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Biomedical subjects

S R Santos

Publications and source records attributed to S R Santos.

At least 19 recordsLinked to original sources
PubMed1996

Influence of renal failure on cytochrome P450 activity in hypertensive patients using a "cocktail" of antipyrine and nifedipine.

OBJECTIVE: Two substrates were coadministered in a "cocktail" approach to evaluate the contribution of renal failure to drug oxidation. PATIENTS: Nineteen hypertensive patients, nine of them with chronic renal failure (CLCR 38.9 vs 102.3 ml.min-1 1.73 m-2), were investigated after peroral administration of a combination of antipyrine (500 mg, in capsules) and nifedipine (10 mg, in Oxcord capsules) in the morning after an overnight fast. RESULTS: This "cocktail" approach made it possible to characterize in vivo the activities of different forms of cytochrome P450 in a single-study protocol using the total clearance of nifedipine and clearance for production of 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine (OHA) and norantipyrine (NORA). With this "cocktail" approach (antipyrine plus nifedipine), we can suggest a selective effect on the activities of cytochrome P450 forms associated with the formation of dehydronifedipine (P450 III A4) and of NORA in patients with mild renal failure under long-term antihypertensive therapy.

Adult↗
PubMed1995

Prolongation of the PQ interval as a measure of therapeutic inequivalence between two formulations of diltiazem.

We studied the use of atrioventricular (AV) conduction time to assess the therapeutic equivalence of two diltiazem formulations in 20 volunteers in a double-blind, cross-over trial. ECG recording was carried out before and at several intervals after drug administration, and prolongation of the PQ interval (delta PQ) was taken as a pharmacodynamic response. In addition, diltiazem plasma concentrations were determined in 8 subjects. The effect of diltiazem increased proportionally with the plasma concentration and could be detected up to 10 h after administration. The area under the effect-time curve (AUEC(0-10)), the peak effect (Emax), and the effect mean residence time (MRTE) showed significant differences. In contrast to the pharmacodynamics, the pharmacokinetic profiles of diltiazem do not vary to the same extent. We conclude that the formulations are therapeutically different. Furthermore, at the administered dose, delta PQ appears to be a sensitive measure for assessing the electrophysiological properties of diltiazem.

Adult↗
PubMed1995

[Kinetic distribution of cyclosporine after single dose subcutaneous administration; experimental study in rats].

Adequate dose of cyclosporin A shows immunosuppressor effect, and low toxicity. The doses reported previously ranged from 2.5 to 25 mg/kg every 24, 48 hours and even 7 days. Routes for cyclosporin A administration are subcutaneous or intramuscular preferentially. In the present study, cyclosporin A (CSA) single dose subcultaneous was administered to 21 Wistar-Furth rats, adult, males, weighing 350-450g. The animals were divided in 3 groups receiving 2.5 mg/kg (group 1), 5.0 mg/kg (group 2) and 10.0 mg/kg (group 3). Blood samples were collected at 1, 4, 8, 12, 24, 48 and 72 hours after drug collection into plastic tubes containing sodium EDTA. Blood cyclosporin A levels were determined by a commercially available radioimmunoassay kit (Sandoz RIE Kit Basel) after whole hemolysis using liquid nitrogen. Cyclosporin A blood concentrations vs time curve were plotted (log C vs t). Two compartment open model was applied to estimate the kinetic parameters as t(1/2) beta e beta. A model independent calculation was applied to estimate the kinetic parameters as AUCT, CIT and Vd. Initially, parametric and nonparametric tests were applied. Due to the high dispositional variability, nonparametric statistics (Wilcoxon's test) was applied for analysis of results obtained. Based on data obtained in the present study the authors suggest linear pharmacokinetics where Cmax AUCT showed proportional increases with the dose administered, remaining unchanged the Kinetic parameters as t(1/2) B,B, CIT and Vd.

Analysis of Variance↗
PubMed1995

Theophylline-ranitidine interaction in elderly COPD patients.

Most controlled studies in humans indicate that ranitidine does not alter theophylline metabolism, even at high doses. However, there have been several case reports published recently which demonstrate the development of theophylline toxicity mostly in older patients receiving stable oral doses of this drug when ranitidine was administered simultaneously. We studied eleven elderly (mean age, 69.0 +/- 6.2 years) patients with chronic obstructive pulmonary disease (COPD). During one week the patients took slow-release theophylline, 200 mg every 12 h, followed by one week intake of the same dose of theophylline plus ranitidine tablets, 150 mg every 12 h. At the end of each period, blood samples were obtained 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12 h after the morning dose for the determination of serum theophylline levels. The peak theophylline concentration (Tmax) was achieved after 4.1 +/- 0.9 h while the patients were taking theophylline, and after 2.9 +/- 1.4 h with the combined regimen. This difference was statistically significant (P < 0.01). In only 3/11 subjects did Tmax remain unchanged during both phases of the study. The mean theophylline clearance rates while the patients were receiving theophylline alone (39.58 +/- 19.89 ml/min) and when they were receiving both medications (34.42 +/- 10.55 ml/min) were similar. The mean serum levels while the patients were receiving theophylline alone were slightly higher but not statistically different. These results suggest that the reported increases in serum theophylline levels in older patients receiving theophylline and ranitidine cannot be ascribed to slower theophylline metabolism in the geriatric patients with COPD who is also given ranitidine.

Age Factors↗
PubMed1992

Theophylline metabolism in patients with hepatosplenic mansoniasis and cirrhosis.

The pharmacokinetics of theophylline were studied in 12 patients with hepatosplenic mansoniasis, 14 patients with cirrhosis and 16 normal controls. Following a single intravenous dose of aminophylline volumes of distribution, serum half-lives and body clearances were determined. Volumes of distribution of theophylline in patients with schistosomiasis (mean 0.624 l/kg) did not differ from cirrhotic patients (mean 0.616 l/kg) or normal controls (mean 0.593 l/kg). Cirrhotic patients had a prolonged half-life compared to normal subjects (mean 22.1 vs. 9.9 h), while patients with schistosomiasis did not substantially differ from normal controls (15.8 vs. 9.9 h). Body clearance in patients with schistosomiasis was similar to controls (34.02 vs. 49.20 ml/h per kg) but decreased (29.24 ml/h per kg) in patients with cirrhosis. Individual analysis of the group with schistosomiasis disclosed three patients with reduced theophylline elimination. No relationship was found between laboratory tests of liver function and the pharmacokinetics of theophylline in any group. The administration of theophylline to patients with hepatosplenic schistosomiasis, although less dangerous than in cirrhosis, must be closely followed.

Adolescent↗
PubMed1992

Higher salt consumption, digoxin-like factor, and nifedipine response are associated with salt sensitivity in essential hypertension.

In addition to demonstrating evidences of increased sympathetic nervous system activity and marked left ventricular hypertrophy in salt-sensitive hypertensives, our group has also reported increased weight gain with salt overload in these patients. The increased weight gain suggests volume expansion, a situation already shown to increase plasma levels of a Na, K-ATPase inhibitor. Therefore, in the present study, digoxin-like factor (DLF) serum levels, spontaneous salt ingestion, nifedipine hypotensive effect, and plasma renin activity were evaluated in essential hypertensive subjects. Thirteen essential hypertensive outpatients were studied sequentially on an ad lib diet, a low salt diet (LSD = 30 mEq Na/day), and a high salt diet (HSD = LSD + 171 mmol/L NaCl/day), 1 week each. On the seventh day of LSD and HSD, DLF levels, mean blood pressure (MBP) response to nifedipine (10 mg sublingual), and plasma renin activity were measured. The MBP percent change from the seventh day of LSD to the seventh day of HSD (salt sensitivity) ranged from -13.7 to 20.9%. A positive correlation (r = 0.64, P < .01) was observed between salt sensitivity and 24-h urinary sodium excretion with an ad lib diet. The DLF serum levels correlated with the salt sensitivity both on LSD (r = 0.50, P < .05) and on HSD (r = 0.53, P < .05). Salt sensitivity was positively correlated with the difference of response to nifedipine between HSD and LSD (r = 0.78, P < .001). Plasma renin activity correlated inversely with DLF on LSD (r = -0.51, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Simplified micromethod for the HPLC measurement of diclofenac in plasma.

A simple and sensitive micromethod based on HPLC is described for the measurement of diclofenac in 200 microliters plasma. A single extraction with dichloromethane in acidic medium was an essential clean-up step. Diclofenac and its internal standard (cyclohexendiphenyl propionic acid) was eluted at 3.3 and 6.5 min from a 4-micron C18 reverse-phase column using a mobile phase consisting of 0.75 M sodium acetate buffer, pH 5.0, and acetonitrile (55:45, v/v) at a flow rate of 0.9 ml/min with detection at 282 nm. The method, validated on the basis of parameters evaluated for the confidence limits of diclofenac measurements in spiked plasma, presented 1 ng/ml sensitivity, 10-10,000 ng/ml linearity, and 3.5% and 5.7% intra- and interassay precision, respectively. Peak plasma diclofenac levels ranging from 177 to 841 ng/ml and from 276 to 1008 ng/ml were obtained for two slow-release formulations. A wide range (1 ng/ml-3 micrograms/ml) was observed for plasma diclofenac levels of volunteers during a 24-h study period.

Chromatography, High Pressure Liquid↗
PubMed1992

Ranitidine increases the bioavailability of nitrendipine in patients with arterial hypertension.

1. In a randomized placebo-controlled study, 12 hypertensive patients were treated po for one week with 20 mg nitrendipine once daily plus placebo, twice daily and later with the same dose of nitrendipine plus 300 mg ranitidine (150 mg twice a day). 2. When ranitidine was coadministered, plasma nitrendipine levels (0-24 h) were significantly increased (P < 0.001), although no significant increase in peak plasma nitrendipine level (Cmax) was observed due to the wide range of variation of this parameter (Cmax) in hypertensive patients. 3. Ranitidine coadministration increased the area under the curve for 24-h (AUC0-24) plasma concentration vs time, from 49.07 +/- 6.28 micrograms.h/l to 82.35 +/- 2.57 micrograms.h/l (P < 0.01). This significant increase caused a reduction in total body clearance from 2008.33 +/- 246.33 to 1284.00 +/- 182.16 ml/min (P < 0.002). 4. Nitrendipine bioavailability was increased by 89% when ranitidine was coadministered but the kinetic effect of this drug interaction is unlikely to be of clinical relevance since no adverse effects were observed in patients evaluated after ranitidine association.

Adult↗
PubMed1989

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

In 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 x min-1) was 196 ng x ml-1 x h compared to 97.8 ng x ml-1 x h in control subjects (median creatinine clearance 94.4 ml x 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.

Aged↗
PubMed1989

Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements.

In a randomized placebo-controlled study 12 healthy volunteers were treated for 1 wk each with 10 mg of nifedipine four times daily plus placebo or the same dose of nifedipine concurrently with 40 mg of famotidine once a day. Famotidine did not significantly alter pharmacokinetic parameters of nifedipine. Determination of systolic time intervals showed that the preejection period and the ratio of the preejection period and the left ventricular ejection time were significantly reduced by administration of nifedipine plus placebo. Coadministration of famotidine and nifedipine, however, led to a significant increase of these parameters. In an additional double-blind study, a significant rise of the preejection period and of the ratio was detected after administration of famotidine alone. In impedance cardiography stroke volume and cardiac output were significantly reduced by famotidine. Heart rate and blood pressure values were not altered by the H2-antagonist. For the first time, to our knowledge, the observed changes of hemodynamic parameters appear to indicate that famotidine may exert negative effects on cardiac performance which, in our opinion, could be of clinical relevance in elderly subjects or in patients with heart failure.

Adult↗
PubMed1988

Influence of nitrendipine and verapamil on plasma levels, urinary excretion, and beta-blocking effect of metoprolol.

Following randomized allocation eight healthy volunteers were treated for 1 week each with metoprolol alone (100 mg twice daily), verapamil 80 mg three times a day plus metoprolol 100 mg twice daily, and with nitrendipine 20 mg twice daily. Plasma levels and urinary recovery of the beta-blocker, antipyrine clearance, and heart rate on exercise were measured. Verapamil and nitrendipine slightly prolonged elimination half-life of metoprolol. The urinary recovery of the parent beta-blocker and of its alpha-hydroxy metabolite was elevated by both calcium antagonists (verapamil and nitrendipine). Exercise tachycardia (150 beats/min without drugs) was inhibited more pronounced on the combination therapies than under metoprolol administration alone. Results of the present study indicate that calcium antagonists enhance inhibition of exercise tachycardia caused by metoprolol, possibly due to their binding to myocardial beta-adrenergic receptors which is known from the literature. As both calcium antagonists did not increase plasma levels of metoprolol, in the present study a kinetic interaction between the beta-blocker and the calcium channel blockers investigated does not appear to be responsible for the pharmacodynamic effects observed.

Adult↗
PubMed1987

Simultaneous analysis of digitoxin and its clinically relevant metabolites using high-performance liquid chromatography and radioimmunoassay.

A specific assay for determining the urinary excretion of unchanged digitoxin and its metabolites is described. The procedure includes solvent extraction of urine at pH 8.5, reversed-phase high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA) of equivalent fractions. Confidence limits showed good linearity and precision of recovery and high sensitivity, accuracy and specificity. Cross-reactivities were high for digitoxigenin (DGTN) and digitoxigenin bisdigitoxoside (Bis-DGTN), they were low for digitoxigenin monodigitoxoside (Mono-DGTN) or digoxin when [125I]digitoxin RIA was used. The interference of endogenous compounds in urine in the RIA was overcome by using HPLC. Compared with results reported in the literature, the urinary recovery of unchanged digitoxin was lower, being only 8.11 +/- 1.51% of the dose administered. Amounts of 6.52 +/- 1.31% were excreted hydrolysed as Bis-DGTN, Mono-DGTN, DGTN or C12-hydroxylated as digoxin.

Adult↗
PubMed1987

Bioavailability and elimination of nitrendipine in liver disease.

Twenty 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. Afterwards 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.

Administration, Oral↗
PubMed1987

Nitrendipine/digoxin interaction.

The effect of nitrendipine in two different dosages on digoxin plasma levels, urinary recovery, and systolic time intervals was investigated in eight healthy volunteers. Following an adequate loading dose of the glycoside, 0.25 mg digoxin twice daily was given alone for 2 weeks orally. After that, 0.25 mg digoxin twice daily was administered for two 1-week periods combined with nitrendipine, 10 mg or 20 mg once daily. The study was completed with a second digoxin monotherapy phase lasting seven days. Nitrendipine, 20 mg daily, led to a significant increase of the digoxin plasma concentration and of its area under the plasma concentration-time curve (AUC0-12) compared with digoxin monotherapy. Thus, AUC0-12 was 9.7 +/- 0.75 ng ml-1 h (X +/- SEM) when digoxin was given alone and was 11.2 +/- 0.92 ng ml-1 h under coadministration of the calcium antagonist (p less than 0.05). Nitrendipine in the dosage of 10 mg once daily caused a small, insignificant tendency to elevate digoxin plasma levels. In conclusion, nitrendipine, 20 mg daily, causes a significant increase of digoxin plasma concentration and of its AUC, which in certain patients might be of clinical relevance.

Adult↗
PubMed1986

Effect of two different doses of nitrendipine on steady-state plasma digoxin level and systolic time intervals.

The effect of two different doses of nitrendipine on plasma digoxin levels, urinary recovery and systolic time intervals was investigated in 8 healthy volunteers. Following a loading dose, digoxin 0.25 mg b.d.p.o. was given alone for 2 weeks. Then 0.25 mg digoxin b.d. was administered for two 1-week periods combined with nitrendipine 10 mg or 20 mg once daily. The study was completed with another digoxin monotherapy phase lasting 7 days. Nitrendipine 20 mg daily led to a significant increase in plasma digoxin levels and in its area under the plasma concentration-time curve AUC (0-12) was 9.7 ng ml-1h when digoxin alone was given and 11.2 ng ml-1h on co-administration of the calcium antagonist. Urinary recovery and renal clearance of digoxin were slightly but not significantly increased by nitrendipine. Nitrendipine 10 mg once daily caused a small, insignificant tendency to elevate the plasma digoxin level. Nitrendipine co-administration (10 and 20 mg once daily) did not significantly alter systolic time intervals, as non-invasively measured haemodynamic parameters, compared to digoxin treatment alone. Thus, nitrendipine 20 mg daily caused a significant increase in plasma digoxin concentrations and in its AUC, which would rarely be of clinical relevance.

Adult↗
PubMed1986

Influence of nisoldipine on haemodynamic effects and plasma levels of digoxin.

In a placebo controlled double-blind study including 10 patients with heart failure the nisoldipine/digoxin interaction was studied. Nisoldipine was shown to elevate digoxin plasma concentrations significantly by about 15% (trough levels). During chronic combination therapy with nisoldipine trough levels and plasma concentrations 4 h after the morning dose of digoxin were 1.35 +/- 0.14 and 1.92 +/- 0.16 ng ml-1 respectively, whereas they averaged to 1.16 +/- 0.14 and 1.52 +/- 0.16 ng ml-1 with digoxin and placebo (P less than 0.05; mean +/- s.e. mean). Systolic time intervals were significantly altered by nisoldipine co-administration compared with digoxin plus placebo. In certain patients the elevation of digoxin plasma levels due to nisoldipine co-administration could be of clinical relevance.

Adult↗