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PubMedDate not supplied

Effect of hyperthermia on intracellular drug accumulation and chemosensitivity in drug-sensitive and drug-resistant P388 leukaemia cell lines.

Enhancements of the drug-induced cytotoxicity and modifications of drug transmembrane equilibria caused by hyperthermic treatment were analysed on P388/S and P388/R murine leukaemia cell lines. The P388/R cell line was derived from the P388/S cell line by drug selection of mutant, drug-resistant clones; it expresses a pleiotropic drug resistance towards some chemotherapeutic drugs such as doxorubicin, daunorubicin and etoposide, but is only weakly resistant towards other drugs as cis-diammine-dichloroplatinum. Hyperthermic treatment enhanced the drug cytotoxic effects much more on the P388/R cell line than on the P388/S line, but the cytotoxic enhancements were consistent only for the drug towards which the P388/R cell line expresses pleiotropic resistance. Intracellular drug accumulation analysis and drug transmembrane equilibria determinations indicated that the resistance of both cell lines to the intracellular drug was not affected by hyperthermic treatment, whereas variations in drug influx, but not in drug extrusion, were induced by heat treatment. The study suggested, therefore, that hyperthermia does not modify intracellular chemosensitivity of either cell line, but acts on membrane permeability by facilitating attainment of the intracellular drug concentrations needed to cause the cytotoxic effect.

Animals↗
PubMed1998

Effects of drug solubility, drug loading, and polymer molecular weight on drug release from Polyox tablets.

This study investigated the effects of polymer molecular weight, drug solubility, addition of a water-soluble excipient, and drug loading on zero-order release kinetics and elucidated the release mechanism of a drug from directly compressed tablets. Directly compressed tablets consisting of polyethylene oxides (PEO) (MW = 0.9, 2.0 and 4.0 x 10(6)) and drugs (solubility ranging from 290 to 25,000 mg/l) were formulated with or without a water-soluble excipient (lactose). For PEO tablets (MW = 0.9 x 10(6)), drug release is primarily swelling/erosion controlled for drugs for which solubility is below 1%, resulting in zero-order release kinetics. For PEO tablets (MW = 4.0 x 10(6)), drug release is controlled at a zero-order rate by the dissolution rate of the drug at high loading (39%). At low loading (20%), drug diffusion through the swollen gel layer becomes the governing release mechanism. For a highly water-soluble drug (e.g., diclofenac Na), drug diffusion is the controlling mechanism regardless of the molecular weight of the PEOs. Zero-order release kinetics can be achieved with PEO tablets (MW = 0.9 x 10(6)) for drugs for which solubility is below 1%. PEO tablets (MW = 2.0 x 10(6)) provided zero-order release for poorly water-soluble drugs (below 0.2%) at 39% drug loading. It is possible to attain zero-order release kinetics with PEO tablets (MW = 4.0 x 10(6)) using a drug which has a solubility of less than 0.1%.

Diclofenac↗
PubMed1990

Drug metabolism by leukocytes and its role in drug-induced lupus and other idiosyncratic drug reactions.

This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin and in platelets, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases. Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Agranulocytosis↗
PubMed2003

Drug-drug interactions: an important negative attribute in drugs.

Drug-drug interactions that arise by the alteration of the pharmacokinetics of one drug by another are of concern to the pharmaceutical industry, drug regulatory agencies, health-care professionals and patients. However, distinction needs to be made between interactions that only result in alterations in exposure levels and interactions that truly have an impact on efficacy and patient safety. To make this distinction, both the magnitude of the pharmacokinetic interaction and the therapeutic index of the affected drug must be taken into account. In this review, a description of the mechanistic underpinnings of drug interactions that has been developed over the past two decades is presented, with particular emphasis on drug-metabolizing enzymes and clearance concepts. The research approaches used to study drug interactions in vitro and in vivo are described. Finally, an accounting of major pharmacokinetic drug-drug interactions is made, organized by the drug-metabolizing enzyme or transporter protein affected. For each drug-metabolizing enzyme and transporter discussed, a position is offered on the severity of the issue of whether a new drug were to affect, or be affected by, a drug interaction through alteration of the activity of that enzyme.

Animals↗
PubMed1998

Drug-metabolism research challenges in the new millennium: individual variability in drug therapy and drug safety.

One of the most challenging research areas in pharmacology in the new millennium is to understand why individuals respond differently to drug therapy and to what extent that individual variability in disposition is responsible for the observed differences in therapeutic efficacy and adverse reactions. To answer these complex questions, drug-metabolism research will rely on multidisciplinary approaches more than ever to investigate the many components involved in drug metabolism and disposition. Major research challenges include the following: (1) the genetic variation of drug targets (receptors, enzymes, etc.), drug transporters (multispecific organic anion transporter, P-glycoprotein, alpha-1-acid glycoprotein, etc.), and drug-metabolizing enzymes (cytochrome P450s and other enzymes); (2) the structure and function of all genetic variants of drug receptors, transporters, and metabolizing enzymes; (3) the induction, repression, and inhibition of all components involved in drug disposition; (4) the development of noninvasive in vivo methods to determine the physiological significance of various components in the handling of specific therapeutic agents in humans; (5) the mechanism of idiosyncratic adverse drug reactions; and (6) the pharmacokinetic and pharmacodynamic relationships to explain the individual differences in therapeutic efficacy and drug safety. Thus successful drug-metabolism research in the new millennium must integrate receptor biology, enzymology, recombinant DNA technology, biochemical toxicology, and drug disposition into study design and conduct balanced in vitro and in vivo experiments to allow a full understanding of the mechanisms of individual variability in drug therapy and drug safety.

Animals↗
PubMed2005

Targeted drug delivery with dendrimers: comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex.

Dendrimers have unique characteristics including monodispersity and modifiable surface functionality, along with highly defined size and structure. This makes these polymers attractive candidates as carriers in drug delivery applications. Drug delivery can be achieved by coupling a drug to polymer through one of two approaches. Hydrophobic drugs can be complexed within the hydrophobic dendrimer interior to make them water-soluble or drugs can be covalently coupled onto the surface of the dendrimer. Using both methods we compared the efficacy of generation 5 PAMAM dendrimers in the targeted drug delivery of methotrexate coupled to the polymer. The amine-terminated dendrimers bind to negatively charged membranes of cells in a non-specific manner and can cause toxicity in vitro and in vivo. To reduce toxicity and to increase aqueous solubility, modifications were made to the surface hydroxyl groups of the dendrimers. For targeted drug delivery, the dendrimer was modified to have a neutral terminal functionality for use with surface-conjugated folic acid as the targeting agent. The complexation of methotrexate within a dendrimer changes the water insoluble drug into a stable and readily water-soluble compound. When this dendrimer complexed drug, however, was placed in a solution of phosphate buffered saline, the methotrexate was immediately released and displayed diffusion characteristics identical to free methotrexate. Covalently coupled methotrexate dendrimer conjugates were stable under identical conditions in water and buffered saline. Cytotoxicity tests showed that methotrexate as the dendrimer inclusion complex had an activity identical to the free drug in vitro. In contrast, folic acid targeted dendrimer with covalently conjugated methotrexate specifically killed receptor-expressing cells by intracellular delivery of the drug through receptor-mediated endocytosis. This study demonstrates that while drug as a dendrimer inclusion complex is readily released and active in vitro, covalently conjugated drug to dendrimer is better suited for specifically targeted drug delivery.

Cell Survival↗
PubMed2006

Drugs in other drugs: a new look at drugs as fragments.

The authors of this review have examined the complete set of marketed drugs, with regards to looking for structural similarities between drugs. By comparing the structures of all drugs, it has been established how many times one marketed drug occurred as a substructure within another marketed drug. A total of 209 from 1386 marketed drugs sized between 100 and 1500 Da (i.e. 15% of the 1386 total) are contained within other drugs, differing by one or more continuous chemical fragment, and as many as 418 drugs from the total of 1386 (i.e. 30%) contain other drugs as substructure fragments. Many smaller drugs occur in multiple larger drugs. Most of the small changes tend to retain primary indicated pharmacology, whereas larger changes more often lead to different primary pharmacology. We identify a subset of drugs that can be used in fragment-based drug discovery strategies. In addition, the analysis enhances understanding of marketed drug space from the chemical building-block perspective.

Drug Design↗
PubMedDate not supplied

Drug-induced changes in P450 enzyme expression at the gene expression level: a new dimension to the analysis of drug-drug interactions.

Drug-drug interactions (DDIs) caused by direct chemical inhibition of key drug-metabolizing cytochrome P450 enzymes by a co-administered drug have been well documented and well understood. However, many other well-documented DDIs cannot be so readily explained. Recent investigations into drug and other xenobiotic-mediated expression changes of P450 genes have broadened our understanding of drug metabolism and DDI. In order to gain additional information on DDI, we have integrated existing information on drugs that are substrates, inhibitors, or inducers of important drug-metabolizing P450s with new data on drug-mediated expression changes of the same set of cytochrome P450s from a large-scale microarray gene expression database of drug-treated rat tissues. Existing information on substrates and inhibitors has been updated and reorganized into drug-cytochrome P450 matrices in order to facilitate comparative analysis of new information on inducers and suppressors. When examined at the gene expression level, a total of 119 currently marketed drugs from 265 examined were found to be cytochrome P450 inducers, and 83 were found to be suppressors. The value of this new information is illustrated with a more detailed examination of the DDI between PPARalpha agonists and HMG-CoA reductase inhibitors. This paper proposes that the well-documented, but poorly understood, increase in incidence of rhabdomyolysis when a PPARalpha agonist is co-administered with a HMG-CoA reductase inhibitor is at least in part the result of PPARalpha-induced general suppression of drug metabolism enzymes in liver. The authors believe this type of information will provide insights to other poorly understood DDI questions and stimulate further laboratory and clinical investigations on xenobiotic-mediated induction and suppression of drug metabolism.

Animals↗
PubMed2003

Drug-drug interactions among elderly patients hospitalized for drug toxicity.

CONTEXT: Drug-drug interactions are a preventable cause of morbidity and mortality, yet their consequences in the community are not well characterized. OBJECTIVE: To determine whether elderly patients admitted to hospital with specific drug toxicities were likely to have been prescribed an interacting drug in the week prior to admission. DESIGN: Three population-based, nested case-control studies. SETTING: Ontario, Canada, from January 1, 1994, to December 31, 2000. PATIENTS: All Ontario residents aged 66 years or older treated with glyburide, digoxin, or an angiotensin-converting enzyme (ACE) inhibitor. Case patients were those admitted to hospital for drug-related toxicity. Prescription records of cases were compared with those of controls (matched on age, sex, use of the same medication, and presence or absence of renal disease) for receipt of interacting medications (co-trimoxazole with glyburide, clarithromycin with digoxin, and potassium-sparing diuretics with ACE inhibitors). MAIN OUTCOME MEASURE: Odds ratio for association between hospital admission for drug toxicity (hypoglycemia, digoxin toxicity, or hyperkalemia, respectively) and use of an interacting medication in the preceding week, adjusted for diagnoses, receipt of other medications, the number of prescription drugs, and the number of hospital admissions in the year preceding the index date. RESULTS: During the 7-year study period, 909 elderly patients receiving glyburide were admitted with a diagnosis of hypoglycemia. In the primary analysis, those patients admitted for hypoglycemia were more than 6 times as likely to have been treated with co-trimoxazole in the previous week (adjusted odds ratio, 6.6; 95% confidence interval, 4.5-9.7). Patients admitted with digoxin toxicity (n = 1051) were about 12 times more likely to have been treated with clarithromycin (adjusted odds ratio, 11.7; 95% confidence interval, 7.5-18.2) in the previous week, and patients treated with ACE inhibitors admitted with a diagnosis of hyperkalemia (n = 523) were about 20 times more likely to have been treated with a potassium-sparing diuretic (adjusted odds ratio, 20.3; 95% confidence interval, 13.4-30.7) in the previous week. No increased risk of drug toxicity was found for drugs with similar indications but no known interactions (amoxicillin, cefuroxime, and indapamide, respectively). CONCLUSIONS: Many hospital admissions of elderly patients for drug toxicity occur after administration of a drug known to cause drug-drug interactions. Many of these interactions could have been avoided.

Aged↗
PubMed2000

Drug-drug interactions in medical patients: effects of in-hospital treatment and relation to multiple drug use.

OBJECTIVES: Adverse drug reactions (ADRs) are a major cause of hospital admissions, thereby leading to significant medical and economical problems. Drug interactions contribute to a major part of ADRs, especially in elderly patients and in patients under polymedication. As a peculiarity of the German health care system the general practitioner is less involved in patient care during hospital stay than in other countries. Consequently, changes in medication at the transition point from out-patient to in-patient care and back may contribute to drug-related problems. PATIENTS: In the present study we investigated potential interactions in 169 consecutive patients with the diagnosis CHD (coronary heart disease) or COLD (chronic obstructive lung disease) who were admitted to the University Hospitals of Hannover and Magdeburg. METHODS: For each patient, potential interactions between prescribed drugs at admission, at discharge, and 3 months after discharge were assessed by using drug interaction data bases. RESULTS: We found that the number of drugs taken per patient as well as the number of interactions per patient are higher during hospitalization than before admission (pre-admission), and fall back after the hospital stay (post-discharge), but not to the pre-admission level. The number of potential interactions was significantly correlated in a polynomial manner to the number of drugs taken by each patient. The number of patients without a potential interaction was 44.4% pre-admission, 39.6% at discharge, and 39.1% post-discharge. Patients with potential interactions had a mean of 2.8, 2.7, and 2.4 interactions at each of the time points. Drug classes mainly involved with potential interactions were kaliuretic diuretics (recorded by 43.3% at discharge), ACE inhibitors (30.3%), anticoagulants and aggregation inhibitors (20.4%) and digitalis glycosides (14.7%). Regarding the frequency of the interaction categories, 68-70% of the potential interactions demand clinical attention, while 1-2% are life-threatening. 17-19% may result in therapeutic benefit; 10-12% are without clinical relevance. CONCLUSIONS: The risk of drug interactions increases exponentially with the number of drugs given to a patient. Although we have no data on the fraction of interactions that became clinically manifest, our study indicates that prescribing fewer drugs can reduce the risk of suffering from sickness secondary to drug interactions. Taking this risk into account may help to improve the quality of drug treatment and to save costs.

Adult↗
PubMed1999

Utilization of cardiovascular drugs (blood pressure lowering drugs, lipid lowering drugs and nitrates) and mortality from ischaemic heart disease and stroke. An ecological analysis based on Sweden's municipalities.

OBJECTIVE: To perform an ecological study in an effort to generate questions concerning the preventive impact of various cardiovascular drugs on mortality from stroke and ischaemic heart disease (IHD) in the community, and to explore the association between sales of nitrates and mortality from stroke and IHD. METHODS: Out-patient drug utilization (sales) of blood pressure lowering drugs, lipid lowering drugs and nitrates were categorized in four groups of equal size by quartiles and compared with mortality from IHD and stroke, using the group of municipalities with the lowest utilization as reference, from 1989 to 1993 in 283 of Sweden's 288 municipalities, by Poisson regression. Adjustments were made for population size, age and gender proportions, the utilization rate of cardiovascular drugs other than the tested drug group and location of the municipality. RESULTS: Compared with the group of municipalities with the lowest sales and adjusting only for population size, mortality from IHD and stroke increased with the extent of utilization of blood pressure lowering drugs and nitrates. In contrast, mortality decreased with increased utilization of lipid lowering drugs. After further adjustments by percentage of men, age structure, geographical location (mid-points) of the municipalities, and, as a proxy for cardiovascular disease, the sales of cardiovascular drugs other than the tested drug group, the increased risk associated with blood pressure lowering drugs disappeared, and there was a dose-response association between sales of diuretics and old antihypertensives and decreasing mortality, sales of nitrates continued to be associated with an increased risk, and the low mortality risk associated with sales of lipid lowering drugs persisted. CONCLUSION: Lipid lowering drugs may have a preventive impact in the general population, but the preventive impact of blood pressure lowering drugs, with the exception of diuretics and old antihypertensives, may be low in many municipalities. The safety of nitrates needs more investigation at the individual level.

Antihypertensive Agents↗
PubMed2006

Non drug use- and drug use-specific spirituality as one-year predictors of drug use among high-risk youth.

The present article explored two different dimensions of spirituality that might tap negative and positive relations with adolescent drug use over a 1-year period. Non-drug-use-specific spirituality measured how spiritual the person believes he or she is, participation in spiritual groups, and engagement in spiritual practices such as prayer, whereas drug-use-specific spirituality measured using drugs as a spiritual practice. Self-report questionnaire data were collected during 1997-1999 from a sample of 501 adolescents in 18 continuation high schools across southern California. Participants ranged in age from 14 to 19 and were 57% male, with an ethnic distribution of 34% White, 49% Latino, 5% African American, 7% Asian, and 5% other. A series of general linear model analyses were conducted to identify whether or not two different spirituality variables predict drug use (cigarettes, alcohol, marijuana, hallucinogens, and stimulants) at 1-year follow-up. After controlling for baseline drug use, non-drug-use-specific spirituality was negatively predictive of alcohol, marijuana, and stimulant use, whereas drug-use-specific spirituality failed to be found predictive of these variables one year later. Conversely, drug-use-specific spirituality was positively predictive of cigarette smoking and hallucinogen use, whereas non-drug-use spirituality failed to be found predictive of these variables. Our results provide new evidence that suggests that spirituality may have an effect on drug use among adolescents. The drug-use-specific measure of spirituality showed "risk effects" on drug use, whereas the other measure resulted in "protective effects," as found in previous research. Knowledge of the risk and protective patterns and mechanisms of spirituality may be translated into future drug use prevention intervention programs.

Adolescent↗
PubMed2001

Do national medicinal drug policies and essential drug programs improve drug use?: a review of experiences in developing countries.

Increasing concerns regarding access to and appropriateness of medicinal drug use have led many governments in developing countries to develop national policies and regulations intended to increase the affordability, supply, safety, and rational use of pharmaceuticals. However, little is known about the intended and unintended impacts of these social experiments on actual drug use. We conducted a critical review and synthesis of the international literature in an attempt to define the current state of knowledge regarding drug policy effects on drug use, and to extract from the evidence important lessons for future policy and research. Literature sources included the archives and computerized databases, articles published in medical and pharmacy journals, as well as published annotated bibliographies. The evaluated interventions included three broad categories: (1) multi-component national drug policies including essential drug programs; (2) drug supply and cost-sharing programs; and (3) regulatory measures. Most of these studies utilized weak research designs that evaluated programs solely on the basis of post-intervention measures. Only two studies measured pre-policy utilization, but did not include a control group. Thus, none of the results are conclusive, and the findings represent, at best, hypotheses for more rigorous studies of policy impacts. Some suggestive findings include an association between increases in the supply of essential drugs (combined with training) and more appropriate use of medications in primary care settings. In addition, preliminary data suggest some unintended effects of de-registration of drugs or upward reclassification of specific medicines. Similarly, loosening restrictions have sometimes been accompanied by increased dispensing of specific drugs by unqualified personnel. The available studies focused only on a few categories of national and regulatory policies. Because of poor study design, the results do not provide valid data to determine whether national drug policies improve drug use. Moreover, no studies have evaluated the effects of major and recent changes, such as increased use of product patents, national pharmaceutical insurance policies, and increased privatization of pharmaceutical products and services. Future studies need to explore the consequences of these emerging developments on drug access and use. Despite the difficulties inherent in evaluation of national policies, stronger research designs can and should be carried out. Interrupted time-series analysis and other more rigorous designs should become standard designs for policy evaluation in the same way that standard treatment guidelines are intended to guide medical practice.

Developing Countries↗
PubMed1997

Applications of primary human hepatocytes in the evaluation of pharmacokinetic drug-drug interactions: evaluation of model drugs terfenadine and rifampin.

The utility of primary human hepatocytes in the evaluation of drug-drug interactions is being investigated in our laboratories. Our initial approach was to investigate whether drug-drug interactions observed in humans in vivo could be reproduced in vitro using human hepatocytes. Two model drugs were studied: terfenadine and rifampin, representing compounds subjected to drug-drug interactions via inhibitory and induction mechanisms, respectively. Terfenadine was found to be metabolized by human hepatocytes to C-oxidation and N-dealkylation products as observed in humans in vivo. Metabolism by human hepatocytes was found to be inhibited by drugs which are known to be inhibitory in vivo. Ki values for the various inhibitors were derived from the in vitro metabolism data, resulting in the following ranking of inhibitory potency: For the inhibition of C-oxidation, ketoconazole > itraconazole > cyclosporin approximately troleandomycin > erythromycin > naringenin. For the inhibition of N-dealkylation, itraconazole > or = ketoconazole > cyclosporin > or = naringenin > or = erythromycin > or = troleandomycin. Rifampin induction of CYP3A, a known effect of rifampin in vivo, was also reproduced in primary human hepatocytes. Induction of CYP3A4, measured as testosterone 6 beta-hydroxylation, was found to be dose-dependent, treatment duration-dependent, and reversible. The induction effect of rifampin was observed in hepatocytes isolated from all 7 human donors studied, with ages ranging from 1.7 to 78 years. To demonstrate that the rifampin-induction of testosterone 6 beta-hydroxylation could be generalized to other CYP3A4 substrates, we evaluated the metabolism of another known substrate of CYP3A4, lidocaine. Dose-dependent induction of lidocaine metabolism by rifampin is observed. Our results suggest that primary human hepatocytes may be a useful experimental system for preclinical evaluation of drug-drug interaction potential during drug development, and as a tool to evaluate the mechanism of clinically observed drug-drug interactions.

Cells, Cultured↗
PubMed1984

The relationship of parental drug use and parents' attitude concerning adolescent drug use to adolescent drug use.

The purpose of this study was to examine the relationship of two variables, parental drug use and parental attitude toward adolescent drug use, both as perceived by the adolescent respondent to his or her own use or nonuse of drugs. A sample of 106 drug-using and 96 nondrug-using adolescents was obtained through the use of the anthropological " snowball " technique. All respondents were administered a drug use history profile and a personal data questionnaire. In order to be classed as drug users, respondents had to have been using two or more recreational substances on a regular basis. Nondrug users were those who used no recreational drugs, although individuals who had tried alcohol or tobacco experimentally were included in this group. On the personal data form, respondents were asked to describe their parents' use of alcohol, tobacco, or other substances, and to indicate their parents' attitudes concerning adolescent use of drugs. Parental attitudes were classed as permissive if the respondent indicated that parents were indifferent about drug use, if they accepted a certain range of drugs, or if the decision were left up to the youth. A nonpermissive attitude was defined as one which would not accept drug use by the adolescent. Four 2 x 2 Chi-square analyses were used to determine significance of the relationship between adolescent drug use and parents' use or nonuse of drugs, parents' attitudes about adolescent use or nonuse and actual adolescent use or non-use, and this same attitudinal relationship looking at parent users and nonusers separately.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2004

Remission from drug dependence symptoms and drug use cessation among women drug users in puerto rico.

BACKGROUND: Studies of remission from drug dependence have most often been based on treatment samples, with limited generalizability to persons who may benefit from but never seek substance abuse treatment. Little is known about remission patterns among drug users in the community. OBJECTIVE: To identify patterns and predictors of remission in a community sample of drug users followed up prospectively. DESIGN: Three waves of data on a range of individual and interpersonal correlates of drug abuse and health care service use were collected between April 1997 and October 2000. SETTING: Areas of metropolitan San Juan where drug sales were known to occur. PARTICIPANTS: Two hundred seventy-five women aged 18 to 35 who were crack cocaine or injecting drug users. MAIN OUTCOME MEASURES: Self-reported drug use validated with urine screens and drug use dependence criteria based on the DSM-IV. RESULTS: Most (86.9%) of the women were drug dependent at baseline. By wave 3, fewer than half (42.6%) of the women were dependent, 13.8% had subthreshold disorder, and 17.8% used substances but did not endorse any dependence criteria. Cessation of use and decreases in the number of dependence criteria endorsed were significantly less likely for women with depressive symptoms (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.88-0.96; and OR, 0.88; 95% CI, 0.86-0.90; respectively), with a partner who engaged in criminal activities (OR, 0.30; 95% CI, 0.16-0.58; and OR, 0.63; 95% CI, 0.46-0.85; respectively), and who traded sex for money or drugs (OR, 0.12; 95% CI, 0.05-0.29; and OR, 0.26; 95% CI, 0.19-0.35; respectively). CONCLUSIONS: Drug use patterns and rates of dependence fluctuated substantially over time among drug users recruited from the community. Findings regarding the characteristics that impede remission suggest that mental health practitioners have an important role to play in community-based outreach and interventions designed to support women's efforts to stop using drugs.

Adult↗
PubMed2005

Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions.

PURPOSE: To assess the frequency of potential azole-drug interactions and consequences of interactions between fluconazole and other drugs in routine inpatient care. METHODS: We performed a retrospective cohort study of hospitalized patients treated for systemic fungal infections with an oral or intravenous azole medication between July 1997 and June 2001 in a tertiary care hospital. We recorded the concomitant use of medications known to interact with azole antifungals and measured the frequency of potential azole drug interactions, which we considered to be present when both drugs were given together. We then performed a chart review on a random sample of admissions in which patients were exposed to a potential moderate or major drug interaction with fluconazole. The list of azole-interacting medications and the severity of interaction were derived from the DRUGDEX System and Drug Interaction Facts. RESULTS: Among the 4,185 admissions in which azole agents (fluconazole, itraconazole or ketoconazole) were given, 2,941 (70.3%) admissions experienced potential azole-drug interactions, which included 2,716 (92.3%) admissions experiencing potential fluconazole interactions. The most frequent interactions with potential moderate to major severity were co-administration of fluconazole with prednisone (25.3%), midazolam (17.5%), warfarin (14.7%), methylprednisolone (14.1%), cyclosporine (10.7%) and nifedipine (10.1%). Charts were reviewed for 199 admissions in which patients were exposed to potential fluconazole drug interactions. While four adverse drug events (ADEs) caused by fluconazole were found, none was felt to be caused by a drug-drug interaction (DDI), although in one instance fluconazole may have contributed. CONCLUSIONS: Potential fluconazole drug interactions were very frequent among hospitalized patients on systemic azole antifungal therapy, but they had few apparent clinical consequences.

Adverse Drug Reaction Reporting Systems↗
PubMedDate not supplied

Important role of proinflammatory cytokines/other endogenous substances in drug-induced hepatotoxicity: depression of drug metabolism during infections/inflammation states, and genetic polymorphisms of drug-metabolizing enzymes/cytokines may markedly contribute to this pathology.

Analysis of literature data on drug-induced hepatotoxicity reveals that often upper respiratory febrile illnesses and/or inflammation states precede liver injury/diseases related to administration of drugs or hepatotoxicity associated with administration of therapeutic doses of acetaminophen in some genetically predisposed subjects. The goals of this paper are to review the potential role of alterations in the balance between TH1 cells producing cytokines associated with a cell-mediated response and TH2 cells associated with an antibody response, as well as other endogenous substances, eg, growth factors, leading to a shift in immune response to one that may participate in the liver cells injury during administration of certain drugs, especially in subjects with genetic polymorphisms in drug-metabolizing enzymes. The papers cited in this review were selected to illustrate specific issue related to how profuse and dysregulated production of cytokines, growth factors, and/or other endogenous substances during viral/bacterial infections and inflammation states play a role in the development of drug-induced liver injury. Several cases of liver injury related to administration of drugs appear to be initiated or intensified by upper respiratory febrile illnesses and/or inflammation states, which stimulate sometimes dysregulated production of interferon gamma and/or other proinflammatory cytokines/growth factors. This, in turn, results in down-regulation of various induced and constitutive isoforms of cytochromes P-450, and other enzymes involved in the metabolism of several exogenous (eg, drugs) and endogenous lipophilic (eg, steroids) substances, thus having an important impact on the alterations in bioactivation and detoxication processes in the body and on the balance between production, utilization, and elimination of endogenous bioproducts of these reactions. Activation of systemic host defense mechanisms results in down-regulation of various enzymes involved in drug metabolism and elimination, as well as in production, utilization, and excretion of many endogenous substances that have beneficial effects on vital processes in the body. It seems that treatment of acute and chronic infections and/or inflammations with, for example, antibacterials not metabolized in the liver, and use of medications that decrease proinflammatory cytokine levels (eg, pentoxifylline, a TNF-alpha synthesis inhibitor, directed against TNF-alpha-induced priming of human neutrophils, immunotherapy with IL-4, IL-1 receptor antagonists or factors inducing IL-1ra, dietary supplementation with long-chain n-3 fatty acids, and other antioxidant agents) may perhaps, in some cases, be helpful in the prevention and management of drug-induced hepatotoxicity. Drug-mediated injuries may eventually be prevented by screening methods that can identify genetic polymorphism of drug-metabolizing enzymes and gene polymorphisms or RNA-expression profiles of some proinflammatory cytokines before a patient uses a drug.

Bacterial Infections↗