Effect of diclofenac alone or in combination with alpha-tocopherol on the oxidative activity of polymorphonuclear leukocytes in healthy and osteoarthritic individuals.

OBJECTIVE: To investigate the effects of diclofenac alone or when combined with alpha-tocopherol on the oxidative activity of polymorphonuclear leukocytes (PMNs) in healthy and osteoarthritic (OA) patients. METHODS: The study was carried out at the College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia, over the period 1999 to 2000. Twelve healthy controls and 12 osteoarthritic patients were recruited to the study. Twelve healthy controls and osteoarthritic patients were given diclofenac 50 mg thrice daily orally, initially for 5 days then alpha-tocopherol at 200 mg thrice daily orally, was added for another 5 days. Blood samples were drawn before the start of the study (pre-treatment) and at 5 days following treatment with diclofenac alone and 10 days following treatment with diclofenac and alpha-tocopherol. Chemiluminescence (CL) response was measured for whole blood and isolated polymorphonuclear leukocytes (PMNs) on all samples. RESULTS: Diclofenac enhanced CL response of whole blood and of PMNs of healthy controls when stimulated with phorbol myristate acetate (PMA) and opsonized zymosan (OPZ). Co-treatment with alpha-tocopherol resulted in no appreciable change in the CL response of whole blood when stimulated with PMA or OPZ but a further significant enhancement of CL response of isolated PMNs when these cells were stimulated by either PMA or OPZ. In osteoarthritic patients, diclofenac alone and when combined with alpha-tocopherol showed no significant change in CL response of whole blood. The CL response of PMNs from OA patients was decreased by diclofenac alone. However, this inhibitory effect was not observed when alpha-tocopherol was used together with diclofenac. CONCLUSION: The effect of diclofenac alone or in combination with alpha-tocopherol did not produce a consistent effect on the CL response of whole blood or isolated PMNs of healthy or osteoarthritic patients.

Sucralfate attenuates gastric mucosal lesions and increased vascular permeability induced by ischaemia and reperfusion in rats.

Recent evidence suggests that oxygen-derived free radicals are involved in mediating gastric microvascular and parenchymal cell injuries induced by ischaemia and reperfusion. Therefore, the effect of the locally acting anti-ulcer drug, sucralfate, was studied on ischaemia and reperfusion (e.g. induced gastric lesions, intraluminal bleeding, changes in vascular permeability and non-protein sulfhydryl levels in the rat stomach). Allopurinol was used as a known standard antioxidant drug. Rats were subjected to 30 min of gastric ischaemia in the presence of 100 mmol/L hydrochloric acid and reperfusion periods of 15, 30 or 60 min duration. The gastric lesions were assessed microscopically under an inverted microscope. The vascular permeability was quantified by measuring the extravasated Evans blue in the stomach. There were significantly greater numbers of gastric lesions, intraluminal bleeding and leakage of Evans blue during all reperfusion periods as compared with those of ischaemia, with maximum effects occurring at 60 min following reperfusion. Pretreatment with sucralfate (31.25-250 mg/kg, p.o.) or allopurinol (12.5-50 mg/kg, i.p.) 30 min before the procedure, dose-dependently reduced the gastric lesions, intraluminal bleeding, and decreased the vascular permeability induced by ischaemia and reperfusion. Furthermore, sucralfate dose-dependently reverses the ischaemia and reperfusion-induced depletion of mucosal non-protein sulfhydryl levels and inhibited the superoxide radical production in both cell-free xanthine-xanthine oxidase and in the stimulated polymorphonuclear cellular systems. These results suggest that the protection produced by sucralfate against gastric injury may be due to its antioxidant effects.

Pharmacokinetic interactions between erythromycin, clarithromycin, roxithromycin and phenytoin in the rat.

The effects of the macrolide antibiotics, erythromycin, clarithromycin and roxithromycin, on the pharmacokinetic profile of phenytoin were studied in rats. Animals were injected with phenytoin (100 mg/kg, i.p.) daily for 4 days and then they were given phenytoin (20 mg/kg, i.p.) alone or the same dose of phenytoin together with erythromycin (50 mg/kg, i.p.), clarithromycin (50 mg/kg, i.p.) or roxithromycin (50 mg/kg, i.p.). In another set of experiments, the same protocol was followed except that erythromycin (100 mg/kg), clarithromycin (100 mg/kg) and roxithromycin (100 mg/kg) were given by the oral route. The concentrations of phenytoin in plasma were determined using a high-performance liquid chromatographic method. The area under the curve the maximum plasma concentration and the elimination half-life (t1/2) of phenytoin were significantly (p < 0.05) increased by the macrolides. In addition, the macrolides significantly (p < 0.05) reduced the level of hepatic cytochrome P-450 in the rats. These results suggest that a potentially harmful drug-drug interaction may occur if phenytoin is administered concurrently with erythromycin, clarithromycin or roxithromycin.

Ciprofloxacin decreases plasma phenytoin concentrations in the rat.

The pharmacokinetic interaction between phenytoin and ciprofloxacin was studied in rats. One group of animals was given phenytoin (20 mg/kg, p.o.) as a single daily dose for 7 days. In another group of animals, the same protocol was followed except that ciprofloxacin was given in two equal doses (15 mg/kg, i.p., each) on days 5, 6 and 7. On day 8, phenytoin blood sampling was performed at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0 and 12.0 h. Similarly, urine samples were collected at 4, 6 and 8 h following drug administration from the same animals that had received either phenytoin alone or phenytoin together with ciprofloxacin. The concentrations of phenytoin in the plasma and urine were measured using an HPLC method. Ciprofloxacin significantly (P < 0.05) reduced the area under the curve (AUC), the maximum plasma concentration (Cmax) and the elimination half-life (t1/2) of phenytoin. Additionally, ciprofloxacin increased phenytoin concentrations in urine at 4, 6 and 8 h. These results show that ciprofloxacin decreases the plasma levels of phenytoin when the two drugs are given concurrently.

Enhancement of anti-inflammatory effects of calcium channel blockers by allopurinol and dimethylsulphoxide.

The effects of the calcium channel blockers, nifedipine, verapamil and flunarizine, and the antioxidants, allopurinol and dimethylsulphoxide, were investigated on carrageenan-induced rat paw oedema and changes in vascular permeability. Paw volume was measured by using a plethysmometer and vascular permeability was quantified by measuring the extravasated Evans blue dye 3 h after injecting the phlogistic agent. Intraperitoneal administration of nifedipine (1,2 and 4 mg/kg), verapamil (5, 10 and 20 mg/kg), flunarizine (2.5, 5 and 10 mg/kg), allopurinol (6.25, 12.5 and 25 mg/kg) and dimethylsulphoxide (20, 40 and 80 mg/kg) 30 min before carrageenan, dose dependently inhibited oedema formation and increased vascular permeability. Co-administration of the lowest doses of calcium channel blockers with the lowest doses of antioxidants produced synergistic inhibitory effects. These results indicate that both calcium influx and oxygen-derived free radicals are involved in carrageenan-induced inflammatory responses. Thus, the synergistic effects of their combination may be due to the blockade of calcium entry and reduction in the generation of oxygen-derived free radicals.

Selenium protects against ischemia-reperfusion-induced gastric lesions in rats.

Recent studies have shown that selenium afforded protection against ethanol and stress-induced gastric lesions in rats. The present study was undertaken to investigate the effect of selenium on ischemia-reperfusion-induced gastric injuries in which rats were subjected to 30 minutes of ischemia in the presence of 100 mM HCI and a reperfusion for 60 minutes duration. Intraluminal bleeding was assessed macroscopically and gastric lesions were graded microscopically under an inverted microscope. Nonprotein sulphydryl levels were measured spectrophotometrically. The severity of gastric lesions, intraluminal bleeding as well as the depletion of nonprotein sulphydryls during the reperfusion periods was significantly different from that of control. Pretreatment with selenium (0.125-2.0 mg/kg, intraperitoneally) 30 minutes before the ischemia-reperfusion, dose-dependently attenuated the gastric lesions, reduced the severity of intraluminal bleeding and prevented the depletion of nonprotein sulphydryls in the stomach. These results suggest that the gastric protection effect of selenium may be due to its antioxidant properties. Furthermore, endogenous nonprotein sulphydryls may play a significant role in the protective mechanisms of selenium.

Natural honey prevents ischaemia-reperfusion-induced gastric mucosal lesions and increased vascular permeability in rats.

OBJECTIVE: It has been proposed that natural honey may contain a 'sucralfate-like' substance. Recent studies have shown that sucralfate affords protection against ischaemia-reperfusion-induced injuries in the rat stomach. Therefore, the effect of honey was studied on ischaemia-reperfusion-induced gastric lesions, intraluminal bleeding, vascular permeability and non-protein sulphhydryls (NP-SH) in the rat stomach. METHODS: Rats were subjected to 30 min of gastric ischaemia in the presence of 100 mM HCl and reperfusion period of 60 min. Intraluminal bleeding was assessed macroscopically and the gastric lesions were graded microscopically under an inverted microscope. Vascular permeability was quantified by measuring spectrophotometrically the extravasated Evans blue dye in the stomach. NP-SH levels were measured spectrophotometrically. A luminol-dependent chemiluminescence method was used to assess antioxidant effects of honey in vitro. RESULTS: There were significantly more gastric lesions, more severe intraluminal bleeding, more leakage of Evans blue and depletion of NP-SH during the reperfusion period as compared to controls. Pre-treatment with honey (0.078-0.625 g/kg, orally) or dimethyl sulphoxide (0.02-0.08 g/kg, intraperitoneally) 30 min before the ischaemia-reperfusion dose-dependently reduced the gastric lesions and intraluminal bleeding and decreased the vascular permeability. Furthermore, honey reversed the ischaemia-reperfusion-induced depletion of NP-SH levels and inhibited the luminol-dependent chemiluminescence induced in a cell-free xanthine-xanthine oxidase system. CONCLUSION: These results suggest that gastric protection by honey may be a result of its antioxidant effect. It is suggested that this property of honey may be due to the presence of a 'sucralfate-like' substance.

Inhibitory effect of natural honey on Helicobacter pylori.

Honey is widely used in folk-medicine throughout the world. However, it has a limited use in modern medicine due to lack of scientific support. Based on some recent reports, an in vitro study was undertaken to evaluate its antibacterial activity on Helicobacter pylori and a few other pathogenic organisms. All isolates of H. pylori were inhibited by 20 per cent of honey. Most of the other bacteria examined (including both Gram-positive and Gram-negative) were also inhibited at concentrations of 20 per cent of honey; and half of them were inhibited by 10 per cent of honey. Furthermore, it was observed that some isolates were resistant to various antimicrobial agents but honey inhibited these organisms and the sensitive ones equally. Our study advocates carrying out clinical investigation of the effect of honey on gastroduodenal disorders colonised by H. pylori.

Enhancement of antithrombotic effect of aspirin by metoclopramide in rats.

The potential antithrombotic effect of aspirin and metoclopramide were studied in a model of arterial thrombosis in rats. Thrombosis was produced in the abdominal aorta by the combination of local partial obstruction and intravenous administration of hypotonic saline containing 5-HT. The resulting aortic occlusion and the effects of drugs were quantified by measuring rectal temperature. Metoclopramide as well as ketanserine effectively reversed while zacopride failed to alter thrombotic effect. Metoclopramide or ketanserine when combined with aspirin enhanced the antithrombotic effect of the latter. On the other hand, co-administration of metoclopramide with ketanserine failed to show any synergistic effect. As with ketanserine, the antithrombotic effect of metoclopramide appeared to be mediated through the blockade of 5-HT2 receptors in the platelets.

Effect of diltiazem, nifedipine and verapamil on the antinociceptive action of acetylsalicylic acid in mice.

1. Diltiazem, verapamil and nifedipine produced a dose-dependent analgesic response in mice. 2. A fixed oral dose of acetylsalicylic acid increased this analgesic response. 3. Analgesia was maintained when mice were treated chronically with calcium channel blockers alone or when combined with aspirin.

Elevation of carbamazepine plasma levels by diltiazem in rabbits: a potentially important drug interaction.

The effect of diltiazem on the plasma level of carbamazepine (CBZ) was investigated in rabbits. The animals were given either CBZ alone or in combination with diltiazem and plasma samples were collected at different time intervals. The concentration of CBZ was detected using an HPLC method. Diltiazem significantly increased the area under the curve (AUC), the maximum plasma concentration (Cmax), and the elimination half-life (t1/2) of CBZ (p less than 0.05). These results suggest that a potentially harmful drug-drug interaction may occur if CBZ and diltiazem are administered concurrently.