Acute myocardial infarction in a young South African Indian-based population: patient characteristics on admission and gender-specific risk factor prevalence.

BACKGROUND: Myocardial infarction (MI) is a complex disease caused by interaction of a number of genetic and environmental factors. This disease has reached epidemic proportions in South African Indian descendants. The aim of this study was to survey the prevalence of coronary heart disease risk factors in a sub-group of young Indian patients (< or = 45 years) who presented to the Coronary Care Unit at the R. K. Khan Hospital in Durban, a major referral centre for patients with acute MI in the province of Natal. METHODS AND RESULTS: A total of 245 patients < or = 45 years of age were recruited from patients consecutively admitted to the Coronary Care Unit at the R. K. Khan Hospital, Durban, KwaZulu Natal, South Africa between 1996 and 1999 with a diagnosis of acute MI. All patients were of Indian origin living in the Durban area in the province of KwaZulu-Natal. Demographic and risk factor data were obtained from all patients and included anthropometric measures, family history and the traditional cardiovascular risk factor assessment (smoking, lipids, hypertension, and diabetes mellitus). Clinical data included in-hospital presentation, management and complications and angiographic classification of coronary atherosclerosis. The most prevalent risk factors were previous: smoking (74%), and hypertriglyceridaemia (54%). Only 14% of the population presenting with an acute MI were women. Smoking was more common among men (81%) than in women (35%). Abnormal high density lipoprotein (HDL) cholesterol levels were detected in 38% of the patients with a dear gender difference: 43% and 9%, in men and women, respectively. In contrast hypertension was more prevalent in young women with MI than in men: 38% and 19%, respectively. Coronary angiography was performed in 79 patients on admission; a single vessel stenosis was found in 28%, two vessel disease in 20% and triple vessel disease in 52%, respectively. On admission, 92% of patients were in Killip class I. Overt heart failure and cardiogenic shock were uncommon and were seen in 3.3% and 0.8%, respectively. Patients who received thrombolytic therapy had fewer complications (8%) compared to those who did not (11%). However, the difference towards a benefit of thrombolysis did not reach significance. Recurrent angina (6%) was the commonest complication, while ventricular arrhythmias were observed in 2% of patients. There was a strong familial link: 54% of the patients had a family background of coronary heart disease (CHD) while 42% and 41% had family members who suffered from diabetes mellitus and hypertension, respectively. CONCLUSION: Smoking and dyslipidaemia (predominantly hypertriglyceridaemia, and low HDL-cholesterol) were the most common cardiovascular risk factors of MI in young South African Indians. A strong familial link was observed not only for a history of CHD/MI, but also for hypertension and diabetes mellitus, supporting a genetic basis for the development of premature CHD. Therefore, further analysis of potential genetic factors such as variance of genes involved in vascular homeostasis, haemostatic factors, lipid metabolism and other metabolic factors seems warranted.

Effect of ramipril on ambulatory blood pressure and albuminuria in renal hypertension.

Inhibition of the angiotensin-converting enzyme (ACE) exerts a renoprotective effect in adult patients with chronic kidney disease. We evaluated prospectively changes in blood pressure (BP), protein excretion and renal function after administration of the long-acting ACE inhibitor ramipril as monotherapy during 6 months in 14 moderately hypertensive children aged 5-18 years with various nephropathies. Four patients initially had a decreased glomerular filtration rate (GFR below 60 ml/min/1.73 m2). BP was evaluated by ambulatory 24-h monitoring. After 2 weeks of treatment by oral ramipril (1.5 mg/m2 once daily), mean values of systolic and diastolic 24-h ambulatory BP fell by more than 5 mmHg in nine patients. In eight patients the dose was doubled. At the end of the study systolic BP was below the 95th percentile in 9 and diastolic BP in 13 patients. The initially reduced nocturnal dip increased significantly. Of 11 patients with an increased albumin excretion (median 1.3 g/g creatinine), 6 responded to ramipril by a median reduction of 78% (range 24-83%), whilst in 5 albuminuria increased (median +19%). GFR was well preserved and no other adverse effects from the drug were noted. The study demonstrates that ramipril is an efficacious antihypertensive agent in children with renal hypertension. It is well tolerated, even in mild renal insufficiency. In addition, the drug has a persistent antiproteinuric action in about half of the patients contributing to conserve renal function.

Effects of felodipine ER, a dihydropyridine calcium antagonist, on blood pressure and serum lipids.

In an open trial, the antihypertensive efficacy of felodipine and its effects on lipid metabolism were investigated in 117 Nordic patients with mild to moderate essential hypertension and hyperlipidaemia. In the intent-to-treat analysis (n = 106) a significant (p < 0.01) drop in the mean systolic and diastolic blood pressure values was observed between baseline and 24 weeks' treatment from 157/100 mmHg to 145/92 (supine) and from 155/103 to 145/96 mmHg (erect). No relevant differences were seen in the pulse rate. Median total cholesterol and triglycerides remained unchanged, whereas HDL-cholesterol increased significantly from 1.30 mmol/l to 1.33 mmol/l (p < 0.02); LDL- and VLDL-cholesterol, apolipoprotein A1 and apolipoprotein B remained unchanged during the 24-week treatment period. In the per protocol analysis (n = 76), blood pressure values changed significantly from 158/100 mmHg to 144/91 mmHg (supine) and from 157/104 mmHg to 143/95 mmHg (erect) (p < 0.01 for both). HDL-cholesterol increased significantly (p = 0.03), whereas LDL- and VLDL-cholesterol, total cholesterol and triglycerides, as well as the apolipoproteins, remained unchanged during the trial. Felodipine thus proved to possess positive effects on lipid parameters in hypertensive patients.

Efficacy of ramipril in therapy-resistant hypertension.

In an open, 48-week study the antihypertensive efficacy of ramipril when administered as add-on therapy to existing triple antihypertensive treatment (diuretics, beta-blockers, vasodilators) was investigated in 56 patients (24 females, 32 males) with therapy-resistant hypertension. The main variable (sitting diastolic blood pressure) decreased from 112 mmHg at baseline to 91 mmHg at week 8 (p < 0.01) and remained stable thereafter until the end of the trial. The systolic blood pressure in the sitting position decreased from 175 mmHg at baseline to 146 mmHg at week 8 (p < 0.01) and also remained stable thereafter until the end of the trial. Ramipril doses between week 8 and the end of the trial were not changed in 82% of patients. 45% of patients were treated with 5 mg ramipril/day, 33% with 10 mg/day and 22% with 20 mg/day at the end of the study. Addition of ramipril allowed a reduction in the doses of concurrrent therapy, especially in relation to beta-blockers (p < 0.02) and vasodilators (p < 0.01). The safety was good--no serious adverse events were observed. Ramipril is, therefore, a suitable drug for the patients with therapy-resistant hypertension allowing reduction of the doses of concomitant medication.

Efficacy of ramipril versus enalapril in patients with mild to moderate essential hypertension.

This double-blind, randomised, cross-over study investigated the antihypertensive efficacy of ramipril and enalapril was completed by 30 patients with mild-to-moderate essential hypertension. After a four-week placebo run-in phase, the patients received either 2.5mg ramipril or 10mg enalapril once daily for four weeks. The dosages were increased to 5mg ramipril and 20mg enalapril for a further four weeks. After a placebo washout phase of four weeks, the patients were crossed over to the alternative treatment. The decrease in average 24-hour ambulatory diastolic blood pressure from week 0 to week 8 was 1.6mmHg greater with ramipril than enalapril (90% confidence interval 0.6-2.7mmHg). The corresponding reduction in for systolic blood pressure was also greater with ramipril than enalapril by 2.4mmHg (90% confidence interval: 0.5-4.2mmHg). For the difference in the drop of 24-hour ambulatory diastolic blood pressure between ramipril and enalapril the lower level of the 90% confidence interval (CI) is above the clinically relevant difference of -3mmHg. This is an indication that ramipril (2.5 and 5mg dose) is at least as effective as enalapril (10 and 20mg dose) in decreasing blood pressure in patients with mild-to-moderate essential hypertension. The duration of adequate antihypertensive effect was relatively long for both ramipril and enalapril; however, ramipril tended to have a more prolonged antihypertensive effect. Ramipril had a higher diastolic and systolic trough/peak ratio than enalapril, resulting in a more uniform antihypertensive effect over the 24-hour treatment period. Both ramipril and enalapril were well tolerated and the two treatment groups had similar safety profiles.

Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with increased plasma angiotensin-converting enzyme activity but not with increased risk for myocardial infarction and coronary artery disease.

BACKGROUND: Previous research has shown that the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene is a major determinant of plasma ACE activity. It has been suggested that persons with the DD genotype (those who express, on average, the highest levels of circulating ACE) have an increased risk for myocardial infarction and coronary artery disease, particularly if they are otherwise at low risk. Subsequent studies, however, have not confirmed that ACE I/D gene polymorphism is a risk factor for coronary artery disease and myocardial infarction. OBJECTIVE: To investigate the association between the I/D polymorphism of the ACE gene and the risk for coronary artery disease and myocardial infarction in patients in whom coronary artery disease status was documented by angiography. DESIGN: Cross-sectional study. SETTING: University medical center. PATIENTS: 209 male case-patients with coronary artery disease and 92 male controls without coronary artery disease, as documented by coronary angiography. MEASUREMENTS: Assessment of the cardiac risk profile by questionnaire; classification of patients by the degree of coronary artery stenosis; levels of lipoproteins, apolipoproteins, and fibrinogen; and ACE I/D gene polymorphism assessed by polymerase chain reaction amplification. RESULTS: Plasma ACE activity was significantly associated with ACE I/D gene polymorphism. The ACE genotype was not associated with the presence of coronary artery disease or myocardial infarction. If a recessive effect of the D allele was assumed (DD compared with DI and II), the relative risk was 1.00 (95% CI, 0.76 to 1.30) for coronary artery disease and 1.03 (CI, 0.77 to 1.38) for myocardial infarction. Results of analyses were also negative when a dominant effect of the D allele was assumed and when low-risk subgroups were examined. The established risk factors age and apolipoprotein B level emerged as the most important risk predictors in multivariate analyses, followed by diastolic blood pressure and fasting glucose levels. CONCLUSIONS: In an angiographically defined study sample, ACE I/D gene polymorphism was not associated with an increased risk for coronary artery disease or myocardial infarction, despite its effects on plasma ACE activity.

A simple prognostic index for patients with acute renal failure requiring dialysis. French Multicentric Prospective Study on Furosemide in Acute Renal Failure Requiring Dialysis.

The probability of death in patients with acute renal failure (ARF) remains high. A valid prognostic index available on patient admission and during follow-up could be helpful for decision making. In this study, 94 ARF patients requiring dialysis (not responding to a previous single dose of furosemide 15 mg/kg) were included. On admission, patients were classified according to a Simplified Acute Physiology Score (SAPS) of < or = 15 or > 15. The prognostic value of 11 risk factors was analyzed. Only 6 in 11 risk factors were significant by univariate analysis: age (> 55 years) (0.02), mechanical ventilation (0.008), oliguria (< 500 mL/day during the first 5 days) (0.02), sepsis (0.001), shock (0.007), and serum bilirubin (> 30 mumol) (0.001). Only oliguria and sepsis were significant risk factors by multivariate analysis. Overall mortality rate was 41%. Mortality rate was higher in patients with SAPS > 15 (65%) than in those with SAPS < or = 15 (22%) (0.001). Patients with > 3 risk factors showed a significantly higher mortality rate than patients with < 3 risk factors (all patients disregarding SAPS) (0.001). Considering the worst combination of risk factors by univariate analysis, mortality prediction was 56% if oliguria, sepsis, and high serum bilirubin were present, and reached 80% if an older age was added (four risk factors). Ventilation increased probability of death to 92% (five risk factors). If all six risk factors were present, the probability rose to 96%. The corresponding observed mortality rate was 32% for three risk factors, 70% for four, 81% for five and 100% for six risk factors. The results suggest that probability of death in ARF requiring dialysis can be correctly estimated when more than three significant risk factors are present. If confirmed, they could avoid using a more complex severity scoring system in patients with ARF requiring dialysis.

Pharmacokinetics of levofloxacin in comparison to the racemic mixture of ofloxacin in man.

After oral administration of a single dose of 200 mg of levofloxacin and 400 mg racemic mixture of ofloxacin to 6 healthy male volunteers in a double-blind, randomised cross-over study, concentrations of the unchanged isomers were determined at various times in serum and urine, over 28 hours and 48 hours, respectively. Each dosing was followed by a wash-out period of one week. Ofloxacin concentrations were determined using an enantioselective and a non-enantioselective high pressure liquid chromatography (HPLC) assay. The two measurements obtained were compared by linear distribution independent regression, and were found to be equivalent. Maximum serum concentration (Cmax) of levofloxacin after the administration of 200 mg of the levo-isomer was 2.42 mg/l (chiral derivatization HPLC, mean values); the corresponding area under the serum concentration-time curve (AUC0-28) was 17.0 mg x h/l. The corresponding Cmax values after the administration of 400 mg (+/-)-isomer (chiral derivatization HPLC and reversed phased HPLC, mean values) were 2.05 mg/l, 1.98 mg/l and 4.41 mg/l for (-)-, (+)- and (+/-) isomer, respectively. The AUCS0-28 were 17.0, 14.6 and 32.7 mg x h/l, respectively. The pharmacokinetics of the (-)- and (+)-isomer were shown to be almost equal. In serum and urine no reracemisation of the (-)-isomer to a racemic mixture was observed. General tolerability was good; no side effects were reported.

Pharmacokinetics, metabolism and biliary and urinary excretion of oral ramipril in man.

In order to evaluate the pharmacokinetics and excretion of ramipril in man, 8 cholecystectomy patients aged between 53 and 68 years received 5 mg ramipril orally as a single dose. All patients had a T-drain inserted to permit bile collection; all gave their informed consent to participate in the trial. Serum samples were collected half-hourly until 2 hours, then hourly until 6 hours, then at 8, 10, 24 and 25 hours after intake. Urine was collected in 2-hour fractions until 8 hours, followed by a 4- and a 12-hour fraction. Bile was collected hourly until 6 hours, followed by a 6- and a 12-hour collecting fraction. Concentrations of ramipril and ramiprilat in serum, and determinations in urine and bile of ramipril, ramiprilat, ramipril glucuronide, ramiprilat glucuronide, diketopiperazine and diketopiperazine acid were made; total amounts excreted were calculated. Peak concentrations of ramiprilat in plasma (8.7 +/- 1.6 ng/ml) were reached after about 8 hours. AUC0-8 and AUC0-24-values were 36.5 and 111.9 ng.h/ml, respectively. Ramiprilat Cmax-concentrations were about 300-fold higher in bile than in plasma, the corresponding difference for ramipril between bile and plasma was about 4-fold. The main fractions excreted in the urine were diketopiperazine acid and ramiprilat amounting to 13.2 +/- 5.6 and 4.4 +/- 2.4%, respectively, of the dose administered. Only a very small fraction of the dose was excreted with urine as unchanged ramipril, on average 0.9 +/- 1.0%. The main fractions excreted in the bile were diketopiperazine acid, ramiprilat glucuronide and diketopiperazine, 9.0 +/- 5.3, 3.4 +/- 4.2 and 2.0 +/- 1.2% in 24 hours, respectively, of the dose administered. Only a negligible fraction of the dose (average 0.1 +/- 0.1%) was excreted with bile as unchanged ramipril. In conclusion, there is strong evidence that circulating ramipril and ramiprilat are eliminated by both the liver and the kidneys. For the patients studied it can be estimated from late collection periods that some 2/3 of circulating ramipril and ramiprilat are eliminated by the kidneys and 1/3 eliminated by the liver.

Multiple-dose pharmacokinetics of ramipril in patients with chronic congestive heart failure.

Thirteen patients with chronic congestive heart failure of NYHA class II-III received multiple doses (14 days) of ramipril (5 mg once daily); the concentrations of ramipril and ramiprilat in plasma, as well as ramipril, ramiprilat, glucuronides, diketopiperazine, and diketopiperazine acid in urine were measured at various times for 14 days. One patient dropped out after the first day due to hypotension and another who accidentally received another ACE inhibitor additionally was excluded, so that 11 patients completed the study. Ramipril and ramiprilat in plasma were determined by radioimmunoassay, and ramipril and its metabolites in urine were measured by gas chromatography in the laboratories of Hoechst AG. Peak concentrations of the active substance ramiprilat were reached after about 4 h and amounted to 22.3 +/- 11.1 ng/ml after the first dose, and a peak concentration of 26.6 +/- 10.0 ng/ml was observed 2.5 +/- 1.4 h on average after administration on day 14. Practically no accumulation was observed for ramiprilat; the AUD (0-24 h) values increased from 191.3 +/- 83.1 ng.h/ml for the first study day to 238.3 +/- 98.0 ng.h/ml for day 14. As expected, only very small fractions of the dose were excreted with urine as unchanged ramipril and ramipril glucuronide. Ramiprilat is excreted with urine to a larger extent than is rampiril--on average 6.6 +/- 3.0% on the first day and 12.2 +/- 3.8% on day 14. The total amount excreted increased by 34% on average, and was mainly due to an increased ramiprilat excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of ramipril on plasma atrial natriuretic peptide, antidiuretic hormone, angiotensin II and aldosterone in patients with chronic congestive heart failure.

UNLABELLED: In an open trial 5 mg ramipril daily for 2 weeks was administered to 11 patients with congestive heart failure. 24-hour plasma profiles of atrial natriuretic peptide (ANP), antidiuretic hormone (ADH), angiotensin II (Ang II) and aldosterone (Aldo) were determined before and on days 1 and 15 of ramipril treatment, respectively. Urinary sodium excretion was also measured at the same time points. There were no relevant differences in the 24-hour profiles of ANP and ADH. Ang II values dropped as expected on the first day of ramipril treatment from 11.2 pg/ml to 2.9 pg/ml at 3 h post administration and from 6.7 pg/ml (predose) to 1.8 pg/ml at 2 h post administration on day 15. Plasma aldosterone values increased slightly from day 1 to day 15, sodium excretion increased from 125.9 mmol to 166.5 mmol/24 h; however, both changes in the 24-hour profiles were nonsignificant. A clinically relevant improvement in the severity of CHF was observed. From a total of 121 reported symptoms according to McKee et al., 35 showed an improvement; 81 remained unchanged, in only 5 symptoms a deterioration was observed. According to the NYHA-classification 5 patients improved from grade III to II, 6 remained unchanged. CONCLUSION: ACE inhibition does not induce changes in ANP or ADH levels in the resting state while Ang II decreases. A slight increase in aldosterone levels may be due to increased sodium excretion.

Preliminary results of biliary excretion of ramipril after T-drainage in cholecystectomy patients.

Four cholecystectomy patients, aged between 52 and 56 years, weighing between 64 and 90 kg, received 5 mg of ramipril as a single dose in order to investigate the pharmacokinetics and excretion pattern of ramipril. All patients had a T-drainage that allowed bile collection. Serum was collected at regular intervals, bile was collected hourly for 6 h followed by a 6- and 12-h fraction, and urine was collected every 2 h for 8 h followed by a 4- and 12-h fraction. The concentrations of ramipril and ramiprilat in serum and ramipril, ramiprilat, ramipril glucuronide, ramiprilat glucuronide, diketopiperazine, and diketopiperazine acid in bile and urine were determined and the amounts excreted in urine and bile over 24 h were calculated. There were great interindividual differences in maximum concentrations as well as in the time to reach maximum concentrations in plasma and bile as well as in the excretion pattern between urine and bile. The highest concentrations in bile were found for diketopiperazine acid (3,080 ng/ml) and ramipril glucuronide (2,414 ng/ml). In general, only minimal amounts of unchanged ramipril (prodrug) were detected in the bile. In the urine, the major metabolites excreted were diketopiperazine acid, ramiprilat, and diketopiperazine in amounts of 537, 188, and 124 micrograms, respectively. In bile, the main substances excreted were diketopiperazine acid and ramiprilat glucuronide, which amounted to 501 and 314 micrograms, respectively. Biliary excretion may be the explanation for the noncomplete urinary recovery of ramipril and its metabolites.

Antihypertensive efficacy, tolerance, and safety of long-term treatment with ramipril in patients with mild-to-moderate essential hypertension.

A total of 555 hypertensive patients took part in a 2-year multicenter, open-label study to determine the efficacy, tolerance, and safety of long-term therapy with ramipril. In the beginning, all patients were to receive 5 mg of ramipril/day. The dosage was then adjusted in accordance with response to treatment and ranged from 1.25-20 mg of ramipril daily. Of these patients, 129 also received 25 mg of hydrochlorothiazide daily at some point during the trial. To evaluate whether tolerance to ramipril developed during long-term treatment, a subgroup of 202 patients was analyzed for efficacy maintenance. Prior to enrolling in the 2-year study, these patients had received ramipril monotherapy in a short-term, double-blind study and had been classified as responders, i.e., their diastolic blood pressure had been maintained at less than or equal to 90 mm Hg. At the end of 104 weeks of treatment, 45.9% of patients were on 2.5 mg of ramipril alone and 43.6% were on 5 mg of ramipril alone. Only four patients required the addition of 25 mg of hydrochlorothiazide. No clinically important changes occurred, and kidney function was well maintained. The most frequently reported adverse events excluding intercurrent illnesses were dizziness/vertigo (6%), asthenia (4%), nausea (3%), headache (2%), and abdominal pain, gastrointestinal disorder, rash, and increased cough (1% each). Ramipril was safe, effective, and well tolerated in the long-term treatment of patients with mild-to-moderate essential hypertension.

Influence of ramipril on renal function in patients with chronic congestive heart failure.

Ramipril was administered to 13 patients, aged 49-80 years, weighing 53.5-90.3 kg, with congestive heart failure (CHF) for 2 weeks in an open trial. One patient dropped out after day 1 and another accidentally received another angiotensin-converting enzyme (ACE) inhibitor, so that 11 patients remained for analysis. Each patient received 5 mg of ramipril daily for 2 weeks, followed by a 1-week washout period. Urine was collected in 4-h fractions for 12 h followed by a 12-h fraction on days 1, 8, and 15. Creatinine clearance, as well as the excretion of albumin and the urinary brush border enzymes gamma-glutamyl transferase (GGT), alanine aminopeptidase (AAP), N-acetyl-beta-D-glucosaminidase (NAG), and lactate dehydrogenase (LDH) were determined. The values for albumin excretion, creatinine clearance, GGT, AAP, NAG, and LDH obtained for the various days during the time course before and during multiple dosing were subjected to an analysis of variance followed by Scheffe's test for means. Daily albumin excretion decreased during treatment with ramipril from 23.8 +/- 27.4 mg/24 h (baseline) to 12.9 +/- 15.1 (day 1), 10.8 +/- 15.6 (day 8), and 12.4 +/- 12.7 mg/24 h (day 15). The differences were significant (alpha = 0.05) when compared to pretreatment albumin excretion. Creatinine clearance increased from 78.8 +/- 38.3 ml/min (baseline) to 82.4 +/- 34.6 (day 1), 85.1 +/- 28.5 (day 8), and 91.7 +/- 36.4 ml/min (day 15). The change on day 15 was significant (alpha = 0.05) when compared to pretreatment values.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium.

The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC. The mean Cmax of 4-MAA increased linearly with dose whereas its AUC was not proportional to dose after administration of 1500 and 3000 mg. With 4-AA, the increase in mean Cmax was linear, but the increase in AUC was not. The increases in mean Cmax and AUC for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose. The increases in mean Cmax and AUC for 4-AcAA were roughly proportional to the increase in dose. There were no significant differences in renal clearance between doses for any of the four metabolites. The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested.

Pharmacokinetics and dose linearity testing of methylprednisolone phosphate.

The pharmacokinetics of methylprednisolone and methylprednisolone phosphate were investigated after intravenous administration of methylprednisolone phosphate to six healthy subjects at seven different doses between 16 and 1000 mg. Plasma, urine, and saliva were analyzed for methylprednisolone and methylprednisolone phosphate. Furthermore, endogenous hydrocortisone was measured in plasma. No non-linearity in the total body clearance of methylprednisolone phosphate or methylprednisolone could be detected. The average elimination half-life for the prodrug was 3.7 min indicating rapid hydrolysis. After 15 min more than 90 per cent of the phosphate has been hydrolyzed. No prodrug could be detected in saliva; very little of the ester (average 0.9 per cent of the dose) was excreted unchanged into the urine. Methylprednisolone is formed rapidly. The total body clearance was 21 1h-1, the terminal half-life 2.8 h. In the post-distribution phase methylprednisolone levels in saliva went parallel to plasma levels. The mean saliva/plasma ratio was 0.22. An average of 5.2 per cent of the dose was eliminated into the urine in the form of methylprednisolone. Hydrocortisone suppression was dose-dependent. For doses above 125 mg hydrocortisone levels were significantly lowered after 24 h. For doses above 500 mg the suppression was still significant after 48 h. The results indicate a rapid and predictable in vivo conversion of methylprednisolone phosphate to its active form methylprednisolone.

Absence of interaction between ramipril, a new ACE-inhibitor, and phenprocoumon, an anticoagulant agent.

In a double-blind, placebo-controlled crossover trial, the effects of ramipril, a long-acting non-sulphydryl angiotensin I converting enzyme inhibitor, on phenprocoumon steady-state pharmacodynamics were investigated in 8 healthy male volunteers taking individually fixed doses of phenprocoumon. The results showed that 5 mg ramipril or placebo once daily for 7 days did not alter the anticoagulant response (Quick values) to phenprocoumon after a stabilization phase of 2 weeks. Mean Quick values during the steady-state phase with ramipril and placebo were 67.5% and 69.3%, respectively. The clotting factors II, VII, IX and X as well as protein C decreased in the run-in phase and remained stable both during ramipril and placebo treatment. There were no differences between ramipril or placebo treatments. As the phenprocoumon dosage was kept unchanged during the double-blind phase, the results indicate that ramipril does not interfere with the vitamin K-dependent cascade.

Effects of penbutolol on plasma atrial natriuretic peptide and antidiuretic hormone levels before and after exercise: a double-blind comparison against placebo.

A double-blind crossover trial was carried out in 7 healthy male volunteers to investigate the effects of penbutolol and a placebo on plasma atrial natriuretic peptide (ANP) and antidiuretic hormone (ADH) levels before and after exercise. Each subject underwent several bicycle ergometric exercises lasting 6 min before and after the application of test medications. Ergometric exercises were performed before medication, and at 2, 5, 9 and 24 hours after medication. Blood samples for ANP and ADH levels were drawn before, after 15 min, after 2 hours (immediately after ergometry) and 5, 7, 9, and 24 hours after medication (immediately before ergometry). Urine was collected as follows: -2 to 0, 0 to 2, 2 to 4, 4 to 7, 7 to 14 and 14 to 24 hours after medication, and the volume as well as sodium excretion were documented. Penbutolol caused suppression of the exercise-induced increase in ANP. The 2 to 4 hour fractional sodium excretion was significantly decreased from 12.1 +/- 4.9 mmol/fraction after placebo treatment to 7.8 +/- 3.0 mmol/fraction after penbutolol application (p less than 0.03). There were no differences in the urinary outputs between penbutolol and placebo until 4 hours after medication, but penbutolol caused the total urinary output to increase from 1390 +/- 388 ml/24 hr during placebo treatment to 1725 +/- 549 ml/24 hr (p less than 0.02) due to the last collection fraction. Blood pressure and pulse rate both decreased during exercise after penbutolol. As opposed to the suppressing influence of penbutolol on ANP, ADH plasma levels were increased after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative pharmacokinetics of methylprednisolone phosphate and hemisuccinate in high doses.

The pharmacokinetics of methylprednisolone and two methylprednisolone esters, the phosphate and the hemisuccinate, were investigated after intravenous administration of the esters to 12 healthy male subjects in two different doses (250 and 1000 mg). Methylprednisolone was formed more rapidly from phosphate than from hemisuccinate. During the first 30 min methylprednisolone levels were three to four times higher after phosphate administration than after hemisuccinate. The mean residence time of the hemisuccinate was significantly longer and the total-body clearance lower than those of the phosphate. Whereas very little of the phosphate (mean, 1.7%) was eliminated unchanged into the urine, there were significant amounts of hemisuccinate (mean, 14.7%) excreted renally and therefore not bioavailable. Methylprednisolone saliva levels paralleled plasma levels; the average saliva/plasma ratio was 0.22. Neither phosphate nor hemisuccinate could be detected in saliva. An average of 7.2% of the administered dose was eliminated in the form of methylprednisolone in urine. Renal clearance was 24 ml/min and not dose or prodrug dependent. For both doses endogenous hydrocortisone levels were lowered after 24 hr. For the 1000-mg dose the depression was still significant after 48 hr. The results indicate that methylprednisolone phosphate results in a faster and more efficient conversion to its active form, methylprednisolone, than methylprednisolone hemisuccinate.