Long-term tacrine treatment in Alzheimer's disease.
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Alzheimer Disease↗
Biomedical subjects
M Farré
Publications and source records attributed to M Farré.
[Ecstasy, the drug of the route of bakalao].
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Hallucinogens↗
A comparison of the acute behavioral effects of flunitrazepam and triazolam in healthy volunteers.
Flunitrazepam is an hypnotic benzodiazepine marketed in different European countries. Epidemiological studies have shown that it is frequently abused by opioid addicts. In a survey, "liking" scores for flunitrazepam in methadone maintenance patients were higher than ratings for other benzodiazepines. A double-blind, placebo controlled, crossover clinical trial was conducted to assess the acute behavioral effects of flunitrazepam (0.50 and 2 mg) and triazolam (0.25 and 0.50 mg) in healthy male volunteers. Drug effects on physiological measures, psychomotor performance, and subjective rating scales, including specific questionnaires to evaluate abuse liability (e.g., ARCI or "liking" scores), were assessed before and 6 h after drug administration. Flunitrazepam 2 mg produced the most intense disruptive effects on all the performance tasks, triazolam 0.50 impaired performance except balance. All study drugs at all doses produced sedation symptoms in all or part of the subjective effects questionnaires. Only flunitrazepam 2 mg induced significative increases in some of the scales ("liking", "good effects", "high") that could be related to a possible abuse potential. The results seem to indicate that flunitrazepam, when administered to healthy subjects, produces some pleasurable subjective feelings, that could indicate a higher abuse liability of this drug as compared with other benzodiazepines.
Adult↗
Gingival enlargement induced by drugs.
Gingival enlargement, an abnormal growth of the periodontal tissue, is mainly associated with dental plaque-related inflammation and drug therapy. Its true incidence in the general population is unknown. Gingival enlargement produces aesthetic changes, pain, gingival bleeding and periodontal disorders. Although gingival overgrowth has been traditionally recognised as an adverse effect of phenytoin therapy, it has recently been reported in association with the use of cyclosporin and calcium antagonists. These 3 classes of drugs produce important changes in fibroblast function, which induce an increase in the extracellular matrix of the gingival connective tissue. In the majority of those patients for whom dosage reduction, or drug discontinuation or substitution is not possible, and for whom prophylactic measures have failed, surgical excision of gingival tissue remains the only treatment of choice.
Anticonvulsants↗
Respiratory and analgesic effects of meperidine and tramadol in patients undergoing orthopedic surgery.
The respiratory and analgesic effects of i.v. meperidine, tramadol and their correlation with plasma concentrations of meperidine, tramadol and O-demethyltramadol were determined. Forty-eight patients after total hip or knee replacement were randomly distributed into 3 groups (n = 16 each). At the time of analgesia request, they received in a double-blind manner, i.v. single doses of 100 mg meperidine, 100 mg tramadol, or saline. Thirty minutes after treatment, patients who requested additional analgesia were rescued with 75 mg diclofenac and morphine as required. Patients were evaluated at the time of analgesia request and at set intervals during 4 h. Meperidine induced sedation (p < 0.05), respiratory depression (tidal volume, p < 0.047; respiratory rate, p < 0.004; % O2 Sat, p < 0.036), and hypercapnia (PaCO2, p < 0.002). Incidence of nausea and vomiting was higher with tramadol (p < 0.02). For the first 30 min, meperidine produced lower pain intensity scores than tramadol or saline (p < 0.05). At this time, 14/16 patients on saline, 8/16 on meperidine and 11/16 on tramadol were rescued. Onset for meperidine analgesia was 10 min and > 30 min for tramadol. Both opioids produced similar degree of analgesia in patients who were not rescued. A negative correlation (r = -0.99) between analgesia and tramadol concentrations and a poor positive correlation (r = +0.54) with O-demethyltramadol (a metabolite of tramadol) was observed. Pain intensity differences correlated negatively with meperidine plasma concentrations during the first 30 min (r = -0.97) and positively thereafter (r = +0.92). In the present study, meperidine and tramadol produced comparable analgesia, with a different time course profile, but meperidine induced sedation and respiratory depression while tramadol did not.
Aged↗
Radiolocalization of squamous lung carcinoma with 131I-labeled epidermal growth factor.
Overexpression of epidermal growth factor receptor (EGFr) in squamous carcinomas has been demonstrated extensively. Preliminary clinical studies have shown that radiolabeled anti-EGFr monoclonal antibodies can localize to these tumors. The aims of this study were to determine the tolerance, pharmacokinetics, and radiolocalization properties of 131I-labeled EGF in patients (n = 9) with advanced squamous lung cancer. Patients' vital signs and symptoms were monitored regularly for 3 days. Daily scintigrams and biological samples for pharmacokinetic analysis were obtained for 3-4 days. 99mTc-labeled human serum albumin was administered to patients with positive tumor scans. Six patients had positive tumor scans, and five of them had received >/=1.0 mg EGF. In all of these cases, tumors were visualized the same day of the infusion, although best tumor-background contrast was obtained at 50-74 h. There were no false-positive images. Whole-body radioactivity retention rose significantly with increasing EGF doses; most labeled EGF was eliminated by urinary excretion. Tumor:normal tissue uptake ratios increased during the course of the study. All patients presented self-limited, dose-related gastrointestinal adverse effects. In conclusion, recombinant 131I-labeled EGF administered i.v. can localize to squamous lung cancer efficiently, can be administered safely to patients, and has more advantageous pharmacokinetic properties than monoclonal antibodies. Further studies are warranted to determine more accurately the potential of EGF and EGF-related peptides in the imaging and/or therapy of EGFr-overexpressing human cancers.
Aged↗
[Clinical pharmacologists and clinical research ethics committees].
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Ethics Committees↗
Inadequate levels of metronidazole in subcutaneous fat after standard prophylaxis.
The efficacy of antibiotic prophylaxis depends on appropriate tissue levels of the drug being present at the time of potential wound contamination. Metronidazole concentrations in serum, muscle and subcutaneous fat were measured after a single intravenous dose given at two different intervals before operation. Twenty-six patients undergoing abdominal wall procedures were divided into two groups. Patients in group 1 received metronidazole 500 mg intravenously 2 h before surgery, and those in group 2 were given the drug during induction of anaesthesia. Mean plasma levels of metronidazole at the beginning of the procedure were significantly lower (P = 0.01) in group 1 (7.3 (95 per cent confidence interval 5.7-8.9)) micrograms/ml than in group 2 (12.3 (8.9-15.7)) micrograms/ml although in both cases were above the minimum inhibitory concentration for 90 per cent of Bacteroides fragilis. Similar therapeutic concentrations of metronidazole were achieved in plasma and muscle in both groups at the end of the operation. However, patients in both groups had non-therapeutic concentrations of metronidazole in subcutaneous fat: group 1 0.9 (0.6-1.2) micrograms/mg, group 2 1.2 (0.7-1.7) micrograms/mg at the beginning of operation, and 1.2 (0.8-1.6) and 1.5 (0.9-2.1) micrograms/mg respectively at the end of the procedure. It is concluded that infusion of metronidazole 2 h before surgery or during induction of anaesthesia achieved adequate plasma and muscle levels but failed to achieve therapeutic levels in subcutaneous fat.
Adipose Tissue↗
Determination of cocaine and its metabolites in human urine by gas chromatography/mass spectrometry after simultaneous use of cocaine and ethanol.
Cocaethylene is an active metabolite produced when cocaine is consumed jointly with ethanol. The development of analytical techniques for determining cocaethylene and other cocaine metabolites is highly relevant for pharmacokinetic and toxicology studies of the cocaine and alcohol interaction in humans. The gas chromatography/mass spectrometry (GC/MS) method here reported is based on a single solid-phase extraction together with deuterated internal standards previously added to urine, followed by derivatization with pentafluoropropionic anhydride (hydroxyl and amine functions) and 1,1,1,3,3,3 hexafluor-2-propanol (carboxylic acid function) and injection into a capillary GC system coupled to a mass spectrometric detector in the selected ion monitoring acquisition mode. A sensitivity of 1-2 ng ml-1 for the quantitative analysis of cocaine and its main metabolites (ecgonine methyl ester, benzoylecgonine, cocaethylene and norcocaine) was achieved. In addition, some other minor metabolites were easily extracted and detected.
Adult↗
Sensation seeking amongst healthy volunteers participating in phase I clinical trials.
1. Phase I clinical trials are usually carried out in healthy volunteers. In addition to economic gain, factors that may influence willingness to participate include scientific interest, curiosity and choice for risky activities. 2. We assessed the relationship between personality variables and volunteering for clinical pharmacology research. Two personality questionnaires, the Sensation Seeking Scale (SSS, form V) and the Eysenck Personality Questionnaire (EPQ), were administered to 48 male healthy university students who volunteered to participate in a phase I clinical trial and to 43 male university students who were not willing to participate in phase I clinical trials. General norm data were also used for the comparison of results. 3. When healthy volunteers were compared with unwilling subjects, significant differences were found in thrill-and-adventure seeking (7.9 vs 6.7, P = 0.0034), experience seeking (6.4 vs 5.2, P = 0.0012), disinhibition (6.2 vs 4.3, P < 0.0001), boredom susceptibility (3.9 vs 2.8, P = 0.0073), total sensation seeking trait (24.3 vs 19.0, P < 0.0001), extraversion (15.1 vs 13.3, P = 0.0490), and psychoticism (4.4 vs 3.5, P = 0.0086). When healthy volunteers were compared with general norm data similar statistically significant differences were found in all these scales, except for boredom susceptibility and psychoticism. 4. The personality profile of healthy volunteers was characterized by a higher sensation seeking trait and extraversion as compared with individuals who were not willing to participate in phase I clinical trials and general norm data.
Adult↗
CYP1A2-catalyzed conversion of dietary heterocyclic amines to their proximate carcinogens is their major route of metabolism in humans.
The contribution of CYP1A2 to the metabolism of the dietary heterocyclic amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in vivo in humans, has been determined with furafylline, a highly selective inhibitor of this enzyme. The inhibitory potential of furafylline in vivo was first assessed by determining its effect on clearance of phenacetin to paracetamol by the model CYP1A2-dependent O-deethylation pathway. Furafylline inhibited this reaction by > 99% in all subjects, thus demonstrating its applicability to determining the contribution of CYP1A2 to a given reaction in vivo. A group of 6 healthy male volunteers received either placebo or 125 mg furafylline, in a double-blind balanced crossover design, 2 h prior to consuming a test meal of fried beef containing a known amount of amines. The excretion of PhIP and MeIQx in urine was determined during the subsequent 28 h, using gas chromatography-mass spectrometry. Following furafylline, the excretion of unchanged MeIQx increased 14.3-fold, while that of PhIP increased 4.1-fold (P < 0.01, paired t test). Elimination of both amines was first order and very rapid, with half-lives of < 5 h. The elimination rate constants did not change following furafylline, suggesting that total clearance is limited by hepatic blood flow. Because the elimination of the amines was first order, it was possible to calculate the contribution of CYP1A2 to the clearance of the amines. CYP1A2-catalyzed metabolism accounts for 91% of the elimination of ingested MeIQx and 70% of ingested PhIP, most likely via N-hydroxylation.
Adult↗
Spanish version of the 49-item short form of the Addiction Research Center Inventory (ARCI).
The Spanish version of the 49-item short form of the Addiction Research Center Inventory (ARCI) was assessed in simulated drug conditions. After the translation process was completed, the questionnaire was administered to forty-five adult polydrug abusers who were residing in a general hospital. Subjects answered the questionnaire on four occasions, describing the feelings they usually experienced under the effects of four classes of drugs of abuse (morphine-like opioids, alcohol, stimulants and hallucinogens). The scales showed an acceptable level of internal consistency. A characteristic pattern of response was obtained for each condition. A discriminant analysis revealed that four scales PCAG (pentobarbital-chlorpromazine-alcohol group), MBG (morphine-benzedrine group), LSD (lysergic acid dyethylamide scale) and BG (benzedrine group) significantly discriminated between the conditions studied. Sixty percent of the questionnaires answered were correctly classified according to the discriminant functions constructed. The results from this study are similar to those obtained with the English ARCI, and suggest that the Spanish version of the 49-item ARCI may be an useful instrument for the evaluation of subjective effects produced by psychoactive drugs in Spanish populations.
Adult↗
Effects of morphine in postaddict humans: a meta-analysis.
The literature on assessment of abuse liability of opioid drugs in humans was reviewed, and meta-analysis (a statistical method designed to combine results of different studies) was performed to study a dose-effect relationship for some variables commonly used for the evaluation of the subjective and physiological effects of morphine. Thirty-five studies, published between 1964 and 1991, including the i.m. or s.c. administration of morphine to non-dependent subjects with prior history of opioid abuse, were selected. Logistic regression models were applied for categorically dependent variables, and linear regression models were used for quantitative dependent variables. The log-transformation of the dose of morphine, stratifying by studies, acted as predictor variable. A dose-effect function was demonstrated. Doses producing an average effect across studies ranged from 7 mg (observers-reported 'liking') to 12 mg (subjects-reported 'liking'). Average effect on pupil diameter decreases was obtained for a dose of 8 mg. Doses producing a 50% of maximum positive responses were 10 mg for subjects' opioid classification, and 20 mg for the ARCI-MBG scale. The heterogeneity between studies obtained, along with the large variability present in most of the variables, supports the usefulness of a concurrent assessment of several indexes when assessing the effects of morphine.
Arousal↗
Acute effects of tramadol in methadone-maintained volunteers.
The opioid agonist and antagonist properties of tramadol were assessed in 6 male opioid-dependent volunteers enrolled in a methadone maintenance programme. Subjects participated in 3 experimental sessions in which the effects of intramuscular tramadol 100 and 300 mg and placebo were evaluated. Tramadol neither produced morphine-like effects nor precipitated a withdrawal syndrome; its subjective, behavioural and physiological effects were not different from those of placebo. Although the results of this study suggest that tramadol has a low abuse liability in opioid-dependent subjects, higher doses should be tested to confirm these data.
Adult↗
Flunitrazepam consumption among heroin addicts admitted for in-patient detoxification.
The use of benzodiazepines among 973 heroin addicts admitted for inpatient detoxification over a 10-year period was assessed in a cross-sectional study. A total of 780 (80.2%) patients had a history of benzodiazepine use; 666 (68.5%) were consuming benzodiazepines at the time of admission and 419 (43.1%) on an almost daily basis. Seventy-five (7.7%) patients fulfilled criteria for sedative-hypnotic abuse or dependence. Consumption of benzodiazepines began after subjects had become addicted to heroin. Flunitrazepam was ranked first by 68.4% of patients, followed by clorazepate (13%), and diazepam (12.4%). The prevalence of benzodiazepine use, in particular flunitrazepam, among heroin addicts is very high. Specific abuse liability studies are needed to determine whether pharmacologic reasons exist to explain heroin addicts' preference for this compound.
Anti-Anxiety Agents↗
Alcohol and cocaine interactions in humans.
The effects of 100 mg of intranasal cocaine (COC) in acute alcohol intoxication (1 g/kg) was assessed in nine experienced and non-dependent healthy volunteers in a double-blind, controlled, randomized, cross-over clinical trial. Alcohol alone impaired psychomotor performance, whereas COC alone produced subjective effects related to euphoria and well-being, improved the reaction time and increased heart rate and blood pressure. The combination of COC and alcohol induced a nonsignificant decrease in the subjective feelings of drunkeness, an increase in COC-induced euphoria, a significant improvement in alcohol-related changes in psychomotor performance and a marked increase in heart rate. Subjects experienced subjective and performance effects that could be self-interpreted as more pleasant compared to the effects of alcohol alone. When alcohol was given simultaneously, COC plasma levels were higher (possibly as a result of an inhibition of hepatic metabolism of COC produced by alcohol), norcocaine plasma levels almost doubled and cocaethylene was detected in plasma, so that its basic pharmacokinetic profile could be described. The simultaneous use of both drugs produced changes in heart rate and blood pressure that could increase the risk of cardiovascular toxicity associated with the use of COC.
Adult↗
Volunteering for research.
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Clinical Trials, Phase I as Topic↗
[Treatment of acute pain in a general hospital: opinions of physicians and nurses].
A survey was carried amongst physicians and nurses of a general hospital, in order to know their opinion about acute pain treatment. Out of 106 physicians and 153 nurses questioned, 72 and 105 respectively answered the questionnaire. Two thirds of them though that analgesic treatment was currently good, although, it could be improved if they increased their knowledge about it. Twenty nine per cent of physicians thought that their patients were receiving lower doses than what they had prescribed and that this fact could be responsible for the treatment failure. Those questioned believed that approximately 30% of patients treated with opium derivatives for over a week could develop addiction problems. Our study confirmed the existence of inadequate attitudes towards the need for analgesics in patients with acute pain.
Acute Disease↗