Clinical and experimental pharmacology & physiology
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Clin. Exp. Pharmacol. Physiol. · Jul 2000
ReviewNeuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites.
1. Morphine is recommended by the World Health Organization as the drug of choice for the management of moderate to severe cancer pain. 2. Education of health professionals in the past decade has resulted in a large increase in the prescribing of opioids, such as morphine, and in the magnitude of the doses administered, resulting in an improvement in the quality of pain relief available for many cancer patients. 3. ⋯ Several studies have shown that, following chronic oral or subcutaneous morphine administration to patients with cancer pain, the cerebrospinal fluid (CSF) concentrations of M3G exceed those of morphine and morphine-6-glucuronide (analgesically active morphine metabolite) by approximately two- and five-fold, respectively. 9. These findings suggest that when the M3G concentration (or H3G by analogy) in the CSF exceeds the neuroexcitatory threshold, excitatory behaviours will be evoked in patients. 10. Thus, rotation of the opioid from morphine/HMOR to a structurally dissimilar opioid, such as methadone or fentanyl, will allow clearance of M3G/H3G from the patient central nervous system over hours to days, thereby producing a time-dependent resolution of the neuroexcitatory behaviours while maintaining analgesia with methadone or fentanyl.
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Clin. Exp. Pharmacol. Physiol. · Jul 2000
Enalapril prevents aortic hyperreactivity and remodelling in one-kidney, one-clip hypertensive rats without reducing arterial pressure.
1. The present study was designed to evaluate the blood pressure-independent effects of angiotensin-converting enzyme (ACE) inhibition on cardiovascular structure and function in one-kidney, one-clip (1K1C) hypertensive rats. 2. The study was conducted in four groups of rats: (i) uninephrectomized normotensive rats (1K); (ii) 1K1C hypertensive rats; (iii) 1K rats treated with enalapril; and (iv) 1K1C rats treated with enalapril. ⋯ However, enalapril prevented the increase in aortic media thickness and cross-sectional area and restored the hypersensitivity to PE in aortic rings of 1K1C rats. The endothelium-dependent response to ACh was enhanced by enalapril in the aorta of 1K but not 1K1C rats. 5. These results suggest a role for activated local angiotensin II generation in aortic but not cardiac hypertrophy secondary to 1K1C hypertension.
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Clin. Exp. Pharmacol. Physiol. · Apr 2000
Biography Historical ArticleA short history of nitroglycerine and nitric oxide in pharmacology and physiology.
1. Nitroglycerine (NG) was discovered in 1847 by Ascanio Sobrero in Turin, following work with Theophile-Jules Pelouze. Sobrero first noted the 'violent headache' produced by minute quantities of NG on the tongue. 2. ⋯ Ferid Murad discovered the release of nitric oxide (NO) from NG and its action on vascular smooth muscle (in 1977). Robert Furchgott and John Zawadski recognized the importance of the endothelium in acetylcholine-induced vasorelaxation (in 1980) and Louis Ignarro and Salvador Moncada identified endothelial-derived relaxing factor (EDRF) as NO (in 1987). 9. Glycerol trinitrate remains the treatment of choice for relieving angina; other organic esters and inorganic nitrates are also used, but the rapid action of NG and its established efficacy make it the mainstay of angina pectoris relief.
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Clin. Exp. Pharmacol. Physiol. · Jan 2000
Renal acid-base and sodium handling in hypoxia and subsequent mild metabolic acidosis in foetal sheep.
1. To measure the renal contribution to acid-base homeostasis during hypoxia (not associated with hypercapnia) and in response to the subsequent mild metabolic acidosis and to determine the effects of this hypoxia on the renal handling of sodium, studies were performed in six chronically catheterized foetal sheep (129-138 days gestation) before, during and for 1 h after a 2 h period of hypoxia. 2. Hypoxia was induced in the conscious ewe by infusing nitrogen into the trachea. ⋯ This natriuresis was due to a fall in the reabsorption of sodium by the proximal tubule (P < 0.05). Proximal reabsorption of sodium was directly related to foetal pH (P < 0.0001) and bicarbonate reabsorption (P < 0.001). 5. It was concluded that: (i) the foetal kidneys began to contribute to the maintenance of acid-base balance within the first hour of recovery from a 2 h episode of hypocapnic hypoxia, even though the acidosis was relatively mild; and (ii) a reduction in bicarbonate reabsorption was probably the most important factor that limited sodium reabsorption by the renal tubule during this experiment.
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Clin. Exp. Pharmacol. Physiol. · Jan 2000
Effect of uranyl nitrate-induced renal failure on morphine disposition and antinociceptive response in rats.
1. The aims of the present study were to administer morphine (14.0 mumol/kg, s.c.) to male Hooded Wistar rats and to determine the effect of uranyl nitrate-induced renal failure on: (i) the antinociceptive effect of morphine; (ii) the pharmacokinetics of morphine and morphine-3-glucuronide (M3G); and (iii) the relationship between antinociceptive effect and the pharmacokinetics of morphine in plasma and brain. 2. Renal failure was induced by a single s.c. injection of uranyl nitrate and kinetic/dynamic studies were performed 10 days after its administration, when creatinine clearance was 17% of the control group. ⋯ For both control and renal failure rats, the relationships between antinociceptive effect and plasma morphine concentration were characterized by counterclockwise hysteresis loops, probably reflecting a delay for the relatively polar morphine to cross the blood-brain barrier. The relationship between antinociceptive effect and brain morphine concentration in control rats revealed no evidence of acute tolerance and was described by a sigmoidal function. In contrast, the relationship in renal failure rats was characterized by clockwise hysteresis, which is consistent with acute tolerance development.