British journal of clinical pharmacology
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Br J Clin Pharmacol · Apr 2002
Randomized Controlled Trial Comparative Study Clinical TrialThe bioavailability and pharmacokinetics of subcutaneous, nebulized and oral morphine-6-glucuronide.
Morphine-6-glucuronide (M6G), one of the active metabolites of morphine, has attracted considerable interest as a potent opioid analgesic with an apparently superior therapeutic index. To date studies have used the intravenous route, which is generally unacceptable in the treatment of cancer related pain. The aim of this study was to define the pharmacokinetics, toxicity and cardio-respiratory effects of three alternative routes of administration of M6G. ⋯ With the minimal toxicity reported in this and previous studies, subcutaneous infusion of M6G may potentially provide clinically useful analgesia for advanced cancer pain. Nebulized M6G is not significantly absorbed via the lungs, and if opiates are shown to have a local effect in the lung, reducing the sensation of breathlessness, then nebulized administration is likely to minimize systemic effects. Oral M6G has poor bioavailability, but is significantly hydrolysed in the gut to morphine, which is subsequently glucuronidated following absorption. This circuitous route accounts for the majority of systemically available M6G after oral administration.
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Br J Clin Pharmacol · Mar 2002
Randomized Controlled Trial Comparative Study Clinical TrialComparative activity of cetirizine and mizolastine on histamine-induced skin wheal and flare responses at 24 h.
The aim of our study was to compare the activity of cetirizine 10 mg with that of mizolastine 10 mg vs placebo at 24 h after intake in healthy volunteers. ⋯ This study shows that cetirizine (10 mg) suppresses skin reactivity to histamine more effectively than mizolastine (10 mg) 24 h after intake in healthy volunteers.
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Br J Clin Pharmacol · Mar 2002
Randomized Controlled Trial Clinical TrialActivated charcoal alone or after gastric lavage: a simulated large paracetamol intoxication.
Activated charcoal is now being recommended for patients who have ingested potentially toxic amounts of a poison, where the ingested substance adsorbs to charcoal. Combination therapy with gastric lavage and activated charcoal is widely used, although clinical studies to date have not provided evidence of additional efficacy compared with the use of activated charcoal alone. There are also doubts regarding the efficacy of activated charcoal, when administered more than 1 h after the overdose. The aim of this study was to examine if there was a difference in the effect of the two interventions 1 h post ingestion, and to determine if activated charcoal was effective in reducing the systemic absorption of a drug, when administered 2 h post ingestion. ⋯ These results suggest that combination treatment may be no better than activated charcoal alone in patients presenting early after large overdoses. The effect of activated charcoal given 2 h post ingestion is substantially less than at 1 h, emphasizing the importance of early intervention.
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Br J Clin Pharmacol · Mar 2002
Investigation of the effect of chlormethiazole on cerebral chemistry in neurosurgical patients: a combined study of microdialysis and a neuroprotective agent.
Promising pre-clinical results from laboratory studies of neuro-protective drugs for the treatment of patients with stroke and head injury have not been translated into benefit during clinical trials. The objective of the study was to assess the feasibility of administrating a potential neuro-protective drug (chlormethiazole) in conjunction with multimodality monitoring (including microdialysis) to patients with severe head injury in order to determine the effect of the agent on surrogate endpoints and penetration into the brain. ⋯ Chlormethiazole can be safely given to ventilated patients with severe head injury. There was no evidence of hypotension or withdrawal seizures. Combining a pilot clinical study of a neuro-protective agent with multimodality monitoring is feasible and, despite the lack of effect on physiological and chemical parameters in this study, may be a useful adjunct to the development of neuro-protective drugs in the future. Further investigation of the capability of microdialysis in this setting is required. By investigating the effect of a drug on surrogate end-points, it may be possible to identify promising agents from small pilot clinical studies before embarking on large phase III clinical trials.
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Br J Clin Pharmacol · Feb 2002
Randomized Controlled Trial Clinical TrialDose-effect relationship for several coagulation markers during administration of the direct thrombin inhibitor S 18326 in healthy subjects.
We conducted a phase I placebo-controlled trial with two i.v. doses (0.5 mg h-1 and 3 mg h-1) of S 18326, a selective thrombin inhibitor that interacts with the catalytic site of thrombin, with the aim to study the relationships between increasing plasma levels of S 18326 and changes in coagulation tests and thrombin generation markers. ⋯ Our results support specific monitoring of the thrombin inhibitor S 18326 with ACT and APTT to establish the safety range of the drug in further studies. Moreover, the fall in F1 + 2 prothrombin fragments suggests that S 18326 effectively reduces the retroactivation of factors V and VIII by thrombin.