Grounds for the integration of pharmacokinetic-pharmacodynamic data.
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Biomedical subjects
Publications and source records attributed to F Jané.
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The aim of the present study was to determine whether or not the pharmacokinetic and hemodynamic response to a 20 mg single oral dose of lisinopril was sex-dependent. Thirty-two young healthy volunteers (16 males and 16 females) were included in the trial. Blood samples to assess lisinopril plasma concentrations, determined indirectly by inhibition of the angiotensin converting enzyme (ACE) and hemodynamic variables, were obtained before and at different times following drug intake. No significant differences in pharmacokinetic parameters were observed between males and females. An hypotensive response was obtained between 2 and 10 h for systolic blood pressure and between 2 and 24 h for diastolic blood pressure. Again, no significant sex-related differences were noted. Lisinopril was well tolerated.
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1. The dynamic and kinetic interactions of alcohol and caffeine were studied in a double-blind, placebo controlled, cross-over trial. Treatments were administered to eight healthy subjects in four experimental sessions, leaving a 1 week wash-out period between each, as follows: 1) placebo, 2) alcohol (0.8 g kg-1), 3) caffeine (400 mg) and 4) alcohol (0.8 g kg-1) + caffeine (400 mg). 2. Evaluations were performed by means of: 1) objective measures: a) psychomotor performance (critical flicker fusion frequency, simple reaction time and tapping test), b) long latency visual evoked potentials ('pattern reversal'); 2) subjective self-rated scales (visual analogue scales and profile of mood states); 3) caffeine and alcohol plasma concentration determinations. 3. The battery of pharmacodynamic tests was conducted at baseline and at +0.5 h, +1.5 h, +2.5 h, +4 h and +6 h. An analysis of variance was applied to the results, accepting a P < 0.05 as significant. The plasma-time curves for caffeine and alcohol were analysed by means of model-independent methods. 4. Results obtained with caffeine in the objective measures demonstrated a decrease in simple reaction time and an increase in the amplitude of the evoked potentials; the subjects' self-ratings showed a tendency to be more active. Alcohol increased simple reaction time and decreased amplitude of the evoked potentials, although the subjects rated themselves as being active. The combination of alcohol + caffeine showed no significant difference from placebo in the objective tests; nevertheless, the subjective feeling of drunkenness remained. The area under the curve (AUC) for caffeine was significantly higher when administered with alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of this study was to investigate the gender-related pharmacokinetic differences after a single oral dose of diltiazem (120 mg) in 12 healthy subjects (6 males and 6 females). Kinetic parameters were calculated from serum concentrations obtained by means of a specific HPLC method. The total area under the concentration-time curve (AUC0-infinity) was 917.03 +/- 342.13 ng.h-1/ml for females and 1,192.97 +/- 329.93 ng.h-1/ml for males. Peak serum levels (Cmax) were 181.29 +/- 48.03 ng/ml and 194.29 +/- 93.81 for females and males, respectively. The time to reach maximum concentration (Tmax) was 2.2 +/- 0.8 h for both. The biological elimination t1/2 was 4.58 +/- 2.08 h and 5.59 +/- 2.44 h, showing an elimination rate (kel) of 0.174 +/- 0.062 h-1 and 0.149 +/- 0.075 h-1, and a mean residence time (MRT) of 8.56 +/- 1.94 h and 8.88 +/- 2.78 h for females and males, respectively. Male subjects showed higher values than females, but no significant difference was observed when comparing pharmacokinetic parameters by gender. Diltiazem was well tolerated by all subjects.
The methodological quality of 50 clinical trial protocols submitted to our hospital has been assessed by means of a check-list. The most frequent methodological deficiencies found were related to statistical analysis, selection criteria, sample size, incorrect use of placebo, homogeneity of the groups, concomitant medication, randomisation plan, monitoring of adverse events and study design. Lack of insurance for the patients and inadequacies in the investigators' brochure and case report forms were observed in a significant number of cases. The results suggest the importance of a multidisciplinary team in the elaboration of clinical trial protocols to prevent methodological errors.
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In a placebo-controlled, double-blind, crossover study with a washout phase of 2 months between each treatment period, single daily doses of 10 and 30 mg of astemizole were given to 12 patients with extrinsic asthma during 28 consecutive days. Albuterol was allowed as concurrent medication when needed. On days 0, 7, and 28 specific bronchial provocation with Dermatophagoides pteronyssinus and cutaneous tests with histamine and D. pteronyssinus extracts were carried out. The requirements of beta-agonist inhalations and the number of bronchospasm episodes were recorded throughout the study period. Inhibition of allergen-induced bronchoconstriction appeared on day 7 with 30-mg doses of astemizole, while it was not observed until day 28 with 10-mg doses. Wheal responses caused by histamine were reduced only after active treatment. The wheal response to the highest allergen concentration was reduced on days 7 and 28 after 30 mg of astemizole, whereas doses of 10 mg only caused a reduction on day 28. It is concluded that astemizole could be useful as a therapeutic agent in the treatment of certain types of asthma.
Droxicam acts by inhibition of PGE2 varies. Although it belongs to the oxicam family, it is characterised by being a pro-drug of piroxicam, the molecule undergoing conversion by hydrolysis once dissolved in the digestive tract. This allows us to suppose in principle that, there being less contact between the active drug (piroxicam) and the gastric mucosa, the side effects in the said mucosa would be slight. The studies which have already been performed in healthy volunteers and in patients with osteoarthritis and rheumatoid arthritis, to evaluate the efficacy and the tolerance of droxicam in patients suffering from such clearly inflammatory processes demonstrate an analgesic potential and anti-inflammatory effects which become noticeable after two weeks of treatment, and the drug is well-tolerated.
Most allergic reactions to aminophylline are caused by hypersensitivity to ethylendiamine. We present 3 asthmatic patients, 2 of whom had immediate allergic symptoms after the administration of aminophylline. The third patient presented generalized erythrodermia 24 hours after receiving aminophylline. In all three cases sensitivity to ethylendiamine was observed in skin testing. These patients can tolerate other theophylline preparations not containing ethylendiamine.
We present evidence showing that paraxanthine (1,7-dimethylxanthine), the main metabolite of caffeine in man, displaces the binding of [3H]SCH 23390, a radioligand which selectively labels dopamine D-1 receptors when used at low concentrations, from striatal membranes of the rat. The displacement was competitive and indicated the existence of two affinity states (Hill coefficient = 0.49; K(high) = 0.15 microM; K(low) = 95.9 microM, %R(high) = 32.4). When the stable GTP analog Gpp(NH)p was included, the displacement curve indicated the presence of only the low-affinity state (Hill coefficient = 1.16; Ki = 72.1 microM). However, paraxanthine did not displace the specific binding of [3H]spiperone. After injection of 30 mg/kg s.c. of caffeine, a maximum of 10 microM of paraxanthine was found in striatal homogenates, which could be sufficient to occupy dopamine D-1 receptors. Our results suggest that a dopaminergic action of paraxanthine could be involved in the behavioural stimulation produced by caffeine.
The effects of chronic haloperidol treatment (0.5 mg/kg/day for 21 days) on maze learning in the rat were studied. There were no differences between haloperidol- and saline-treated groups in percentage of correct responses, but the latency to respond was longer and extinction was faster in the haloperidol-treated group. We speculated that differences between both groups were due to a decrease of appetitive motivation in haloperidol-treated animals, probably caused by a decrease of dopaminergic neurotransmission.
The use of psychotropic drugs in general has become more extended in the past 20 years. The elderly, particularly geriatric inpatients, are the group with the highest consumption. The aim of the present study was to evaluate in two groups of elderly, hospitalized patients (H) vs. nonhospitalized subjects (nH), psychotropic drug consumption related to psychological distress. This was carried out in a total 238 subjects aged above 65 years (112 geriatric inpatients and 126 interviewed in social welfare centers). Sociodemographic, clinical and pharmacological data, general health and psychological distress were evaluated. The latter was assessed by means of the Symptom Distress Checklist (SCL-90) which included 9 subscales. 23% of the subjects received psychotropic drugs (P), of which 84% were benzodiazepines, 10% antidepressants and 1.5% antipsychotics. After evaluating the SCL-90 subscales, it was noted that anxiety, depression and obsessiveness/compulsiveness scored higher in P subjects than in those not receiving psychotropic drugs (nP). When treated nH and H were analyzed separately, it was observed that the former scored higher in anxiety and depression, while the latter showed higher scores in anxiety and obsessiveness/compulsiveness. Considered globally, the H group compared to nH showed higher scores in depression. Although evaluating psychotropic drug utilization in geriatric patients is complex due to the large number of influencing factors, SCL-90 has proved to be useful for assessing the qualitative aspects of this drug consumption in the elderly.
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The contralateral rotational behaviour produced by apomorphine and caffeine has been studied in 100 rats with unilateral lesion of the nigrostriatal pathway induced with 6-OHDA. Rats with a two-peak rotational pattern induced by apomorphine, showed a greater number of contralateral turns, induced by apomorphine and caffeine, than rats which did not show this rotational pattern. A correlation was observed between the number of rotations induced by apomorphine and those induced by caffeine. A relationship between the two-peak rotational pattern induced by apomorphine and the initial-peak pattern induced by caffeine was also observed.
We studied apomorphine- and theophylline-induced rotational behaviour in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. It was seen that there was a direct correlation between the number of apomorphine- and theophylline-induced contralateral turns. These data suggest the existence of a relationship between theophylline-induced rotational behaviour and the degree of supersensitivity of the striatal dopaminergic receptors. Because the rotational behaviour induced by theophylline is in the same direction as dopaminergic agonists, contralateral to the nigrostriatal pathway lesion, these results suggest the possibility of a direct dopaminergic agonism of methylxanthines.
Drugs influencing hepatic microsomal enzyme systems, such as isoniazid, may affect the elimination pattern of theophylline. The case reported here refers to an adult female patient with a history of chronic asthma and intestinal tuberculosis who, during isoniazid therapy, presented with theophylline plasma concentrations above the therapeutic range and developed toxic symptoms. The initial episode of theophylline toxicity occurred after one month of coadministering isoniazed 300 mg/d and theophylline 350 mg bid. The theophylline plasma concentration during this episode was 24.1 micrograms/mL and was associated with the typical symptoms of theophylline toxicity. Rechallenge with isoniazide 300 mg/d and theophylline 400 mg bid showed a progressive increase in trough morning theophylline plasma levels, reaching a toxic concentration of 25.1 micrograms/mL on day 55. After withdrawal of isoniazid, theophylline concentrations gradually declined, reaching 12.9 micrograms/mL in 35 days. Theophylline toxicity in this patient might have been induced by chronic administration of isoniazid.