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A pathway of research is described, leading from the finding of an inhibitory effect of 3-methylcholanthrene on the carcinogenicity of an aminoazo dye, to the induction of drug-metabolizing enzymes by 3-methylcholanthrene, benzo[a]pyrene, and other polycyclic aromatic hydrocarbons, to the demonstration of enhanced drug metabolism in cigarette smokers, coffee drinkers, and people who eat charcoal-broiled beef. The results of these studies indicate that cigarette smoking, coffee drinking, and the ingestion of charcoal-broiled beef (all resulting in exposure to polycyclic aromatic hydrocarbons) can influence the dosing regimen needed for proper drug therapy and are potential confounders of clinical trials with drugs metabolized by polycyclic aromatic hydrocarbon-inducible enzymes.

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The World Health Organization (WHO) has estimated that half of all medicines are inappropriately prescribed, dispensed, sold, or taken. Selection from a list limited to the best medicines available for the conditions being treated can decrease inappropriate prescribing. It precludes prescribing less effective or more toxic drugs when better ones are on the list. Prescribers need know about fewer drugs, which enables them to have a better understanding of the drugs they do prescribe. The disadvantages of using such a list--limited ability to prescribe unlisted drugs when desired and delay in listing new drugs--can be overcome by administrative actions. Implementing the essential medicines concept will decrease inappropriate drug use. A much more global, comprehensive, and committed approach needs to be taken by all of us to eliminate it.

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The debate over the scope of clinical pharmacology--and the clinical pharmacologist--is ongoing. The stated content of clinical pharmacology is therapeutics, whereas the recommended training programs are geared to train researchers. Most clinical pharmacologists make their living in research. People who do not identify themselves as clinical pharmacologists do much research on drug effects in humans. The professional clinical pharmacologist's role must be re-evaluated in the context of society's needs and sources of funding.

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The concept of essential medicines is as relevant to the whole world now as it was for some countries in 1975 when the concept was developed. Basically, the concept is that medicines needed to satisfy the priority health-care needs of a population should be made available at all times to everyone in the population within the context of a functioning health-care system.

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Many patients in pain receive inadequate doses of opioids. Fear of government action against prescribing doctors is one cause of this inadequate treatment. The purpose of the study was to assess criminal prosecutions by reviewing press reports of indictments or trials of doctors for opioid offenses during 2 years. Forty-seven cases were reported involving 53 doctors. Fifteen cases were for offenses unrelated to medical practice. In 32 cases, the charge was based on determining the prescriptions for opioids were outside the bounds of proper medical practice. Only two of these cases were evaluated by a state medical board before indictment. Five doctors were indicted for murder related to drug overdose deaths. None were found guilty of murder. Prosecutorial excesses and hyperbole were common. The state medical board's review of appropriateness of prescribing opioids when a doctor-patient relationship is presumed to exist could decrease inappropriate criminal indictments and reduce this component of fear of prescribing adequate opioid therapy for patients in pain.

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The WHO program on essential medicines advises governments about how to determine which medicines are needed to meet the health care needs of the majority of the population and how to make them available to everyone. A Model List of these medicines proposed in 1977 included 186 drugs; the current list exceeds 300. The principle of making essential medicines available to everyone is accepted by 156 countries. Implementation is variable. Problems currently being considered for solution include whether drugs effective for rare diseases are ever essential and getting pediatric dosage forms of essential drugs manufactured and registered for sale. With all societies dealing with the rising cost of medical care and having to make choices, the concept of essential medicines is a relevant to all now as it was to countries with limited resources when the WHO program started in 1975.

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Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50 mg per day. Gossypol plasma levels were measured (n = 8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n = 4). Grade I-II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50 mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with > 50% decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.

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Gossypol, a polyphenolic compound from cotton seed, caused hypokalemia in some men receiving it in a trial of its contraceptive activity. Searching for the mechanism for its hypokalemic action led to the observation that it inhibited 11beta-hydroxysteroid dehydrogenase. This would enhance mineralocorticoid effect in the kidney. Many other polyphenols also inhibit this enzyme including those in grapefruit juice. Ingesting 1-2 l of grapefruit juice inhibited this enzyme in two men in a clinical experiment. Tea polyphenols inhibit this enzyme and add to the inhibition caused by gossypol. Men in China have lower serum potassium values than men elsewhere and this is due to the environment, presumably the diet, in China. The importance of dietary and other exogenous inhibitors of this enzyme in electrolyte metabolism remains to be determined.

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The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only one man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects on the 7.5 mg/day dose group, 12 recovered sperm counts >20 million/mL within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. Eight of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

PIP: The safety and efficacy of gossypol continues to be controversial. The aim of this study was to evaluate gossypol as a contraceptive pill for men at doses lower than those previously prescribed and in men from various ethnic origin. A total of 151 men from Brazil, Nigeria, Kenya, and China were divided into two groups. Both groups received 15 mg gossypol/day for 12 or 16 weeks to reach spermatogenesis suppression. Subjects were then randomized to either 7.5 or 10 mg/day for 40 weeks. In addition, 51 men were enrolled as a control group. In all, 81 subjects attained spermatogenesis suppression. Only 1 man discontinued treatment because of tiredness. Potassium levels fluctuated within the normal range. FSH increased consistently. Testicular volume decreased, but after discontinuation, values returned to levels not statistically different from admission. Of 19 subjects in the 7.5 mg/day dose group, 12 recovered sperm counts higher than 20 million/ml within 12 months of discontinuing gossypol. In the 10 mg/day group, sperm counts recovered in only 10 of 24 subjects. 8 of the 43 patients remained azoospermic 1 year after stopping gossypol. All men diagnosed with varicocele failed to reverse spermatogenesis suppression. Gossypol blood levels indicated that sperm suppression occurs independently of concentration, whereas spermatogenesis recovery appears to be concentration-dependent. Gossypol may become a medical alternative to surgical vasectomy when the delay in onset of infertility is acceptable. When taken for 1 year, gossypol causes no reduction in sexual desire or frequency of intercourse. The possibility of reversal, occurring in 51% of the men on this regimen within 1 year after stopping gossypol, is an advantage of this compound as compared with surgical sterilization in many parts of the world.

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Gossypol, a polyphenolic compound which depletes cellular energy by inhibition of several intracellular dehydrogenases, has been shown to have antiproliferative activity against human glial tumor cell lines in vitro and in nude mouse xenografts. Human trials of gossypol as a male contraceptive have demonstrated safety of long-term administration. We studied the activity of Gossypol 10 mg PO bid in 27 patients with pathologically confirmed glial tumors which had recurred after radiation therapy. Fifteen patients had glioblastoma, 11 patients anaplastic astrocytoma, 1 patient relapsed low grade glioma. Response was assessed every 8 weeks using CT/MRI scan and clinical criteria including decadron requirement. Treatment was continued until disease progression. Two patients had partial response (PR); 4 had stable disease for 8 weeks or more. One patient maintained a PR with improved KPS for 78 weeks. The other had a PR lasting 8 weeks. Toxicity was mild: 2 heavily pretreated patients had mild thrombocytopenia, 5 patients developed hypokalemia, 3 patients developed grade 2 hepatic toxicity and peripheral edema. Gossypol levels measured by HPLC did not correlate with response or toxicity in this study. We conclude that gossypol is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma. The presumed novel mechanism of action, lack of significant myelosuppression, and activity in patients with advance glioma support further study of gossypol as an antineoplastic agent.

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