Simultaneous administration of cimetidine and nifedipine to six healthy volunteers produced an about 80% rise in maximal plasma levels and the area under the plasma level-time curve of nifedipine compared with results on nifedipine administration alone (P less than 0.05). After treatment for one week with 4 X 10 mg nifedipine daily and 3 X 200 mg cimetidine daily and 400 mg at night plasma level peaks of nifedipine averaged 87.7 +/- 19.1 ng/ml, while after 4 X 10 mg nifedipine alone they were only 46.1 +/- 10.6 ng/ml. Ranitidine produced an approximately 25%, nonsignificant, rise in plasma level-time curve and peak plasma levels of nifedipine. Seven hypertensives (WHO stage I and II) had a mean arterial blood pressure level of 127 +/- 2.5 mm Hg after two-week placebo administration, and of 109 +/- 2.38 mm Hg after four weeks of nifedipine alone at 4 X 10 mg daily (P less than 0.01). After additional administration of 1 g cimetidine daily for two weeks the mean blood pressure fell significantly to 95 +/- 3.1 mm Hg (P = 0.02), while blood pressure fell to 103 +/- 3.88 mm Hg after two weeks of additional administration of 300 mg ranitidine daily, a fall which was not significant (P greater than 0.05). The interaction of nifedipine and cimetidine is thus of clinical significance because of its pharmacodynamic effect.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

The elimination of pindolol in 25 patients with various degrees of renal failure has been studied after an intravenous dose of 3 mg. A linear correlation was not found between the elimination rate of pindolol and the endogenous creatinine clearance, and the half-life of the unchanged drug was independent of the severity of the renal failure. This implies greater metabolism of pindolol in anuric patients and the extrarenal elimination rate constantkmwas increased. Three patients with severe renal failure were given 3 mg14C-pindolol. They showed almost constant plasma levels of radio-activity for 6 h and then slow excretion with a half-life of 48 h, because of accumulation of metabolites in the blood. Up to 90% of the metabolites are glucuronides and sulphates which have no beta-blocking or other clinical activity. Thus, to produce beta-adrenergic blockade the same dose of indolol is required in healthy patients as in those with uraemia.

Following chronic oral administration of digitoxin 0.1 mg day-1 the pharmacokinetics of this glycoside were studied in seven patients with hepatorenal insufficiency and were compared with those of seven healthy volunteers. Liver cirrhosis of the patients was confirmed by liver biopsy. Mean creatinine clearance of the healthy subjects was 129.7 +/- 3.3 ml min-1 (mean +/- SEM), that of the patients was 25.6 +/- 20.4 ml min-1. Mean antipyrine clearance (parameter of oxidative liver function) was 49.7 +/- 6.0 ml min-1 in the volunteers and 22.0 +/- 2.9 ml min-1 in the patients. Plasma protein binding of digitoxin (PPB) was 95.0 +/- 1.1% in the patients and 96.7 +/- 0.6% in the healthy subjects (n.s.). Total body clearance of digitoxin (Cltot) was 0.0728 +/- 0.0120 ml min-1 kg-1 in the patients and 0.0615 +/- 0.0027 ml min-1 kg-1 in normals (n.s.]. Mean steady state plasma levels (Css) of the patients were 18.3 +/- 4.7 ng ml-1 and 15.8 +/- 1.3 ng ml-1 in the normals (n.s.). Our data obtained from chronic oral administration do not indicate a reduced total body clearance of digitoxin in patients with hepatorenal insufficiency.

The interaction between felodipine and digoxin was studied after a single oral dose and at steady state in 14 patients with congestive heart failure. Felodipine (10 mg) was randomly given as an extended release (FER) tablet in a double-blind, placebo-controlled, cross-over fashion. In addition, felodipine (10 mg) was given openly as a plain tablet, following the double-blind period. Each period lasted for 7 d. Felodipine ER did not alter the pharmacokinetics of digoxin when given as a single dose or at steady state compared with placebo. At steady state the felodipine plain tablet resulted in an 11% increase (P less than 0.05) in peak plasma concentrations of digoxin. Systolic time intervals as noninvasively measured haemodynamic parameters were not significantly altered following the felodipine ER period, while the felodipine plain tablet significantly decreased the pre-ejection/left ventricular ejection time ratio compared to placebo.

The effect of probenecid on the pharmacokinetics of phenprocoumon (PPC) given as a single oral or intravenous dose, on the vitamin-K-dependent protein-C-antigen, and on the pharmacokinetics of antipyrine and 6 beta-hydroxycortisol was determined in 14 healthy volunteers. Probenecid caused a 75% decrease in urinary excretion of PPC and PPC-glucuronide and shortened the plasma half-life of PPC significantly (by about 35%). The results after oral and intravenous administration of PPC did not differ significantly. Plasma protein-C-antigen concentrations following intravenous PPC were significantly increased by probenecid. The plasma half-life of antipyrine after 7 days of probenecid therapy was significantly diminished. Accordingly, urinary excretion of 6 beta-hydroxycortisol was significantly increased. These data appear for the first time to reveal enzyme-inducing properties of probenecid, which may be responsible for the shortening of PPC plasma half-life when probenecid is given simultaneously. In addition, the influence of probenecid on plasma protein-C-antigen concentrations may indicate further effects of probenecid on liver metabolism.

Summary: 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 μg/ml • h to 9.0 ± 2.0 μg/ml • h (p = 0.05). It is concluded that cimetidine inhibits cisapride metabolism, whereas cisapride enhances the gastrointestinal absorption of cimetidine.

Previous observations suggest that salt loading can help reverse amphotericin-B induced nephrotoxicity. Evidence is presented indicating that sodium supplements provide prophylaxis against the development of amphotericin-B nephrotoxicity. In a retrospective study at Vanderbilt University, 14/21 patients receiving amphotericin B (target dose, 25 mg/day) without salt supplements developed impaired renal function; in 10 instances amphotericin B was temporarily withdrawn. In contrast, only 2/17 patients who received amphotericin B with ticarcillin (with its obligatory sodium supplement) developed nephrotoxicity (P<0.01). All four patients, who were receiving the combination of amphotericin B and ticarcillin and who had their ticarcillin therapy stopped, developed nephrotoxicity in the subsequent week. In a prospective observational study at Essen, 20 patients had 24 courses of amphotericin B (target dose, 40 mg/day) with routine supplementation of 1 liter of 0.9% sodium chloride daily. Only two patients showed evidence of nephrotoxicity and no dosage modification of amphotericin B was required in any patient. Four patients with initial evidence of mildly impaired renal function received full supplements without adverse effects or the development of nephrotoxicity. These observations suggest that routine parenteral administration of sodium supplements can help minimize the nephrotoxic potential of amphotericin B.

In the present study, lung tissue of patients suffering from tuberculosis and undergoing thoracic surgery was investigated. All these patients were treated prior to surgery by an anti-tuberculous drug regimen, including rifampicin, for 3-6 months. Patients having non-malignant lung disease served as controls. In the lung tissue obtained, 7-ethoxycoumarin-0-deethylase as a substrate of monooxygenase activity, epoxide hydrolase and glutathione-S-transferase were measured. Monooxygenase activity increased from 0.62 + 0.10 pmol mg protein-1 min-1 in the control group to 1.55 +/- 0.34 pmol mg protein-1 min-1 (P less than 0.02) following anti-tuberculous drug treatment, while the other enzymes remained unchanged. Rifampicin, a potent inducer of hepatic metabolism in man, seems a likely cause for the changes in monooxygenase activity, since for other anti-tuberculous drugs no enzyme-inducing effect has so far been reported in any tissue in man. In addition, the activity of the disease seems to be of great importance for the extent of induction. Thus, in patients with active tuberculosis, higher monooxygenase activities were found, compared to those with inactive disease (1.92 +/- 0.53 vs. 0.99 +/- 0.24 pmol mg protein-1 min-1), both showing even higher values than controls.

We have studied the effect of hepatic enzyme induction on vitamin K1 elimination in patients on long-term anticonvulsant therapy and in volunteers given rifampicin.

Between 1978 and 1984, 169 patients were admitted to the hospital for fever of unknown origin which was repeatedly above 38.3° C. After a retrospective analysis of their records the patients were divided into two groups on the basis of the following new criteria. The first group (74 patients) was described as having “monosymptomatic fever”, i.e. fever without any other physical signs, whereas the second group (95 patients) had “polysymptomatic fever”, i.e. fever with additional physical signs. In 56 patients (76%) of the monosymptomatic group fever had lasted longer than 3 weeks prior to admission. In 86% of these paitents case history, physical examination, microbiological tests, serological tests for microganisms and outoimune antibodies, and microscopic inspections of tissue and/or bone marrow led to a diagnosis. Malignancies, factitious fever and fever of unknown origin were found only in this group. The patients with malignancies were generally older than the rest of the patients (p<0.05), and eight of ten patients suffering from connective tissue diseases also had monosymptomatic fever. The incidence of infections in this group was 42% (31 cases), in contrast to 88% (84 cases) in the poly-symptomatic group (p<0.05). Whereas the latter had significantly more bacterial infections (p<0.05), viral infections prevailed in the monosymptomatic group (p<0.05). Thus, the etiology of polysymptomatic fever distinctly differed from that of monosymptomatic fever. Since the frequency distribution of etiologies in the monosymptomatic group corresponded to that of the cases of fever of unknown origin in the literature, differentiation into monosymptomatic and polysymptomatic fever might be helpful in determining further diagnostic workup of patients with fever of unknown origin.

The effects of antipyrine (1200 mg day-1), phenobarbitone (100 mg day-1) and rifampicin (600 mg and 1200 mg day-1, respectively) administration for 7 days on sparteine metabolism and 6 beta-hydroxycortisol excretion were studied in panels of extensive (EM) and poor metaboliser (PM) subjects. Drug metabolism was induced in both EM and PM subjects by antipyrine and rifampicin pretreatment as indicated by increased excretion of 6 beta-hydroxycortisol. A 30% increase in metabolic clearance of sparteine was observed in EM subjects following rifampicin administration whereas in PM subjects no effect on the overall elimination of the drug was seen. The data indicate that the regulation of cytochrome P-450 isozyme involved in polymorphic debrisoquine/sparteine metabolism is predominantly under genetic control and that enzyme induction exerts only a marginal effect.

: Between 1978 and 1984, 169 patients were admitted to the hospital for fever of unknown origin which was repeatedly above 38.3 degrees C. After a retrospective analysis of their records the patients were divided into two groups on the basis of the following new criteria. The first group (74 patients) was described as having \"monosymptomatic fever\", i.e. fever without any other physical signs, whereas the second group (95 patients) had \"polysymptomatic fever\", i.e. fever with additional physical signs. In 56 patients (76%) of the monosymptomatic group fever had lasted longer than 3 weeks prior to admission. In 86% of these patients case history, physical examination, microbiological tests, serological tests for microorganisms and outoimune antibodies, and microscopic inspections of tissue and/or bone marrow led to a diagnosis. Malignancies, factitious fever and fever of unknown origin were found only in this group. The patients with malignancies were generally older than the rest of the patients (p less than 0.05), and eight of ten patients suffering from connective tissue diseases also had monosymptomatic fever. The incidence of infections in this group was 42% (31 cases), in contrast to 88% (84 cases) in the polysymptomatic group (p less than 0.05). Whereas the latter had significantly more bacterial infections (p less than 0.05), viral infections prevailed in the monosymptomatic group (p less than 0.05). Thus, the etiology of polysymptomatic fever distinctly differed from that of monosymptomatic fever. Since the frequency distribution of etiologies in the monosymptomatic group corresponded to that of the cases of fever of unknown origin in the literature, differentiation into monosymptomatic and polysymptomatic fever might be helpful in determining further diagnostic workup of patients with fever of unknown origin.

A possible interaction of penbutolol and cimetidine was investigated in healthy volunteers treated orally for 7 days.

Six patients with primary biliary cirrhosis (PBC) were treated with a daily oral dose of 600 mg rifampicin for 2 weeks to induce the hepatic metabolism of drugs and bile acids. On rifampicin 5 of 6 patients experienced a pronounced decrease of their pruritus. In all patients the oxidative cytochrome P-450 dependent drug metabolism was induced as shown by an increase of antipyrine-clearance from 36.3±8.8 to 80.6±20.1 ml/min and an enhanced urinary excretion of 6-β-hydroxycortisol from 454±1.99 to 1607±362 µg/24 h. Furthermore, in all 6 patients the serum alkaline phosphatase declined. In the 3 cholestatic patients (bilirubin>1.0 mg/dl) the serum concentration of total and conjugated bile acids was strikingly reduced. Thus, rifampicin is an inducer of hepatic metabolism in PBC-patients, ameliorates the pruritus and can lower serum concentrations of alkaline phosphatase and bile acids.

Human hepatic microsomes were isolated from wedge biopsies of the liver from 13 patients undergoing abdominal surgery. Ultrasonic homogenisation was used to increase the yield of microsomal monooxygenase activity (7-ethoxycoumarin O-deethylase, NADPH-cytochrome c reductase), resulting in a 30% higher total enzyme activity per g liver than preparation by other techniques. In 4 individual microsomal preparations the influence of cimetidine and ranitidine on Michaelis-Menten kinetics of O-deethylation and of reductase activity were studied. Without the H2-receptor blocking drugs, enzyme kinetics of O-deethylation with a Km of 51.0±16.4 µM (n=3) were obtained using Lineweaver-Burke plots. Both, cimetidine and ranitidine inhibited the O-deethylation; cimetidine had a five-fold higher inhibitory affinity (Ki 1.01 and 3.94 mM) to the monooxygenase than ranitidine (Ki 4.96 and 17.70 mM) in the uninduced liver. However, in liver from a patient with induced enzyme activity (Km=478.0 µM), the Ki of ranitidine was similar to that of cimetidine (Ki ran 3.57 versus Ki cim 2.49 mM). The reductase activity was not inhibited by ranitidine and only marginally so by cimetidine.

Observations of a variable anticoagulatory response in patients being treated by phenprocoumon and wheat bran resulted in a study of seven healthy volunteers. Up to 168 h after the administration of phenprocoumon, both in the fasting state and following the ingestion of 35 g wheat bran in a crossover design, blood samples were taken and urine was collected. The usual pharmacokinetic parameters were calculated from the concentrations measured. Following the ingestion of wheat bran, a decreased absorption rate for phenprocoumon but no decrease in overall bioavailability was observed. In addition, a decrease in total body clearance of phenprocoumon and an increase in the free plasma fraction of phenprocoumon, resulting in decreased free drug clearance, was seen after wheat bran administration. No differences were observed in the urinary excretion of either phenprocoumon or its metabolite. These findings cannot be completely explained by our present knowledge and need further investigation.

In six healthy volunteers pharmacokinetic and pharmacodynamic interaction of metoprolol and nifedipine with Cimetidine and ranitidine was investigated after 1 week of monotherapy with nifedipine and metoprolol and after 1 week each of combined treatment of these drugs with the H2-receptor antagonists. Ranitidine led to a 50% increase in mean peak plasma levels and in the area under the plasma level time curve (AUC) of metoprolol (p < 0.05) and to an insignificant 30% rise in these parameters of nifedipine (p > 0.05). Cimetidine increased metoprolol’s peak plasma levels of AUC by about 60% (p < 0.05) and those of nifedipine by 80% (p < 0.05). Compared to monotherapy with metoprolol beta blocking activity measured by exercise induced tachycardia was not significantly stronger inhibited under the combined treatment of metoprolol with each of the two H2-receptor antagonists. On the other hand the antihypertensive effect of nifedipine was significantly increased during concurrent administration of Cimetidine in seven hypertensive patients when compared with monotherapy.