IV, IM Inhalation IV, IM

Duration 3 weeks

Com m on Side Effects Nausea, vom iting, fever, rash, GI upset, decreased W BCs

no limit

Nausea, vom iting, fever, rash,

3 weeks

Throm bocytopenia, hypotension, m etallic taste. renal dam age

no lim it

PO

3 weeks

Particularly if patient cannot tolerate Bactrim/Septra

Dapsone 100 m g q day PO + Trimethoprim, 15-20 mg PO, IV per Kg per day Pyrimetham ine + Sulfadoxine (Fansidar) 0.5 - 1 tablet/week PO

3 weeks

no limit

Sam e as for Co-Trim oxazole but usually less so

Clindam ycin 600 m g q 8 hrs + Primaquine 30 mg q day Trimetrexate 45 m g/M 2 IV + Leucovorin 20 mg/M 2 q day Prednisone 40 m g BID then 40 mg QD then 20 mg QD PO

PO 3 weeks

3 weeks

5 days 5 days No lim it

For severe PCP and low oxygen

Isosporiosis is a protozoan parasitic infection of the gut that leads to a fatal debilitating diarrhea, especially in the im m unocomprom ised patient. Although cotrim oxazole (Bactrim , Septra) is used, there is no definitive treatment to eradicate Isospora belli infections. Drug and Dose Co-Trimoxazole two Septra-DS BID Route(s) PO Duration 2-4 weeks Com m on Side Effects Sam e as above

Pyrimethamine 50-75 mg PO + Folinic Acid 5-10 mg q day

unlimited

Cryptococcus neoform ans is a fungal infection, especially of the m eninges but also of the blood and lungs. India ink stains are used to identify the organism . Always use com bination therapy. Drug and Dose Route(s) Duration Com m on Side Effects Am photericin B, IV no limit Nausea, vom iting, fever, chills, anemia, phlebitis, 0.8 - 1 m g per Kg hypotension, renal dam age, Mg and K loss per day to a total dose of 14 to 21 mg/Kg Fluconazole, 400 m g q day 200 - 400 mg/day PO, IV PO 6-10 weeks Nausea, vom iting, rash, diarrhea, life long liver toxicity possible

Page 39

Candida albicans infections are usually "topical" in nature but may be systemic. the drugs used for other fungal infections could be used for systemic infections, Otherwise, oral or "swished and swallowed" liquid or throat lozenges (MM route) are used to treat "topical" infections. Drug and Dose Fluconazole 100 m g q day Route(s) PO Duration Com m on Side Effects 2 weeks or See below until sym ptom s resolve 7-10 days m ay repeat Nausea, vom iting, increased liver function tests

Nystatin, 500,000 u q 4 hrs Clotrimazole, 10 m g lozenge MM

PO MM

7-10 days m ay repeat PRN up to 6 per day up to 2 wks

Bad taste, nausea

Ketoconazole PO 300-400 mg/day

GI upset, nausea, vom iting increased liver function tests

Mycobacterium tuberculosis is all too com m on in AIDS patients and requires more vigorous therapy than standards in the non-im m unocomprom ised patient. The current recomm endation calls for the use of not less than four drugs to reduce the potential for developm ent of resistance. Drug and Dose Route(s) Duration Com m on Side Effects Isoniazid, 300 mg per day PO 6 m onths Hepatotoxicity, rash, B-6 depletion m inim um Rifam pin, 600 m g per day PO but life long Red fluids, protease inhibitors therapy Ethambutol, 15-20 mg/kg/day PO m ay be Ocular toxicity needed Pyrazinam ide, 2 gms per day PO Renal and liver toxicity Streptomycin 25 mg/kg/day IM 28 days Am inoglycoside toxicity

Coccidiom ycosis and Histoplasm osis are two com m on fungal diseases that will som etim es appear in an AIDS patient. Although they often begin in the lungs, both diseases can m ove to any part of the body and are difficult to eradicate in norm al patients. Drug and Dose Am photericin B Route(s) IV Duration 4-8 weeks Com m on Side Effects As above; give total dose 1-2.5 gm s at a rate of 0.8 - 1 mg/Kg/day Interaction with protease inhibitors; liver, nausea, rash PO PO 3days unlim ited unlim ited As above

Itraconazole, 300 m g q 12 hr 200 m g q 12 hours

Fluconazole, 400 m g/day PO, IV

Giardia lam blia is one protozoal infections that affects both norm al and im m unocom prom ised individuals. It involves the sm all intestine and results in nutritional problem s and diarrhea. Drug and Dose Route(s) Quinacrine HCl, PO 300 m g/day Metronidazole 750 - 1500 m g/day PO Duration 2 weeks Com m on Side Effects Fever, jaundice

2 weeks

Nausea, neuropathy, disulfiram-like reaction famous but actually rare

Page 40

Herpes simplex virus infections can be m ild to severe and are usually mucocutaneous but the treatment is the sam e if they are system ic, only the doses and routes of adm inistration change. Drug and Dose Route(s) Duration Com m on Side Effects Acyclovir 15 m g/kg daily IV 7-10 days Increased liver function tests, increased or 800 mg 5 tim es/day PO 7-10 days Dem erol effect, renal dam age, CNS effects Famciclovir, 125-500 m g q 12 hrs Valacyclovir, 1 gm TID PO 5 or m ore days Headache nausea, increased cost

PO IV

10 days 21 days

Valacyclovir is a prodrug for acyclovir See toxicities below

Foscarnet 40 m g/kg q 8 hr

Mycobacterium avium complex is a relative of tuberculosis and prim arily causes lung problems. Drug and Dose Route(s) Clarithromycin, PO 500 m g q 12 hr + Etham butol, PO 15 m g/kg q day plus either Ciprofloxacin, PO 500-750 m g q 12 hr or Rifabutin, 300 m g q day PO (azithrom ycin 500 m g q day PO m ay be used for clarithrom ycin) Clofazimine, 100 mg TID PO + Amikacin, 10-15 mg/kg/day IV Duration 6 weeks Com m on Side Effects Bad taste, som e GI discom fort Ocular toxicity

6 weeks

GI upset, reduced absorption if gastric pH too elevated; theophylline and protease inhibitor m etabolism

unlim ited

6 weeks

Stains skin purple to black Am inoglycoside side effects

Herpes (Varicella) Zoster Virus is usually only topical and self-lim iting. A vaccine is available if epidemics are a concern or for use in selected individuals. Drug and Dose Route(s) Acyclovir, 30 m g/kg/day IV Valacyclovir, 60m g/kg every 12 hours Duration 10+ days Com m on Side Effects See above Valacyclovir is a prodrug for acyclovir, so the side effects are the sam e See toxicities below

PO 10+days

Foscarnet, 40 m g/kg q 8 hr

IV

10+ days

Cytomegalovirus (CM V) is especially comm on in hom osexual m ales (>95% ) and is rarely curable. Once CMV retinitis occurs, patients are likely to go blind and life span is shortened. Drug and Dose Ganciclovir 5 m g/Kg q 12 hrs Route(s) IV Duration 14-21 days induction Com m on Side Effects Nausea, vom iting, hypotension, rash, delirium, bone m arrow depression, lethargy, renal dam age See above; patient often relapses 60 days days after induction

Ganciclovir, 5 m g/Kg q day IV unlim ited Ganciclovir, 1 gm . q 8 hrs PO Ganciclovir ocular im plant ocular 6-8 m os Cidofovir, 20-40 mcg Ocular Injection ocular

unlim ited

Foscarnet, 60 m g/Kg q 8 hrs then 90-120 m g/Kg/day

IV

14-21 days maintenance

Nephrotoxic, but patient can continue to take zidovudine

Page 41

No consideration of the possible infections and other com plications of AIDS could ever be exhaustively complete due to the ever increasing number of cases and alm ost unlim ited potential opportunistic diseases. All the "usual" diseases that affect people can also affect AIDS patients and one would anticipate their treatm ent would be even m ore difficult than in non-AIDS patients. Because of the cost of receiving treatm ent in a hospital, m any AIDS patients opt for care in their home or in other settings. The ability to pay, alone, may be the reason for selecting non-hospital care. Pharm acists who provide hom e health care services can expect to encounter AIDS patients seeking their services. NUTRITION is a com m on problem for AIDS patients. They are ill and not want to eat and the likely problem of oral candidiasis m akes it uncom fortable to eat. Enteral nutrition is possible if a suitable feeding tube can be introduced but parenteral nutrition is m ore likely. Be especially watchful of potassium levels in these patients as m any of the medications for fungal infections will result in altered serum potassium levels. AIDS patients m ay need to obtain fewer days of therapy of parenteral nutrition solutions to avoid waste. The progestin m egestrol (Megace) can be used to help patients gain weight. INFECTIONS can be m anaged through outpatient IV therapy, especially if the hom e health care pharm acy is providing nursing assistance or a knowledgeable care giver is present in the home. The patient should be fairly stable and not going through wide variations in mental or physical state. Pharm acists m ay encounter com binations of drugs and doses not com m only used in other cases. PREVENTION of spread of the HIV to nurses, other personnel, or to future patients who may use durable m edical equipm ent previously used by an AIDS patient is important. Persons working with AIDS patients need not wear masks, as a routine, but m ust w ear gloves and long sleeves. All bedding and clothing soiled with body fluids must be either destroyed or thoroughly cleaned. Autoclaving is the preferred way to sterilize everything, but chlorine based solutions (Dakins Solution, diluted Chlorox) m ay be applied and allowed to stay for not less than one m inute. Other sterilizing solutions can be used; especially those that are phenol based. Ideally, pharm acists should select IV administration devices for use by AIDS patients that m inimize the contact between the patient's blood and the infusion device. Non-electrical infusion devices can be chosen that are easier to clean. Personnel caring for infusion access points in AIDS patients must be sure to avoid against introducing infection to the patient. Recommended laboratory evaluation for nonoccupational postexposure prophylaxis (nPEP) of HIV infection. During 4-6 W eeks 3 M onths 6 Months Test Baseline nPEP after exposure after exposure after exposure HIV antibody testing CBC with differential Serum liver enzym es BUN /creatinine E, S E E E E E E E* E* E* E* E E* E* E+ E+ S E+ E+ E+ E+ E+ E+ E+ E E E E

STDs screen E, S (gonorrhea, chlam ydia, syphilis) Hepatitis B serology Hepatitis C serology Pregnancy test HIV viral load HIV resistance testing S CD4 T lymphocyte count E, S E, S E S

Page 42

Other specific tests m ight be indicated dependent on the antiretrovirals prescribed. Literature pertaining to individual agents should be consulted. E = exposed patient, S = source. HIV antibody testing of the source patient is indicated for sources of unknown serostatus. Additional testing for pregnancy, sexually transmitted diseases, and hepatitis B should be performed as clinically indicated. If determ ined to be HIV infected on follow-up testing; perform as clinically indicated once diagnosed. Parkinson's Disease Parkinson's Disease generally com m ences in m iddle or late life and leads to progressive disability with time. The disease occurs in all ethnic groups, has an equal sex distribution, and is com m on, with a prevalence of 1 to 2 per 1000 of the general population and 1 per 100 am ong people older than 65 years. Signs of parkinsonism are extrem ely com m on in the elderly; a recent survey indicated that 15 percent of individuals between 65 and 74 years of age, and more than half of all individuals after age 85, have abnorm alities on exam ination consistent with the presence of an extrapyram idal disorder. Parkinsonism is a syndrom e consisting of a variable com bination of trem or, rigidity, bradykinesia, and a characteristic disturbance of gait and posture. Parkinsons Disease is a chronic, progressive disorder in which idiopathic parkinsonism occurs without evidence of m ore widespread neurologic involvem ent. Sym ptom s of Parkinson's are caused by loss of nerve cells in the pigm ented substantia nigra pars compacta and the locus coeruleus in the m idbrain. Cell loss also occurs in the globus pallidus and putamen. Eosinophilic intraneural inclusion granules (Lewy bodies) are present in the basal ganglia, brain stem, spinal cord, and sym pathetic ganglia; they do not occur in other disorders in which parkinsonism is a feature. In Parkinson's disease, loss of dopam inergic cells in the substantia nigra leads to striatal dopamine depletion. Because dopam ine activates excitatory D 1 receptors in the direct pathway and represses inhibitory D 2 receptors in the indirect pathway, this depletion results in decreased activity of the direct pathway and increased activity of the indirect pathway and so in reduced thalam ic excitation of the m otor cortex. Other neurotransm itters, such as norepinephrine, are also depleted, with clinical consequences that perhaps contribute to depression. The cause of Parkinson's Disease is unknown. One possibility is exposure to an unknown environmental toxin that m ay have occurred years before the onset of any clinical disturbance, because sym ptoms will not develop until the cum ulative cell loss from toxin exposure and natural aging approxim ates 80% of the original cell population. Alternatively, endogenous toxins m ay be responsible. Dopam ine readily oxidizes to produce free radicals, which cause cell death by oxidizing various cellular constituents. Although the precise role of dopam ine itself remains unclear, the evidence relating Parkinson's Disease to damage by free radicals remains compelling. Epidem iology: The incidence is about 20 cases per 100,000 population yearly but reaches one case per 100 in the population over the age of 60. It is m ore com m on in m en than wom en, m ore widespread in northern countries and race has no influence. Parkinsons Disease is due to cell death related to the aging process. M any patients m ay have a relative with a fine trem or or Parkinson's disease, but no known gene or genes are thought to cause the illness. Environm ental factors m ay be involved, especially exposure to toxic agents such as pesticides and industrial chemicals. Physiology: Human m ovem ent is controlled from m any different, but interrelated brain centers and the corpus striatum is one of the body's m otor control centers. The corpus striatum is m ade up of two structures, the putam en and caudate nucleus, it receives and integrates information about body position and m ovem ent from several different parts of the brain. The corpus striatum is also responsible for m aintaining norm al m uscle tone and, therefore, proper body posture. After the corpus striatum makes computations, it sends im pulses to other parts of the brain's m otor control system, from there, messages are transmitted to the spinal cord, then through the peripheral nerves to the m uscles them selves. The

Page 43

substantia nigra lies beneath the striatum in a part of the brain called the m idbrain. Neuronal death in the substantia nigra inhibits dopam ine function, therefore decreasing the activity of the corpus striatum. Although dopam ine insufficiency is the m ain cause of Parkinson's disease, involvem ent of serotonin, acetylcholine, and other neurotransm itters in the brain m ay cause an im balance that aggravates the disease state. Dopam ine is a neurotransm itter used to fuel the m illions of synaptic transmissions required to create sm ooth, continuous voluntary m ovem ent or m aintain posture and m uscle tone. Two other neurotransm itters, acetylcholine and serotonin also play roles in the brain's m otor control system , although their role is not defined, there is som e evidence that Parkinson's disease effects their level and function. Although its role in body m ovement is unknown, serotonin is found in high concentrations in the basal ganglia. Acetycholine is an excitatory substance, an excess of acetylcholine in the brain results in the increased rate of synaptic transm ission within the basal ganglia. Hyperstim ulation of neurons by acetylcholine can cause sym ptom s similar to those caused by a depletion of dopam ine. Sym ptom s and Diagnosis: Primary Sym ptoms trem or, rigidity (stiffness), bradykinesia (decreased m ovement) and postural instability (unsteadiness, falling) Secondary Sym ptom s gait disturbances, dexeterity and coordination difficulties, freezing, speech and swallowing difficulties, visual symptoms, depression, dementia, pain and sensory discomfort, sexual difficulty, blood pressure changes, derm atological changes and gastrointestinal or urinary difficulty Diagnosis currently there is no specific test or specific examination that can provide a definitive diagnosis. Physicians m ust study a com posite picture of the patients historical signs and symptom s, along with test results to rule out other conditions. Tests MRI Magnetic Resonance Im aging EEG Electroencephalogram PET Positron Em ission Tom ography to detect the level and location of brain chem icals

Idiopathic Parkinsonism disease state which cannot be directly traced to disease, drugs or toxins. Secondary Parkinson's Disease or Vascular Parkinsonism in which dam age caused by stroke m ay mimic Parkinson's Disease with its stiffness and slowness, a tendency to walk with short shuffling steps and difficulty speaking clearly. Infectious Parkinsonism due to an outbreak of Encephalitis Lethargica, a viral epidemic during the 1910's and 1920's in central Europe and the United States and caused parkinsonian symptoms. Autopsies found the virus selectively destroyed neurons in the substantia nigra. Drug-Induced Parkinsonism occurs when various drugs and chem icals induce Parkinsonian symptoms by one of two mechanism s. Either (1) blockage of receptors for dopam ine in the striatum , or (2) depletion of neurotransm itters in the brain such as dopam ine and serotonin. This form of the disease is usually reversable upon discontinuance of the causative drug. Stages of Disease Progression Stage 0 - No visible disease Stage 1 - Disease involves one side of body Stage 2 - Disease involves both sides of body, but doesn't im pair balance Stage 3 - Disease im pairs balance or walking Stage 4 - Disease markedly im pairs balance or walking Stage 5 - Disease results in com plete im m obility Treatm ent: Drug Therapy Several classes of drugs are available 1. Anticholinergic Therapy Blocks the action of the neurotransm itter aceytlcholine, helping to regain balance between acetylcholine and dopam ine. 2. Replacem ent Therapy Replacem ent of dopam ine by another source. Levodopa, Carbidopa and Sinem et. 3. Dopamine Agonist Dopam ine agonist directly stim ulate dendrite receptors, bypassing the need for dopam ine itself.

Page 44

4. MonoAmine Oxidase B Inhibitors Increases the effect of dopam ine by blocking the enzyme MAO B that normally breaks down dopam ine. 5. Catechol-o-m ethyltransferase Inhibitors Increases the effect of dopam ine by blocking the enzyme COMT that normally breaks down dopam ine. Surgery . New techniques that m ay be able to replenish dopamine levels in the brain or electrodes that m ade send signals to various sections of the brain Diet and Exercise. Vitam in Therapy - Slight evidence that Vitam in C and E m ay help reduce the sym ptoms of Parkinson's Disease and even retard the progression of the disease. A well balanced diet will keep your im m une system healthy. Obesity m ay cause mobility problems. Relaxation Therapy . Stress aggravates Parkinson's Disease Prognosis: There is currently no cure for Parkinson's Disease. Due to the fact that it is a disease of the aged, usually occurring in individuals 60 and over, life expectancy after the onset of the disease is norm ally 10 to 14 years. Average duration of life is 74 years. Young patients diagnosed with the disease, less than 50 years of age, may live a long productive life. E.g., Michael J. Fox. Drug Nam e Levodopa Carbidopa Com m ents on Use Converts to dopam ine in brain; m ost generaly used; m ost effective Inhibits peripheral conversion of levodopa to dopam ine; used in com bination with levodopa to enhance effect of levodopa; cannot cross blood brain barrier Dopam inergic; comm only used as an adjunct Dopam inergic; monoamine oxidase inhibitor; com m only used as an adjunct; concerns over mortality data Dopam inergic; used as an adjunct Dopam inergic; generally used and effective as an adjunct Dopam inergic; used in Europe in various dosage form s; not widely used in US Dopam inergic; also available for hyperprolactinem ia D 2 dopam ine receptor agonist D 2 dopam ine receptor agonist D 2 dopam ine receptor agonist Selective D 2 dopam ine receptor agonist Dopam ine modulating effects; m ixed reports of im provement and worsening of Parkinsons Disease Monoam ine oxidase inhibitors; rarely used at present

Brom ocriptine Selegiline (Eldepryl) Am antadine Pergolide Apomorphine Cabergoline Terguride Talipexole Pramipexole Ropinirole Estrogen

Pargyline Phenelzine Entacapone Tolcapone

Catechol-0-methyltransferase inhibitors

Benztropine Anticholinergics; used as an adjunct Trihexyphenidyl

Page 45

Ritanserin

Specific central serotonin S2antagonist does not affect norepinephrine, acetylcholine or central dopam ine antagonism Antioxidant; m ost results derived from uncontrolled trials ANTIEM ETIC AGENTS

Vitam in E

Phenothiazines have been in use since the 1950's for a wide range of conditions. Their m ost prominent early use was in the m anagem ent of m ental disorders. They are routinely used as centrally acting antiem etics, especially drugs such as prochlorperazine (Com pazine), prom ethazine (Phenergan), thiethylperazine (Torecan), and chlorprom azine (Thorazine). Although effective against many types of nausea and vomiting, phenothiazines have not been successful against chemotherapy induced nausea except when m ild cases are involved. The side effects of high doses of phenothiazmes (dystonia, pseudoparkinsonism , dry mouth, hypotension, etc) also lim it their usefulness. Butyrophenones are chem ically distinct, but pharm acologically sim ilar, to the phenothiazines. Droperidol (Inapsine) and haloperidol (Haldol) are m ore potent centrally active antiem etics than the phenothiazines and this is droperidol's prim ary use. Again, the side effect profile (same as phenothiazines, but enhanced) is the lim iting factor. Substituted Benzam ides are represented by m etoclopram ide (Reglan). One of its antiem etic actions is to facilitate stomach em ptying. Metoclopram ide was the first agent to exert an antidopam inergic action in the gastrointestinal tract in addition to that same effect in the central nervous system. This has made m etoclopram ide particularly effective against nausea and vom iting associated with chem otherapy agents since m any of these drugs produce nausea and vom iting by direct action on the dopam ine receptors of the GI tract. High doses (150 m g) can be used and, at these levels, may produce an antiserotonin activity. The incidence of extrapyramidal effects is highest m children and the elderly (often true for all drugs) but can be reduced by pretreatment with diphenhydram ine (Benadryl) and lorazepam (Ativan). These three drugs are often com bined into a prechem otherapy antiem etic "cocktail". 5-HT-3 (Serotonin) Antagonists are the newest class of antiem etics and include granisetron (Kytril) and ondansetron (Zofran). Serotonin antagonists act both centrally and in the GI tract to antagonize the nauseating effects of chem otherapy agents. Unlike other antinausents, these dm gs block serotonin (not dopamine) and so are spared the extrapyram idal effects seen with other agents. Most side effects are mild (headache, drowsiness) and do not necessitate withdrawal of the drug. In clinical trials, 5-HT-3 antagonists have proven to be superior to all other agents in controlling the nausea and vom iting induced by cisplatin (the usual standard). Benzodiazepines have lim ited usefulness as true antiem etics but are effective in relieving the anxiety associated with chemotherapy and with limiting the side effects of the prim ary agents. Diazepam (Valium) and lorazepam (Ativan) are the most used agents. Corticosteroids are used as adjunctive agents in prophylactic antinauseant therapy, especially dexamethasone (Decadron), hydrocortisone (Solu-Cortef), and methylprednisolone (Solu-Medrol). They are not as effective against early onset nausea and vom iting as the agents mentioned earlier, but are useful against late onset nausea. The rapid IV adm inistration of the large doses used often causes systemic flushing and itching, especially in the groin. Cannabinoids were discovered to have antiemetic properties when m arijuana users undergoing cancer chem otherapy reported the benefits to physicians. As an antiemetic, dronabinol (Marinol) is taken orally. Dronabinol is m ore effective than prochlor-perazine, but not as effective as the butyrophenones or m etoclopram ide. The sam e am ount of cannabinoid is required for antiem etic effect as is needed for the typical m arijuana "high" and m any patients find the central nervous system effects unsettling. This has been the prim ary lim iting factor on the use of dronabinol as an antiemetic. Antihistam ines such as diphenhydramine (Benadryl) have only lim ited effects against chemo-therapy induced em esis. Their anticholinergic and lim ited central effects are mild compared to those of the other

Page 46

agents. The prim e usefulness of diphenhydram ine is in its sedative effect and in reduction of the extrapyram idal effect of other agents. Non-Drug Therapy of Nausea . Sm all frequent m eals are better tolerated than large ones. Liquids with sugar (coke syrup, m aple syrup, corn syrup, honey) can have a settling effect by causing GI muscle relaxation. Em etrol is a brand nam e agent that contains dextrose and phospholipids. Em etrol tastes m uch better when chilled, but it cannot be diluted without losing its effect. Pouring the drink over cracked ice is a good method to achieve rapid cooling without significant dilution. It can be used by pregnant wom en. Is the Dose Different Because of Poor Absorption or is it Due to First Pass M etabolism ? Use your knowledge of dosage form strengths to predict bioavailability issues w ith drug products. For exam ple, several drugs have different oral and IV doses, proving they have oral bioavailability issues. For the H 2 antagonists, Pepcid and Tagam et have the sam e oral and IV doses, while Zantac has different doses. Trade Nam e Tagamet Pepcid Zantac Axid Generic Nam e Cim etidine Fam otidine Ranitidine Azatidine Single Oral Dose 300 mg 20 mg 150 mg 150 m g Single IV Dose 300 mg 20 mg 50 mg not available IV

The general principle to be learned is as follows: Only one m em ber of the fam ily has a different oral and IV dose, therefore, the difference is probably due to poor oral absorption of the individual agent rather than a problem with the whole class. Consider, however, the exam ple of the beta blockers. In this case, four m em bers of the class are available in both oral and parenteral form and are listed below. Trade Nam e Inderal Lopressor Trandate Tenormin Generic Nam e Propranolol Metoprolol Labetalol Atenolol Single Oral Dose 20 mg 50 mg 100 mg 50 m g Single IV Dose 1 mg 5 mg 10 mg 5 mg

The sam e can be said for the few calcium channel blockers available parenterally and orally. Trade Nam e Calan, Isoptin Cardizem Generic Nam e Verapam il Diltiazem Single Oral Dose 40 m g 30 m g Single IV Dose 5 mg 5 mg

The general principle to be learned is as follows: Every m em ber of the fam ily has a different oral and IV dose, therefore, the difference is probably due to first pass m etabolism in which liver m etabolism greatly alters the amount of drug reaching the general circulation. A sim ilar example could be given for calcium channel blackens. Any drugs adm inistered by the sublingual route would also be likely candidates for first pass m etabolism (e.g., nitroglycerin, Hydergine, nifedipine).

Page 47

The Anem ias Value Measured Change as increase ( + ) or decrease ( ) or no change ( 0 ) Anem ia of Chronic Disease dec

Type of Anem ia

Vit B-12

Folic Acid

Iron deficiency

Blood Loss

Hem olytic Anem ia

Red Blood Cell (Erythrocyte) Count Hem oglobin (Hgb) in grams per dl Hem atocrit (% ) Mean corpuscular volum e (MCV) in cubic microns Mean corpuscular hem oglogin (MCH) in picograms per RBC Mean corpuscular Hgb concentration (MCHC) in gm /dl Reticulocytes (% ) Vitamin B-12 levels Folic acid levels Serum Iron levels Total Iron binding capacity Transferrin saturation Ferritin RBC distribution width Antiglobulin test in imm une types Serum haptoglobin Plasm a (free) Hgb

dec

dec

dec

dec

dec

dec dec inc m acrocytic

dec dec inc m acrocytic

dec dec dec m icrocytic

dec 0 or dec

dec dec

dec dec

0 or dec

inc

inc

dec

0 or dec

0 normochrom ic 0 or dec dec

0 norm ochrom ic 0 or dec

dec hypochrom ic 0 or dec

0 norm ochrom ic inc

0 or dec norm or hypo 0 or dec

inc

dec dec inc dec dec

dec dec inc 0

inc dec inc hypochromic (low) = decreased m ean corpuscular Hgb concentration normochromic (norm al) = norm al m ean corpuscular Hgb concentration hyperchromic (high) = increased m ean corpuscular Hgb concentration m icrocytic (sm all) = decreased m ean corpuscular volum e norm ocytic (norm al) = norm al m ean corpuscular volum e m acrocytic (high) = increased m ean corpuscular volum e

RBC color

RBC size

Page 48

Page 49