W. Kirch

Pharmacodynamic Action and Pharmacokinetics of Moxonidine After Single Oral Administration in Hypertensive Patients

Moxonidine is a new centrally acting alpha2‐adrenoceptor agonist that differs from others by a lower incidence of side effects in hypertensive patients. The effects of moxonidine and placebo on blood pressure, pulse rate, plasma catecholamines, plasma renin activity, sedation, and salivary flow were evaluated in eight hypertensive patients by an intraindividual comparison. Moxonidine induced a significant decrease in blood pressure that corresponded with its plasma concentrations. The maximum antihypertensive effect appears to be delayed when compared with the peak plasma level. Plasma norepinephrine, epinephrine, and plasma renin activity were significantly reduced by moxonidine, and blood pressure reduction corresponded with decrease of plasma norepinephrine. Heart rate, sedation, and salivary flow were not different using moxonidine compared with placebo. Only one patient mentioned dry mouth. No further relevant adverse effects were seen in the patients. This study demonstrates a significant decrease of blood pressure, plasma renin activity, norepinephrine, and epinephrine with a single dose of 0.25 mg moxonidine, but no significant effect on pulse rate, salivation, and sedation.

Isolation of human hepatic microsomes and their inhibition by cimetidine and ranitidine

SummaryHuman 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.The results suggest that in human hepatic microsomes oxidative drug metabolism is inhibited by both H2-receptor antagonists. However, the inhibitory potency of the compounds seems to depend on the individual isozyme pattern of the hepatic microsomes. Thus, while cimetidine is an relatively nonspecific enzyme inhibitor, ranitidine might more selectively inhibit induced drug metabolizing enzymes.

Bioavailability and elimination of nitrendipine in liver disease.

SummaryTwenty one patients with liver disease (cirrhosis 11, chronic hepatitis 5 and acute hepatitis 5) and 6 healthy volunteers were given a single i.v. dose of nitrendipine 5 mg. Afterwords nitrendipine 20 mg once daily were administered orally for seven days.With the intravenous injection a significant increase in the AUC and elimination half-life of nitrendipine was found in patients with cirrhosis as compared to the normal volunteers. After chronic oral dosing, the area under the plasma concentration-time curve, AUC (0–24), was 94.5 ng ml−1 h and the plasma clearance CL was 1380.6 ml/min in the healthy controls; in patients with cirrhosis the AUC (0–24) h was significantly greater at 309.4 ng ml−1 h and CL had fallen to 686.6 ml/min. Considerable accumulation of nitrendipine was also found in the patients with chronic hepatitis. Nitrendipine could not be detected in urine from any of the subjects. Blood pressure and heart rate were not significantly influenced by the treatment in the various groups investigated. Antipyrine clearance in the patients with cirrhosis was correlated with the nitrendipine plasma clearance.Thus, accumulation of nitrendipine has been demonstrated in the patients with cirrhosis and chronic hepatitis.

Hemodynamic effects of different H2‐receptor antagonists

In a randomized, placebo‐controlled, double‐blind study, 10 healthy volunteers were treated orally once a day for 1 week each with placebo, 800 mg Cimetidine, 300 mg ranitidine, and 40 mg famotidine. On the seventh treatment day, heart rate, blood pressure, systolic time intervals, and impedance cardiography were measured before the morning dose and at 2, 6, 12, and 24 hours after the morning dose. Heart rate and blood pressure were not markedly altered by any of the H2‐receptor antagonists compared with the findings for placebo. Cimetidine and ranitidine did not markedly alter parameters of systolic time interval and impedance cardiography compared with placebo in contrast to famotidine, which significantly decreased stroke volume, cardiac output, and the Heather Index in impedance cardiography (p < 0.05) and also significantly increased the ratio of the preejection period to the left ventricular ejection time in systolic time interval (p < 0.05) 2 hours after the morning dose. Six hours after administration, most of these alterations could no longer be detected. The observed changes in hemodynamic parameters confirm that famotidine exerts negative effects on cardiac performance, whereas such influences could not be shown for Cimetidine and ranitidine.

Elimination and haemodynamic effects of nitrendipine in patients with chronic renal failure

SummaryIn sixteen patients with arterial hypertension and differing degrees of renal function the pharmacokinetics and haemodynamic effects of nitrendipine have been studied after treatment for 7 days. The AUC (0–24) and the elimination half-life of nitrendipine were significantly increased; the AUC (0–24) in patients with renal failure (median creatinine clearance 27.1 ml × min−1) was 196 ng × ml−1 × h compared to 97.8 ng × ml−1 × h in control subjects (median creatinine clearance 94.4 ml × min−1). The corresponding elimination half-lives were 13.5 h in renal failure and 4.4 h in the controls. The haemodynamic effects of nitrendipine were not enhanced in the patients.

Twenty-four-hour analysis of lymphocyte subpopulations and cytokines in healthy subjects.

Fourteen healthy male subjects were studied under resting conditions for 24 or 48 h. The 24-h variations of ACTH and cortisol with peaks in the morning were confirmed. Interleukin-2 release was profoundly reduced at 8: 00. A cosine function could be fitted to lymphocyte subpopulations including populations such as T helper-memory cells (CD4+/CDw29) and HLA-DR-bearing cells displaying peak values during the night and minimal values at 9:00. Numbers of natural killer cells (CD57) were not correlated to other cell populations and no rhythm could be detected. Interleukin- 1 beta was detectable in some plasma samples only with an interleukin- 1 ELISA kit (Quantakine HS(R)), but neither a 24-h rhythm nor reproducible results could be obtained for day 1 and 2 of the study. We conclude that there might be a temporal relation between the parameters analyzed: Higher levels of endogenous cortisol in the morning hours probably inhibit the cellular interleukin-2 synthesis and are responsible for an enhanced migration of lymphocytes from the blood into the tissues of the reticuloendothelial system. These results might be indicative of a circadian organization of the immune system which may play a role in both physiological and pathological functioning.

Influence of prolonged neuropsychological testing on immunoregulatory cells and hormonal parameters in patients with systemic lupus erythematosus

SummaryThe influence of a 2-h neuropsychological stress test on plasma catecholamines, cortisol, and on the distribution of lymphocyte subpopulations was studied in 14 patients with systemic lupus erythematosus (SLE), 10 patients on prednisone treatment (without collagenosis), and 14 sex-and-age-matched healthy controls. Psychological stress induced comparably significant increases in plasma adrenaline and noradrenaline levels as compared with baseline values (P<0.05) in all three groups, whereas plasma cortisol remained unchanged. The rise in plasma catecholamines was accompanied by a significant cell mobilization in healthy subjects and prednisone-treated patients, but not in patients with SLE. CD19+ cells increased significantly in number from baseline in healthy subjects and prednisone-treated controls (P<0.05), while remaining unchanged, in SLE patients. In conclusion, SLE patients showed a reduced cell mobilization due to psychological stress despite hormonal alterations paralleling those of healthy subjects or prednisone-treated patients without collagenosis.

Hemodynamic effects of quinidine and famotidine in patients with congestive heart failure

In a randomized, placebo‐controlled, double‐blind study, 12 patients with congestive heart failure (New York Heart Association class II) were successively treated for 1 week each with placebo, 40 mg famotidine, and 1000 mg quinidine. On the seventh treatment day, heart rate, blood pressure, systolic time intervals, impedance cardiography, and Doppler ultrasound were measured. Heart rate and blood pressure were not markedly altered by either drug. By contrast, quinidine and famotidine significantly decreased stroke volume and cardiac output in impedance cardiography and Doppler ultrasound (p < 0.05). A high correlation between both noninvasive methods was found for cardiac output and stroke volume (r = 0.93 and r = 0.97 for stroke volume 1½ hours after quinidine and placebo administration, respectively). In addition, the mechanocardiographic ratio of the preelection period to the left ventricular ejection time in systolic time intervals increased significantly 1½ and 3 hours after administration of quinidine and famotidine (p < 0.05). In conclusion, both quinidine and famotidine exert similar negative effects on cardiac performance, with no significant differences in hemodynamic parameters emerging between the antiarrhythmic agent and the H2‐receptor antagonist.

Divergent effects of different enzyme-inducing agents on endogenous and exogenous testosterone

SummaryThe effects of three different enzyme-inducing drugs (antipyrine 1200 mg, phenobarbital 100 mg, rifampicin 600 mg per day for 7 days) on plasma and urinary testosterone concentrations, plasma gonadotropin levels, antipyrine kinetics, and urinary 6β-hydroxycortisol excretion were studied in 18 healthy volunteers. Changes in plasma and urinary testosterone concentrations following exogenous testosterone undecanoate (TU) were also investigated.Although both antipyrine and rifampicin increased antipyrine clearance by about 60%, they produced contrary effects on testosterone: antipyrine lowered the total morning plasma testosterone and plasma testosterone AUC following TU, while rifampicin led to increases of about 20% and 78%, respectively. By contrast, phenobarbital did not significantly alter the endogenous and exogenous plasma testosterone concentrations, but it increased the urinary excretion of testosterone by more than 60%. The other two enzyme inducers did not alter this parameter. Gonadotropin levels remained unchanged.The results indicate that different enzyme-inducing agents exert divergent effects on endogenous and exogenous testosterone concentrations and suggest that the effect of enzyme induction on endogenous testosterone depends on the type of microsomal enzyme-inducing drug used rather than on the extent of the induction achieved.

Changes of immunoregulatory cells induced by acoustic stress in patients with systemic lupus erythematosus, sarcoidosis, and in healthy controls.

Abstract. In order to determine whether the characteristically attenuated cell mobilization after physical stress in patients with systemic lupus erythematosus (SLE) or sarcoidosis is disease specific or the result of lower tolerance for such stress, SLE and sarcoidosis patients as well as healthy volunteers were subjected to an acoustic stress model, independent of physical capacity. After a 10‐min period of intermittent acoustic stress, healthy subjects showed significant increases in leucocyte and lymphocyte counts, marked relative elevations of B and T suppressor cytotoxic lymphocytes (P < 0.01), and a relative reduction in T helper lymphocytes (P < 0.01). By contrast, this degree of change was significantly less pronounced in the 14 female SLE patients studied (P < 0.01) as compared with the healthy controls, but not in the 12 sarcoidosis patients tested. No dependence was found between the severity of disease or administration of corticosteroid therapy and cell mobilization. It is yet to be determined whether the attenuated response of SLE patients to stress is a consequence of pathophysiological mechanisms or plays an aetiopathogenic role in the course of the disease.