The search for a nonaddicting opioid.
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Analgesics, Opioid↗
Biomedical subjects
D F Lehmann
Publications and source records attributed to D F Lehmann.
Observation and experiment on the cusp of collaboration: a parallel examination of clinical pharmacology and pharmacoepidemiology.
Despite a common interest in the effect of drugs in humans, clinical pharmacologists and pharmacoepidemiologists often operate in isolation since the knowledge base underlying the respective parent disciplines of pharmacology and epidemiology is quite distinct. This lack of communication may lead to a potential for lost opportunities that would otherwise be mutually beneficial. Accordingly, this article juxtaposes the two disciplines to emphasize common areas of interest despite differences in methodology. In addition, weaknesses and strengths are contrasted in an effort to document the mirror image nature of both clinical pharmacology and pharmacoepidemiology in this regard. Specific examples underlying the complementary nature of the two disciplines are also offered that may help to stimulate collaboration. The possibility of greater formal cooperation between societies representing the two disciplines is also suggested to cross-educate both clinical pharmacologists and pharmacoepidemiologists as a means to foster collaboration.
Causality↗
The association of opportunistic infections with the occurrence of trimethoprim/sulfamethoxazole hypersensitivity in patients infected with human immunodeficiency virus.
Hypersensitivity from trimethoprim/sulfamethoxazole (TMP/SMX) has been linked to a reactive nitroso intermediate from sulfamethoxazole metabolism, which may be altered in patients with human immunodeficiency virus (HIV) infection. The authors determined the clinical factors that are associated with TMP/SMX hypersensitivity in patients with HIV. In a case control study, 54 controls currently tolerating TMP/SMX prophylaxis were randomly matched by date of hypersensitivity reaction in case patients to 28 patients with a history of a rash consistent with erythema multiforme from TMP/SMX. Demographic data, coadministered medications, laboratory data, and histories of opportunistic infections were extracted on all patients. A highly significant association was observed between the number of opportunistic infections and the occurrence of TMP/SMX hypersensitivity (p < 0.001), despite comparability of CD4 counts between case patients and controls (p > 0.1). A tendency for protection from TMP/SMX hypersensitivity in blacks was also observed (p = 0.066). These observations suggest that the mechanisms by which HIV produces cellular immune dysfunction and alters drug detoxification may be linked.
AIDS-Related Opportunistic Infections↗
The effect of cimetidine on the formation of sulfamethoxazole hydroxylamine in patients with human immunodeficiency virus.
Hypersensitivity reactions from trimethoprim/sulfamethoxazole are likely caused by a reactive nitroso intermediate formed from sulfamethoxazole hydroxylamine. This pilot study tested whether cimetidine inhibits the urinary excretion of sulfamethoxazole hydroxylamine. Ten outpatients infected with human immunodeficiency virus (HIV) and currently receiving trimethoprim/sulfamethoxazole prophylaxis were randomly selected from 59 eligible patients. Five received cimetidine 800 mg twice daily for 1 week and five served as controls. Two spot urine samples one week apart were obtained after a trimethoprim/sulfamethoxazole dose for all patients. Patients taking cimetidine had a significant decrease in excretion of sulfamethoxazole hydroxylamine relative to total excreted drug in the two urine samples compared with control patients. Cimetidine likely caused this decrease in sulfamethoxazole hydroxylamine excretion through inhibition of CYP3A4. Because of potential differences between HIV-infected patients and healthy subjects in oxidative metabolism, future studies of inhibitors of sulfamethoxazole hydroxylamine formation should be conducted in the HIV population.
Adult↗
A pharmacoeconomic model to aid in the allocation of ambulatory clinical pharmacy services.
Drugs of choice in secondary prevention strategies reduce complication rates of certain diseases. Unfortunately, these strongly indicated drugs remain underused. A model was developed to predict the cost-effectiveness of clinical pharmacy services assumed to improve use of drugs of choice to unity in hypothetical cohorts of three diseases that commonly accompany hypertension and in which clear drugs of choice exist. Use of angiotensin-converting enzyme (ACE) inhibitors in patients with diabetes who have proteinuria, use of beta blockers after myocardial infarction, and use of ACE inhibitors in patients with asymptomatic left ventricular dysfunction were analyzed. Clinical pharmacy services could be cost-saving in all three diseases in this model if use of the drug of choice in standard practice did not exceed 0.899 in patients with diabetes who have proteinuria, 0.512 in patients after infarct, and 0.804 in patients with asymptomatic left ventricular dysfunction. This model may help decision makers by accessing local patient demographics and prescribing habits before any resource allocation.
Adrenergic beta-Antagonists↗
Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors.
BACKGROUND: Procarbazine usage in brain tumors has a high incidence of hypersensitivity reactions compared with its use in other malignancies. Procarbazine oxidation to a reactive intermediate is enhanced by phenobarbital. Patients with primary brain tumors would have a preferential exposure to anticonvulsants compared to patients with other malignancies. OBJECTIVE: To determine whether anticonvulsant exposure is associated with procarbazine hypersensitivity reactions in patients with primary brain tumors. METHODS: This retrospective cohort study included 83 patients with primary brain tumors who were treated with procarbazine between 1981 and 1996 at a university hospital-based regional oncology center. Data were extracted by chart review. The data collected included age, sex, race, tumor type, smoking, alcohol usage, and all concomitant medications, as well as creatinine, aspartate aminotransferase, total bilirubin, and anticonvulsant serum levels. Anticonvulsant exposure was determined by the presence of detectable serum levels. Cases of procarbazine hypersensitivity reactions were identified through a review of progress notes. RESULTS: There were 20 patients with procarbazine hypersensitivity reactions. A significant association between the exposure to anticonvulsants and the development of procarbazine hypersensitivity reactions was found (p = 0.05). In addition, there was a significant dose-response association between the development of procarbazine hypersensitivity and the presence of therapeutic anticonvulsant serum levels (p = 0.03). CONCLUSIONS: Concomitant exposure to anticonvulsants is associated with procarbazine hypersensitivity reactions, possibly though a reactive intermediate generated by CYP3A isoform induction. All patients in this cohort received enzyme-inducing anticonvulsants. New anticonvulsants devoid of this property are available. These data support trials that use these newer agents for the prophylaxis of seizures in patients with brain tumors who are to receive procarbazine.
Adult↗
Comparisons of oxidative metabolism and reductive capacity in sulfonamide-tolerant and -intolerant patients with human immunodeficiency virus.
Hypersensitivity reactions to trimethoprim/sulfamethoxazole occur with a high frequency in human immunodeficiency virus (HIV)-infected patients. This study tested whether differences in oxidative metabolism and plasma reductive capacity correlate with sulfonamide intolerance in patients with HIV. Eighteen stable outpatients with HIV were prospectively studied. Nine patients had documented histories of hypersensitivity reactions to trimethoprim/sulfamethoxazole and nine did not. Urinary caffeine metabolite ratios assessed the activity of two oxidative enzymatic pathways: cytochrome P-450 1A2 (demethylation) and 8-hydroxylation. Plasma cyst(e)ine was used as a measure of reductive capacity. The trimethoprim/sulfamethoxazole-intolerant group showed greater rates of 8-hydroxylation, lower rates of demethylation, and lower cyst(e)ine levels. The results of this pilot study extend previous observations of differences in oxidative metabolism and reductive capacity that exist within the population of HIV-infected individuals. In addition, these findings lay the groundwork for future interventional studies that could use agents to inhibit sulfonamide oxidation and increase reductive capacity in sulfonamide-intolerant patients with HIV when rechallenged with trimethoprim/sulfamethoxazole.
Adult↗
Effect of a prior-authorization requirement on the use of nonsteroidal antiinflammatory drugs.
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Anti-Inflammatory Agents, Non-Steroidal↗
Improving family ties: an examination of the complementary disciplines of pharmacoepidemiology and clinical pharmacology.
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Bias↗
Primidone crystalluria following overdose. A report of a case and an analysis of the literature.
Seven cases of crystalluria following primidone overdose have been reported since the 1950s. An eighth case of primidone crystalluria following overdose is presented. Because of low aqueous solubility (600 mg/L at 37 degrees C) which is directly proportional to temperature, any factor increasing renal excretion of unchanged primidone predisposes to crystal formation. Renal clearance is dependent on dosage because of negligible protein binding, zero-order conversion to phenobarbitone (phenobarbital) and first-order conversion to phenylethylmalonamide. Therapy with other anticonvulsants known to induce the metabolism to phenobarbitone does not appear to be protective against crystalluria in overdose situations. The critical serum primidone concentration for crystalluria presence seems to be 80 mg/L. There is evidence for nephrotoxicity of the crystals themselves if formed in vivo (actual crystal presence during voiding). The chemical phenomenon of supersaturation of a solution is protective against in vivo crystal formation with subsequent nephrotoxicity. Vigorous hydration to augment elimination and to lessen the propensity for renal toxicity is recommended.
Adult↗