British journal of clinical pharmacology
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Br J Clin Pharmacol · Dec 2002
Randomized Controlled Trial Clinical TrialNo effect on central or peripheral blood pressure of systemic urotensin II infusion in humans.
In rodent and primate studies, urotensin II is an extremely potent vasoconstrictor peptide with effects in the central aortic and arterial vasculature as well as on cardiac function. The aim of the present study was to assess systemic haemodynamic responses to intravenous urotensin II infusion in humans. ⋯ Intravenous urotensin II infusion did not affect systemic haemodynamics or arterial stiffness, despite achieving an approximately 100-fold increase in plasma immuno-reactivity. We conclude that urotensin II is unlikely to have a physiological role in the short term regulation of vascular tone or blood pressure in man. Further confirmatory studies with urotensin II receptor antagonists are required.
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Br J Clin Pharmacol · Sep 2002
Meta AnalysisDose-response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data.
To define by amalgamation of data obtained in contemporaneous case-control studies, the risks associated with individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) according to doses used. ⋯ The risk of upper gastrointestinal bleeding with NANSAIDs varies twenty-fold depending on the drug, and by three to seven-fold depending on the dose chosen. Risk is maximal during the first week and decreases thereafter. Paracetamol (acetaminophen) is not associated with upper gastrointestinal bleeding at any dose and should be the first-line analgesic wherever possible.
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Br J Clin Pharmacol · Aug 2002
Randomized Controlled Trial Clinical TrialIntestinal first pass metabolism of midazolam in liver cirrhosis --effect of grapefruit juice.
Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite alpha-hydroxymidazolam was studied in patients with cirrhosis of the liver. ⋯ A marked interaction between oral midazolam and grapefruit juice was found and the data are consistent with a reduced first-pass metabolism of midazolam. This is likely to occur at the intestinal wall inhibition of CYP3A4 activity by grapefruit juice. These results indicate that patients with liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4 substrates than subjects with normal liver function.
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Br J Clin Pharmacol · Jun 2002
Randomized Controlled Trial Multicenter Study Clinical TrialAnalgesic efficacy of sustained release paracetamol in patients with osteoarthritis of the knee.
Paracetamol is widely recommended as the initial treatment for pain associated with osteoarthritis (OA). A sustained release (SR) paracetamol formulation (Panadol Extend) was compared with standard immediate release (IR) paracetamol (Panadol) in patients with knee pain secondary to OA. The primary parameter for assessment of efficacy was patient-assessed global pain relief as determined on day 8 of the treatment period. ⋯ SR paracetamol taken three times daily was statistically and therapeutically noninferior to IR paracetamol taken four times daily in patients with knee pain due to OA. SR paracetamol may be more convenient for patients with chronic pain and has the potential to enhance compliance and therefore pain relief.
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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.