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At least 19 recordsLinked to original sources
PubMed1975

Alteration of drug pharmacodynamics by hyperlipidemia.

Circulating lipid levels, when elevated, can alter the pharmacodynamics of lipophilic drugs presumably by acting as an additional storage depot for such drugs. Prostaglandin E1 (PGE1) and phenylephrine produced less effect on the blood pressure of atherosclerotic-hyperlipidemic rabbits than of control rabbits. This difference was apparently not due to alterations in vascular smooth muscle since aortic strips from the normal and severely atherosclerotic rabbit responded identically to the contractile effects of these drugs. Further, hyperlipidemic rats which had not yet become atherosclerotic were less responsive to the convulsant effects of fluorthyl, a highly lipophilic drug. In the presence of emulsified fat the contractile response of the rat ileum in vitro to PGE1 and acetylcholine was greatly reduced. The inhibition was reversed when fat was removed from the bathing solution. The response to PGE1, which is more lipid-soluble than acetylcholine, was more sensitive to inhibition by the presence of lipid. Finally, the pharmacokinetics of intravenously administered sulfamerazine, a lipophilic drug, appeared to be altered in the hyperlipidemic rabbit.

Animals↗
PubMedDate not supplied

[Characteristics of drug pharmacodynamics in irradiated rats].

A whole-body exposure of rats to 8 Gy radiation is ineffective in 3 days, and in 6 days, it prolongs considerably the effect and increases the pharmacological activity of hexenal, meprobamate, ethylmorphine, and amidopyrine, inhibits the activity of amidopyrine demethylase, aniline hydroxylase, NADPH-cytochrome c reductase, and reduces the content of protein, cytochromes P-450 and b5 in a microsomal liver fraction.

Acute Disease↗
PubMed1979

Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine.

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time-independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non-equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first-order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least-squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d-tubocurarine (dTC). In 7 normal subjects, the (mean +/- SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 +/- 0.04 min-1 and the (mean +/- SD) steady-state Cp required to produce 50% paralysis is 0.37 +/- 0.05 microgram/ml.

Adult↗
PubMedDate not supplied

[The effect of phytin, benzonal and their combination administered prophylactically on the pharmacodynamics of drugs metabolized in the liver in hypokinesia].

Hexenal, meprobamate, amidopyrine and ethylmorphine produced a significantly marked effect in animals under hypokinesia as compared with normal rats. When phytin, benzonal and their combination were used for preventive purposes, impaired pharmacodynamics of the tested drugs metabolizing in the liver disappeared. The investigations demonstrated that the preventive use of phytin in combination with benzonal is the most optimal in correcting the impairments of drug pharmacodynamics in hypokinesia.

Aminopyrine↗
PubMedDate not supplied

Anxiety and substance use disorders: the treatment of high-risk patients.

Primary care physicians routinely treat patients with various anxiety disorders. These patients may have a substance use disorder or may be at high risk for abuse or addiction. Routine treatment of anxiety disorders with psychoactive drugs is successful in many patients, but it can lead to iatrogenic dependence in high-risk patients. This article describes addiction risk factors, drug pharmacodynamics, environment and environmental cues, and genetics. With these addiction risk factors in mind, the physician can apply a stepwise treatment protocol described in three progressive levels: conservative, nonpharmacological approaches; nonpsychoactive pharmacotherapy; and psychoactive pharmacotherapy. In addition, proper prescribing practices for high-risk patients are described in terms of diagnosis, dosage, duration, discontinuation, dependence, and documentation.

Anxiety Disorders↗
PubMed1989

Doxylamine and diphenhydramine pharmacokinetics in women on low-dose estrogen oral contraceptives.

Thirteen women chronically using low-dose estrogen-containing oral contraceptives (50 micrograms or less of ethinyl estradiol or its equivalent for a minimum of 3 months) and 12 age-matched drug-free control women received a single 25 mg oral dose of doxylamine succinate in the fasting state. Ten women taking oral contraceptives and ten controls received a single 50 mg oral dose of diphenhydramine hydrochloride. Multiple plasma samples drawn during 30 hours following the dose of doxylamine, and 12 hours after diphenhydramine dosage, were analyzed by gas chromatography using nitrogen-phosphorus detection. Mean pharmacokinetic variables for doxylamine in control and oral contraceptive groups were: peak plasma concentration, 103 vs 100 ng/ml; time of peak, 2.40 vs 1.87 hours after dosage, elimination half-life, 10.1 vs 10.2 hours; and total clearance, 3.70 vs 3.88 ml/min/kg. Mean pharmacokinetic variables for diphenhydramine in control and oral contraceptive groups were: peak plasma concentration, 63.7 vs 73.8 ng/ml; time of peak, 2.7 vs 2.2 hours after dosage; elimination half-life, 6.0 vs 5.1 hours; and total clearance, 21.8 vs 25.5 ml/min/kg. None of these differences were statistically significant. Thus, low-dose estrogen-containing oral contraceptives do not significantly influence the pharmacokinetics of the antihistamines doxylamine or diphenhydramine.

Adult↗
PubMed1990

Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal.

The single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10-20 cigarettes day). The plasma clearance of diflunisal was significantly higher in men (0.169 ml.min-1.kg-1) and in women on OCS (0.165 ml.min-1.kg-1) as compared to control women (0.108 ml.min-1.kg-1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml.min-1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml.min-1 respectively). Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2-87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.

Adult↗
PubMed1992

Population pharmacokinetics of imipramine in children.

The population pharmacokinetics of imipramine (IMI) and its active metabolite desipramine (DMI) have been evaluated using 177 IMI and DMI serum levels from 49 enuretic children (6-13 y) on IMI treatment. Standard two stage (STS) and maximum likelihood (ML) methods were used to estimate fixed and random effect parameters of IMI. Simultaneous estimation of the drug and metabolite parameters was carried out by the STS method. The mean value of the elimination constant of the drug and metabolite were 0.0425 h-1 and 0.0359, h-1 respectively. Significantly higher variability was found in the pharmacokinetic parameters of the metabolite. According to these estimated pharmacokinetic parameters, the recommended dose for enuretic children should be 1.7 mg.kg-1.day-1. The population pharmacokinetic parameters obtained in the study permit dosage individualisation using a bayesian algorithm.

Adolescent↗
PubMed1990

Influence of oral contraceptives on drug therapy.

Interferences between drugs and oral contraceptives are considered to alter pharmacokinetics and thus the efficacy of steroidal hormones. It should be noted, however, that steroids can also modify the metabolism and pharmacodynamic effects of various substances. To the present knowledge, phase I (i.e., oxidation, demethylation) and phase II reactions (conjugation) are concerned. Drugs sharing those enzymatic systems with oral contraceptives experience either an increase in bioavailability by inhibition of oxidative metabolism or undergo accelerated elimination by induced conjugation. Such interaction may be of practical interest in subjects who take oral contraceptives and are simultaneously treated with antidepressants, antihypertensives, insulin, synthetic glucocorticoids, theophylline, and caffeine.

Biological Availability↗
PubMed1992

Comparison of artemether and chloroquine for severe malaria in Gambian children.

Artemether is an oil-soluble methyl ether of artemesinin (qinghaosu). It has been studied extensively in China, where it has been shown to be rapidly effective in severe falciparum malaria. Nearly all the patients studied previously were adults. We have investigated the efficacy of artemether in children with moderate or severe falciparum malaria. In the preliminary study of moderately severe malaria, 30 Gambian children were randomised in pairs to receive either intramuscular artemether (4 mg/kg loading dose followed by 2 mg/kg daily) or intramuscular chloroquine ('Nivaquine') 3.5 mg base/kg every 6 h. Both drugs were well tolerated and rapidly effective. The times to parasite clearance were significantly shorter in the artemether recipients (mean 36.7 [SD 11.3] vs 48.4 [16.8] h, p less than 0.05). 43 children with severe malaria were then randomised to receive intramuscular treatment with the same regimens of artemether (n = 21) or chloroquine (n = 22) as used in the preliminary study. 8 children (19%) died. There were no significant differences between the two groups in the clinical, haematological, biochemical, or parasitological measures of therapeutic response in survivors and there was no evidence of local or systemic toxicity. Despite similar parasite counts on admission, clearance times overall were longer in severe malaria than in moderate malaria. Artemether is a well tolerated and rapidly effective parenteral treatment for severe malaria in children, and would be especially valuable in areas with chloroquine-resistant P falciparum.

Animals↗
PubMed1992

Epidemiology of isotretinoin exposure during pregnancy.

BACKGROUND: Exposure to isotretinoin during pregnancy is associated with a high risk of major fetal malformations. OBJECTIVE: Our purpose was to determine the reasons for and outcomes of in utero isotretinoin exposure. METHODS: On the basis of 433 spontaneous reports, we describe the likely reasons these exposures occurred and the outcomes of these pregnancies. In our analysis of the outcomes of pregnancy, we separately consider the pregnancies known to us before their outcomes were determined as prospective cases. RESULTS: Timing of conception in relation to initiation of therapy with isotretinoin was known for 396 women. Of these, 130 patients (33%) were already pregnant when they started isotretinoin. An additional 65 patients (16%) became pregnant in the first 3 weeks of isotretinoin use. Pregnancy outcomes were known on 409 pregnancies. Among these, 222 (54%) ended in elective abortion and 29 (7%) in spontaneous or missed abortion. Of 151 births, 72 (48%) were normal, 71 (47%) had congenital malformations, and 8 (5%) had abnormalities other than malformations. Of 94 prospectively ascertained pregnancies that ended in births, 28% had congenital malformations (95% confidence interval 19% to 37%). Exposure to isotretinoin during any time and for as little as one capsule within the first trimester have been associated with congenital malformations. CONCLUSION: The high proportion of exposures in already or recently pregnant women illustrates the importance of obtaining a negative pregnancy test before the initiation of isotretinoin therapy and of delaying the commencement of isotretinoin therapy until the onset of the next menstrual period. Furthermore, the importance of reliable contraceptive methods should be emphasized to patients when isotretinoin is prescribed. Young women seem to be at an especially high risk of pregnancy exposure to isotretinoin. There is a substantial risk of congenital malformation at all therapeutic doses of isotretinoin, even when the duration of exposure is brief.

Abnormalities, Drug-Induced↗
PubMed1988

Pharmacodynamics of the antiprogesterone RU486 in women after oral administration.

The pharmacokinetic characteristics of RU486 and its acute effects on anterior pituitary hormone secretion after oral administration were examined in six normal women. Serum RU486 concentrations were determined by a radioimmunoassay. The absorption of RU486 was rapid with peak serum levels reached approximately 90 minutes after a single oral dose (4 mg/kg). The disappearance of RU486 and its metabolites conformed to a noncompartmental model with a mean apparent half-life of 53.7 +/- 6.9 hours. The mean apparent volume of distribution and clearance rate were 1.47 +/- 0.25 l/kg and 1.04 +/- 0.09 1/hour, respectively. In comparison with a control group of normal women (n = 9), there were significant elevations in transverse mean cortisol levels in the RU486 group (P less than 0.01). However, mean adrenocorticotropic hormone (ACTH) levels and the diurnal pattern of ACTH and cortisol secretion were not changed. RU486 induced a mild prolactin (PRL) elevation (P less than 0.01), whereas thyroid-stimulating hormone (TSH) and luteinizing hormone (LH) levels were not altered. In view of the relatively slow clearance rate for RU486 and its metabolites, our findings suggest that the pharmacologic action of RU486 is prolonged after a single oral dose.

Administration, Oral↗
PubMedDate not supplied

Drug interactions with fluconazole.

Fluconazole, a water-soluble bis-triazole antifungal agent that effectively penetrates the cerebrospinal fluid, is a highly selective inhibitor of the fungal cytochrome P450 system. In single-dose studies, coadministration of cimetidine and fluconazole (100 mg) resulted in an insignificant decrease in the absorption of fluconazole. The coadministration of rifampin and fluconazole (200 mg) decreased both the half-life and the area under the plasma concentration-time curve (AUC) of fluconazole. In multiple-dose studies, fluconazole (50 mg) did not significantly alter the pharmacokinetics of the two steroid components of an oral contraceptive. Coadministration of tolbutamide with fluconazole (100 mg) increased both the maximal plasma concentration and the AUC of tolbutamide without changing levels of blood glucose. The coadministration of cyclosporin A with a low dose of fluconazole (100 mg) was not associated with significant changes in the minimal and the maximal plasma concentrations of cyclosporin A. While higher doses of fluconazole (200 mg) did not affect endogenous steroids, coadministration resulted in changes in the pharmacodynamics of warfarin and the pharmacokinetics of phenytoin and cyclosporin A.

Adrenal Glands↗
PubMed1988

The effect of RU486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium.

Seventeen healthy women aged 24-45 years with regular menstrual periods, proven fertility and not using steroidal contraceptives or IUD were recruited for the study. The volunteers were followed during one control, one treatment and one follow-up cycle. Daily morning urine samples were obtained during the control and the treatment cycle. The samples were analysed with regard to pregnanediol glucuronide (P2-G), oestrone glucuronide (E1-G), oestradiol (E2), progesterone (P4), LH and creatinine. During the entire 3-month study the subjects kept a record of uterine bleeding and side effects. The subjects received 50 mg RU486 daily either on cycle days 7-10 (n = 7) or on cycle days 20-23 (n = 10). An endometrial biopsy was taken on cycle day 10 in the first group and on cycle days 21-28 in the second group of patients. Treatment during the proliferative phase caused significant prolongation of the cycle length due to a delay of the oestrogen and LH surge. However, once the oestrogen concentration started to increase, the remaining part of the cycle was normal. The length of the follow-up cycle was similar to that of the control cycle. The morphology of the endometrium did not differ from control samples taken from untreated women at the same time of the cycle. All ovulating women (n = 9) treated in the mid-luteal phase started to bleed on the 3rd to 4th day of the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

The effect of H2-receptor antagonist premedication on the duration of vecuronium-induced neuromuscular blockade in postpartum patients.

The clinical duration of vecuronium was measured in two groups of postpartum patients undergoing elective tubal ligation. Ten patients received no premedication and ten others ranitidine 150 mg orally the morning of surgery. The mean duration of action of vecuronium was 57.2 +/- 9.9 min in the unmedicated patients and 54.0 +/- 12.9 min in the ranitidine treated patients. These values were significantly greater than the mean value for nonpregnant control patients (35.3 +/- 8.4 min) but indistinguishable from the mean value for cimetidine pretreated patients (63.0 +/- 17.6 min) reported previously. The combined results of the previous and present studies provide convincing evidence that the clinical duration of vecuronium-induced neuromuscular blockade is significantly longer in the postpartum patient and independent of cimetidine or ranitidine pretreatment.

Female↗