South African medical schools: Current state of selection criteria and medical students' demographic profile.

BACKGROUND: Selection of medical students at South African (SA) medical schools must promote equitable and fair access to students from all population groups, while ensuring optimal student throughput and success, and training future healthcare practitioners who will fulfil the needs of the local society. In keeping with international practices, a variety of academic and non-academic measures are used to select applicants for medical training programmes in SA medical schools. OBJECTIVES: To provide an overview of the selection procedures used by all eight medical schools in SA, and the student demographics (race and gender) at these medical schools, and to determine to what extent collective practices are achieving the goals of student diversity and inclusivity. METHODS: A retrospective, quantitative, descriptive study design was used. All eight medical schools in SA provided information regarding selection criteria, selection procedures, and student demographics (race and gender). Descriptive analysis of data was done by calculating frequencies and percentages of the variables measured. RESULTS: Medical schools in SA make use of academic and non-academic criteria in their selection processes. The latter include indices of socioeconomic disadvantage. Most undergraduate medical students in SA are black (38.7%), followed by white (33.0%), coloured (13.4%) and Indian/Asian (13.6%). The majority of students are female (62.2%). The number of black students is still proportionately lower than in the general population, while other groups are overrepresented. CONCLUSION: Selection policies for undergraduate medical programmes aimed at redress should be continued and further refined, along with the provision of support to ensure student success.

Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcgammaRIIA.

Heparin-induced thrombocytopenia/thrombosis (HIT/HITT) is a severe, life-threatening complication that occurs in 1% to 3% of patients exposed to heparin. Interactions between heparin, human platelet factor 4 (hPF4), antibodies to the hPF4/heparin complex, and the platelet Fc receptor (FcR) for immunoglobulin G, FcgammaRIIA, are the proposed primary determinants of the disease on the basis of in vitro studies. The goal of this study was to create a mouse model that recapitulates the disease process in humans in order to understand the factors that predispose some patients to develop thrombocytopenia and thrombosis and to investigate new therapeutic approaches. Mice that express both human platelet FcgammaRIIA and hPF4 were generated. The FcgammaRIIA/hPF4 mice and controls, transgenic for either FcgammaRIIA or hPF4, were injected with KKO, a mouse monoclonal antibody specific for hPF4/heparin complexes, and then received heparin (20 U/d). Nadir platelet counts for KKO/heparin-treated FcgammaRIIA/hPF4 mice were 80% below baseline values, significantly different (P <.001) from similarly treated controls. FcgammaRIIA/hPF4 mice injected with KKO and 50 U/d heparin developed shock and showed fibrin-rich thrombi in multiple organs, including thrombosis in the pulmonary vasculature. This is the first mouse model of HIT to recapitulate the salient features of the human disease and demonstrates that FcgammaRIIA and hPF4 are both necessary and sufficient to replicate HIT/HITT in an animal model. This model should facilitate the identification of factors that modulate disease expression and the testing of novel therapeutic interventions.

Bioavailability of penclomedine and systemic exposure to 4-O-demethylpenclomedine in patients receiving oral and intravenous penclomedine.

PURPOSE: Oral administration of penclomedine was investigated based on preclinical studies indicating that an oral schedule of penclomedine treatment may prevent the neurotoxicity observed in phase I studies of an intravenous (i.v.) formulation, possibly by reducing maximum plasma concentrations (Cmax) of the neurotoxic parent species. METHODS: Penclomedine was administered i.v. (200 mg/m2) and orally (250 mg/m2) in alternate sequences to patients with solid tumor malignancies. Plasma concentrations of parent drug and the principal metabolite, 4-O-demethylpenclomedine, were determined by a reversed-phase HPLC assay. RESULTS: Penclomedine was detectable in the plasma of all patients within 1 h of oral penclomedine treatment and Cmax was reached within 1 to 4 h. Consistent with the hypothesis that an oral schedule of administration may circumvent neurotoxicity, a paired data analysis demonstrated a significant reduction in Cmax values following oral administration (P=0.017). However the magnitude of this reduction was highly variable. Similarly an extensive range in the relative exposure to both parent drug and metabolite were observed. The bioavailability of penclomedine ranged from 28% to 98% (median 73%). CONCLUSIONS: Oral penclomedine does produce systemic exposure, but substantial interpatient variability in absorption and systemic exposure is present which may limit the clinical role of the oral route of administration.

Substituted amylose as a matrix for sustained-drug release: a biodegradation study.

Substituted amylose polymers are prepared by reacting amylose chains with a suitable substituent such as 1,2-epoxypropanol (glycidol). Substituted amylose polymers are introduced as novel excipients for controlled release of bioactive materials. Since substituted amylose polymers are amylose-based polymers, they are subject to biodegradation by alpha-amylase enzymes present in the gastro-intestinal tract; thus, gamma spectroscopy is used to follow the release of the natural abundant rhenium (VII) oxide used as a drug model, and to test their resistance to alpha-amylase enzymatic degradation. Two substituted amylose solid dosage forms were prepared: (i) matrix system and (ii) dry-coated tablets. Matrix systems and dry-coated tablets maintained their structure, and controlled the release of [186Re] showing no significant degradation of tablets by alpha-amylase.

Effects of cytochrome P450 inducers on 17alpha-ethinyloestradiol (EE2) conjugation by primary human hepatocytes.

AIMS: Our objective was to elucidate further the underlying mechanism responsible for therapeutic failures observed with concomitant administration of the oral contraceptive 17alpha-ethinyloestradiol (EE2 ) and rifampicin. METHODS: We investigated both oxidative and direct conjugative [3H]-EE2 metabolism by human liver S9 fraction and the effect of known enzyme-inducing drugs using a human hepatocyte induction model in vitro. RESULTS: Cofactor dependent [3H]-EE2 metabolism by human liver S9 fraction produced 2-hydroxy-[3H]-EE2, 2-methoxy-[3H]-EE2, and direct [3H]-EE2 sulphate and glucuronide conjugates. Only two detectable metabolites of [3H]-EE2 were produced by the S9 fraction in the presence of all cofactors: [3H]-EE2-3-sulphate (75.7+/-7.6% s. d.) and 2-methoxy-3H-EE2 (2.6%+/-0.5% s.d.). Human hepatocytes extensively metabolized [3H]-EE2 to its glucuronide and sulphate conjugates. Small amounts of a 2-methoxy-[3H]-EE2 3-conjugate, < or = 10%, was observed but no. 2-hydroxy-[3H]-EE2 was detected. An unexpected finding in our study was increased [3H]-EE2-3-sulphate production (1.5-3.3 fold, n=3 donor livers) by hepatocytes pretreated with rifampicin compared to control hepatocytes. No statistically significant increase in [3H]-EE2-3-sulphation was observed in hepatocytes pretreated with 3-methylcholanthrene, phenobarbitone, dexamethasone, or omeprazole over nontreated hepatocytes. To our knowledge, this is the first observation of sulphotransferase induction by rifampicin in human hepatocytes in vitro resulting in increased [3H]-EE2 sulphation. CONCLUSIONS: Our data indicate that the major EE2 metabolic products formed by human hepatocytes in vitro are direct EE2 conjugates with EE2 oxidation representing minor pathways. Further studies are required to establish the mechanism of sulphotransferase induction and the clinical relevance of our findings.

Development of a rapid response biosensor for detection of Salmonella typhimurium.

An integrated optic interferometer for detecting foodborne pathogens was developed. The interferometer is a planar waveguide with two thin antibody-coated channels of immunochemically selective agents that interact with antigen molecules. One channel is coated with antibody to Salmonella as a sample, and the other is coated with human immunoglobulin G as a reference channel by using reductive amination. Salmonella was introduced onto the sensing channels through the flow cell on the channels. Phase shift (pi) generated by refractive index variation, as determined by interfering the perturbed sample channel with an unperturbed reference channel and observing the fringe shift, was used for detection. Salmonella Typhimurium (heat-treated or boiled) was detected by binding to antibody against Salmonella common structural antigen immobilized on a silane-derived sensor surface at concentrations in the range of 1x10(5) to 1x10(7) CFU/ml. Salmonella (1x10(7) CFU/ml) mixed with Escherichia coli (1x10(7) CFU/ml) were readily detected without any decrease in sensitivity by the direct assay. Application of a sandwich assay with a second antibody or a gold-conjugated antibody increased the detection limit to 1x10(5) CFU/ml within a 10-min reaction time. Various methods for the immobilization of the capture antibody to the biosensor channels were compared. The greatest binding response was observed in a direct reductive amination method with a long reaction period and increased the detection limit of direct binding of Salmonella antigen to 1x10(4) CFU/ml. The biosensor was able to detect Salmonella Typhimurium in chicken carcass wash fluid originally inoculated at a level of 20 CFU/ml after 12 h of nonselective enrichment. The planar optic biosensor shows promise as a fast, sensitive, reliable, and economical means of detecting food pathogens in the future.

The in vitro metabolism of penclomedine in mouse, rat, and human systems.

Penclomedine is a multi-chlorinated alpha-picoline derivative that has demonstrated activity in several murine breast cancer models and is currently in clinical testing for use against solid tumors. This study evaluates the metabolism of penclomedine in several in vitro hepatic models, including microsomes, fresh liver slices, and the isolated perfused rat liver (IPRL). Both human and mouse liver slices as well as human and mouse liver microsomes under aerobic conditions resulted in limited metabolism of penclomedine to several oxidized metabolites, including penclomic acid, 4-demethylpenclomic acid, and 4-demethylpenclomedine. Microsomes under anaerobic conditions vigorously produced mainly reduced metabolites, primarily penclomedine dimers. This is in contrast to in vivo data, which showed rapid metabolism of penclomedine to primarily 4-demethylpenclomedine. The IPRL preparation, however, metabolized 50 microM penclomedine 90% within 90 min, producing primarily 4-demethylpenclomedine and penclomic acid. These were formed in roughly equimolar amounts and did not undergo significant further metabolism over 4 hr. Numerous highly polar biliary metabolites were also found. The IPRL preparation thus seems to most accurately reflect the in vivo situation.

Studies of the continuing susceptibility of group A streptococcal strains to penicillin during eight decades.

BACKGROUND: In view of the widespread use of penicillin for >50 years for the treatment of group A streptococcal infections, we examined the question of whether there has been a change in susceptibility to penicillin in group A streptococcal strains collected during a span of 80 years (1917 to 1997). METHODS: One hundred thirty-three group A streptococcal strains collected during 80 years were tested for changes in penicillin susceptibility. Three tests were used: (1) the microtiter broth minimal inhibitory concentration (MIC); (2) the minimal bactericidal concentration (MBC); and (3) the penicillin E strip MIC. RESULTS: The results indicate there has been no change in the susceptibility to penicillin in these group A streptococci during the past 80 years. The microtiter broth MIC90 for the oldest strains (0.032 microg/ml) was not significantly different from those collected most recently (0.032 microg/ml); there is no statistical difference between the raw MIC data for the four collection periods (P=0.468, analysis of variance on ranks). CONCLUSIONS: There has been no change in the susceptibility of group A streptococci during this time in spite of well-documented cases of penicillin resistance in other Gram-positive organisms and despite recognized resistance of group A streptococci to other antibiotics.

Effects of the D2 receptor agonist bromocriptine on sleep bruxism: report of two single-patient clinical trials.

An altered dopamine receptor status has been associated with sleep bruxism. Evidence from a functional neuro-imaging study has implicated an abnormal side imbalance in striatal D2 receptor expression in its pathophysiology. To assess the significance of this finding, we studied the effects of short-term administration of the preferential dopamine D2 receptor agonist bromocriptine on sleep bruxism in a double-blind, placebo-controlled polysomnographic and neuro-imaging study with a single crossover design. Six otherwise healthy and drug-free patients with sleep bruxism were entered into the trial. One of the patients dropped out due to an intercurrent illness, while three others were discontinued from the study due to severe adverse reactions to bromocriptine. Because of the high frequency and intensity of the side-effects, the trial was interrupted. Two patients, however, completed the trial without any adverse reactions. Their outcome measures are presented as single-patient clinical trials. Following a two-week administration of bromocriptine, both patients showed a decrease in the number of bruxism episodes per hour of sleep of about 20% to 30% with respect to the placebo. WHile no significant differences between both conditions (i.e., placebo and bromocriptine) were found for the number of bruxism bursts per episode, significantly lower root-mean-squared EMG levels per bruxism burst occurred during bromocriptine use. In association with this polysomnographically established attenuation of sleep bruxism, bromocriptine afforded a decreased normal side distribution of striatal D2 receptor binding, as was evidenced by single-photon-emission computed tomography using the radioactive D2 receptor antagonist iodine-123-iodobenzamide. This study supports previous suggestions that the central dopaminergic system may be involved in the modulation of sleep bruxism. To see if the present findings apply across a population, investigators should use a peripheral D-2 antagonist to prevent side-effects.

Hartman interferometer: versatile integrated optic sensor for label-free, real-time quantification of nucleic acids, proteins, and pathogens.

The Hartman interferometer, a proprietary integrated optic sensor, provides a basis for a broad range of biomedical diagnostics, including antibody-based and gene probe-based assays. As with other evanescent-wave optical sensors, the interferometer measures the refractive index change resulting from biomolecular binding on a waveguide surface. The exciting promise of evanescent-wave sensors lies, in general, in their potential to be used as label-free, real-time transducers that can operate in a true mix-and-read fashion and provide fast, quantitative results. One of the major issues facing their development, however, is creating a simple, low-cost configuration for multianalyte testing. The Hartman interferometer addresses this challenge by relying on linearly polarized light and a planar waveguide format, thereby avoiding the problems associated with circular polarization and channel waveguides. We report preliminary experiments that demonstrate the applicability of this sensor configuration to detection of a wide range of protein, nucleic acid, and pathogen analytes.

Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. PATIENTS AND METHODS: Penclomedine (45 to 550 mg/ m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. RESULTS: On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. CONCLUSION: Neurotoxicity was the dose-limiting toxicity (DLT) of penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.

Reversed-phase high-performance liquid chromatographic determination of the new antitumor agent cyclopentenyl cytosine in biological fluids.

Cyclopentenyl cytosine (CPE-C) is a synthetic carbocyclic nucleoside that possesses diverse antitumor and antiviral activity. CPE-C has been studied extensively at the preclinical level and has been evaluated in a Phase I clinical trial involving patients with solid tumors. A narrow-bore, reversed-phase HPLC method that has been developed for the sensitive measurement of CPE-C in plasma and urine in order to carry out these studies is described. Covalent solid-phase extraction based on an immobilized phenylboronic acid ligand is employed to isolate both CPE-C and endogenous ribonucleosides from the biological matrix selectively and efficiently. This is followed by isocratic elution of the extract with pH 5.0, 0.1 M ammonium formate buffer at 0.150 ml/min on a tandem, switchable, C18 narrow-bore (2.1 mm I.D.) column system in which the precolumn is automatically backflushed to eliminate late-eluting components. UV detection at 278 nm provides a limit of quantitation of 0.1 microM for CPE-C in rat and human plasma with a precision better than 4% for the range 1-20 microM in rat plasma. Application of this assay to the determination of the bolus dose plasma kinetics and disposition of 2 mg/kg CPE-C in rats is illustrated. This method is amenable to partial automation and is well-suited for the analysis of clinical samples.

4-Demethylpenclomedine, an antitumor-active, potentially nonneurotoxic metabolite of penclomedine.

Penclomedine [3,5-dichloro-4,6-dimethoxy-2-(trichloromethyl)pyridine], an antitumor agent, is currently in Phase I clinical trials and is believed to be a prodrug. In these studies, cerebellar effects have been dose limiting. Previous studies identified 4-demethylpenclomedine (4-DM-PEN) as the major plasma metabolite in rodents and humans. 4-DM-PEN was demonstrated to be an antitumor-active metabolite of penclomedine in vivo when evaluated against the penclomedine-sensitive MX-1 human breast tumor xenograft implanted either s.c. or intracerebrally and is believed to be on the metabolic activation pathway of penclomedine. Because earlier studies revealed an absence of neurotoxic cerebellar effects for 4-DM-PEN in contrast to penclomedine in a rat model, this metabolite may be a candidate for an alternative to penclomedine in the clinic for treatment of breast cancer or brain tumors, if the cerebellar effects of penclomedine preclude its further clinical development. Because neither penclomedine nor 4-DM-PEN were very active in vitro, the metabolism of penclomedine was also investigated using rat liver microsomes in an attempt to identify the ultimate active form of the drug. Metabolites and putative metabolites were prepared by chemical synthesis for antitumor evaluation in vitro and in vivo. A reductive metabolite, alpha,alpha-didechloro-PEN, was observed to be much more cytotoxic than penclomedine or 4-DM-PEN in vitro, but evaluation of this and the other metabolites and putative metabolites in vivo against the MX-1 tumor failed to identify any active metabolite among the structures evaluated other than 4-DM-PEN. The limited activity of 4-DM-PEN in vitro indicates that it, like penclomedine, is also a prodrug, demonstrating a need for additional studies on the metabolic activation of penclomedine to identify the ultimate active form of the drug.

The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.

BACKGROUND: Transdermal nicotine therapy is widely used to aid smoking cessation, but there is uncertainty about its safety in patients with cardiac disease. METHODS: In a randomized, double-blind, placebo-controlled trial at 10 Veterans Affairs medical centers, we randomly assigned 584 outpatients (of whom 576 were men) with at least one diagnosis of cardiovascular disease to a 10-week course of transdermal nicotine or placebo as an aid to smoking cessation. The subjects were monitored for a total of 14 weeks for the primary end points of the study (death, myocardial infarction, cardiac arrest, and admission to the hospital due to increased severity of angina, arrhythmia, or congestive heart failure); the secondary end points (admission to the hospital for other reasons and outpatient visits necessitated by increased severity of heart disease); any side effects of therapy; and abstinence from smoking. RESULTS: There were 48 primary and 78 secondary end points noted in a total of 95 subjects. At least one of the primary end points was reached by 5.4 percent of the subjects in the nicotine group and 7.9 percent of the subjects in the placebo group (difference, 2.5 percent; 95 percent confidence interval, -1.6 to 6.5 percent; P=0.23). In the nicotine group, 11.9 percent of the subjects had at least one of the secondary end points, as compared with 9.7 percent in the placebo group (difference, 2.2 percent; 95 percent confidence interval, -2.2 to 7.4 percent; P= 0.37). After 14 weeks the rate of abstinence from smoking was 21 percent in the nicotine group, as compared with 9 percent in the placebo group (P=0.001), but after 24 weeks the abstinence rates were not significantly different (14 percent vs. 11 percent, P= 0.67). CONCLUSIONS: Transdermal nicotine does not cause a significant increase in cardiovascular events in high-risk outpatients with cardiac disease. However, the efficacy of transdermal nicotine as an aid to smoking cessation in such patients is limited and may not be sustained over time.

Technetium-99m-tetrofosmin as a substrate for P-glycoprotein: in vitro studies in multidrug-resistant breast tumor cells.

UNLABELLED: The accumulation of 99mTc-tetrofosmin (TFos) was studied in wildtype (WT) and doxorubicin-resistant (AdrR) variants of the rat MatB and human MCF-7 breast tumor cell lines to determine whether TFos, like 99mTc-sestamibi (MIBI), is a substrate for P-glycoprotein (P-gp), a multidrug-resistance transporter. METHODS: The time course of accumulation of TFos and MIBI in WT and AdrR cells over 1 hr was studied using single-cell suspensions at 1 x 10(6) cells/ml incubated at 37 degrees C in the presence or absence of PSC833, a potent modulator of P-gp. Modulator dose-response curves were generated for PSC833, cyclosporin A, and verapamil. RESULTS: In both MatB and MCF-7 cells, TFos and MIBI accumulated extensively in WT cells and accumulation was not affected by PSC833. In contrast, ADrR cell lines accumulated very little of either tracer, but addition of PSC833 or other modulator increased this accumulation in a dose-dependent fashion. TFos and MIBI did not differ significantly in their behavior. CONCLUSION: TFos shares with MIBI the property of being a substrate for P-gp and thus TFos may be useful for functional imaging of tumor P-gp status.

Myocardial kinetics of technetium-99m teboroxime in the presence of postischemic injury, necrosis and low flow reperfusion.

OBJECTIVES: This study evaluated technetium-99m (Tc-99m) teboroxime kinetics in postischemic and partially necrotic myocardium with complete and low flow reperfusion using an isolated perfused rat heart model. BACKGROUND: Technetium-99m teboroxime has been proposed for use in the early diagnosis of reperfusion after thrombolysis on the basis of models of myocardial necrosis with complete reperfusion. Clinically, however, reperfusion is frequently incomplete, resulting in a mixture of necrotic, ischemic and postischemic tissue. METHODS: Hearts were classified into five groups: group 1 (n = 8, control); group 2 (n = 7, 30 min of no flow with complete reperfusion); group 3 (n = 12, 60 min of no flow to induce partial necrosis, followed by complete reperfusion); group 4 (n = 8, continuous low flow without flow interruption); and group 5 (n = 9, 60 min of no flow with low flow reperfusion). Buffer containing Tc-99m teboroxime was perfused for 15 min, followed by tracerfree buffer for 35 min, to evaluate uptake and clearance, respectively. RESULTS: Uptake slopes for groups 1 to 5 were (mean +/- SD) 3.0 +/- 0.7, 2.6 +/- 0.8, 2.1 +/- 0.5, 0.8 +/- 0.2 and 0.8 +/- 0.3, respectively (p < or = 0.0005 for groups 1, 2 and 3 vs. groups 4 and 5, and p = 0.003 for group 3 vs. groups 1 and 2). Clearance curves from groups 1 to 3 were best fit by a biexponential function (p < 0.001); those from groups 4 and 5 were monoexponential. In groups 1, 2 and 3, the initial clearance rate constants (ki) (0.9 +/- 0.5 x 10(-3); 1.0 +/- 0.2 x 10(-3); 1.1 +/- 0.5 x 10(-3) s-1, respectively) and the monoexponential rate constants (Kmono) (2.0 +/- 0.3 x 10(-4); 2.2 +/- 0.4 x 10(-4); 2.1 +/- 0.2 x 10(-4) s-1, respectively) were significantly greater than those in groups 4 and 5 (0.9 +/- 0.5 x 10(-4); 1.2 +/- 0.3 x 10(-4) s-1, respectively, p < or = 0.005). CONCLUSIONS: The uptake and initial clearance kinetics of Tc-99m teboroxime depend mainly on myocardial flow in this model. The presence of partial necrosis and postischemic injury has little effect on the initial clearance but leads to some reduction in uptake at normal flow rates. Evaluation of Tc-99m teboroxime kinetics may permit early noninvasive detection of inadequate reperfusion in acute myocardial infarction.

Murine and human in vivo penclomedine metabolism.

Penclomedine is a multichlorinated alpha-picoline derivative which has shown prominent activity in murine breast cancer models and is currently undergoing clinical development. Previous in vitro research has identified several penclomedine metabolites. In this study, human and murine in vivo penclomedine metabolism was examined. Upon i.v. administration to mice, no penclomedine was detectable in plasma at time points as early as 1 h postinfusion. The principle metabolite was demethyl-penclomedine [3, 5-dichloro-2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine]. Both penclomedine and demethyl-penclomedine could be recovered from tissues. Greater than 60% of the penclomedine dose remaining in the body at 22 h was indelibly bound to tissue and plasma proteins. Urinary metabolites of penclomedine consisted mainly of penclomic acid and additional polar metabolites. The results obtained after p. o. administration were nearly identical to i.v. administration with respect to the extent, level, and type of metabolites found in the plasma, tissues, and urine and with respect to the extent of protein binding. In human subjects administered penclomedine daily for 5 consecutive days, demethyl-penclomedine could be detected in plasma and accumulated with successive doses of penclomedine, reaching peak plasma concentrations of up to 10 times that of penclomedine itself and plasma exposures of nearly 400 times that of the parent drug. It appears that patients eliminate penclomedine largely through metabolism and that this drug may be amenable to p.o. administration.

Tissue and tumor distribution of C-penclomedine in rats.

Penclomedine, a lipophilic alpha-picoline derivative, is undergoing clinical development presently because of its pronounced antitumor activity against intracerebral (i.c.) tumor xenografts. Penclomedine may be metabolized in vivo to a more potent compound. Although it may be useful in the treatment of brain tumors, the drug has caused significant neurotoxicity in early clinical trials. The possibility that antitumor activity and neurotoxicity may be mediated by different mechanisms prompted a study assessing the differential distribution of penclomedine and penclomedine metabolites to brain and i.c.-implanted tumors in rats. In the present study, quantitative autoradiographic analysis demonstrated a homogenous distribution of 14C-penclomedine in all organs within 1 h of administration. Levels of 14C-penclomedine in both i.c. and s.c. tumors were three times higher than in normal brain tissue. High-performance liquid chromatography combined with gas chromatography and mass spectrophotometry demonstrated that two metabolites, O-demethyl penclomedine and penclomic acid, were responsible for most of the plasma radioactivity. Penclomic acid was also the most common urinary metabolite of penclomedine. In liver samples, although a large number of metabolite peaks were detected, no parent compound could be identified. However, in tumors and all other tissues, penclomedine was the main compound detected. The finding of penclomedine in normal brain tissue indicates not only that this drug may be useful in tumors with normal blood-brain barrier function, but also that it may be directly neurotoxic.