Asystole following endotoxin administration.
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Adult↗
Biomedical subjects
T Fullerton
Publications and source records attributed to T Fullerton.
The pharmacodynamics of sumatriptan in nitroglycerin-induced headache.
Migraine is a common disorder that causes significant morbidity in those afflicted. Many novel antimigraine compounds are in clinical development, yet full characterization of each one's pharmacodynamic behavior is a formidable task due to the difficulty in studying a migraineur during an attack. Nitroglycerin (NTG) administration commonly causes a headache with some features similar to those of a migraine. As such, NTG has been used as a model of vascular headaches, including migraine. The pharmacodynamic effects of nitroglycerin and sumatriptan on middle cerebral artery blood flow velocity (MCAv) and headache scores were studied in 10 healthy male volunteers. An intravenous infusion of NTG titrated to 0.5 mcg/kg/min over 30 minutes resulted in a median reduction from baseline in MCAv of 27% (range: 16.4%-37.3%). Nine of the subjects developed a headache with a median verbal score of 3.5 of 10 (range: 0-5). Subjects received sumatriptan either 2 mg intravenously or 6 mg subcutaneously, which abated clinical headache in 9 of the 10 subjects (p = 0.030). A median sumatriptan-induced increase in MCAv of 21% (p = 0.054) suggested a constricting effect on the NTG-induced dilated MCA. A two-compartment pharmacokinetic/indirect-effects pharmacodynamic model was fit to the sumatriptan concentration and MCAv data using iterative two-stage analysis. This model was unbiased and fit the concentration (r2 = 0.98) and the MCAv (r2 = 0.79) data well. These results suggest that NTG-induced headache and the development of pharmacokinetic/pharmacodynamic models could serve as a useful method for exploring the mechanisms of abortive migraine drugs.
Adult↗
Penetration of tacrine into cerebrospinal fluid in patients with Alzheimer's disease.
Tacrine is widely used for the treatment of Alzheimer's disease, but data are limited regarding cerebrospinal fluid (CSF) concentrations at steady state. To evaluate CSF penetration, seven patients with Alzheimer's disease who were receiving tacrine at doses of 40 to 140 mg/day as a part of a double-blind trial were studied. After 6 weeks of tacrine therapy, concomitant plasma and CSF samples were collected 30 minutes after the morning dose of tacrine. Although this time point is before the peak oral absorption in most patients, the critical issue for this study is that the plasma and CSF samples were collected concomitantly so that a percentage of tacrine penetration could be derived. The morning dose of tacrine ranged from 10 to 40 mg, which was given in the fasting state. Mean (+/-SD) plasma levels of tacrine were 8.01+/-7.07 ng/mL, whereas mean (+/-SD) CSF levels of tacrine were 5.21+/-6.00 ng/mL. The mean (+/-SD) ratio of CSF to plasma tacrine concentration was 0.50+/-0.45, with wide interindividual variability. No relationship between dose and percentage of penetration was observed. Plasma concentrations ranged from 0.99 to 22.6 ng/mL and were unrelated to dose, suggesting erratic oral absorption and/or rapid metabolism. CSF concentrations ranged from not detectable to 15.92 ng/mL. The authors support that penetration of tacrine into CSF is highly variable in patients with Alzheimer's disease and that disparity in tacrine concentrations at the site of action may be one reason for conflicting results from studies of the efficacy of tacrine in Alzheimer's disease.
Aged↗
Treatment of acute ischemic stroke, Part 2.
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Acute Disease↗
Pharmacodynamic analysis of sparse data from concentration- and effect-controlled clinical trials guided by a pilot study. An investigation by simulations.
The purpose of this investigation was to explore, by computer simulation, the utility of two different clinical trial designs with sparse sampling (three concentration--effect measurements per subject) for population pharmacodynamic studies when the targeted drug concentration or effect measurements are determined by application of optimal sampling theory based on the results of a preceding, data-intensive pilot study. The two design paradigms were concentration-controlled and pharmacologic effect-controlled randomized clinical trials, respectively. The drug concentration--pharmacologic effect relationship was assumed to be describable by the Hill (sigmoid Emax) equation without hysteresis. Intersubject variability was represented by coefficients of variation of 30, 40, and 30% for Emax, EC50, and gamma, respectively. Random controller imprecision and measurement errors were included. Concentration and effect data for 100 subjects were generated by Monte Carlo simulation (ADAPT II), and pharmacodynamic parameter values were obtained by iterative two-stage analysis. These were then used to predict effect intensities over a range of drug concentrations, and the results were compared with those obtained by use of the true parameter values. Concentration- and effect-controlled trial designs were simulated in two forms: unconstrained and constrained with respect to the highest allowed targeted drug concentration or effect intensity. It was found that both types of unconstrained trials yielded good and comparable parameter estimates whereas the constrained trials (which are clinically more realistic) yielded more biased and imprecise estimates of individual pharmacodynamic parameters. Nevertheless, use of the latter to determine the effect intensities produced by different drug concentrations yielded good estimates but only in the range covered by the targeted concentration or effect measurements. For concentration-controlled trials it appears essential that the individuals in the pilot group and the clinical study group be drawn from the same population. Effect-controlled trials gave good results even when the pilot group was not representative of the population (e.g., for an aberrant subpopulation).
Clinical Trials as Topic↗
Treatment of acute ischemic stroke, Part 1.
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Brain Ischemia↗
Evaluation of the renal protective effect of misoprostol in elderly, osteoarthritic patients at risk for nonsteroidal anti-inflammatory drug-induced renal dysfunction.
An age greater than 60 and diuretic use have been implicated as risk factors for nonsteroidal anti-inflammatory drug (NSAID)-induced decreases in renal function. Misoprostol, a prostaglandin E1 analog, was studied in nine elderly osteoarthritic patients at risk for NSAID-induced renal dysfunction to determine whether it could prevent NSAID-induced renal dysfunction. Subjects received ibuprofen 2400 mg/day and either misoprostol 800 mcg/day or placebo for 14 days in a randomized, double-blinded, crossover trial. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) studies using inulin and PAH plasma clearance, urinary prostaglandin E2 (PGE2) and protein excretion, and serum electrolytes were obtained at baseline, after the first dose, and on day 7 and 14 of each treatment period. Prostaglandin E2 excretion was significantly reduced after the first dose of ibuprofen and throughout the 14 days in both the misoprostol and placebo treatment groups. No statistically significant differences in GFR, ERPF, protein excretion, serum potassium, or serum sodium were detected between misoprostol and placebo treatment during the 14 days of ibuprofen treatment. However, a subset of two patients who exhibited a decrease of greater than 20% in GFR during placebo treatment, appeared to demonstrate an attenuation of this decline when treated with misoprostol. Effect of time, independent of treatment group, indicated that ERPF was significantly decreased from baseline after the first dose of ibuprofen (P < or = 0.05), whereas GFR was notably diminished from baseline on day 14 only (P < or = 0.05). Misoprostol does not influence GFR and ERPF in unselected subjects purportedly at risk for NSAID-induced renal dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Sumatriptan: a selective 5-hydroxytryptamine receptor agonist for the acute treatment of migraine.
OBJECTIVE: The clinical pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and associated drug interactions of the novel antimigraine drug sumatriptan are reviewed. DATA SOURCES: English-language publications pertaining to sumatriptan were identified via a search of the MEDLINE computerized database. STUDY SELECTION: Open and controlled clinical studies were reviewed in assessing clinical efficacy, although only the results of controlled, randomized trials from the basis for the conclusions pertaining to the effectiveness of sumatriptan. DATA EXTRACTION: The primary measure of drug effectiveness in all clinical studies was significant improvement in headache severity scores. Secondary measures included functional ability, time to relief, rescue medication use, associated symptoms of nausea/vomiting and photo/phonophobia, and, in some studies, headache recurrence rate. These data were obtained from each published clinical trial and used in the overall analysis of sumatriptan efficacy. DATA SYNTHESIS: Sumatriptan is a serotonin agonist that has been studied for the acute treatment of migraine and cluster headache. The drug appears to work via specific serotonin receptors to mediate selective vasoconstriction within the cranial vasculature and to prevent the release of inflammatory mediators from trigeminal nerve terminals. The recommended dose of sumatriptan is 6 mg given subcutaneously at the onset of headache; an oral formulation is under investigation. In the published clinical trials of the oral and subcutaneous dosage forms to date, sumatriptan was effective in reducing headache severity from moderate/severe to mild/absent in approximately 70-80 percent of patients treated with active drug, compared with only 20-30 percent in the placebo groups, and 48 percent in the oral ergotamine tartrate/caffeine (Cafergot)-treated group. Secondary measures of effectiveness also favored sumatriptan. There may be a higher rate of headache recurrence with sumatriptan compared with placebo or Cafergot, although further study is necessary to confirm this observation. Adverse effects associated with sumatriptan administration generally were mild and transient and included tingling, warm/hot sensations, and pressure and tightness in the chest and neck. No significant drug interactions have yet been identified. CONCLUSIONS: Sumatriptan appears to represent a safe and effective alternative to the ergot alkaloids for the abortive treatment of acute migraine. However, further clinical trials, especially those yielding comparative data with current antimigraine agents, are needed to determine the full therapeutic contribution of sumatriptan.
Clinical Trials as Topic↗
Prolonged nausea and vomiting associated with buprenorphine.
We conducted a trial to evaluate the histamine-releasing characteristics of morphine, meperidine, and buprenorphine when administered intravenously to 20 healthy adults without pain. Substantially more nausea and vomiting occurred with buprenorphine than with the other compounds, and was more intense on ambulation. High-affinity receptor binding may play a role in the long duration of nausea and vomiting after a single dose of this agent.
Adult↗
Oculogyric crisis possibly related to pentazocine.
OBJECTIVE: To report and describe the apparent first case of acute oculogyric crisis following administration of pentazocine, and to discuss the possible mechanism for this reaction. DATA SOURCES/CASE SUMMARY: Patient case and relevant review of literature. The patient, a 39-year-old woman, developed acute oculogyric crisis following administration of Talacen (pentazocine and acetaminophen) for pain relief. The crisis resolved after discontinuation of the medication and administration of intravenous diphenhydramine 50 mg. CONCLUSIONS: Based on the temporal relationship of drug administration to occurrence of the event, pentazocine is implicated as the cause of this acute oculogyric crisis. A plausible mechanism for precipitation of this crisis is the agonism of pentazocine on sigma opiate receptors, with postulated subsequent modulation of dopamine receptors.
Acute Disease↗