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PubMed2000

Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics).

BACKGROUND: Enuresis (bedwetting) is a socially unacceptable and stressful condition which affects around 15-20% of five year olds, and up to 2% of young adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs to the children can be great. OBJECTIVES: To assess the effects of drugs other than desmopressin and tricyclics on nocturnal enuresis in children, and to compare them with other interventions. SEARCH STRATEGY: The following electronic databases were searched: MEDLINE to June 1997; AMED; ASSIA; BIDS; BIOSIS Previews (1985-1996); CINAHL; DHSS Data; EMBASE (1974 to June 1997); PsycLIT and SIGLE. Organisations, manufacturers, researchers and health professionals concerned with enuresis were contacted for information. The reference sections of obtained studies were also checked for further trials. Date of the most recent search: July 1997. SELECTION CRITERIA: All randomised trials of drugs (excluding desmopressin or tricyclics) for nocturnal enuresis in children were included in the review. Trials were eligible for inclusion if: children were randomised to receive drugs compared with placebo, other drugs or other conservative interventions for nocturnal bedwetting; participants with organic causes for their bedwetting were excluded; and baseline assessments of the level of bedwetting were provided. Trials focused solely on daytime wetting were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the quality of the eligible trials, and extracted data. MAIN RESULTS: None of the drugs (phenmetrazine, amphetamine sulphate/ephedrine + atropine, furosemide (sic) or chlorprotixine) were better than placebo during treatment. The numbers were too small to draw reliable conclusions, and none are used in current practice in the UK. Imipramine (a tricyclic) was better than each of the three drugs with which it was compared (meprobamate, ephedrine sulphate and furosemide) even though the numbers were small. Alarm treatment was better than drugs in one small trial. REVIEWER'S CONCLUSIONS: There was not enough evidence to suggest that the included drugs reduced bedwetting. There was limited evidence to suggest that imipramine and alarms were better, and in other reviews, desmopressin, tricyclics and alarm interventions have tentatively been shown to be effective.

Child↗
PubMed2000

Second-order schedules of drug reinforcement in rats and monkeys: measurement of reinforcing efficacy and drug-seeking behaviour.

RATIONALE AND OBJECTIVES: To review the literature on the use of second-order schedules of drug reinforcement in the context of experimental investigations of the neural and pharmacological mechanisms underlying addictive behaviour in general and drug-seeking behaviour in particular. METHODS: Second-order schedules of drug reinforcement are described in which responding is maintained not only by the self-administered drug, but also by contingent presentation of drug-paired stimuli that serve as conditioned reinforcers of instrumental behaviour. RESULTS: The behaviour of rats and monkeys responding under second-order schedules is discussed in relation to self-administered drug dose and the importance of drug-associated cues in maintaining responding for cocaine, morphine or heroin. Drug-seeking behaviour during the period before drug is self-administered is described and compared with drug-seeking behaviour derived from other procedures. In addition, results are summarised that demonstrate the differential involvement of the amygdala and prefrontal cortex in the acquisition of cue-controlled cocaine- and heroin-seeking behaviour, as well as the effects of drugs interacting with D3 dopamine, NMDA and AMPA receptors on drug-seeking behaviour and dopaminergic correlates of drug-paired stimuli presented non-contingently and during responding for cocaine under a second-order schedule. CONCLUSIONS: We argue that the first, drug-free interval (or other period) of responding under a second-order schedule of reinforcement has particular utility in that it provides a measure of drug-seeking behaviour and reinforcing efficacy that are not affected by the pharmacological effects of recently administered drug. It also provides a means of investigating the role of drug-paired stimuli in drug-seeking behaviour, including its behavioural, neural and neurochemical basis.

Animals↗
PubMed1999

Novel oral colon-specific drug delivery systems for pharmacotherapy of peptide and nonpeptide drugs.

The increasing number of peptide and protein drugs being investigated demands the development of dosage forms which exhibit site-specific release. Delivery of drugs into systemic circulation through colonic absorption represents a novel mode of introducing peptide and protein drug molecules and drugs that are poorly absorbed from the upper gastrointestinal (GI) tract. Oral colon-specific drug delivery systems offer obvious advantages over parenteral administration. Colon targeting is naturally of value for the topical treatment of diseases of the colon such as Crohn's disease, ulcerative colitis and colorectal cancer. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Peptides, proteins, oligonucleotides and vaccines are the potential candidates of interest for colon-specific drug delivery. Sulfasalazine, ipsalazide and olsalazine have been developed as colon-specific delivery systems for the treatment of inflammatory bowel disease (IBD). The vast microflora and distinct enzymes present in the colon are being increasingly exploited to release drugs in the colon. Although the large intestine is a potential site for absorption of drugs, some difficulties are involved in the effective local delivery of drugs to the colon bypassing the stomach and small intestine. Furthermore, differential pH conditions and long transit time during the passage of drug formulations from mouth to colon create numerous technical difficulties in the safe delivery of drugs to the colon. However, recent developments in pharmaceutical technology, including coating drugs with pH-sensitive and bacterial degradable polymers, embedding in bacterial degradable matrices and designing into prodrugs, have provided renewed hope to effectively target drugs to the colon. The use of pH changes is analogous to the more common enteric coating and consists of employing a polymer with an appropriate pH solubility profile. The concept of using pH as a trigger to release a drug in the colon is based on the pH conditions that vary continuously down the GI tract. Polysaccharide and azopolymer coating, which is refractory in the stomach and small intestine yet degraded by the colonic bacteria, have been used as carriers for colon-specific targeting. Finally, the availability of optimal preclinical models and clinical methods fueled the rapid development and evaluation of colon-specific drug delivery systems for clinical use. Future studies may hopefully lead to further refinements in the technology of colon-specific drug delivery systems and improve the pharmacotherapy of peptide drugs.

Journal Article↗
PubMed2002

Drug transporters: their role and importance in the selection and development of new drugs.

Drug transporters expressed in various tissues play a significant role in drug disposition. By regulating the function of such transporters, it may be possible to eventually develop drugs with ideal pharmacokinetic profiles. In this article, we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug development process. The ability to manipulate transporter function offers the opportunity of being able to deliver a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side-effects), controlling the elimination process, and/or improving oral bioavailability. During drug development, it would be very useful to be able to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The use of specific inhibitors of transporters is also an attractive approach to controlling drug disposition, leading to improved efficacy. Currently, optimizing the pharmacokinetic properties of a drug during the early stages of its development is widely accepted as being of great importance. High-throughput screening systems using transporter gene transfected cells or computational (in silico) approaches are efficient tools for assessing transport activity during the early stage of drug development. In addition, drug-drug interactions involving drug transporters and functional genetic polymorphisms of drug transporters are also described. It would also be extremely valuable to be able to quantitatively predict inter-individual pharmacokinetic differences caused by transporter polymorphisms or pharmacokinetic changes caused by drug-drug interactions involving transporters during drug development.

Journal Article↗
PubMed1991

Pharmacokinetics of rectal drug administration, Part I. General considerations and clinical applications of centrally acting drugs.

Generally, oral administration is the route of choice in the daily practice of pharmacotherapy. However, in some circumstances this is impractical or even impossible (during nausea and vomiting or convulsions, in uncooperative patients and before surgery). In these cases, the rectal route may represent a practical alternative and rectal administration is now well accepted for delivering, for example, anticonvulsants, non-narcotic and narcotic analgesics, theophylline, antiemetics and antibacterial agents, and for inducing anaesthesia in children. It may also represent an interesting alternative to intravenous or other injection routes of drug administration. The rate and extent of rectal drug absorption are often lower than with oral absorption, possibly an inherent factor owing to the relatively small surface area available for drug uptake. In addition, the composition of the rectal formulation (solid vs liquid, nature of the suppository base) appears to be an important factor in the absorption process by determining the pattern of drug release. This relation between formulation and drug uptake has been clearly demonstrated for drugs like diazepam, paracetamol (acetaminophen), indomethacin, methadone and diflunisal. Coadministration of absorption-promoting agents (surfactants, sodium salicylate, enamines) represents another approach towards manipulating rectal drug absorption, although this concept requires further research concerning both efficacy and safety. For a number of drugs the extent of rectal absorption has been reported to exceed oral values, which may reflect partial avoidance of hepatic first-pass metabolism after rectal delivery. This phenomenon has been reported for morphine, metoclopramide, ergotamine, lidocaine (lignocaine) and propranolol. Rectal drug delivery in a site- and rate-controlled manner using osmotic pumps or hydrogel formulations may provide opportunities for manipulating systemic drug concentrations and drug effects. The extent of first-pass metabolism may be influenced (lidocaine), depending on the site of drug administration in the rectum. The rate of delivery may determine systemic drug action and side effects (nifedipine), and it may affect the local action of concurrently administered absorption promoters on drug uptake (cefoxitin). Local irritation is increasingly being acknowledged as a possible complication of rectal drug therapy. Long term medication with rectal ergotamine and acetylsalicylic acid, for example, may result in rectal ulceration, and irritation after a single administration of several drugs and formulations has been described. The assessment of tolerability and safety is imperative in the design of rectal formulations. Recent studies corroborate the clinical relevance of rectal drug therapy, and the value of the rectal route as an alternative to parenteral administration has been assessed for several drugs, e.g. diazepam, midazolam, morphine and diclofenac.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Rectal↗
PubMed2005

Comparison of potentially hepatotoxic drugs among major US drug compendia.

BACKGROUND: Although a large number of drugs include warnings or listed adverse reactions that describe reports of associated hepatotoxicity, the hepatotoxic risk is documented with different definitions in major drug compendia. OBJECTIVES: The purposes of this study were to compare inclusion of potentially hepatotoxic drugs, and analyze the ratings of hepatotoxic risk among major drug compendia. METHODS: To assess the risk of drug-associated hepatotoxicity, we used current literature of epidemiological studies and developed a 4-level rating scale of hepatotoxic drugs: 3, clear literature evidence of life-threatening hepatotoxicity; 2, multiple case reports or significant liver injuries; 1, no significant liver damage has been reported; and 0, no information. All drugs were evaluated using the 5 major US drug compendia: American Hospital Formulary Service (AHFS), United States Pharmacopeia Drug Information (USPDI), Facts and Comparisons (F&C), Physicians' Desk Reference (PDR), and Clinical Pharmacology (CP). Average rating scores were calculated as the sum of each drug rating score divided by the total number of drugs. One-way analysis of variance and independent t tests were conducted to compare the difference among the rating scores. RESULTS: In total, 175 different drugs and 3 therapeutic classes with hepatotoxic effects were identified in the compendia, including 59 antineoplastics, 28 anti-infectives, 17 nonsteroidal anti-inflammatory drugs, 17 antipsychotics or phenothiazine derivatives, 9 angiotensin-converting enzyme inhibitors, 6 anticonvulsants, 4 histamine-2 receptor antagonists, and other drugs. Average rating scores were 1.65 for AHFS, 1.10 for USPDI, 1.27 for F&C, 1.34 for PDR, and 1.61 for CP (F=7.93, P<.0001). The risk categories were significantly different among compendia in 4 therapeutic classes of antipsychotics and/or phenothiazines (F=3.471, P=.011), nonsteroidal anti-inflammatory drugs (F=7.866, P<.0001), antineoplastics (F=2.476, P=.044), anti-infectives (F=2.003, P=.098), and angiotensin-converting enzyme inhibitors (F=38.125, P<.0001). CONCLUSIONS: Rating scores of hepatotoxicity were significantly different among drug compendia. The different compendium put different emphasis on hepatotoxicity severity. Comprehensive evaluations of hepatotoxic-related drugs provide critical information for health practitioners.

Chemical and Drug Induced Liver Injury↗
PubMed2001

Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions.

Skin testing with a suspected drug has been reported to be helpful in determining the cause of cutaneous adverse drug reactions (CADR). Many isolated reports of positive drug skin tests are published, but without detailed information concerning the clinical features of the CADR and the method used in performing drug skin tests, such data are not very informative. A working party of the European Society of Contact Dermatitis (ESCD) for the study of skin testing in investigating cutaneous adverse drug reactions, has proposed the herein-reported guidelines for performing skin testing in CADR in order to standardize these procedures. In each reported case, the imputability of each drug taken at the onset of the CADR and a highly detailed description and characterization of the dermatitis need to be given. Drug skin tests are performed 6 weeks to 6 months after complete healing of the CADR. Drug patch tests are performed according to the methods used in patch testing in studying contact dermatitis. The commercialized form of the drug used by the patient is tested diluted at 30% pet. (pet.) and/or water (aq.). The pure drug is tested diluted at 10% in pet. or aq. In severe CADR, drug patch tests are performed at lower concentrations. It is also of value to test on the most affected site of the initial CADR. Drug prick tests are performed on the volar forearm skin with the commercialized form of the drug, but with sequential dilutions in cases of urticaria. Intradermal tests (IDT) are performed with sterile sequential dilutions (10-4, 10-3, 10-2, 10-1) of a pure sterile or an injectable form of the suspected drug with a small volume of 0.04 ml. Drug skin tests need to be read at 20 min and also later at D2 and D4 for patch tests, at D1 for prick tests and IDT. All these tests also need to be read at 1 week. The success of skin tests varies with the drug tested, with a high % of positive results, for example, with betalactam antibiotics, pristinamycin, carbamazepine and tetrazepam on patch testing, or with betalactam antibiotics and heparins on delayed readings of IDT. The results of drug skin tests also depend on the clinical features of the CADR. The use of appropriate control patients is necessary to avoid false-positive results.

Drug Eruptions↗
PubMed2002

Drug benefit plans under managed care: to what extent do older subscribers selecting less drug coverage put themselves at increased financial risk?

Many health maintenance organizations (HMOs) have implemented programs that limit drug benefit coverage for Medicare beneficiaries. A retrospective study was conducted among Medicare beneficiaries enrolled in the Fallon Community Health Plan to evaluate the implications of the implementation of an HMO program that allowed Medicare beneficiaries to choose between three drug benefit plans: full drug coverage, a drug benefit plan with a maximum of $1,000 in coverage, or no drug benefit. The mean costs of prescription drugs and other healthcare services were calculated and compared for 14,762 patients enrolled in the three pharmacy benefit plans during the 6-month period before and the 12-month period after January 1, 1994, the date of benefit selection. Prescription drug utilization and associated costs were greatest among those members selecting full drug coverage, followed by those with a $1,000 maximum coverage benefit, followed by those selecting no drug coverage (P <.001). The proportion of patients that reached or exceeded $2,000 in prescription drug costs during the 12-month period was determined to evaluate the frequency of patients incurring potentially catastrophic drug expenditures if they were not enrolled in a full drug-coverage plan. Only 21 members (0.5%) with the $1,000 maximum drug benefit reached or exceeded this $2,000 threshold; only one member in the no drug coverage group exceeded this level. A relatively small percentage of patients had drug expenditures that exceeded what was allowed under the drug benefit plan selected. The vast majority of older people choosing less-comprehensive drug benefit plans appeared to make appropriate choices of plans based upon past utilization of prescription and other medical services.

Aged↗
PubMed2006

Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the Netherlands.

OBJECTIVE: To compare the prescription of drugs in women over a period from 2 years before until 3 months after pregnancy, regarding the type of drugs used and the fetal risk. DESIGN: A cohort study based on pharmacy records of women giving birth to a child between 1994 and 2003. SETTING: The study was performed with data from the InterAction database, containing prescription-drug-dispensing data from community pharmacies. POPULATION: The study population included 5412 women for whom complete pharmacy records were available. METHODS: Drugs were classified into three categories: (1) drugs for chronic conditions, (2) drugs for occasional use and (3) drugs for pregnancy-related symptoms and also classified according to the Australian classification system. MAIN OUTCOME MEASURES: The prescription rate was calculated as the number of women per 100 women who received one or more prescriptions for a given drug within a specified time period. RESULTS: About 79.1% of the women received at least one prescription during pregnancy. The prescription rate for most drugs for chronic diseases and for occasional use decreased during pregnancy, whereas, as expected, the prescription rate for pregnancy-related drugs increased. During the first trimester of pregnancy, 1.7% of all drugs prescribed for chronic conditions and 2.3% of the occasional drugs were classified as harmful. CONCLUSIONS: The increase in prescription rate during pregnancy is caused by an increase in prescription rate of drugs for pregnancy-related symptoms. The prescription of harmful drugs is more commonly associated with drugs for occasional use rather than with drugs for chronic conditions. Therefore, a more cautious prescribing of drugs to healthy women in the fertile age is necessary.

Abnormalities, Drug-Induced↗
PubMed1998

Important drug-drug interactions in the elderly.

Although drug-drug interactions constitute only a small proportion of adverse drug reactions, they are important because they are often predictable and therefore avoidable or manageable. Their frequency is related to the age of the patient, the number of drugs prescribed, the number of physicians involved in the patient's care and the presence of increasing frailty. The most important mechanisms for drug-drug interactions are the inhibition or induction of drug metabolism, and pharmacodynamic potentiation or antagonism. Interactions involving a loss of action of one of the drugs are at least as frequent as those involving an increased effect. It is likely that only about 10% of potential interactions result in clinically significant events and, while death or serious clinical consequences are rare, low-grade, clinically unspectacular morbidity in the elderly may be much more common. Nonspecific complaints (e.g. confusion, lethargy, weakness, dizziness, incontinence, depression, falling) should all prompt a closer look at the patient's drug list. There are a number of strategies that can be adopted to decrease the risk of potential clinical problems. The number of drugs prescribed for each individual should be limited to as few as is necessary. The use of drugs should be reviewed regularly and unnecessary agents withdrawn if possible, with subsequent monitoring. Patients should be encouraged to engage in a 'prescribing partnership' by alerting physicians, pharmacists and other healthcare professionals to symptoms that occur when new drugs are introduced. Physicians with a responsibility for elderly people in an institutional setting should develop a strategy for monitoring their drug treatment. For those interactions that have come to clinical attention, it is important to review why they happened and to plan for future prevention. Clinicians should also report, via the appropriate postmarketing surveillance scheme, any drug-drug interactions they have encountered. Finally, multidisciplinary education about the nature of physiological aging and its effect on drug handling, and the possible presentations of drug-related disease in older patients, is an important element in reducing interactions in the elderly.

Aged↗
PubMed1996

Drug interactions with antiviral drugs.

Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile. Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised. Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentration of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir. Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated. No interaction has been demonstrated with didanosine per se but care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine. Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid 'Maalox' results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated. Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles.

Antiviral Agents↗
PubMed2004

In vitro testing of drug absorption for drug 'developability' assessment: forming an interface between in vitro preclinical data and clinical outcome.

Drug 'developability' assessment has become an increasingly important addition to traditional drug efficacy and toxicity evaluations, as pharmaceutical scientists strive to accelerate drug discovery and development processes in a time- and cost-effective manner. The fraction of drug absorbed and the maximum absorbable dose (MAD) can be estimated from in vivo clinical pharmacokinetics, mass balance studies or in vivo drug permeability in humans by different calculation methods. Unfortunately, in vivo data are usually unavailable at the early stages of drug discovery and development, and in vitro screening for the permeability, solubility, activity and toxicity of a drug has become a routine measurement in drug discovery and development. These in vitro data could be used to predict drug 'developability' with different calculation methods before selecting candidates for clinical evaluation. The fraction of drug absorbed in human could be predicted by in vivo human permeability or in vitro Caco2 permeability. For example, if drug permeability in Caco2 cells reaches 13.3 to 18.1 x 10(-6) cm/s, its predicted in vivo permeability in humans would reach 2 x 10(-4) cm/s, and its predicted fraction of drug absorbed would be > 90%, which is defined as highly permeable. The MAD could also be predicted with in vitro permeability, or calculated absorption rate constant. In addition, in vitro solubility and permeability data can also be used for the biopharmaceutics classification system (BCS) and, subsequently, to direct formulation optimization strategies. If drug 'developability' becomes an obstacle for drug delivery based on these in vitro data and predictions at the early stages of drug discovery and development, options such as prodrug approaches could be explored to enhance drug 'developability', in addition to different formulation methods. Therefore, in vitro absorption testing is a highly valuable tool in the decision-making process to select candidates for in vivo clinical studies at early-stage drug discovery and development.

Biological Transport↗
PubMed2000

Three- or four- versus two-drug antiretroviral maintenance regimens for HIV infection.

BACKGROUND: Combination antiretroviral therapy administered to HIV-infected individuals has been shown to improve immunologic function and delay the progression of HIV infection. However, because patient adherence to complicated combination-therapy antiretroviral regimens is difficult and because of concerns regarding cumulative toxicity of antiretroviral drugs, regimens that utilize fewer antiretroviral agents are desirable. OBJECTIVES: To compare the use three- or four- versus two-drug antiretroviral maintenance regimens following successful induction therapy for HIV infection. SEARCH STRATEGY: The following electronic databases were searched for relevant randomized trials or reviews: 1. MEDLINE for the years 1982-1999 using the search terms human immunodeficiency virus, antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, AIDS, anti-HIV agents, HIV infection and HIV seropositivity 2. AIDSLINE for the years 1982-1999 using the search terms antiretroviral therapy, maintenance therapy, zidovudine, lamidvudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, anti-HIV agents 3. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register in the Cochrane Library, Issue 2, 1999. 4. The specialist register of trials maintained by the Cochrane Collaborative Review Group on HIV Infection and AIDS 5. AIDSTRIALS, a specialist registry of current and completed trials maintained by the U.S. National Library of Medicine The abstracts of relevant conferences, including the International Conferences on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Infectious Disease Society of America annual meeting and the Interscience Conference on Antimicrobial Agents and Chemotherapy, as indexed by AIDSLINE, were also reviewed. All reference lists of all review articles and primary articles identified were searched. SELECTION CRITERIA: Randomized controlled trials in which HIV-infected adults who had successfully completed three- or four-drug antiretroviral induction therapy were randomized to maintenance therapy with three or four drugs or maintenance therapy with two drugs. Successful induction therapy was defined by a plasma viral load of less than 500 copies/ml. DATA COLLECTION AND ANALYSIS: Two reviewers assessed eligibility and trial quality. Attempts were made to contact the authors of the included abstract. Data on the number of patients experiencing loss of viral suppression were abstracted by two reviewers. The data were pooled, where appropriate, to yield odds ratios, using random effects models. MAIN RESULTS: Four trials were identified including three published studies and one abstract. Compared to three- or four-drug maintenance therapy, maintenance therapies including fewer drugs were associated with a higher risk of virologic failure (loss of HIV suppression to non-detectable levels). Combining the results of all four studies yielded an odds ratio of 5.55 (95% confidence interval, 3.14 - 9.80). Similar results were obtained when the one abstract was excluded (odds ratio, 5.48; 95% confidence interval, 2.82 - 10.65). Performing subgroup analyses of studies using the same induction and maintenance regimens gave similar results. Maintenance regimens of zidovudine and lamivudine compared to maintenance regimens with zidovuine, lamivudine and indinavir, were associated with significantly higher rates of virologic failure (odds ratio, 4.57; 95% confidence interval, 1.80 - 11.58). Similarly, maintenance regimens that discontinued one or more protease inhibitor after including them in induction therapy were also associated with a significantly higher risk of virologic failure (odds ratio, 6.15; 95% confidence interval, 3.40 -11.10). (ABSTRACT TRUNCATED)

Anti-HIV Agents↗
PubMed2002

Effect of the Bamako-Initiative drug revolving fund on availability and rational use of essential drugs in primary health care facilities in south-east Nigeria.

OBJECTIVES: To compare the level of availability and rational use of drugs in primary health care (PHC) facilities where the Bamako Initiative (BI) drug revolving fund programme has been operational, with PHC centres where the BI-type of drug revolving fund programme is not yet operational. METHODS: The study was undertaken in 21 PHC centres with BI drug revolving funds and 12 PHC centres without BI drug revolving funds, all in Enugu State of Nigeria. Data were collected on the essential and non-essential drugs stocked by the facilities. Drug use was determined through analyses of prescriptions in each health centre. Finally, the proportion of consumers that were able to remember their dosing schedules was determined. FINDINGS: An average of 35.4 essential drugs was available in the BI health centres compared with 15.3 in the non-BI health centres (p < 0.05). The average drug-stock was adequate for 6.3 weeks in the BI health centres, but for 1.1 weeks in non-BI health centres (p < 0.05). More injections (64.7 vs. 25.6%) and more antibiotics (72.8 vs. 38%) were prescribed in BI health centres than in the non-BI health centres (p < 0.05). The BI health centres had an average of 5.3 drugs per prescription against 2.1 in the non-BI health centres. However, the drugs prescribed by generic name and from the essential drug list were higher in the BI health centres (80 and 93%) than the non-BI health centres (15.5 and 21%, respectively) (p < 0.05). CONCLUSION: It was observed that the BI facilities had a better availability of essential drugs both in number and in average stock. However, the BI has given rise to more drug prescribing, which could be irrational. The findings call for strategies to ensure more availability of essential drugs especially in the non-BI PHC centres as a strategy to decrease medical costs and improve the quality of PHC services, while promoting rational drug use in all PHC centres. More detailed studies (for example, by focus group discussion or structured interviews) should be undertaken to find out reasons for the over-prescription and to develop future interventions to correct this.

Developing Countries↗
PubMed2002

Exploring generic drug use behavior: the role of prescribers and pharmacists in the opportunity for generic drug use and generic substitution.

OBJECTIVES: The first objective of this study was to examine the prevalence of prescriptions that offer the opportunity for generic drug use (a prescription for a multisource drug product). The second objective was to examine the prevalence of generic drug use by examining the rate of generic drug prescribing for multisource drug products and the rate of generic substitution by pharmacists. The last objective was to examine the association of prescriber, pharmacist, insurance, patient, and drug variables with the prescribing of drugs allowing the opportunity for generic drug use and generic substitution. RESEARCH DESIGN: A database containing information for 6380 prescription orders was used for analysis. MEASURES: Random-effects logistic regression panel data estimation was used to examine the association of independent variables with whether a prescription allowed the opportunity for generic drug use and whether a prescription allowing generic drug use and written using the brand name was generically substituted. RESULTS: The opportunity for generic drug use existed for 63% of prescription orders. Prescriptions covered by private third party and indemnity insurance were 33% (97.5% CI, 0.56-0.80), and 21% (97.5% CI, 0.62-0.98), less likely, respectively, to allow the opportunity for generic drug use relative to uninsured prescriptions. Unobserved prescriber characteristics accounted for 23% (95% CI, 0.14-0.34) of the variance in the opportunity for generic drug use. Pharmacists generically substituted 83.8% of prescriptions that could be generically substituted. Prescriptions covered by Medicaid were 4.57 (97.5% CI, 2.83-7.39), 5.15 (97.5% CI, 3.25-8.13), and 4.85 (97.5% CI, 2.83-8.17) times more likely, respectively, to be generically substituted relative to uninsured, private third party and indemnity prescriptions. Unobserved characteristics of pharmacists accounted for 44% (95% CI, 0.33-0.55) of the variance in the occurrence of generic substitution. CONCLUSIONS: Pharmacists play a large and important role in generic drug use and efforts to increase generic drug use directed at pharmacists should be maintained. Additional efforts to increase generic drug use likely should be targeted at prescribers.

Adult↗
PubMed2004

The impact of unlicensed and off-label drug use on adverse drug reactions in paediatric patients.

BACKGROUND AND OBJECTIVE: Many drugs that are used to treat children are either not licensed for use in paediatric patients (unlicensed) or prescribed outside the terms of the product licence (off label). The incidence of adverse drug reactions (ADRs) associated with the use of such drugs is yet to be established. This study investigates, for the first time in a German patient population, the impact of unlicensed and off-label drug use on ADRs in paediatric patients. PATIENTS AND METHODS: An 8-month prospective pharmacoepidemiological cohort-based survey was conducted on a ten-bed paediatric isolation ward at the University Hospital Erlangen-Nuremberg, Germany. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were characterised according to international classification methods. All drug prescriptions were evaluated retrospectively as to unlicensed or off-label use on the basis of the product information. RESULTS: A total of 178 patients were included in the study and 740 drug prescriptions were given to 156 patients (median three prescriptions per patient). In 198 cases (27.7% of all prescriptions) drugs were used in either an unlicensed (n = 3) or off-label (n = 195) manner. A total of 46 ADRs were observed in 31 patients (17.4%). Patients receiving at least one unlicensed or off-label drug prescription during hospitalisation (n = 92) experienced an ADR significantly more frequently (n = 26 patients) than patients receiving only licensed drugs (n = 64 vs 5 patients). ADRs were associated with 29 (5.6%) of the 517 licensed drug prescriptions and with 12 (6.1%) of the 198 unlicensed or off-label drug prescriptions. The majority of ADRs caused by unlicensed and off-label drug use were recognised by the attending physician. However, statistical analysis revealed no significant difference in the number of licensed and unlicensed/off-label drug prescriptions causing ADRs. CONCLUSION: This study demonstrated that at a paediatric isolation ward the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to possess a significantly increased risk for developing ADRs.

Adolescent↗
PubMed2006

Long-lasting reactivity and high frequency of drug-specific T cells after severe systemic drug hypersensitivity reactions.

BACKGROUND: Drug-reactive T cells are involved in most drug-induced hypersensitivity reactions. The frequency of such cells in peripheral blood of patients with drug allergy after remission is unclear. OBJECTIVE: We determined the frequency of drug-reactive T cells in the peripheral blood of patients 4 months to 12 years after severe delayed-type drug hypersensitivity reactions, and whether the frequency of these cell differs from the frequency of tetanus toxoid-reactive T cells. METHODS: We analyzed 5 patients with delayed-type drug hypersensitivity reactions, applying 2 methods: quantification of cytokine-secreting T cells by enzyme-linked immunospot (ELISpot), and fluorescent dye 5,6-carboxylfluorescein diacetate succinimidyl ester (CFSE) intensity distribution analysis of drug-reactive T cells. RESULTS: Frequencies found were between 0.02% and 0.4% of CD4(+) T cells reacting to the respective drugs measured by CFSE analysis, and between 0.01% and 0.08% of T cells as determined by ELISpot. Reactivity was seen neither to drugs to which the patients were not sensitized nor in healthy individuals after stimulation with any of the drugs used. CONCLUSION: About 1:250 to 1:10,000 of T cells of patients with drug allergy are reactive to the relevant drugs. This frequency of drug-reactive T cells is higher than the frequency of T cells able to recognize recall antigens like tetanus toxoid in the same subjects. A substantial frequency could be observed as long as 12 years later in 1 patient even after strict drug avoidance. Patients with severe delayed drug hypersensitivity reactions are therefore potentially prone to react again to the incriminated drug even years after strict drug avoidance.

Adult↗
PubMed1999

Controlled release of dual drug-loaded hydroxypropyl methylcellulose matrix tablet using drug-containing polymeric coatings.

A dual drug-loaded hydroxypropylmethylcellulose (HPMC) matrix tablet simultaneously containing drug in inner tablet core and outer coated layer was formulated using drug-containing aqueous-based polymeric Eudragit RS30D dispersions. Effects of coating levels, drug loadings in outer layers, amount and type of five plasticizers and talc concentration on the release characteristics were evaluated on the characteristics in simulated gastric fluid for 2 h followed by a study in intestinal fluids. Melatonin (MT) was selected as a model drug. The surface morphology of dual drug-loaded HPMC tablets using scanning electron microscope (SEM) was smooth, showing the distinct coated layer with about 75-microm coating thickness at the 15% coating level. Unlike the uncoated and conventionally coated HPMC tablet, the dual drug-loaded HPMC matrix tablet gave a biphasic linear release, showing a zero-order for 4 h (first) followed by another zero-order release when fitted using linear regression (r(2) = 0.99). As the coating levels (15, 25%) increased, the release rate was further decreased. The biphasic release profiles of dual drug-loaded HPMC matrix tablet was unchanged except when 25% coating level containing 0.5% drug concentration was applied. As the drug concentration in polymeric coating dispersion increased (0.25-1.0%), the amount of drug released increased. The time for the first linear release was also advanced. However, the biphasic release pattern was not changed. The biphasic release profiles of dual drug-loaded HPMC matrix tablet were highly modified, depending on the amount and type of five plasticizers. Talc (10-30%) in coating dispersion as an anti-sticking material did not affect the release profiles. The current dual drug-loaded HPMC matrix tablet, showing biphasic release profiles may provide an alternative to deliver drugs with circadian rhythmic behaviors in the body but needs to be further validated in future in human studies. The dual drug-loaded coating method is also interesting for the modified release of poorly water-soluble drugs because solubilizers and other additives can be added in drug-containing polymeric coating dispersions.

Anticonvulsants↗