Is it possible to predict treatment response to a proton pump inhibitor in functional dyspepsia?

BACKGROUND: The efficacy of proton pump inhibitors in functional dyspepsia is modest and the prognostic factors are almost unknown. METHODS: Data were pooled on patients (n = 826) with a diagnosis of functional dyspepsia from two placebo-controlled trials who were treated with omeprazole, 10 or 20 mg once daily, for 4 weeks. Self-administered questionnaires for the assessment of symptoms and health-related quality of life were completed before entry, and epigastric pain/discomfort was recorded on diary cards. Treatment success was defined as the complete absence of epigastric pain/discomfort on each of the last 3 days of week 4. Prognostic factors were identified by multiple logistic regression analysis. RESULTS: The most discriminating predictor of treatment success (P < 0.0001) was the number of days with epigastric pain/discomfort during the first week of treatment. Fewer days with symptoms during the first week led to higher response rates at 4 weeks. In addition, age > 40 years, bothersome heartburn, low scores for bloating, epigastric pain and diarrhoea, history of symptoms for < 3 months and low impairment of vitality at baseline were identified as positive predictors of outcome. CONCLUSIONS: Early response to treatment with a proton pump inhibitor, during the first week, seems to predict the outcome after 4 weeks in patients with functional dyspepsia.     

Mitochondrial abnormalities--a link to idiosyncratic drug hepatotoxicity?

Idiosyncratic drug-induced liver injury (DILI) is a major clinical problem and poses a considerable challenge for drug development as an increasing number of successfully launched drugs or new potential drugs have been implicated in causing DILI in susceptible patient subsets. Although the incidence for a particular drug is very low (yet grossly underestimated), the outcome of DILI can be serious. Unfortunately, prediction has remained poor (both for patients at risk and for new chemical entities). The underlying mechanisms and the determinants of susceptibility have largely remained ill-defined. The aim of this review is to provide both clinical and experimental evidence for a major role of mitochondria both as a target of drugs causing idiosyncratic DILI and as mediators of delayed liver injury. We develop a unifying hypothesis that involves underlying genetic or acquired mitochondrial abnormalities as a major determinant of susceptibility for a number of drugs that target mitochondria and cause DILI. The mitochondrial hypothesis, implying gradually accumulating and initially silent mitochondrial injury in heteroplasmic cells which reaches a critical threshold and abruptly triggers liver injury, is consistent with the findings that typically idiosyncratic DILI is delayed (by weeks or months), that increasing age and female gender are risk factors and that these drugs are targeted to the liver and clearly exhibit a mitochondrial hazard in vitro and in vivo. New animal models (e.g., the Sod2(+/-) mouse) provide supporting evidence for this concept. However, genetic analyses of DILI patient samples are needed to ultimately provide the proof-of-concept.     

Is it possible to apply secondary stroke prevention guidelines to very old populations?

The aging population is an undeniable reality which must be faced by all health systems all over the world. Among people over 80 years old, increase in stroke incidence, high mortality rates and adverse outcomes are problems of major public concern. Lack of evidence-based data to guide rational decision making on vascular risk factors management to avoid recurrence in elderly stroke patients increases the areas of uncertainty, and sometimes favors medical inertia at the time of taking care of this growing elderly population.     

Is it possible to measure differences in the cost of antidepressant overdoses?

In this paper an attempt is described to measure the cost differential between treating episodes of overdose on older antidepressants (e.g. TCAs) and those involving newer antidepressants (e.g. SSRIs). Data is presented showing that it is possible to demonstrate a marked cost differential between older and newer agents; although there are difficulties in precisely quantifying the difference. The limitations of the data are discussed and recommendations made for the methodology of a larger, more sensitive, study. Copyright © 1999 John Wiley & Sons, Ltd.     

Adverse drug reactions in neonates: could we be documenting more?

Neonates are vulnerable to adverse drug reactions but reports of these events are relatively infrequent. Reporting can be increased by adapting a number of standard techniques to the unique features of neonatal care and pathology. However, clinicians and parents will be reluctant to report information about harms in the absence of mechanisms to ensure that reports affect clinical practice. Improved reporting will depend on education and cultural change that are informed by research about pharmacovigilance in neonatal settings. The efficient use of neonatal adverse drug reaction reports will require harmonization of terminology and interoperable databases.     

Is it possible to reduce polypharmacy in the elderly? A randomised, controlled trial

OBJECTIVE: The present trial was originally designed to investigate the effectiveness of comprehensive day hospital care in chronically ill elderly patients. Another aim, reported here, was to investigate to what extent it is possible to reduce polypharmacy and simplify drug regimens during the short term tight control conditions of day hospital care. PATIENTS: All home care patients (n = 174, mean age 77 years) in a rural area, Kirkkonummi-Siuntio, in Finland. DESIGN AND SETTING: Patients were randomised into 2 groups, one of which was offered a 2-month period of day hospital care. Patients assumed to be noncompliant (because they did not want day hospital care) were also included in order to see the effect of intervention in 'real-life'. The medications of all participants were reviewed and counted during an in-home assessment by a home nurse. In the intervention group, necessary revisions (dose reduction, discontinuation, possible additions) were performed through the tight monitoring of day hospital care and in co-operation with the patient. The patients were followed up for 10 months after completion of the intervention programme. OUTCOME MEASURES: Number of prescribed medications, number of over-the-counter (OTC) drugs, number of doses taken daily by the patients. Assessments were performed at baseline, and after 2, 5 and 12 months. RESULTS: There were no significant changes in the number of prescribed medications. In patients in day hospital care, the number of doses was reduced significantly (p = 0.02) during the 2-month day hospital period compared with the control group. However, the patients compensated for the reductions by increasing the use of OTC drugs during the day hospital period (p = 0.05). In addition, only 3 months after the trial, the number of drugs had already returned to the baseline level. CONCLUSIONS: In real life it seems to be difficult to reduce polypharmacy in the elderly. Some drug reductions may be achieved with tight control under trial conditions, but when the intervention ceases the number of drugs used soon returns to its earlier level.     

Is the oral route possible for peptide and protein drug delivery?

Oral delivery of peptides and proteins remains an attractive alternative to parenteral delivery and has challenged various attempts at delivery development. Incorporation of new tools into the delivery systems that can raise membrane permeability of macromolecules is essential to attain high oral bioavailability that is acceptable in clinical applications. In developing oral protein delivery systems with high bioavailability, three practical approaches might be most helpful: (1) modification of the physicochemical properties of macromolecules; (2) addition of novel function to macromolecules; or (3) use of improved delivery carriers. Clearly, it is essential that these approaches maintain the biological activity of the proteins.     

Telomerase as an anti-cancer drug target: will it fulfil its early promise?

The discovery that the ribonucleoprotein telomerase is responsible for the immortality of human cancer cells represents a major advance in our quest to identify a distinguishing biochemical feature of the malignant phenotype that could be useful as a target for novel anti-cancer drug development. However, recent observations on telomere dynamics and cell lifespan using telomerase 'knockout' mouse models together with improved techniques to assay telomerase in normal human tissues have raised certain questions regarding potential side effects of anti-telomerase treatments. More importantly, such work has also demonstrated the propensity of mouse cell populations, in which telomerase has been experimentally inactivated, to generate immortal variants capable of maintaining their telomeres by alternative mechanisms. These recent findings and their implications for the potential success of anti-telomerase therapies are subjected to critical review. The wide differences between telomerase and telomere biology in mouse and human cells are highlighted, and the urgent need to obtain direct experimental evidence concerning the behaviour of a wide variety of human cancer cells under conditions of telomerase inhibition is stressed. It is concluded that, despite the caveats, the development of small molecule drugs that powerfully inhibit telomerase should remain a top priority area for those engaged in the rational design of novel cancer therapeutics.