Drug Adverse Drug Reactions Research Articles

Colorectal adenomas: a prototype for the use of surrogate end points in the development of cancer prevention drugs.

Carcinogenesis is a multiyear, multistep, multipath disease of progressive genetic alterations and associated tissue damage. Chemoprevention is the use of drugs or other agents to inhibit, delay, or reverse this process. Despite the enormous population at risk of cancer who would benefit, drug

Introducing triage logic as a new strategy for the detection of signals in the WHO Drug Monitoring Database.

An important role for the WHO Programme for International Drug Monitoring is to identify signals of international drug safety problems as early as possible. The signal detection strategy, operated at the Uppsala Monitoring Centre (UMC), gave too many drug-adverse drug reaction (ADR) combinations for individual review. Therefore additional selection strategies were needed to improve the likely signal-to-noise ratio and for the UMC to complement the efforts of national centres in an efficient way. The combinations database of the first quarter of 2001 was analysed using algorithms representing different strategies for finding relevant signals using triage logic. The strategies that together gave a manageable number of combinations, i.e. around 600, for further consideration in a single quarter were the algorithms for 'Rapid reporting increase', 'Serious reaction and new drug' and 'Special interests'. These filters began to be used routinely on the combinations database in late 2001. While stressing that human review is essential, triage strategies are useful when attempting analysis of large amounts of data. By definition, the use of triage strategies may exclude some potential signals from consideration, although the intention is to improve the chances of detection by focussing on areas of greatest importance.

Adverse drug reactions in elderly patients.

Many studies from around the world show a correlation between increasing age and adverse drug reaction (ADR) rate, at least for some medical conditions. More than 80% of ADRs causing admission or occurring in hospital are type A (dose-related) in nature, and thus predictable from the known pharmacology of the drug and therefore potentially avoidable. Frail elderly patients appear to be particularly at risk of ADRs and this group is also likely to be receiving several medicines. The toxicity of some drug combinations may sometimes be synergistic and be greater than the sum of the risks of toxicity of either agent used alone. In order to recognize and to prevent ADRs (including drug interactions), good communication is crucial, and prescribers should develop an effective therapeutic partnership with the patient and with fellow health professionals. Undergraduate and postgraduate education in evidence-based therapeutics is also vitally important. The use of computer-based decision support systems (CDSS) and electronic prescribing should be encouraged, and when problems do occur, health professionals need to be aware of their professional responsibility to report suspected adverse drug events (ADEs) and ADRs. "Rational" or "obligatory" polypharmacy is becoming a legitimate practice as increasing numbers of individuals live longer and the range of available therapeutic options for many medical conditions increases. The clear risk of ADRs in this situation should be considered in the context that dose-related failure of existing therapy to manage the condition adequately may be one of the most important reasons for admission of the elderly to hospital. Thus, age itself should not be used as a reason for withholding adequate doses of effective therapies.

A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database

Background: Two isoforms of cyclooxygenase (COX) have been identified, both of them inhibited by traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-2 has been associated with the therapeutic effects of NSAIDs, whereas inhibition of COX-1 is believed to be the cause of the adverse gastrointestinal effects associated with NSAID therapy. When administered at therapeutic doses, new COX-2—specific inhibitors inhibit only the COX-2 isoform. Objective: This study sought to compare renal safety signals between the COX-2—specific inhibitors rofecoxib and celecoxib, based on spontaneous reports of adverse drug reactions (ADRs) in the World Health Organization/Uppsala Monitoring Centre (WHO/UMC) safety database through the end of the second quarter 2000. Methods: Disproportionality in the association between a particular drug and renal-related ADR was evaluated using a bayesian confidence propagation neural network method in which a statistical parameter, the information component (IC) value, was calculated for each drug-ADR combination. In this method, an IC value significantly greater than 0 implies that the association of a drug-ADR pair is stronger than background; the higher the IC value, the more the combination stands out from the background. The ratio of actual to expected numbers of ADRs was also used to assess disproportionality. Results: As with traditional NSAIDs, both COX-2—specific inhibitors were associated with renal-related ADRs. However, the adverse renal impact of rofecoxib was significantly greater than that of celecoxib. IC values were significantly different for the following comparisons: water retention (1.97 rofecoxib vs 1.18 celecoxib; P < 0.01); abnormal renal function (2.38 vs 0.70; P < 0.01); renal failure (2.22 vs 1.09; P < 0.01); cardiac failure (2.39 vs 0.48; P < 0.01); and hypertension (2.15 vs 1.33; P < 0.01). In an additional analysis, celecoxib was shown to have a similar renal safety profile to that of diclofenac and ibuprofen. Conclusions: Based on spontaneous ADR reports in the WHO/UMC safety database at the end of the second quarter 2000, this analysis indicates that rofecoxib has significantly greater renal toxicity than celecoxib or traditional NSAIDs. This negative renal impact may have the potential to increase the risk for serious cardiac and/or cerebrovascular events.

Prescribing for the elderly patient: why do we need to exercise caution?

Advancing age is accompanied by pharmacokinetic and pharmacodynamic changes which, together with impairment of homeostatic mechanisms and the effect of coexisting disease, contribute to a significant increase in sensitivity to particular drugs and a corresponding increase in the incidence of adverse drug reactions (ADRs). Increasing medical awareness of these facts has not universally been translated into clinical practice as polypharmacy remains a particular problem amongst elderly people and the degree of polypharmacy increases with advancing age [1, 2]. Such prescribing practice serves to further elevate the risk of drug interactions and ADRs, both directly via the synergistic or antagonistic actions of coprescribed drugs, and indirectly by increasing the likelihood of failed compliance.

Avoiding adverse drug reactions in the elderly patient: issues and strategies.

Primary care providers are faced with numerous challenges when prescribing drugs for elderly patients. Multiple drug use, coexisting illness, and normal physiologic changes associated with aging place older persons at increased risk for adverse drug reactions (ADRs). Sample selection bias in drug clinical trials and inappropriate prescribing of contraindicated drugs contribute to the risk profile. Because multiple drug use and ADRs are relatively common in the elderly, special caution should be used when prescribing for this population. The primary care provider should have a good understanding of the factors that put the elderly at increased risk for ADR, the classes of drugs inappropriate for elderly patients, the physiologic changes of aging that may produce an altered pharmacologic response, and the issues associated with adherence to drug therapy. This article identifies factors that contribute to ADRs in the elderly and proposes strategies to reduce or avoid risk. Identifying and preventing ADRs in older Americans is a Healthy People 2000 health protection goal, perhaps more important given projected demographics over the next 20 to 30 years.

Probable adverse drug reactions in a rural geriatric nursing home population: a four-year study.

To quantitate probable adverse drug reactions (ADRs) in a geriatric nursing homes population. A repeated measures prospective study. Two nursing home populations in rural Georgia. All 332 residents present for 30 or more days over a 4-year period. Admission and monthly drug regimen review for each resident, Naranjo algorithm assessment of each ADR, with monthly reports to attending physicians and follow-up within the next month. There were 444 probable ADRs in 217 of 332 residents (67.4%) during this period. The 217 residents had a mean 1.9 +/- 1.3 probable adverse drug reactions (range, 1-9). The ADR group differed statistically from the rest of the population only in the number of drugs per patient (7.8 +/- 2.6 vs 3.3 +/- 1.3), which was almost twice the number of active problems present in both the ADR (4.0 +/- 0.9) and non-ADR populations (3.8 +/- 1.4). The organ systems most commonly involved in the 444 ADRs observed were cardiovascular (188), central nervous system (129), gastrointestinal (82), endocrine (41), immune (17), hematologic (7), pulmonary (6), and renal (5). The drugs most commonly implicated in ADRs were, in decreasing order, diuretics, antipsychotics, anxiolytics, potassium supplements, digoxin, NSAIDs, insulin, theophylline, H2-receptor antagonists, antiinfectives, anticonvulsants, and thyroid supplements. There were 39 multiple drug ADRs in 34 patients. In decreasing order the drug classes in multiple ADRs were CNS depressants, antihypertensives, potassium-altering therapy, and NSAIDs. Numerous patients had repetitions of the same ADR, especially with antipsychotics, NSAIDs, and insulin. ADRs are a common occurrence in a geriatric nursing home population, and may be related to inadequate attention to the patients history as well as to unrealistic therapeutic endpoints.

Inservice teaching and adverse drug reactions in a nursing home.

A prospective study was carried out in two skilled nursing facilities (SNFs) to determine: the feasibility of identifying potential adverse drug reactions (ADRs) by monitoring drug order changes; the ADR rate in the elderly in SNFs; the ease of using an algorithm to assess the probability that an adverse event is drug-related; and whether a one-hour inservice lecture could alter the number of drug order changes or the number of ADRs detected. Over three months, 27 of 248 order changes (10.8 percent) were identified as possible ADRs. Fifteen of 248 (six percent) of the orders were probable or definite ADRs. The ADR rates were 9.5 percent and 14.8 percent, for the study and control SNFs, respectively (p greater than 0.05). This method of detecting ADRs depends on recognition of a clinically observable adverse event by the nurse, nurse practitioner, or physician. Therefore, the hypothesis that an inservice lecture on ADRs could increase the recognition of ADRs was tested. More drug order changes were initiated in the control facility that retained a full-time nurse practitioner, but no change in the number of drug order changes or ADR rates was seen after the inservice lecture in the study facility. This method is the first to identify, prospectively, clinically manifest ADRs and to test a method to influence their rate in nursing home elderly.

Empyema Thoracis in Infants and Children

Acetaminophen (APAP)-induced liver injury (AILI) is the leading cause of acute liver failure in the United States, but its impact on metabolism, therapeutic efficacy, and adverse drug reactions (ADRs) of co- and/or subsequent administered drugs are not fully investigated. The current work explored this field with a focus on the AILI-mediated alterations of cytochrome P450–mediated drug metabolism. Various levels of liver injury were induced in mice by treatment with APAP at 0, 200, 400, and 600 mg/kg. Severity of liver damage was determined at 24, 48, 72, and 96 hours by plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), microRNA miR122, and tissue staining. The expression and activities of CYP3A11, 1A2, 2B10, 2C29, and 2E1 were measured. Sedation efficacy and ADRs of midazolam, a CYP3A substrate, were monitored after APAP treatment. ALT, AST, and miR122 increased at 24 hours after APAP treatment with all APAP doses, whereas only groups treated with 200 and 400 mg/kg recovered back to normal levels at 72 and 96 hours. The expression and activity of the cytochromes P450 significantly decreased at 24 hours with all APAP doses but only recovered back to normal at 72 and 96 hours with 200 and 400, but not 600, mg/kg of APAP. The alterations of cytochrome P450 activities resulted in altered sedation efficacy and ADRs of midazolam, which were corrected by dose justification of midazolam. Overall, this work illustrated a low cytochrome P450 expression window after AILI, which can decrease drug metabolism and negatively impact drug efficacy and ADRs. <h3>SIGNIFICANCE STATEMENT</h3> The data generated in the mouse model demonstrated that expression and activities of cytochrome P450 enzymes and correlated drug efficacy and ADRs are altered during the time course of liver repair and regeneration after liver is injured by treatment with APAP. Dose justifications based on predicted changes of cytochrome P450 activities can achieve desired therapeutic efficacy and avoid ADRs. The generated data provide fundamental knowledge for translational research to drug treatment for patients during liver recovery and regeneration who have experienced AILI.