American Board of Clinical Pharmacology fellowship training and certification in clinical pharmacology: educational value and future needs for the discipline.

Currently, the training and education of young clinical pharmacologist who represent the future of our discipline rest almost entirely on institutions/organizations with established and productive fellowship training programs. Here, we discuss the role of the American Board of Clinical Pharmacology (ABCP) in accrediting fellowship training programs and certifying individual clinical pharmacologists. We also explore how ABCP certification adds value to both individual trainees and the discipline in the evolving world of clinical therapeutics and research in human pharmacology.

Two cases of rapid onset Parkinson's syndrome following toxic ingestion of ethylene glycol and methanol.

Ethylene glycol and methanol are toxic alcohols commonly found in a variety of commercial products. We report two cases, one associated with ethylene glycol and one with methanol poisoning, which both led to acute hemorrhagic necrosis of the basal ganglia and resulted in acute Parkinson's syndrome. It is unlikely that oxalate crystal deposition is the only mechanism for such basal ganglia necrosis, because similar findings were seen following methanol intoxication. We discuss other possible mechanisms that may contribute towards this unusual neurotoxicity. Both of our patients survived their toxic ingestions, but then developed acute Parkinson's syndrome within 10 days of the ingestion. However, the patient who ingested methanol developed respiratory muscle stiffness/weakness, which responded poorly to anti-Parkinsonian drug therapy. Treatment with carbidopa/levodopa improved cogwheel rigidity and bradykinesia in both patients. We conclude that acute Parkinsonism is one of the lesser-recognized devastating complications of both ethylene glycol and methanol poisoning.

Steady-state serum concentration of alpha tocopherol not altered by supplementation with oral beta carotene. The Polyp Prevention Study 1 Group.

BACKGROUND: The antioxidants beta carotene and vitamin E may play a role in cancer prevention. However, some studies have suggested that oral supplements of beta carotene may cause a decrease in serum levels of alpha tocopherol (vitamin E). PURPOSE: We conducted this study to determine if beta carotene supplements affect serum levels of vitamin E and vice versa. METHODS: Five hundred five patients in a clinical trial of antioxidant vitamins, used to prevent recurrences of colonic polyps, received either a placebo, 25 mg of beta carotene per day, 1 g ascorbic acid plus 400 mg alpha tocopherol per day, or all three agents combined. Serum levels of beta carotene and vitamin E were measured before and after 9 months of supplementation, using high-performance liquid chromatography. RESULTS: Vitamin E levels changed very little among the groups receiving placebo or beta carotene and went up substantially and equally in the groups receiving vitamin E plus ascorbic acid or all three agents together. Conversely, beta carotene levels changed very little for the groups receiving placebo or ascorbic acid plus vitamin E but went up substantially and equally for the groups receiving beta carotene alone or all three agents. CONCLUSIONS: We conclude that oral supplementation with beta carotene for 9 months does not alter serum concentration of vitamin E and that supplementation with vitamin E plus ascorbic acid does not alter serum beta carotene levels.

Selective killing of transformed cells by methotrexate with histidine deprivation or with alpha-amino alcohols.

The effects of amino acid deprivation and treatment with amino alcohols upon the growth, viability, and susceptibility to methotrexate (MTX) cytotoxicity were examined in BALB/3T3 cells and their virally transformed counterparts, SV-T2 cells. Cells were deprived of either histidine or tyrosine plus phenylalanine, or they were treated with amino alcohol analogues of histidine and tyrosine (histidinol and tyrosinol). When incubated in medium lacking histidine and supplemented with dialyzed serum (histidine-deficient medium), the BALB/3T3 cells remained viable for at least 3 days, but they ceased logarithmic growth, and the cell number reached an early plateau. In contrast, the SV-T2 cells continued to divide in histidine-deficient medium. Neither cell line ceased division in medium deficient in both phenylalanine and tyrosine. Incubation of the BALB/3T3 cells with 1.5 mM histidinol or 1.0 mM tyrosinol caused an early plateau similar to the effect of histidine deprivation. SV-T2 cells were not affected by these concentrations of histidinol or tyrosinol, but growth was arrested at higher concentrations. Any of the conditions used which caused a plateau in the number of BALB/3T3 cells substantially protected the treated cells from cell death caused by MTX. Therefore, pretreatment of BALB/3T3 cells with histidine deprivation, 1.5 mM histidinol, or 1.0 mM tyrosinol protected this cell line against MTX-induced cell death, while the same pretreatment conditions failed to protect SV-T2 cells. (SV-T2 cells were protected by 4.0 mM histidinol.) Thus, the ability of MTX to kill cells in vitro can be selectively modified by conditions which protect cells which retain normal growth control characteristics, but which do not protect virally transformed cells.

Treatment of nocturnal leg cramps. A crossover trial of quinine vs vitamin E.

OBJECTIVE: This study compared the efficacy and safety of quinine sulfate, vitamin E, and placebo in the treatment of nocturnal leg cramps. DESIGN: A random-order, double-blind, placebo-controlled crossover trial was performed. SETTING: The study was conducted at the Veterans Affairs Medical Center, White River Junction, Vt. PARTICIPANTS: Twenty-seven male veterans, aged 38 to 73 years, who experienced at least six leg cramps per month were recruited through the general medicine walk-in clinic or were referred from other clinics. Fifty-five subjects were contacted, 30 were enrolled consecutively, and 27 completed the study. INTERVENTION: Subjects received, in random order, quinine sulfate (200 mg at supper and 300 mg at bedtime), vitamin E (800 U at bedtime), or placebo for 4-week periods. These periods were separated by 4-week washout intervals. OUTCOME MEASURES: Patients reported cramp frequency, severity, and sleep disturbance caused by cramps. RESULTS: Compared with treatment with placebo, quinine reduced the frequency of cramps and sleep disturbance, but not the average cramp severity. Thirteen of 27 patients had at least a 50% reduction in the number of cramps while receiving quinine; the response was usually seen within 3 days. There was evidence of a mild increase in side effects while subjects received quinine. Vitamin E was not effective in reducing leg cramp frequency, severity, or sleep disturbance. CONCLUSIONS: Quinine sulfate, but not vitamin E, is superior to placebo in the treatment of nocturnal leg cramps.

Mineral spirits inhalation associated with hemolysis, pulmonary edema, and ventricular fibrillation.

A previously healthy 42-year-old woman developed severe dyspnea, chest discomfort, and malaise several hours after prolonged exposure to concentrated vapors from mineral spirits. On the way to the hospital, she sustained a cardiopulmonary arrest; on arrival several minutes later, she was found to be in ventricular fibrillation and was resuscitated. Her hospital course included slowly resolving cardiac abnormalities, amnesia, noncardiogenic pulmonary edema, abrupt hemolytic anemia, sustained rhabdomyolysis, and other metabolic abnormalities. It is highly probable that this syndrome represented acute and near-lethal toxicity caused by the inhalational exposure to the petroleum distillate known as mineral spirits. It is important that physicians be aware of this syndrome in order to recognize it on presentation and to warn patients of the risk of such toxic exposure.

The effects of a required fourth-year clinical pharmacology course on student attitudes and subsequent performance.

Beginning with the class graduating June 1984, Dartmouth Medical School introduced a required clinical pharmacology course. Approximately 89% of the fourth-year students felt that the course was "essential" to their future careers as physicians. As interns, 80% found the course frequently useful or essential during their internships; 84% felt that they were either slightly or much better prepared than their fellow interns with respect to their therapeutic knowledge and skills. Average student performance on a pretest (33% correct answers) improved dramatically on a posttest (87% correct; P less than 0.001). Finally, although student performance on all sections of Part II of the national board examinations showed statistically nonsignificant trends toward improvement (from the 48th to the 52nd percentile), performance on questions testing core concepts in clinical pharmacology improved from the 38th percentile to the 74th percentile (P less than 0.0001). This required fourth-year course in clinical pharmacology was evaluated favorably by our students and resulted in objective improvement in their therapeutic knowledge and skills.

Olsalazine and 6-mercaptopurine-related bone marrow suppression: a possible drug-drug interaction.

A patient with refractory Crohn's disease had two separate episodes of bone marrow suppression while receiving 50 to 75 mg 6-mercaptopurine a day and 1000 to 1750 mg olsalazine a day. This adverse reaction necessitated dose reduction of 6-mercaptopurine on the first occasion and withdrawal of 6-mercaptopurine and olsalazine on the second occasion. The patient's red blood cell thiopurine methyltransferase (TPMT) activity was 1.2 U per milliliter red blood cells (low normal range) and her TPMT genotype was wild-type sequence for all known alleles of TPMT that result in low TPMT enzyme activity. In vitro enzyme kinetic studies confirmed the hypothesis that olsalazine and olsalazine-O-sulfate are potent noncompetitive inhibitors of recombinant human TPMT. We suggest that the patient's relatively low baseline level of TPMT activity was inhibited by olsalazine and olsalazine-O-sulfate, leading to decreased clearance of 6-mercaptopurine and its accumulation. This ultimately increased intracellular 6-thiopurine nucleotide levels to toxic concentrations, which caused bone marrow suppression.

A method for determining concentrations of retinol, tocopherol, and five carotenoids in human plasma and tissue samples.

To explore the relation between plasma and tissue concentrations of seven fat-soluble micronutrients (retinol, alpha-tocopherol, lutein, cryptoxanthin, lycopene, alpha-carotene, and beta-carotene), we developed methods for clarifying plasma and tissue samples and quantitating these seven analytes simultaneously by using HPLC with ultraviolet detection. Clarification of tissue samples was performed by using enzymatic digestion followed by mechanical homogenization; saponification was avoided and tocopherol nicotinate was used as an internal standard. Precision and sensitivity for small samples of plasma and solid tissues were determined. Accuracy for plasma samples was assessed by comparing results obtained by using this method with those obtained by using older, standardized methods. Results from application of this method to patient samples of plasma and various tissues are presented. This method will be of interest to investigators seeking to quantitate these seven micronutrients in solid tissue samples, but desiring to avoid the usual saponification step required in most other reported techniques.

Lack of effect of chronic administration of oral beta-carotene on serum cholesterol and triglyceride concentrations.

Previous studies suggest that chronic oral administration of retinol and other retinoids causes elevation of plasma triglyceride concentrations. The effects of chronic oral administration of beta-carotene, a carotenoid partially metabolized to retinol, on plasma lipid concentrations have not been well studied; therefore, we studied 61 subjects over 12 mo while they were enrolled in a skin-cancer-prevention study in which patients were randomly assigned to receive either placebo (n = 30) or 50 mg beta-carotene/d orally (n = 31). At study entry and 1 y later, fasting blood samples were obtained for measurement of triglycerides, total cholesterol, HDL cholesterol, retinol, and beta-carotene. Retinol concentrations changed minimally in both groups; beta-carotene concentration increased an average of 12.1 +/- 47 nmol/L in the placebo group and 4279 +/- 657 nmol/L in the active-treatment group. Both groups experienced similar small increases in triglyceride and total cholesterol concentrations and small decreases in HDL cholesterol. Daily oral administration of 50 mg beta-carotene/d did not affect plasma lipid concentrations.

Diurnal and seasonal variation of five carotenoids measured in human serum.

We studied within-person variation over time in serum concentrations of five carotenoids. In a diurnal study involving 33 subjects, only the 1700 h blood samples demonstrated carotenoid concentrations different from the original 0800 values. Correlations between serum concentrations of the same carotenoids drawn 1 d apart ranged from 0.93 to 0.98. In a seasonal study involving 29 subjects, no systematic trends were observed for serum concentrations of these carotenoids. Correlations between concentrations of the same carotenoids drawn 1 y apart ranged from 0.57 to 0.82. Concentrations of different carotenoids within an individual tended to be correlated with each other. Obtaining one blood sample from subjects is a relatively imprecise way to estimate their usual serum concentrations of carotenoids. If an epidemiological study was to be based on only one determination of serum carotenoids, within-person variability in serum concentrations would attenuate true regression coefficients by 4-13% and would increase the required numbers of study subjects by 19-65%.

Effects of 4 y of oral supplementation with beta-carotene on serum concentrations of retinol, tocopherol, and five carotenoids.

beta-Carotene has been studied widely as a potential cancer-preventing agent. Recent studies found that subjects who took beta-carotene supplements orally had increases in their serum concentrations of alpha-carotene and lycopene that were large (> 150% increase) and significantly greater than such increases in subjects who received placebo and that similar supplementation was associated with a decrease of approximately 37% in plasma lutein concentrations. A biologic interaction between beta-carotene and other carotenoids was suggested. We measured concentrations of retinol, alpha-tocopherol, and five carotenoids in serum specimens from a random sample of subjects enrolled in a clinical trial of the use of antioxidant vitamins in preventing colonic adenomas. We used serum specimens obtained at enrollment and after the subjects took placebo (n = 54) or 25 mg beta-carotene/d (n = 54) orally for 4 y. In a multivariate analysis, baseline serum concentrations of the analytes, sex, body mass index, diet, smoking status, and age were associated with variable changes in some analytes over the 4-y period but supplementation with beta-carotene was related only to a mean increase in serum beta-carotene itself of 151%. We excluded with 95% confidence an increase in lycopene > 4.9%, an increase in alpha-carotene > 17.6%, and a decrease in lutein > 14.7% in subjects given beta-carotene. These results confirm previous findings that supplementation with beta-carotene given orally does not alter serum concentrations of retinol or alpha-tocopherol. The findings also indicate that beta-carotene supplementation, which results in a moderate increase in serum beta-carotene concentration, does not significantly change serum concentrations of other carotenoids.

Determinants of increase in plasma concentration of beta-carotene after chronic oral supplementation. The Skin Cancer Prevention Study Group.

We studied the relationship between eight variables, including age, sex, baseline plasma beta-carotene (BC) concentration, and smoking status and the increase in plasma BC in 582 subjects receiving oral supplementation with 50 mg BC/d. Median plasma BC concentrations after 1 y of supplementation increased from 335 nmol/L at entry to 3163 nmol/L. Changes in plasma BC concentrations ranged widely from -313 to 16,090 nmol/L (median 2721 nmol/L). Multivariate analysis revealed that the subject's plasma BC concentration before supplementation was the most important indicator of the amount of increase after supplementation. Nonsmokers, women, and leaner subjects all had larger increases in plasma concentrations although the statistical model could account for relatively little of the variability in subjects' plasma response to BC supplementation (R2 = 0.14). We conclude that between-subject variability in response to daily supplementation with oral BC is very large and that the best predictor of this response is the initial plasma BC concentration.

Analysis of within-subject variation of caffeine metabolism when used to determine cytochrome P4501A2 and N-acetyltransferase-2 activities.

Cytochrome P4501A2 (CYP1A2) and N-acetyltransferase-2 (NAT2) are hepatic enzymes that may activate some procarcinogens. Previous reports have determined CYP1A2 and NAT2 phenotypes by quantitating relative amounts of urinary caffeine and metabolites. However, a number of experimental issues with this approach remain. To address these, we measured caffeine and 4 metabolites in urine samples from 20 healthy volunteers on 3 separate occasions at 7-day intervals. Two additional volunteers were studied to measure the pattern of excretion of these analytes in urine over time. The molar ratio of two compounds (1,7-dimethylxanthine/1,3,7-trimethylxanthine) was used to phenotype CYP1A2, while the molar ratio of two other compounds (5-acetylamino-6-formylamino-3-methyluracil/1-methylxanthine) served to phenotype NAT2. Within-subject variation was less than 25% for most participants. In instances when within-subject variation of the metabolic ratio was > 25%, metabolite peaks were usually present in one or more control urine samples. Some caffeine metabolites were observed in urine samples at detectable levels up to 48 h after caffeine ingestion. We conclude that: (a) this assay for determining CYP1A2 and NAT2 activities (phenotyping) has an acceptably low within-subject variation over 3 consecutive weeks for most subjects who were caffeine-free for 36 h prior to study; (b) collecting and analyzing urine samples prior to testing can indicate if subjects are excreting caffeine metabolites and will aid in locating metabolite peaks on chromatograms; (c) refraining from caffeine for 48 h before testing is the best compromise between convenience for the subject and obtaining reproducible results; (d) determining metabolite molar ratios in urine collected 4-5 h after ingesting caffeine provides an acceptable time for the measurement; and (e) different ratios of metabolites for determining CYP1A2 phenotype have different advantages.

Q-aTc interval as a clinical indicator of hypercalcemia.

The charts were reviewed of more than 200 patients discharged from the hospital between 1972 and 1977 with a diagnosis implying abnormal calcium metabolism. When all other variables known to affect the Q-T interval were eliminated, serum calcium concentrations on 65 occasions in 39 patients were found to correlate significantly (P less than 0.001 or better) with the following electrocardiographic intervals: Q-aTc (beginning of QRS complex to apex of T wave), Q-oTc (beginning of QRS complex to onset of T wave) and Q-Tc (beginning of QRS complex to end of T wave). Of these, the Q-aTc interval was the more easily and precisely measured at elevated calcium levels and exhibited the strongest correlation (P less than 0.0001) over the range of calcium levels measured. The relation was linear and could be used to estimate serum calcium levels from measured Q-aTc intervals. For a Q-aTc interval of 0.29 second or less (range 0.23 to 0.29) the serum calcium was estimated to +/- 1.9 mg/dl with 95 percent confidence. For a Q-aTc interval of 0.27 second or less, the correspondence with hypercalcemia in the study series was 90 percent or better. When all other factors known to affect the Q-T interval are ruled out, the shortening of the Q-aTc interval appears to be a useful clinical indicator of hypercalcemia.

Fatal poisoning from liquid dimethylmercury: a neuropathologic study.

Since ancient times, mercury has been recognized as a toxic substance. Dimethylmercury, a volatile liquid organic mercury compound, is used by a small number of chemistry laboratories as a reference material in nuclear magnetic resonance spectroscopy. To our knowledge, dimethylmercury has been reported in only three cases of human poisoning, each proving fatal. Very small amounts of this highly toxic chemical can result in devastating neurological damage and death. We report the neuropathologic findings in a fatal case of dimethylmercury intoxication occurring in a laboratory researcher that resulted from a small accidental spill. We compare these findings to those reported in one previously reported fatal case of dimethylmercury poisoning, and to earlier reports of monomethylmercury poisoning, and discuss the clinicopathologic correlation.

Measuring drug levels in the office: rationale, possible advantages, and potential problems.

New technologies allow plasma levels of several drugs to be measured in the physician's office. Although such assays have the advantage of increased convenience for both physician and patient, they have a number of potential problems as well. Regardless of where plasma assays are performed, the physician must understand the rationale and pitfalls of therapeutic drug monitoring.

The use of "vertical integration groups" to help define and update course/clerkship content.

Faculty at many medical schools are working hard to improve the quality of their curricula. While the world "curriculum" means different things to different people, curricular change often includes improving the structure of the teaching/learning environment (e.g., seminars or problem-based learning groups vs lectures), the content of courses and clerkships (the core set of knowledge, skills, and attitudes that should be learned), and the manner in which student learning of knowledge and skills is evaluated (the sense that evaluation can help "drive" the curriculum). The author describes how "vertical integration groups" have been used over four years at Dartmouth Medical School to improve and modernize the content of courses and clerkships. In this approach, students and faculty work together to address and improve content areas that normally are not associated with traditional, discipline-centered courses or clerkships. The author discusses the advantages of this approach, the challenges encountered during implementation, and examples of how the approach has been put into action.

The impact of early clinical training in medical education: a multi-institutional assessment.

With funding from The Robert Wood Johnson Foundation's Generalist Physician Initiative, Dartmouth Medical School (DMS), New York Medical College (NYMC), and Virginia Commonwealth University School of Medicine (VCU-SOM) adopted early community-based training models for longitudinal clinical experiences. These schools developed different evaluation strategies to assess these models. This paper describes each program, the method used to evaluate an aspect of the program, lessons learned about early clinical teaching and learning, and challenges encountered. Each program used cross-sectional evaluation, and the analysis methods included descriptive statistics, chi-square, t-tests, analysis of variance, and generalized linear models. Dartmouth determined that the type of preceptor does not greatly influence the development of clinical skills, although case-specific differences were discovered. NYMC learned that students taught clinical skills in community-based settings performed as well as or better than their peers who received early patient experience on hospital wards. Virginia Commonwealth discovered that community experiences contributed positively to students' education, critical thinking, and problem-solving skills. Students value early clinical experiences and make important achievements in clinical skills and knowledge development, although logistic challenges exist in conducting these courses. Evaluations are critical to ensure competency, and faculty development must be linked to the evaluation process.

A clinical trial of nafazatrom (Bay g 6575) in advanced cancer.

Nafazatrom (Bay g 6575) has been shown to be a potent inhibitor of tumor metastasis in preclinical models. It is believed to work by stimulating endogenous prostacyclin production. The drug has also been shown to inhibit the growth of certain experimental tumors, to be cytostatic for certain cell lines in tissue culture, and to induce differentiation in HL-60, neuroblastoma, and Friend erythroleukemia cell lines. Furthermore, no toxicity has been seen in animals or human volunteers. We report here a clinical trial of oral nafazatrom at five dose levels in patients with advanced cancer. Thirty patients with a wide variety of advanced malignancies were treated for 26-638+ days (median 82 days). No tumor responses were seen. Toxicity included two cases with mild skin rashes, one case with nausea and vomiting, and one case with diarrhea. Nafazatrom is a safe and well-tolerated agent. Maximum activity would be predicted to occur in the adjuvant treatment of cancer and we feel that further efforts should proceed to identify the appropriate dose for such a trial.