Inhibition of dapsone-induced methaemoglobinaemia by cimetidine in the presence of trimethoprim in the rat.

Administration of dapsone in combination with trimethoprim and cimetidine to male rats resulted in a marked decrease (P less than 0.05) in measured methaemoglobin levels (46.2 +/- 24% Met Hb h) compared with administration of dapsone alone (124.5 +/- 24.4% Met Hb h). The elimination half-life of dapsone (814 +/- 351 min) was more than doubled in the presence of trimethoprim and cimetidine compared with control (355 +/- 160 min, P less than 0.05). However, there were no significant differences in AUC and clearance when dapsone was administered in combination with trimethoprim and cimetidine compared with dapsone alone. Co-administration of trimethoprim with dapsone in the absence of cimetidine did not affect either methaemoglobin formation, AUCs, half-lives, or clearance values of dapsone compared with control. There was a threefold increase in the AUC of trimethoprim (6296 +/- 2249 micrograms min mL-1) in the presence of dapsone compared with trimethoprim alone (2122 +/- 552 micrograms min mL-1). There was also a corresponding decrease in the clearance of trimethoprim in the presence of dapsone compared with control (19.1 +/- 6.9 vs 60.8 +/- 21.0 mL min-1). However, there was no change in the elimination half-life of trimethoprim between the two experimental groups (273 +/- 120 vs 292 +/- 54 min). The AUC of trimethoprim increased more than threefold in the presence of cimetidine (7100 +/- 1501 micrograms min mL-1) compared with trimethoprim alone (2122 +/- 552 micrograms min mL-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of dapsone-induced methaemoglobinaemia in the rat isolated perfused liver

We have investigated the disposition of dapsone (DDS, 1 mg) in the rat isolated perfused liver in the absence and the presence of cimetidine (3 mg). After the addition of DDS alone to the liver there was a monoexponential decline of parent drug concentrations and rapid formation of DDS-NOH (within 10 min) which coincided with methaemoglobin formation (11.7 +/- 3.0%, mean +/- s.d.) which reached a maximum (22.6 +/- 9.2%) at 1 h. The appearance of monoacetyl DDS (MADDS) was not apparent until 30-45 min. Addition of cimetidine resulted in major changes in the pharmacokinetics of DDS and its metabolites. The AUC of DDS in the presence of cimetidine (1018.8 +/- 267.8 micrograms min mL-1) was almost three-fold higher than control (345.0 +/- 68.1 micrograms min mL-1, P less than 0.01). The half-life of DDS was also prolonged by cimetidine compared with control (117.0 +/- 48.2 min vs 51.2 +/- 22.9, P less than 0.05). The clearance of DDS (3.0 +/- 0.55 mL min-1) was greatly reduced in the presence of cimetidine (1.03 +/- 0.26 mL min-1 P less than 0.01). The AUC0-3h for DDS-NOH (28.3 +/- 21.2 micrograms min mL-1) was significantly reduced by cimetidine (8.1 +/- 3.40 micrograms min mL-1, P less than 0.01). In contrast, there was a marked increase in the AUC0-3h for MADDS (32.7 +/- 25.8 micrograms min mL-1) in the presence of cimetidine (166.0 +/- 26.5 micrograms min mL-1 P less than 0.01). The methaemoglobinaemia associated with DDS was reduced to below 5% by cimetidine. Hence, a shift in hepatic metabolism from bioactivation (N-hydroxylation) to detoxication (N-acetylation) caused by cimetidine, was associated with a fall in methaemoglobinaemia. These data suggest that the combination of DDS with a cytochrome P450 inhibitor might reduce the risk to benefit ratio of DDS.     

Gonadal influence on the metabolism and haematological toxicity of dapsone in the rat

Administration of dapsone (33 mg kg-1) to intact rats resulted in a marked elevation of methaemoglobin levels in male (435.0 +/- 105.2% met Hb h) compared with female rats (59.0 +/- 17.2% met Hb h). However, the clearance of dapsone was significantly faster in males compared with females. Female rats showed very low levels of methaemoglobin which were accompanied by significantly higher blood concentrations of parent drug. Clearance of dapsone in castrated animals was less than one-third of that of the intact sham-operated males (252.2 +/- 67.2 vs 81.4 +/- 33.0 mL h-1). Likewise, clearance of dapsone in ovarectomized rats was approximately half that of intact females. There were no significant differences in the disposition of dapsone between the ovarectomized (AUC 431.0 +/- 31.7 micrograms h mL-1; t1/2, 15.62 +/- 1.8 h) and castrated (AUC, 450.6 +/- 150.9 micrograms h mL-1; t1/2, 17.6 +/- 7.9 h) animals. However, methaemoglobin levels in castrated males, although less than a third of those of intact males, significantly exceeded those of ovarectomized animals. There was no significant difference between the four groups of animals with respect to red cell sensitivity to the methaemoglobin-forming capacity of the toxic metabolite of dapsone, the hydroxylamine. Metabolic conversion of dapsone to the hydroxylamine in the presence of NADPH was 7.6 +/- 1.5% for liver microsomes from intact males and was significantly greater (P less than 0.05) than the corresponding values for liver microsomes from castrated rats (5.3 +/- 0.59%). Conversion of dapsone to dapsone-NOH by liver microsomes from intact females and ovarectomized animals was below 1% in both cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

The use of cimetidine as a selective inhibitor of dapsone N-hydroxylation in man.

1. The N-hydroxylation of dapsone is thought to be responsible for the methaemoglobinaemia and haemolysis associated with this drug. We wished to investigate the effect of concurrent administration of cimetidine (400 mg three times per day) on the disposition of a single dose (100 mg) of dapsone in seven healthy volunteers in order to inhibit selectively N-hydroxylation. 2. The AUC of dapsone (31.0 +/- 7.2 micrograms ml-1 h) was significantly increased (P less than 0.001) in the presence of cimetidine (43.3 +/- 8.8 micrograms ml-1 h). 3. Peak methaemoglobin levels observed after dapsone administration (2.5 +/- 0.6%) were significantly (P less than 0.05) reduced in the presence of cimetidine (0.98 +/- 0.35%). 4. The percentage of the dose excreted in urine as the glucuronide of dapsone hydroxylamine was significantly (P less than 0.05) reduced in the presence of cimetidine (34.2 +/- 9.3 vs 23.1 +/- 4.2%). 5. Concurrent cimetidine therapy might reduce some of the haematological side-effects of dapsone.     

The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients.

1. We have attempted to reduce dapsone-dependent methaemoglobinaemia formation in six dermatitis herpetiformis patients stabilised on dapsone by the co-administration of cimetidine. 2. In comparison with control, i.e. dapsone alone, methaemoglobinaemia due to dapsone fell by 27.3 +/- 6.7% and 26.6 +/- 5.6% the first and second weeks after commencement of cimetidine administration. The normally cyanotic appearance of the patient on the highest dose of dapsone (350 mg day-1), underwent marked improvement. 3. There was a significant increase in the trough plasma concentration of dapsone (2.8 +/- 0.8 x 10(-5)% dose ml-1) at day 21 in the presence of cimetidine compared with control (day 7, 1.9 +/- 0.6 x 10(-5)% dose ml-1, P less than 0.01). During the period of the study, dapsone-mediated control of the dermatitis herpetiformis in all six patients was unchanged. 4. Trough plasma concentrations of monoacetyl dapsone were significantly increased (P less than 0.05) at day 21 (1.9 +/- 1.0 x 10(-5)% dose ml-1) compared with day 7 (1.6 +/- 0.9 x 10(-5)% dose ml-1:control). 5. Over a 12 h period, 20.6 +/- 8.9% (day 0) of a dose of dapsone was detectable in urine as dapsone hydroxylamine. Significantly less dapsone hydroxylamine was recovered from urine at day 14 (15.0 +/- 8.4) in the presence of cimetidine, compared with day 0 (control: P less than 0.05). 6. The co-administration of cimetidine may be of value in increasing patient tolerance to dapsone, a widely used, effective, but comparatively toxic drug.     

克林沙星在大鼠体内的药代动力学和生物利用度

目的　研究克林沙星在大鼠体内的药动学和生物利用度。方法　HPLC法测定大鼠ig和iv克林沙星后的血药浓度,计算药动学参数和生物利用度。色谱柱为C₁₈柱(5μm),流动相为乙腈-0.05mol·L^-1柠檬酸三乙胺液(pH2.5)(20∶80),流速为1.0mL·min^-1,检测波长300nm。结果　克林沙星0.1-20μg·mL^-1呈良好线性关系,在大鼠体内的药动学过程符合一室模型,大鼠ig50和100mg·kg^-1后,C_max和AUC均与剂量呈正比,T_1/2与剂量无关;绝对生物利用度(F)为42%。结论　克林沙星50-100mg·kg^-1的吸收和消除呈一级动力学特征,在大鼠体内的生物利用度低。     

Pharmacokinetics of cimetidine in patients with unresponsive duodenal ulcer

The pharmacokinetics of cimetidine after an oral dose of 400 mg were measured in 18 patients with duodenal ulcer, 9 refractory and 9 responders. The peak plasma concentration of cimetidine (2.13 +/- 0.17 micrograms/ml vs 1.43 +/- 0.04 micrograms/ml), the area under the plasma concentration curve (A.U.C.) between 0 to 8 hours after cimetidine (8.49 +/- 0.29 micrograms/ml/h vs 5.83 +/- 0.25 micrograms/ml/h), and the time span in which cimetidine was above 0.5 micrograms/ml (I.C.50) (401 +/- 8.86 min vs 296 +/- 20 min) were all found to be greater in responding patients than in non-responders to the therapy. No differences were detectable between the two groups in urinary excretion, T 1/2 of cimetidine or percentage inhibition (1%) of maximal pentagastrin-stimulated acid output (MAO). The results indicate that clinical healing of duodenal ulcer after cimetidine is related principally to the drug's pharmacokinetics, i.e. to its absorption from the small bowel, and that some other therapeutic approaches might be tried before surgery in cases of duodenal ulcer refractory to cimetidine.     

The influence of cimetidine on the pharmacokinetics of 5-fluorouracil.

The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/- 4.5 micrograms/ml (mean +/- s.e. mean) to 32.6 +/- 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/- 133 micrograms/ml-1 min (mean +/- s.e. mean) to 911 +/- 152 micrograms ml-1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/- 96 micrograms ml-1 min (mean +/- s.e. mean) to 1353 +/- 124 micrograms ml-1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/- 116 ml/min (mean +/- s.e. mean) to 711 +/- 87 ml/min (P less than 0.01). The elimination half-life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.     

Use of a metabolic inhibitor to reduce dapsone-dependent haematological toxicity

Aside from its established use as an antileprotic and anti-inflammatory drug, dapsone is also effective in the therapy of Pneurnocystis carinii pneumonia. Unfortunately, its use is often limited by its dose-dependent toxicity, such as methaemoglobinaemia and haemolysis; the latter condition occurs most frequently in gIucose-6-dehydrogenase deficient individuals. It is also responsible for occasional life-threatening disorders such as agranulocytosis. Dapsone may undergo acetylation, but its toxicity is due to the product of its oxidative metabolism, dapsone hydroxylamine. This is generated in man by the constitutive hepatic cytochrome P450 enzyme IIIA4. Studies in the rat revealed that dapsone-dependent methaemoglobinaemia could be greatly diminished by the co-administration of metabolic inhibitors. In the isolated perfused rat liver, dapsone hydroxylamine levels and hence methaemoglobin formation fell significantly in the presence of cimetidine. In addition, the clearance of the parent drug was retarded, and perfusate concentrations of monoacetyl dapsone increased. The protective effect of cimetidine also reduced methaemoglobin formation in the whole rat during the chronic administration of dapsone. Incubation of dapsone in a two-compartment in vitro system using human tissues in the presence of cimetidine or ketoconazole resulted in a decrease in methaemoglobin formation in all the human livers tested. Although cimetidine was only effective if incubated with microsomes and NADPH prior to the addition of dapsone. Administration of cimetidine (3 × 400 mg daily) to volunteers 3 days prior to and 4 days post administration of a single dose of 100 mg dapsone caused drug concentrations to increase by almost 30%. There was a marked fall in peak methaemoglobin levels and the percentage of the dose excreted in urine as dapsone hydroxylamine N-glucuronide was reduced by almost one third. During high dose dapsone therapy it may be possible that the co-administration of cimetidine might reduce toxicity while maintaining drug efficacy.     

The pharmacokinetics and pharmacodynamics of nifedipine at steady state during concomitant administration of cimetidine or high dose ranitidine.

Ranitidine may be used at doses of up to 300 mg twice daily in the healing of duodenal ulcers, and this study investigated the potential for a pharmacokinetic or pharmacodynamic interaction between nifedipine 10 mg three times daily and ranitidine 300 mg twice daily compared with cimetidine 800 mg daily and placebo in a randomised crossover study in 18 healthy male subjects. Twelve blood samples were taken on the fifth day in each treatment period and assayed for nifedipine by h.p.l.c. Pulse, blood pressure and ECG recordings were also taken. Cimetidine, but not ranitidine, produced significant changes in the pharmacokinetics of nifedipine at steady state. Mean +/- s.d. values of AUC were 105 +/- 40 micrograms l-1 for placebo treatment, 111 +/- 45 micrograms l-1 h for ranitidine and 211 +/- 64 micrograms l-1 h for cimetidine (P less than 0.001), and Cmax values were 33 +/- 14, 39 +/- 27 and 76 +/- 40 micrograms l-1 (P less than 0.001), respectively. Neither ranitidine nor cimetidine produced statistically significant changes in the pharmacological response to nifedipine.     

Enhanced bioavailability of morphine after rectal administration in rats

Plasma morphine levels and the area under the plasma concentration-time curve (AUC) after i.v. (10 mg kg-1), p.o. (100 mg kg-1) and rectal (unrestricted or restricted to 1.5 cm from the anus, 10 mg kg-1) administration of morphine hydrochloride were determined in 10 or 11-week-old male Wistar rats to compare bioavailability of morphine after the rectal dosage with that after oral administration. The AUC value after oral administration (15 micrograms min mL-1), which was normalized by the dose, was only one-tenth of that after i.v. dosing (151 micrograms min mL-1). In contrast, the AUC after rectal administration (unrestricted, 133 micrograms min mL-1; restricted, 142 micrograms min mL-1) was almost comparable with that after i.v. administration. From the comparison of these AUC values, the extent of systemic availability of morphine after rectal (unrestricted or restricted) and p.o. administration was estimated to be approximately 90 and 10%, respectively.     

Disopyramide pharmacokinetics and metabolism: effect of inducers.

1. The disposition of orally administered disopyramide was studied in a population of smokers (n = 6) and non-smokers (n = 8) before and during phenobarbitone treatment (100 mg daily for 21 days; Cp 21st day = 13.9 +/- 2.0 micrograms ml-1). The comparative inducibility of these populations by phenobarbitone was assessed as was the inductive effect of cigarette smoking, per se. Furthermore, the determinants of the intensity of the inductive effect were examined, as well as the effect of the barbiturate on the binding of disopyramide to alpha 1-acid glycoprotein (AGP). 2. Smokers and non-smokers exhibited similar half-lives (6.48 +/- 1.49 vs 6.66 +/- 1.02 h), apparent total body clearances (0.100 +/- 0.020 vs 0.117 +/- 0.034 l h-1 kg-1), mean renal clearances (0.043 +/- 0.0093 vs 0.057 +/- 0.013 l h-1 kg-1) and apparent intrinsic metabolic clearances (0.057 +/- 0.015 vs 0.060 +/- 0.024 l h-1 kg-1) before phenobarbitone treatment. 3. Both populations responded comparably to barbiturate exposure in that apparent intrinsic metabolic clearance more than doubled. Interestingly, the magnitude of this increase was highly dependent on the observed baseline apparent intrinsic metabolic clearance, (r' = 0.81; P less than 0.001). 4. Phenobarbitone treatment of non-smokers resulted in an increase in the AUC of the active metabolite N-despropyl disopyramide (MND), but not significantly (3.8 +/- 1.6 vs 4.1 +/- 2.3 micrograms ml-1 h). Similar results were observed in smokers (3.5 +/- 1.4 vs 3.9 +/- 2.0 micrograms ml-1 h, respectively). 5. The percent of administered dose recovered in urine as disopyramide in non-smokers was significantly decreased upon phenobarbitone treatment (43 +/- 6% vs 25 +/- 5%), whereas the percent of dose recovered as MND increased significantly in this group (25 +/- 6% vs 31 +/- 5%). The population of smokers responded similarly. 6. At doses typically used to achieve hepatic microsomal enzyme induction in man, phenobarbitone treatment caused no significant change or trend towards a change in serum AGP concentrations as measured using the radial immunodiffusion method in nonsmokers (67.4 +/- 19.9 mg dl-1 vs 68.0 +/- 40.7 mg dl-1) or smokers (64.5 +/- 15.7 vs 67.9 +/- 14.9). Similarly, when AGP concentration was estimated in serum from non-smokers using a nephelometric method no effect attributable to phenobarbitone was observed (47.9 +/- 1.3 vs 47.9 +/- 16.8 mg dl-1). Consistent with this observation, disopyramide free fraction was not affected by barbiturate treatment.     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

The effect of ranitidine and cimetidine on imipramine disposition

Summary The pharmacokinetic characteristics of imipramine were studied after a single, oral, 100 mg dose was taken by 12 healthy male subjects following 3 days of pretreatment with placebo, cimetidine (300 mg every 6 h), and ranitidine (150 mg every 12 h) in a randomized, double blind, crossover trial. After each imipramine dose plasma samples were collected for 72 h and assayed for imipramine, desipramine, 2-hydroxyimipramine and 2-hydroxydesipramine by HPLC. Cimetidine preadministration statistically prolonged imipramine t_1/2 compared to ranitidine (22.7 vs. 13.0 h) or placebo (10.8 h). Mean imipramine area under the curve (AUC) following cimetidine pretreatment was more than double that following placebo (2.633 vs. 0.966 µg·h·ml^–1) or ranitidine (1.14 µg·h·ml^–1) pretreatment. Imipramine apparent oral clearance was reduced in all 12 subjects after cimetidine. Compared to ranitidine or placebo, cimetidine pretreatment was associated with an increased imipramine/desipramine AUC ratio, suggesting cimetidine-induced impairment of demethylation of imipramine. Ranitidine was not observed to alter imipramine pharmacokinetics.     

Protective action of cimetidine against ouabain-induced pressor effects, arrhythmias, and lethality in guinea pigs

The effect of the H2-receptor antagonist cimetidine on ouabain cardiotoxicity was studied in anesthetized guinea pigs. Ouabain, infused intravenously at 3.0 micrograms X kg-1 X min-1, was lethal in a dose of 44.0 +/- 3.5 micrograms (n = 6). All control animals died in ventricular fibrillation. Cimetidine, infused concurrently at 10, 30, and 100 micrograms X kg-1 X min-1, significantly increased the lethal dose of ouabain and delayed the onset of various arrhythmias and fibrillation. Cimetidine abolished ouabain-induced pressor effects that have been reported to be neurally mediated; the course of heart-rate changes in ouabain-treated animals, however, was unaffected by cimetidine. In vitro, cimetidine had no effect on the inotropic action of ouabain at concentrations as high as 10(-4) M, whereas serum levels of cimetidine in protected animals did not exceed this concentration. When the ouabain infusion rate was reduced by 50% (to 1.5 microgram X kg-1 X min-1), the lethal dose increased to 72.7 +/- 4.7 micrograms (n = 6), the predominant mode of death changed from fibrillation to cardiac standstill, ouabain-induced pressor effects were absent, and cimetidine no longer exhibited a protective action. Taken together, these findings support the hypothesis that cimetidine acts primarily against indirect components of digitalis toxicity, and so may be potentially valuable for increasing the margin of safety of the cardiac glycosides.     

Cisapride-cimetidine interaction: enhanced cisapride bioavailability and accelerated cimetidine absorption

The pharmacokinetic interaction between the gastrointestinal motility-stimulating substance cisapride and the H2-antagonist cimetidine was examined in 8 healthy volunteers (25 +/- 2 years of age). Steady-state kinetics of both substances were investigated after separate 1-week treatments of oral cisapride, 10 mg t.i.d., cimetidine, 400 mg t.i.d., and the two drugs combined. Cimetidine increased the cisapride peak plasma concentration from 58 +/- 25 ng/ml to 84 +/- 19 ng/ml (p = 0.01) and AUC0-24 from 509 +/- 289 ng/ml.h to 738 +/- 148 ng/ml.h (p = 0.02). Cisapride shortened the time to the peak concentration of cimetidine from 1.3 +/- 0.6 h to 0.6 +/- 0.2 h (p = 0.005) and reduced the cimetidine AUC0-24 from 11.0 +/- 2.3 micrograms/ml.h to 9.0 +/- 2.0 micrograms/ml.h (p = 0.05). It is concluded that cimetidine inhibits cisapride metabolism, whereas cisapride enhances the gastrointestinal absorption of cimetidine.     

Cimetidine versus famotidine: the effect on the pharmacokinetics of theophylline in rats

The effects of cimetidine and a new, potent H2-antagonist, famotidine, on the single dose pharmacokinetics of theophylline were examined in rats. Male Sprague-Dawley rats (6 rats/group) received an i.v. dose of theophylline (6 mg/kg) alone and in conjunction with an i.v. dose of famotidine (10 mg/kg) or cimetidine (10 mg/kg). Venous blood samples were collected serially for seven hours after theophylline infusion and analyzed for theophylline concentration by HPLC. Concomitant famotidine administration did not alter any of the pharmacokinetic parameters of theophylline (AUC0- infinity; 38.1 +/- 8.7 vs. 38.8 +/- 6.3 micrograms.hr.ml-1), while cimetidine demonstrated a significant reduction in theophylline systemic clearance (0.11 +/- 0.02 vs. 0.16 +/- 0.02 L/hr/kg; p less than 0.001), a 40% prolongation of half-life (2.8 +/- 0.9 vs. 2.0 +/- 0.5 hr), with no change in the volume of distribution (0.39 +/- 0.1 vs. 0.41 +/- 0.13 L/kg). These results suggest that in contrast to cimetidine, famotidine, a non-imidazole H2-receptor antagonist, does not interfere with theophylline disposition in the rat.     

金属硫蛋白对大鼠硝酸甘油耐药性的影响(英文)

目的:评价金属硫蛋白(metallothionein, Met)在体内是否能改善硝酸甘油耐药的发生。方法:大鼠给予硝酸甘油(nitroglycerin, Nit)贴剂治疗两天(0.05 mg·h~(-1))以产生耐药。于耐药大鼠预先给予ZnCl_2以诱导内源性Met的合成及给予外源性Met15 mg·kg~(-1)·d~(-1)连续2 d。结果:Nit ZnCl_2组大鼠肝脏、血浆Met明显高于对照组(C组)。Nit组大鼠离体主动脉环的舒张反应最低。Nit ZnCl_2组大鼠及Nit Met组大鼠对SNP的降压反应明显强于Nit组。结论:外源性Met或内源性诱导合成的Met可以改善大鼠Nit耐药的发生。     

Effect of cimetidine and ranitidine on absorption of [125I]levothyroxine administered orally.

Female patients with a simple goiter were pretreated on 2 occasions (at an interval of 4 wk) with po placebo or 400 mg cimetidine (Cim) (Group A, n = 10), or with placebo or 30 mg ranitidine (Ran) (Group B, n = 10), 90 and 150 min, respectively, prior to the po gelatin capsules containing [125I]levothyroxine ([125I]LT4). A double-blind randomized study protocol was kept. Venous blood samples were taken at 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210, and 240 min after po [125I]LT4 and the radioactivities in serum were counted. Similar [125I]LT4 radioactivities were found after placebo pretreatment in both groups: AUC 467 +/- 82 in Group A vs 459 +/- 109 in Group B. Cimetidine decreased the serum [125I]LT4 radioactivities: AUC371 +/- 72 (Cim) vs 467 +/- 82 (placebo) (P < 0.01), but Ran did not: AUC 477 +/- 132 (Ran) vs 459 +/- 109 (placebo) (P > 0.05).     

The relationship between dapsone dose, serum concentration and disease severity in dermatitis herpetiformis

20 patients with dermatitis herpetiformis maintained on once daily dosing of dapsone were studied to investigate the pharmacodynamics of dapsone in suppressing clinical disease. Multiple correlation analysis was performed on variables including dosage requirements, serum concentration of dapsone and monoacetyl dapsone, acetylation ratio, IgA-containing circulating immune complexes, adherence to a gluten-free diet, and clinical disease severity. It was found that: 1. dapsone exhibits good bioavailability in dermatitis herpetiformis with absorption being unaffected by presumed gluten-sensitive enteropathy; 2. there is wide variation in serum concentrations of dapsone and monoacetyl dapsone with no specific "therapeutic level"; 3. acetylator phenotype was unrelated to dapsone dose requirement; 4. serum dapsone concentration had only a weak correlation with disease severity; and 5. there was poor correlation between IgA circulating immune complexes and dapsone serum concentration. The use of daily dapsone dose requirements or dapsone serum concentration necessary for disease suppression as an indicator of disease severity in the research setting is inappropriate. Measurements of serum concentration of the parent drug (dapsone) or principal metabolite (monoacetyl dapsone) do not serve as a useful guide to therapeutic management.