Tonic stimulation of the pharyngeal mucosa causes pain and a reversible increase of inflammatory mediators.

OBJECTIVE AND DESIGN: To develop a model of the inflammatory component of non-infectious sore throat using tonic stimulation and quantification of inflammatory mediators in pharyngeal lavage fluid. MATERIAL OR SUBJECTS: Forty-five healthy volunteers. TREATMENT: Cold dry air. METHOD: Tonic stimulation of the pharynx was achieved using a constant stream of cold dry air to the back of the throat. Following optimization of stimulation conditions (phase 1), pharyngeal pain, irritation, and swallowing discomfort were assessed using visual analog scales, and the concentration of inflammatory markers were measured in pharyngeal lavage fluid (phase 2). RESULTS: Optimum conditions for tonic pharyngeal stimulation were cold dry air at 12 °C, relative humidity 20 %, at a flow rate of 12 L/min for 15 min. Analysis of pharyngeal lavage fluid collected 5 min after stimulation showed significant increases in prostaglandin E2 (P = 0.018), thromboxane B2 (P < 0.001), and substance P (P < 0.001), but no increase in peptidoleukotriene. When the stimulus was removed, the level of inflammatory markers in pharyngeal lavage fluid returned to baseline by 30 min post-stimulation. These objective measures mirrored subjective pain ratings. CONCLUSIONS: Tonic stimulation of the pharyngeal mucosa with cold dry air causes pain and an increase of inflammatory mediators which are reversible.

Cytochrome p450 polymorphisms in geriatric patients: impact on adverse drug reactions--a pilot study.

BACKGROUND AND OBJECTIVE: Up to 23% of the population, depending on their ethnic background, has genetically determined differences in the metabolism of drugs by the cytochrome P450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6. The aim of this survey was to determine the relationship between genetical polymorphisms in these CYP enzymes and adverse drug reactions (ADRs) in geriatric patients. STUDY DESIGN: In a prospective 6-month cohort study of 243 patients in a geriatric rehabilitation ward, mean age 80.2 +/- 7.7 years, ADRs were identified by intensive monitoring by a pharmacoepidemiological team, consisting of pharmacists and physicians. 125 out of these 243 patients were genotyped cross-sectionally for polymorphisms of CYP2C9, CYP2C19 and CYP2D6 by the TaqMan-polymerase chain reaction. The main outcome measures were the prevalence of genetical polymorphisms and the patients' risk for developing an ADR as related to the genotype. RESULTS: Patients received an average of 14.2 drugs during hospitalisation which led to 251 ADRs in the whole cohort and 149 ADRs in the cross-sectional genotyping study. Genotype frequencies of CYP2C9 enzyme were 25.9% (n = 29) intermediate metabolisers (IMs) and 2.7% (n = 3) poor metabolisers (PMs). For the enzyme CYP2C19, 26.8% (n = 33) IMs and 0.8% (n = 1) PMs were detected. For the enzyme CYP2D6, 24.1% (n = 26) IMs and 3.7% (n = 4) PMs were found in the analysed patient population. In total, 61.6% (n = 77) of genotyped patients experienced mutations in at least one of the three cytochrome enzymes. The ADR rate did not differ significantly between patients with genetic mutations and wild-type genotype patients. Moreover, only eight out of 40 ADRs which were associated with drugs metabolised by CYP2C9, CYP2C19 or CYP2D6 were detected in patients with IM genotype and none in patients with PM genotype. CONCLUSION: In this investigation geriatric patients showed a high rate of ADRs. However, no association between the ADR rate and the patients' genotype could be detected, which most likely was a result of the small number of patient samples analysed. Although prophylactic genotyping would have not prevented ADRs in this pilot study, physicians nevertheless have to be aware of potential genetic mutations in patients with polypharmacy.

Identification of adverse drug reactions in geriatric inpatients using a computerised drug database.

INTRODUCTION AND OBJECTIVE: Geriatric patients with multiple comorbidities are at high risk of experiencing an adverse drug reaction (ADR) during hospitalisation. The aim of the study was to compare the rate of ADRs as predicted by a computerised pharmacological database to the actual rate determined by direct observation in a sample of geriatric patients. STUDY DESIGN: During a 4-month period, geriatric patients were monitored using prospective observation. Patients were intensively screened for ADRs by a pharmacoepidemiological team (PET), consisting of two pharmacists and a physician. Actual ADRs detected by the PET were compared with those predicted by a computerised drug database. Furthermore, the set of actual ADRs, which resulted from drug-drug interactions (DDIs), were contrasted with potential DDIs signalled by the database. The main outcome measures were the incidence of actual ADRs. For the detection rate of the database we focused on frequent ADRs (>1% according to product information and database) and all DDIs indicated automatically by the database. RESULTS: 163 patients (121 female), mean age 79.8 +/- 7.1 years (range 60-98), were included in the study which was conducted on a geriatric rehabilitation hospital ward. The mean duration of hospitalisation was 24.3 +/- 8.4 days. Elderly patients received an average of 14.0 drugs (range 2-35) during their hospital stay. Of all patients, 60.7% experienced at least one ADR. The PET detected a total of 153 ADRs, with a mean of 0.9 ADRs per patient (range 0-5). The computerised drug database predicted an average of 309 potential ADRs for each patient; however, only 21 ADRs per patient were of high frequency. In 48% of ADR-positive patients (defined by PET) at least one of these frequent ADRs occurred.DDIs were detected by the PET in 14.7% of patients. Our database indicated a mean of 12 potential DDIs per patient. In 14 out of 24 DDI-positive patients, at least one signal indicated a real DDI. The database sensitivity was consequently 58.3%. CONCLUSION: In geriatric patients the incidence of ADRs is high. Computerised drug databases are a useful tool for detecting and avoiding ADRs. Our software, however, also produced a large number of signals that did not relate to actual ADRs found by the PET. The sheer number of these 'false' signals shows the need for refinement and optimisation of databases for daily clinical use.