Clinical pharmacology and therapeutics
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Advances in biomedical research over recent decades have substantially raised expectations that the pharmaceutical industry will generate increasing numbers of safe and effective therapies. However, there are warning signs of serious limitations in the industry's ability to effectively translate biomedical research into marketed new therapies. Clinical pharmacologists should be aware of these signals and their potential impact. Here, we discuss a strategy, where clinical pharmacology can play an important role to improve the process of drug development.
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In the first week of October, I announced the launch of a national consortium that will transform how clinical and translational research is conducted; ultimately enabling researchers to provide new treatments more efficiently and quickly to patients. This new consortium, funded through Clinical and Translational Science Awards (CTSAs), begins with 12 academic health centers (AHCs) located throughout the nation. An additional 52 AHCs are receiving planning grants to help them prepare to apply for a CTSA.
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Clin. Pharmacol. Ther. · Jan 2007
Randomized Controlled Trial Comparative StudyMechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers.
The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P(ET)CO(2) of 50 mm Hg and P(ET)O(2) of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05-0.6 mg/70 kg and 24 volunteers received fentanyl: 0.075-0.5 mg/70 kg). The PK/PD correlations were analyzed using nonlinear mixed effects modeling. ⋯ The half-time values of biophase equilibration (t(1/2, k(eo))) were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of k(on) was 0.246 ml/ng/min and the value of k(off) was 0.0102 min(-1). The concentration-effect relationship of buprenorphine was characterized by a ceiling effect at higher concentrations (intrinsic activity alpha=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (alpha=0.91, 95% CI: 0.19-1.62).
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Clin. Pharmacol. Ther. · Jan 2007
Randomized Controlled TrialThe partial 5-hydroxytryptamine1A receptor agonist buspirone does not antagonize morphine-induced respiratory depression in humans.
Based on experiments in rats, serotonin receptor 5-hydroxytryptamine (5-HT)(1A) agonists have been proposed as a potential therapeutic strategy for the selective treatment of opioid-induced respiratory depression. We investigated the clinical applicability of this principle in healthy volunteers. Twelve subjects received 0.43 mg/kg morphine (30 mg for 70 kg body weight) administered intravenously (i.v.) over approximately 2 h. ⋯ Buspirone significantly increased the nausea induced by morphine (P=0.011). Oral co-administration of a high dose of the clinically available 5-HT(1A) agonist buspirone cannot be advised as a remedy for opioid-induced respiratory depression. This is indicated by its lack of anti-respiratory depressive effects and by the buspirone-associated increase of morphine-induced nausea.
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Clin. Pharmacol. Ther. · Jan 2007
Case ReportsTwo 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. ⋯ 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.