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At least 163 records · Page 9Linked to original sources
PubMed1976

Assessment of drugs in schizophrenia. Asessment of drug-induced extrapyramidal reactions and of drugs given for their control.

I have tried to bring out some of the important methodological problems found in examining the effectiveness of drugs used in the control of druginduced parkinsonism by referring mainly to studies in which I have taken part. I hope I have shown that the whole topic is far less well understood than is often assumed. The main points may be summarized as follows: there is doubt as to whether many of the drugs used in controlling drug-induced parkinsonism are really effective; the results of many studies are conflicting; many studies contain serious flaws in design; methods for assessing extrapyramidal signs are not well developed; we are ignorant of the way in which drug-induced extrapyramidal signs change spontaneously. There is a clear need for further research in this area to improve techniques of assessment, to provide basic information on drug-induced syndromes, and to rigorously examine the efficacy of the drugs used in controlling them.

Amantadine↗
PubMed2005

Impact of parallel pathways of drug elimination and multiple cytochrome P450 involvement on drug-drug interactions: CYP2D6 paradigm.

The success of in vitro derived Ki values for predicting drug-drug interactions in vivo has been mixed. For example, the use of hepatic input concentration of inhibitor has resolved the negative and positive interactions on the qualitative level, eliminating false negative predictions. However, several examples of false positives and a high incidence of over-predictions of true positive interactions indicated a need for incorporation of additional factors. The aim of this study was to investigate the effect of parallel elimination pathways as a possible reason for false positives and over-predictions. Simulation studies indicated that the degree of interaction (assessed by area under the plasma concentration-time curve ratio in the presence and absence of inhibitor) depends largely on the fraction of substrate metabolized by the particular P450 enzyme (fmCYPi) that is inhibited. The current analysis focused on CYP2D6 interactions due to the well documented genetic polymorphism and the ability to estimate fmCYP2D6 readily from in vivo data obtained in extensive and poor metabolizers. Based on either a phenotype study or an alternative regression analysis approach, the fmCYP2D6 values of 0.37 to 0.94 and 0.25 to 0.89, respectively, were obtained for nine substrates. Prediction of 44 drug-drug interaction studies was improved by the combination of parallel pathways of elimination and their susceptibility to inhibition. The overall success of predicting positive and negative interactions was increased from 54% to 84%, and the number of over-predictions was substantially reduced. It is concluded that incorporating parallel pathways provides a valuable step forward in making quantitative predictions of drug-drug interactions from in vitro data.

Cytochrome P-450 CYP2D6↗
PubMed2003

[Drugs ototoxicity. Part II. Loop diuretics, nonsteroidal anti-inflammatory drugs, antineoplastic and antimalarial drugs ].

Ototoxicity has been recognized since the 1800, when it was learned that quinine and acetylsalicylic acid provoked dizziness, tinnitus and hearing loss. Beside above mentioned other drugs also have joined the list of ototoxic substances: aminoglycoside antibiotics, loop diuretics or antineoplastic drugs. In this review pharmacological and toxicological properties of potentially ototoxic drugs, such as loop diuretics, nonsteroidal anti-inflammatory drugs (salicylates), antineoplastic and antimalarial drugs are presented. Pathophysiology and postulated mechanisms causing drug-induced ototoxicity are also discussed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2003

"All-in-One Assay", a direct phenotypic anti-human immunodeficiency virus type 1 drug resistance assay for three-drug combination therapies that takes into consideration in vivo drug concentrations.

A novel phenotypic anti-human immunodeficiency virus type 1 (HIV-1) drug resistance assay is described. Three drugs at concentrations equivalent to those determined in in vivo pharmacokinetics, were mixed in a well, serially diluted by 10-folds, and added to incubations of clinical HIV-1 isolates and CCR-5 expressing HeLa/CD4+ cells which was previously reported as the MAGIC-5 cells (Antimicrob. Agents Chemother. 45 (2001) 495) to determine the 95% inhibitory dilution (ID(95)) of the combination regimens. The ID(95) of efavirenz (EFV)-containing regimens was ten-times lower than that of nevirapine (NVP)-containing regimens against HIV-1 isolated from antiviral therapy naive patients. However, the difference was not apparent by the conventional fold resistance measurement based on the 50% inhibitory concentration. Furthermore, the synergistic effects of drug combinations against clinical HIV-1 isolates can be evaluated by our assay. The ID(95)s of EFV- and nelfinavir (NFV)- containing regimens against HIV-1 from naive patients were less than 0.01 whereas those against resistant viruses were over 0.05, although the clinical cut-off values are to be determined in larger clinical studies. Our assay, designated "All-in-One Assay", that can examine resistance to three drugs simultaneously under consideration of in vivo drug concentrations described above might be useful in practice.

Anti-HIV Agents↗
PubMed1998

Evolution and revolution in drug labeling: regulation of antiarrhythmic drugs by the Food and Drug Administration 1962-1996.

Between 1962, when the Kefauver-Harris Drug Amendments were passed, and 1996, 20 pharmaceutical compounds were approved and labeled by the FDA as effective antiarrhythmic drugs for some specified cardiac arrhythmia. Drug research and development in the 1970s and 1980s were focused on treatment of premature ventricular beats as a marker for sudden cardiac death and ventricular tachycardia. The Cardiac Arrhythmia Suppression Trial in 1989 irrevocably altered this approach. Recent drug development programs have targeted atrial fibrillation (AF) as epidemiologic data have predicted an increase in the incidence of AF as the United States population ages, and as treating premature ventricular beats has fallen from favor. The FDA, the scientific community, and the pharmaceutical industry have all participated in and been affected by this evolution in drug development.

Anti-Arrhythmia Agents↗
PubMed2002

Antiepileptic drugs: coprescription of proconvulsant drugs and oral contraceptives: a national study of antiepileptic drug prescribing practice.

OBJECTIVES: To determine the frequency of coprescription of antiepileptic drugs (AEDs) and drugs with proconvulsant potential and of coprescription of AEDs and low dose oral contraceptives. METHODS: Using information from all 294 fully computerised general practices participating in the General Practice Research Database who entered complete data in 1995, persons were identified who had a prescription for an antiepileptic drug and who had a diagnosis of epilepsy or epileptic seizures in their medical records. Other medication was also recorded. RESULTS: Of women with epilepsy aged 15-45, 16.7% were on the oral contraceptive pill and of 200 on both an enzyme inducing AED and an oral contraceptive, 56% were on formulations with an estrogen content less than 50 microg. This will be associated with increased risk of contraceptive failure and unwanted pregnancy. Over 10% of all AED prescriptions in adults were associated with simultaneous prescription of at least one drug with a potential proconvulsant effect. CONCLUSIONS: Prescribers should be alert to the possibility of pharmacodynamic and pharmacokinetic interactions between AEDs and other medication. With the aging of the population of people with seizures, and the polypharmacy often associated with old age, the likelihood of adversely interacting drug combinations will increase.

Adolescent↗
PubMed2005

Drug-drug and drug-food interactions between tenofovir disoproxil fumarate and didanosine.

The drug-drug and drug-food interactions between tenofovir DF and didanosine EC were evaluated in 2 pharmacokinetic studies in healthy adult subjects. When 400 mg was dosed with tenofovir DF, mean didanosine AUC was increased by 44% to 60% following fasted or fed administration. Staggered coadministration (2 hour, fasted) of a reduced didanosine dose of 250 mg resulted in equivalent didanosine exposure, while simultaneous administration with tenofovir DF in the fasted and fed state resulted in didanosine AUCs similar to that of the reference treatment of 400 mg alone in the fasted state. These data indicate that a dose reduction of didanosine is warranted when it is used with tenofovir DF. The drug-drug-food interaction of didanosine may offer more flexible dosing of didanosine EC when it is used with tenofovir DF. Patients receiving tenofovir DF and didanosine together should be carefully monitored for safety and efficacy.

Adenine↗
PubMed2005

[Clinically significant drug-drug and drug-food interactions associated with calcium channel blockers].

Calcium channel blockers have been widely used for treatment of hypertension, angina pectoris, arrhythmia, and other heart diseases. Nowadays, combination therapy is widely common for these diseases. However, combination therapy is associated with increasing risks of pharmacokinetic or pharmacodynamic drug-drug interaction, and therefore clinicians should pay attention to prevent it. Furthermore, in addition to drug-drug interactions, we need to be cautions for drug interaction with food and drink including health-food and supplement.

Calcium Channel Blockers↗
PubMed2002

New drug and biological drug products; evidence needed to demonstrate effectiveness of new drugs when human efficacy studies are not ethical or feasible. Final rule.

The Food and Drug Administration (FDA) is amending its new drug and biological product regulations to allow appropriate studies in animals in certain cases to provide substantial evidence of the effectiveness of new drug and biological products used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances. This rule will apply when adequate and well-controlled clinical studies in humans cannot be ethically conducted and field efficacy studies are not feasible. In these situations, certain new drug and biological products that are intended to reduce or prevent serious or life-threatening conditions may be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals and any additional supporting data.

Animals↗
PubMed1984

Assessment of drug state dimensionality via drug-drug training and stimulus generalization testing.

A procedure for determining whether different drugs share a common stimulus dimension is described. This procedure uses the presence of post-discrimination generalization gradient asymmetry as an indication that the training stimuli lay along a common stimulus dimension. Separate groups of hungry pigeons were trained to discriminate a 15 mg/kg dose of phenobarbital which was associated with frequent food reinforcement (S+) from each of 9 different drug conditions which were associated with infrequent reinforcement (S-). S- stimuli were selected to represent a drug from a completely different class (amphetamine), a drug with biphasic effects which may partially correspond with the effects of phenobarbital (delta 9-THC), and a drug from the same class as the S+ (pentobarbital). Following discrimination training subjects were tested for generalization to five dosage levels (5, 10, 15, 20, 25 mg/kg) of phenobarbital. Steep symmetrical generalization gradients around the S+ indicated that delta 9-THC and d-1-amphetamine were both quite discriminable from phenobarbital, and that they were perceived by subjects as representing stimulus dimensions different from phenobarbital, and that it was perceived as lying on a stimulus dimension common to phenobarbital. This procedure may allow better understanding of how different drug states are perceived by animals as similar or dissimilar.

Amphetamines↗
PubMed1998

Drug addiction as a physical disease: the role of physical dependence and other chronic drug-induced neurophysiological changes in compulsive drug self-administration.

Physical-dependence-based theories of addiction regard compulsive drug taking as the behavioral manifestation of a desperate need to relieve aversive autonomic withdrawal symptoms. In the present article, the withdrawal-relief paradigm, or opiate model of addiction, is critically examined in the light of recent experimental and clinical evidence for various addictive drugs. It is concluded that contrary to the opiate model, the constellation of pathological behaviors defining addiction (compulsive drug use, craving, loss of control, and a persistent tendency to relapse) does not primarily reflect a need to relieve actual or conditioned autonomic withdrawal symptoms. Recent theories of addiction emphasize the positive reinforcing properties of drugs and sensitization of brain dopamine systems rather than negative reinforcement or drug-opposing neuroadaptations. Despite the failure of the opiate model, recent evidence suggests that persistent drug-induced changes in the physical brain may underlie addictive behavior, consistent with the general notion of addiction as a physical disease.

Animals↗
PubMed1998

Cytogenetic and molecular characterization of random chromosomal rearrangements activating the drug resistance gene, MDR1/P-glycoprotein, in drug-selected cell lines and patients with drug refractory ALL.

Drug resistance, both primary and acquired, is a major obstacle to advances in cancer chemotherapy. In vitro, multidrug resistance can be mediated by P-glycoprotein (PGY1), a cell surface phosphoglycoprotein that acts to efflux natural products from cells. PGY1 is encoded by the MDR1 gene located at 7q21.1. Overexpression of MDR1 has been demonstrated in many cancers, both in patient tumors and in cell lines selected with a variety of chemotherapeutic agents. Recent studies in drug-selected cell lines and patients samples have identified hybrid mRNAs comprised of an active, but apparently random, gene fused 5' to MDR1. This observation indicates that random chromosomal rearrangements, such as translocations and inversions, leading to "capture" of MDR1 by constitutively expressed genes may be a mechanism for activation of this gene following drug exposure. In this study, fluorescence in situ hybridization (FISH) using whole chromosome paints (WCP) and bacterial artificial chromosome (BAC)-derived probes showed structural rearrangements involving 7q in metaphase and interphase cells, and comparative genomic hybridization (CGH) revealed high levels of amplification at chromosomal breakpoints. In an adriamycin-selected resistant colon cancer line (S48-3s/Adr), WCP4/WCP7 revealed t(4;7)(q31;q21) and BAC-derived probes demonstrated that the breakpoint lay between MDR1 and sequences 500-1000 KB telomeric to it. Similarly, in a subline isolated following exposure to actinomycin D (S48-3s/ActD), a hybrid MDR1 gene composed of heme oxygenase-2 sequences (at 16p13) fused to MDR1 was identified and a rearrangement confirmed with WCP7 and a subtelomeric 16p probe. Likewise, in a paclitaxel-selected MCF-7 subline where CASP sequences (at 7q22) were shown to be fused to MDR1, WCP7 showed an elongated chromosome 7 with a homogeneously staining regions (hsr); BAC-derived probes demonstrated that the hsr was composed of highly amplified MDR1 and CASP sequences. In all three selected cell lines, CGH demonstrated amplification at breakpoints involving MDR1 (at 7q21) and genes fused to MDR1 at 4q31, 7q22, and 16p13.3. Finally, in samples obtained from two patients with drug refractory ALL, BAC-derived probes applied to archived marrow cells demonstrated that a breakpoint occurred between MDR1 and sequences 500-1000 KB telomeric to MDR1, consistent with a random chromosomal rearrangement. These results support the proposal that random chromosomal rearrangement leading to capture and activation of MDR1 is a mechanism of acquired drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Use of psychotropic drugs during pregnancy. A report of the international co-operative drug use in pregnancy (DUP) study. Collaborative Group on Drug Use in Pregnancy (CGDUP).

Drug Use in Pregnancy (DUP) is an international epidemiological survey of drug use in pregnancy conducted from 1988 to 1990 in 148 maternity wards, representing the general delivery practices of 22 countries. Data on exposure of pregnant women to psychotropic drugs, the indications for their use and their correlation with maternal characteristics are reported. Of the 14,778 women interviewed, 520 (3.5%) reported 562 courses of psychotropic drugs. Benzodiazepines (BDZ) accounted for the greatest number of the exposures (444/520 women); neuroleptics and antidepressants were prescribed to tiny minorities of women (83 and 17 respectively), mostly in those few countries were the overall prevalence of use of those drugs was highest. Throughout the majority of the other countries, overall rates were in the low range and were rather heterogeneous. With the exception of small clusters of "unexpected" indications, prescriptions of BDZ were found to be consistent with the target symptoms of anxiety and insomnia; chronic use was reported in 31/444 women. The study was not targeted to the detection of malformations; no suspected clustering was found, however, among the 130 women exposed during the first trimester of pregnancy. The collaborative network now established provides a framework for periodically replicated surveillance to monitor the evolution of this field of knowledge and care in order to provide reliable information for women and society.

Adolescent↗
PubMed1990

A taste aversion model of drug discrimination learning: training drug and condition influence rate of learning, sensitivity and drug specificity.

A model of drug discrimination based on a lithium chloride (LiCl) flavour aversion was described and examined. Mildly thirsty rats were presented daily with 4 ml of a distinctly flavoured solution which was followed on 50% of the days by an IP injection of LiCl. Prior to the flavour presentation, the rats were injection SC with saline or a training drug (0.04 mg/kg fentanyl or 20 mg/kg pentobarbital) to signal whether LiCl would follow. Almost all rats eventually exhibited stable behaviour that involved drinking most or all of the fluid when it was not to be followed by LiCl and little or no drinking when it was. Such discrimination occurred regardless of whether drug predicted LiCl (learned-discomfort) or predicted no LiCl (learned-safety). However, with fentanyl there were clear differences between rats trained with drug under learned-safety and under learned-discomfort conditions for 1) the rate of acquisition of stable performance as a function of LiCl dose, 2) generalization of the training dose to a test dose that was lower, and 3) elicitation of fentanyl responses by pentobarbital. These findings, together with indications that such effects did not always occur with pentobarbital as the training drug, were discussed from theoretical and practical perspectives.

Animals↗
PubMed1997

Drug-induced attack of bronchial asthma in inpatients: a 20-year survey of the Comprehensive Hospital Drug Monitoring Programme on adverse drug reactions, Berne/St. Gallen.

Epidemiological aspects of attacks of bronchial asthma related to drugs are prospectively studied in inpatients of three teaching hospitals in the Comprehensive Hospital Drug Monitoring (CHDM)-programme. Results are based on 34,840 individual patients (among 48,005 consecutive admissions) in the years 1974-1993. Between 1974 and 1993, every patient admitted to any of the three medical clinics in the CHDM programme was monitored for any suspicion of an adverse drug reaction (ADR); every drug exposure period during hospital stay was registered. Nineteen patients (0.05% of the 34,840 individual patients) had at least one attack of bronchial obstruction during hospitalisation, considered as probable or definite ADR. The frequency related to exposure periods in response to penicillins is 0.014%, to non-steroidal anti-inflammatories (NSAIDs) 0.0145, to acetyl salicylic acid (ASA) 0.018%, to paracetamol 0.008% and to beta-adrenoceptor blockers 0.26%. Of the 12 patients reacting to a drug with an allergic or idiosyncrasy/intolerance type of bronchial obstruction, 7 had a history of bronchial asthma (extrinsic or intrinsic), and 3 had the diagnosis chronic obstructive pulmonary disease (COPD). A history of bronchial asthma or COPD is confirmed to be a risk factor for this particular ADR. Of the seven patients with a bronchial obstruction to beta-adrenoceptor blockers, five were diagnosed with COPD, while two had neither COPD nor bronchial asthma. The relative risk for this pharmacological reaction in COPD patients was 96 (95% confidence interval 45-208) compared with non-COPD patients in the group of 3244 exposed to beta-adrenoceptor blockers.

Adrenergic Antagonists↗
PubMed2005

Lack of cataleptogenic potentiation with non-imidazole H3 receptor antagonists reveals potential drug-drug interactions between imidazole-based H3 receptor antagonists and antipsychotic drugs.

Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.

Animals↗
PubMed2003

Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs.

Antiepileptic drugs (AEDs) are commonly prescribed for long periods, up to a lifetime, and many patients will require treatment with other agents for the management of concomitant or intercurrent conditions. When two or more drugs are prescribed together, clinically important interactions can occur. Among old-generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone are potent inducers of hepatic enzymes, and decrease the plasma concentration of many psychotropic, immunosuppressant, antineoplastic, antimicrobial, and cardiovascular drugs, as well as oral contraceptive steroids. Most new generation AEDs do not have clinically important enzyme inducing effects. Other drugs can affect the pharmacokinetics of AEDs; examples include the stimulation of lamotrigine metabolism by oral contraceptive steroids and the inhibition of carbamazepine metabolism by certain macrolide antibiotics, antifungals, verapamil, diltiazem, and isoniazid. Careful monitoring of clinical response is recommended whenever a drug is added or removed from a patient's AED regimen.

Animals↗
PubMedDate not supplied

Preparation and biological characterization of polymeric micelle drug carriers with intracellular pH-triggered drug release property: tumor permeability, controlled subcellular drug distribution, and enhanced in vivo antitumor efficacy.

A novel intracellular pH-sensitive polymeric micelle drug carrier that controls the systemic, local, and subcellular distributions of pharmacologically active drugs has been developed in this study. The micelles were prepared from self-assembling amphiphilic block copolymers, poly(ethylene glycol)-poly(aspartate hydrazone adriamycin), in which the anticancer drug, adriamycin, was conjugated to the hydrophobic segments through acid-sensitive hydrazone linkers. By this polymer design, the micelles can stably preserve drugs under physiological conditions (pH 7.4) and selectively release them by sensing the intracellular pH decrease in endosomes and lysosomes (pH 5-6). In vitro and in vivo studies show that the micelles have the characteristic properties, such as an intracellular pH-triggered drug release capability, tumor-infiltrating permeability, and effective antitumor activity with extremely low toxicity. The acquired experimental data clearly elucidate that the optimization of both the functional and structural features of polymeric micelles provides a promising formulation not only for the development of intracellular environment-sensitive supramolecular devices for cancer therapeutic applications but also for the future treatment of intractable cancers with limited vasculature.

Animals↗