Self-Collected Anterior Nasal and Saliva Specimens versus Health Care Worker-Collected Nasopharyngeal Swabs for the Molecular Detection of SARS-CoV-2.

We prospectively compared health care worker-collected nasopharyngeal swabs (NPS) to self-collected anterior nasal swabs (ANS) and straight saliva for the diagnosis of coronavirus disease 2019 (COVID-19) in 354 patients. The percent positive agreement between NPS and ANS or saliva was 86.3% (95% confidence interval [CI], 76.7 to 92.9%) and 93.8% (95% CI, 86.0 to 97.9%), respectively. The percent negative agreement was 99.6% (95% CI, 98.0 to 100.0%) for NPS versus ANS and 97.8% (95% CI, 95.3 to 99.2%) for NPS versus saliva. More cases were detected by the use of NPS (n = 80) and saliva (n = 81) than by the use of ANS (n = 70), but no single specimen type detected all severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections.

Synchronous metastatic skull base chordoma to the breast: case report and literature review.

CLINICAL SCENARIO: During routine staging work-up for a left breast mass, a 68-year-old woman complained of dysphagia and dysphonia. During further investigations, a left-sided lesion at the foramen magnum was observed on brain imaging. Both lesions were biopsied and showed a classical chordoma. MANAGEMENT: The skull-base lesion and the breast lesion were surgically resected, and adjuvant radiotherapy was given. SUMMARY: Chordoma is a rare primary central nervous system tumour that seldom metastasizes. The lung is the most common site of metastasis. Synchronous breast metastasis from a skull-base chordoma is very rare, and a safe management option includes a maximum resection followed by adjuvant radiotherapy.

Cellular and molecular mechanisms of action of polyherbal preparation UNIM-352 in experimental models of bronchial asthma.

Bronchial asthma is a chronic inflammatory disorder of the airways and pharmacotherapy is dependent on anti-inflammatory and bronchodilator agents. However, adverse effects of these agents on chronic administration and sometimes non-responsiveness to these drugs have prompted the search for viable alternatives from medicinal plant sources. UNIM-352 is a polyherbal preparation traditionally used in the Unani system of Indian medicine for the treatment of bronchial asthma. The present study defines the possible cellular and molecular mechanisms of action of UNIM-352 in experimental models of bronchial asthma and validates the observed therapeutically beneficial effects. Wistar rats were immunized and challenged with ovalbumin, and blood and bronchoalveolar lavage (BAL) fluid were assayed for cytological and biochemical markers. UNIM-352 (200 and 400 mg/kg) markedly reduced the eosinophil and neutrophil counts in both blood and BAL compared to control. The polyherbal agent also attenuated the levels of TNF-α, IL-4, GM-CSF and NF-κB whereas histone deacetylase (HDAC) levels were elevated, in both blood and BAL fluid. All effects of UNIM-352 were comparable with the standard drug, prednisolone. The results demonstrated possible cellular and molecular mechanisms of UNIM-352 and thus explain its beneficial effects in bronchial asthma.

Evaluation of the Effects of Probiotics and Prebiotics on the Salmonella typhi Infections.

Typhoid fever is one of the most commonly disseminated diseases and is considered to be linked to poor sanitation. It is responsible for 2-5% of all deaths, and its causative agent is Salmonella typhi. The current study aimed to investigate the antibacterial activity of prebiotics (inulin and starch) and probiotics against multidrug resistance of S. typhi bacterial isolates. Determination of the inhibitory effect of probiotics and prebiotics against S. typhi isolates was performed by agar well diffusion method and minimal inhibitory concentration. Body samples of all eligible patients were collected and cultured. Finally, 50 (25%) out of the total cultured samples were S. Typhi bacteria isolated from different samples. The bacteria were mainly found in blood, followed by stool and fluid (74%, 24%, and 2%, respectively). On differential medium, xylose lysine deoxycholate agar, the colonies appear red with black centers, while on MacConkey agar, the colonies appear smooth, pale, transparent, colorless, and raised. Regarding the inhibition zone values of bacteriocins of Lactobacillus from Yogurt against S. typhi in plate, significant differences were identified between the ones with and without prebiotic addition. Accordingly, the value of the inhibition zone for those without prebiotic addition (13.18±7.403) was significantly lower than that of cutoff values of 20 with a significant difference of -6.820 (t= -6.514, df 49, P=0.000). Moreover, the inhibition effect of prebiotics (inulin and starch) against S. typhi at 37 °C for 24 h in part dish glucose as control, only the mean of inulin was found to be significantly lower than that of the cutoff value of 18 with the mean difference of -3.900 (t=-4.115, df 49, P=0.000). Other prebiotics of glucose and starch in 24 h showed negative inhibition. Probiotics are live microorganisms that have beneficial host effects by enhancing microbial balance in the intestine, whereas prebiotics are indigestible food components having beneficial effects by enhancing the activity and growth of one or more colonic bacteria. Lactobacillus filtrates had considerable effects against the test S. typhi isolates.

Heavy metal and disinfectant resistance of Listeria monocytogenes from foods and food processing plants.

The persistence of Listeria monocytogenes in food processing plants and other ecosystems reflects its ability to adapt to numerous stresses. In this study, we investigated 138 isolates from foods and food processing plants for resistance to the quaternary ammonium disinfectant benzalkonium chloride (BC) and to heavy metals (cadmium and arsenic). We also determined the prevalence of distinct cadmium resistance determinants (cadA1, cadA2, and cadA3) among cadmium-resistant isolates. Most BC-resistant isolates were resistant to cadmium as well. Arsenic resistance was encountered primarily in serotype 4b and was an attribute of most isolates of the serotype 4b epidemic clonal group ECIa. Prevalence of the known cadmium resistance determinants was serotype associated: cadA1 was more common in isolates of serotypes 1/2a and 1/2b than 4b, while cadA2 was more common in those of serotype 4b. A subset (15/77 [19%]) of the cadmium-resistant isolates lacked the known cadmium resistance determinants. Most of these isolates were of serotype 4b and were also resistant to arsenic, suggesting novel determinants that may confer resistance to both cadmium and arsenic in these serotype 4b strains. The findings may reflect previously unrecognized components of the ecological history of different serotypes and clonal groups of L. monocytogenes, including exposures to heavy metals and disinfectants.

Systematic reviews of adverse effects of drug interventions: a survey of their conduct and reporting quality.

PURPOSE: There is a need for high quality evidence on the adverse effects of medical interventions to inform policy, practice and research. Methods to systematically review adverse effects have not been fully developed. We aimed to assess the current methods and reporting used by such reviews. METHODS: Survey of general medical, drug safety and pharmacology journals published in 2006. Methods including: searching, inclusion criteria, quality assessment and meta-analysis were assessed. RESULTS: Forty three systematic reviews from 2704 abstracts in 16 journals were included. The search strategy was not reported by 10 (23%) of reviews. The collection and reporting of the adverse effects from primary studies was described by 4/37 (12%) reviews and the quality of included studies was assessed by 15 (35%) of reviews. Meta-analysis on rare outcomes and handling of zero event data were inconsistent. A polarity in the standard of reporting between reviews was observed. The reporting standard we found was similar to another survey of systematic reviews. CONCLUSION: Reporting was poor with respect to searching and definition/collection of adverse effects and guidelines such as QUOROM and MOOSE could be employed by authors. Comprehensive and clear reporting should be enforced by journals. The low proportion of reviews assessing quality, and the inconsistencies observed when modelling rare event data reflect the need for empirical research to underpin methods in these areas.

Safety of nateglinide as used in general practice in England: results of a prescription-event monitoring study.

Nateglinide (Starlix((R))) is licensed for the treatment of Type 2 diabetes in patients inadequately controlled with metformin. The study objective was to monitor the safety and use of nateglinide prescribed by primary care physicians (GPs) in England, using the observational cohort technique, Prescription-Event Monitoring. Exposure data were derived from dispensed nateglinide prescriptions issued October 2001-June 2004; demographic and outcome data, from questionnaires sent to patients' GPs at least 6 months after patients' first prescription. Incidence densities (IDs; number of first reports of an event/1,000 patient-months exposure) were calculated for month 1 (ID(1)), months 2-6 (ID(2-6)); rate differences [ID(1)-ID(2-6) (+99% CI)] were examined. Cohort comprised 4,557 patients, median age 60 (IQR 51, 68 years); 2,439 (53.5%) male; 3,463 (76.0%) received nateglinide in combination with metformin. GPs reported 1,625 reasons for stopping in 1,474 (32.3%) patients and 80 events as adverse drug reactions in 66 (1.5%) patients. Events associated with starting treatment included nausea/vomiting [ID(1)-ID(2-6) 9.6 (99% CI 5.3, 13.9)], malaise/lassitude [ID(1)-ID(2-6) 6.03 (99% CI 2.2, 9.9)]. No serious hypersensitivity reactions were reported. Two pregnancies (< 0.1%) and 73 deaths (1.6%) were reported. Nateglinide appeared to be generally well tolerated when used in combination with metformin for the treatment of Type 2 diabetes.

Use of atomoxetine and suicidal ideation in children and adolescents: Results of an observational cohort study within general practice in England.

AIM: To investigate the association between atomoxetine, a drug used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and suicidal ideation, within a cohort of 2-18-year-old patients in England. METHODS: The study was conducted using the observational cohort technique of Modified prescription event monitoring (M-PEM). Patients prescribed atomoxetine were identified from dispensed prescriptions issued by primary care physicians. A customised postal GP questionnaire was used to capture outcome data for suicidal ideation. A matched pair cohort analysis was performed within patients to compare the risk of suicidal ideation in the period after starting atomoxetine with the risk prior to starting atomoxetine; this was stratified by age and concomitant use of methylphenidate. Additional information on patient characteristics, and events of interest was also collected; individual cases of suicidal ideation were qualitatively assessed for drug relatedness. RESULTS: Of the final cohort (n=4509); 85.5% male (n=3857), median age 11 years (IQR: 9,14). Primary prescribing indication for atomoxetine was ADHD (n=4261, 94.6%). Almost a quarter of the cohort had been co-prescribed methylphenidate. Results of the matched pair cohort analysis indicated that the period after starting atomoxetine was not associated with an increase in the incidence of suicidal ideation compared to the period prior to starting treatment (RR: 0.71; CI: 0.48-1.07; P-value: 0.104). Individual case assessment of suicidal ideation suggested a causal association within a number of cases. CONCLUSIONS: This study found no evidence of an increased risk of suicidal ideation during treatment with atomoxetine, compared to the period prior to starting treatment. Amongst age specific subgroups, this risk may change. Nonetheless, individual case assessment suggested a causal relationship in some patients, hence physicians need to be aware of the possibility of developing this event, and furthermore consider how best to detect it in this paediatric population. This study demonstrates the importance of combining quantitative statistical analyses with a qualitative case series assessment.

Safety profile of repaglinide as used in general practice in England: results of a prescription-event monitoring study.

Repaglinide is a prandial glucose regulator indicated for management of type 2 diabetes. This post-marketing study used the observational cohort technique of prescription-event monitoring (PEM) to monitor safety of repaglinide prescribed in primary care in England. Patients were identified from dispensed prescriptions issued by general practitioners (GPs) between December 1998 and January 2001. Demographic and clinical event data were collected from questionnaires posted to GPs at least six months after the date of first prescription for each patient. The cohort consisted of 5731 patients [median age 60 (IQR 51-68), 49.9% male]. Event incidence densities (IDs) [no. 1st reports/1000 patient-months of exposure] were calculated for all events reported. The most frequently recorded clinical events in the first month were diarrhoea (ID(1) 10.3), malaise/lassitude (ID(1) 8.1) and nausea/vomiting (ID(1) 7.9). The most frequently reported reason for stopping was 'not effective' (647), with the most common clinical reasons being diarrhoea (60), malaise/lassitude (55) and intolerance (54). One hundred and thirteen adverse drug reactions (ADRs) were reported, with the most frequently specified being diarrhoea (10), abdominal pain (10) and nausea/vomiting (9). We concluded that repaglinide is generally well tolerated when used in general practice in England and did not identify any serious unrecognised adverse events.

Utilisation of extended release quetiapine (Seroquel XL™): Results from an observational cohort study in England.

BACKGROUND: A post-authorisation safety study was carried out as part of the EU Risk Management Plan to examine the long-term (up to 12 months) use of quetiapine XL as prescribed in general practice in England. AIM: To present a description of the drug utilisation characteristics of quetiapine XL. METHODS: An observational, population-based cohort design using the technique of Modified Prescription-Event Monitoring (M-PEM). Patients were identified from dispensed prescriptions issued by general practitioners (GPs) for quetiapine XL between September 2008 and February 2013. Questionnaires were sent to GPs 12 months following the 1st prescription for each individual patient, requesting drug utilisation information. Cohort accrual was extended to recruit additional elderly patients (special population of interest). Summary descriptive statistics were calculated. RESULTS: The final M-PEM cohort consisted of 13,276 patients; median age 43 years (IQR: 33, 55) and 59.0% females. Indications for prescribing included bipolar disorder (n=3820), MDD (n=2844), schizophrenia (n=2373) and other (non-licensed) indications (n=3750). Where specified, 59.3% (7869/13,276) were reported to have used quetiapine IR (immediate release formulation) previously at any time. The median start dose was highest for patients with schizophrenia (300 mg/day [IQR 150, 450]). The final elderly cohort consisted of 3127 patients and 28.5% had indications associated with dementia. The median start dose for elderly patients was highest for patients with schizophrenia or BD (both 100mg/day [IQR 50, 300]). CONCLUSIONS: The prevalence of off-label prescribing in terms of indication and high doses was common, as was use in special populations such as the very elderly. Whilst off-label use may be unavoidable in certain situations, GPs may need to re-evaluate prescribing in circumstances where there may be safety concerns. This study demonstrates the ongoing importance of observational studies such as M-PEM to gather real-world clinical data to support the post-marketing benefit:risk management of new medications, or existing medications for which license extensions have been approved.

Sudden cardiac and sudden unexpected death related to antipsychotics: A meta-analysis of observational studies.

To estimate the risk of sudden cardiac death (SCD) or sudden unexpected death (SUD) related to individual antipsychotics, a meta-analysis of observational studies was performed. Adjusted odds ratio (OR) of SCD/SUD with 95% confidence intervals (CI) were extracted and pooled; heterogeneity was studied using Q statistic and I(2) index, and its potential causes (e.g., hERG blockade potency) explored using meta-regression. Two cohort (740,306 person-years) and four case-control (2,557 cases; 17,670 controls) studies, investigating nine antipsychotics, were included. Compared with nonusers, the risk was increased for quetiapine (OR = 1.72, 95% CI: 1.33-2.23), olanzapine (OR = 2.04, 1.52-2.74), risperidone (OR = 3.04, 2.39-3.86), haloperidol (OR = 2.97, 1.59-5.54), clozapine (OR = 3.67, 1.94-6.94), and thioridazine (OR = 4.58, 2.09-10.05). Heterogeneity was found (Q = 20.0, P = 0.01; I(2) = 60.0%), and the increasing mean hERG blockade potency (P = 0.01) accounted for 43% of this. The SCD/SUD risk differed between individual antipsychotics, and mean hERG blockade potency could be an explanatory factor. This should be considered when initiating antipsychotic treatment.

Observational cohort study to monitor the use and safety of carvedilol in the treatment of heart failure in clinical practice in England--1st interim report.

AIMS: This is an interim report of a prospective observational cohort study to monitor the safety and tolerability of carvedilol in clinical practice when prescribed for heart failure in England. The utilization of carvedilol, management of adverse events in the community and the symptomatic progression of heart failure were examined. It is a non-interventional, observational cohort surveillance study using questionnaires sent to the patients' general practitioners. METHODS: The general practitioners (GPs) of the patients identified by the Prescription Pricing Authority were sent an eligibility questionnaire if the patient had been newly prescribed carvedilol between September 1999 and July 2001. Further questionnaires requesting baseline clinical information about eligible patients (carvedilol indicated for cardiac failure) and subsequent event data were sent to consenting GPs at 12 months. The questionnaires also requested specific information about initiation and supervision of treatment, including severity of heart failure and treatment withdrawal. The data were analyzed by using descriptive statistics. In addition, the incidence densities (ID) of each event (per 1000 person-months of treatment) were calculated, ranked and the difference between the ID of each event in the first (ID1) and subsequent 5 months of exposure (ID2) was tested by constructing 99% confidence intervals (CI). Selected events of clinical interest would be followed-up for further information to enable causal association with carvedilol to be assessed. RESULTS: In this interim report we have data on a cohort of 847 eligible patients for whom we have received information from the first follow-up questionnaire. The treatment of carvedilol was initiated in a majority of cases by hospital specialists (87%, n = 735), however, for most of them, further supervision of treatment was done under shared care between GPs and hospitals (70%, n = 595). More than 90% of the patients were started on carvedilol in the recommended dose range for the management of cardiac failure. Amongst the patients where NYHA grade of cardiac failure was expressed, the majority of patients treated with carvedilol had NYHA II (37%, n = 281) and III (40%, n = 297) symptoms at the start of carvedilol treatment. On treatment with carvedilol, improvement in NYHA status was reported for 43% (n = 364) of this cohort, whilst less than 2.5% (n = 20) of the patients deteriorated. The events reported with the highest ID1 were malaise/lassitude (14.6), dizziness (12.2), cardiac failure (9.7), dyspnea (9.7) and hypotension (8.5). The most common events reported as reasons for stopping carvedilol were "drug not effective", "dyspnea", "dizziness" and "lassitude". No events were identified as new signals (according to the ID1-ID2 statistic) of adverse events associated with carvedilol. There have been no events identified in this cohort that have required specific follow-up at the time of writing this paper. CONCLUSIONS: In summary, the interim results show that there is effective cooperation between hospital specialists and GPs in the use of carvedilol in the management of patients with heart failure. It also shows that carvedilol was well-tolerated and that patients with mild and moderate heart failure benefit symptomatically when treated with carvedilol in routine clinical practice.

Age- and gender-specific asthma death rates in patients taking long-acting beta2-agonists: prescription event monitoring pharmacosurveillance studies.

OBJECTIVE: Prescription event monitoring is a national drug safety surveillance scheme in which prescribers are prompted to report events and deaths following prescription of newly marketed drugs. This paper presents age- and gender-specific asthma death rates in patients prescribed the long-acting beta2-agonists salmeterol and bambuterol. DESIGN AND SETTING: Pharmacosurveillance cohort study of general practice patients in England. PATIENTS AND PARTICIPANTS: 15 406 patients prescribed salmeterol between December 1990 and May 1991, and 8098 patients prescribed bambuterol between February 1993 and December 1995. METHODS: Patients prescribed these drugs by general practitioners in England were identified using the national pharmacovigilance system of prescription event monitoring, in which details of all dispensed prescriptions were provided in confidence by the Prescription Pricing Authority. Questionnaires were sent to the prescriber asking for details of events occurring after the first prescription. In each study an attempt was made to establish the cause of all deaths reported on the questionnaires, via retrieval of the patients' medical notes or examination of death certificates. OUTCOME MEASURES AND RESULTS: There was little evidence of heterogeneity in the drug-specific death rates and we therefore present the combined age- and gender-specific death rates for the 2 cohorts. Overall, there were 85 asthma deaths among people taking the long-acting beta2-agonists studied (bambuterol and salmeterol cohorts combined). The overall death rate was 2.33 [95% confidence interval (CI) 1.84 to 2.84] per 10000 months of observation. There were 37 asthma deaths among male patients (rate 2.40 per 10000 months of observation; 95% CI 1.74 to 3.40) and 48 asthma deaths among female patients (rate 3.08 per 10000 months of observation; 95% CI 2.21 to 3.98). There was no difference in death rates when male and female patients were compared (rate ratio 0.78; 95% CI 0.49 to 1.22; p = 0.26). CONCLUSION: Prescription event monitoring is a form of prompted surveillance allowing rapid, uniform, national and practical assessment of newly marketed drugs on large cohorts of patients in England. These data provide benchmark rates from which to assess the performance of newly prescribed anti-asthma drugs and generate hypotheses for later analytical investigation in which confounding by indication and asthma severity can be controlled for. Any differences in these rates should be considered as a source of signal generation within the context of a surveillance programme, rather than as robust evidence of any mortality differential between drugs.

Troglitazone and liver function abnormalities: lessons from a prescription event monitoring study and spontaneous reporting.

OBJECTIVES: To investigate whether there were any cases of liver function abnormalities possibly associated with troglitazone use in general practice in England. DESIGN: A prescription-event monitoring (PEM) study was undertaken between October 1997 and December 1997. SETTING: Data from prescriptions were obtained electronically for the troglitazone cohort in the immediate postmarketing period. STUDY PARTICIPANTS: Event data were obtained for a total of 1344 patients. RESULTS: Troglitazone was effective in 394 (75%) of the 529 patients for whom an opinion was given. The most frequent reasons for stopping treatment related to drug tolerability were malaise/lassitude (16 reports), abnormal liver function tests (II reports) and nausea/vomiting (9 reports). The major cause of stopping troglitazone was because the drug was withdrawn from the market (1101 reports). 30 patients with liver dysfunction were identified from the cohort. In 9 of these patients there were alternative explanations for the liver dysfunction and hence these patients were not followed up further. 21 patients were followed up, for whom 19 questionnaires were returned. In 5 patients their liver dysfunction was assessed as possibly related to troglitazone, in 6 patients the liver dysfunction was unlikely to be attributed to troglitazone, while in 7 patients it was difficult to assess the causality because of limited information and confounding factors. The remaining patient was not included as this individual did not fit the inclusion criteria of the study. CONCLUSION: Although the cohort is small (the drug was available for only 3 months in the UK), 5 patients with abnormal liver function, considered possibly related to troglitazone were detected in this PEM study. It is possible for PEM to contribute to the elucidation of safety signals in the UK.

Safety profile of tolterodine as used in general practice in England: results of prescription-event monitoring.

BACKGROUND: Unstable bladder symptoms are a common problem in general practice. Drug therapy with anticholinergic drugs is frequently used in the management of this condition. However such drugs are associated with a high incidence of anticholinergic adverse effects. Tolterodine is a competitive anticholinergic agent, selective for the bladder as opposed to the salivary glands. OBJECTIVE: To monitor the safety of tolterodine as used in general practice patients in England for the treatment of urinary frequency, urgency and incontinence. DESIGN: Prospective observational cohort study. PATIENTS AND PARTICIPANTS: 14,526 patients [mean age 62.7 (SD 16.4) years; 68.6% female]. METHODS: Patients prescribed tolterodine in general practice, soon after the release of the drug in the UK, were followed up for a minimum of 6 months using the technique of prescription-event monitoring (PEM). RESULTS: The most common adverse events reported were dry mouth, headache, malaise, constipation, dyspepsia, nausea and vomiting and pain in abdomen. We identified some uncommon events as possible adverse drug reactions--notably hallucinations, tachycardia and palpitations. The prevalence of these events was compared with that in patient cohorts for other drugs on the PEM database. The age- and sex-adjusted relative risk of hallucinations on tolterodine compared with 10 drugs of other therapeutic classes, and with terodiline, another drug indicated for bladder instability, was 4.85 [95% confidence interval (CI) 2.72 to 8.66] and 1.25 (95% CI 0.62 to 2.53), respectively. There was no significant difference for tachycardia/palpitation in this comparison. CONCLUSIONS: Tolterodine is well tolerated in general practice at the recommended daily dose. Hallucinations, tachycardia and palpitations are infrequently associated with the drug.

Profiles of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolone antibacterials: experience from large cohorts from the Drug Safety Research Unit Prescription-Event Monitoring database.

OBJECTIVE: To investigate how frequently serious dysrhythmic cardiovascular, and hepatotoxic events are reported during routine clinical use of fluoroquinolones (quinolones) in general practice. DESIGN: Cohorts prescribed quinolones (cohort sizes: ciprofloxacin 11 477; enoxacin 2790; ofloxacin 11 033 and norfloxacin 11 110; mean age in each cohort of 48.6 to 57.0 years) were selected from the Drug Safety Research Unit's Prescription-Event Monitoring (PEM) database. The monitoring periods were November 1988 to January 1989 for ciprofloxacin; April 1989 to January 1991 for enoxacin; May 1991 to December 1991 for ofloxacin and October 1990 to October 1991 for norfloxacin. Data collected over the total PEM surveillance period on selected gastrointestinal events were extracted and reviewed to identify possible hepatic events, together with selected cardiovascular events associated with dysrhythmias. For each quinolone, times to onset of the event and patient-months of observation (denominator values) were calculated. The analysis was based on two observation periods: rate of event during the first 7 days following dispensing of a prescription for each drug (W(1)), and rate of event during the second to sixth week inclusive (W(2)). RESULTS: Scrutiny of original green forms revealed no evidence of drug-induced hepatic dysfunction within 42 days of drug administration for any of the quinolones monitored. No evidence was found of drug-induced dysrhythmic events associated with enoxacin within 42 days of drug administration. Of the other quinolones, 'atrial fibrillation' was reported most often within 42 days following ciprofloxacin administration, with no change in event rate over that time, crude relative risk (CRR)[W(1)/W(2)] 1.0 [95% confidence interval (CI) 0.02 to 8.92]. Other less serious events associated with dysrhythmia were reported with varying incidence within 42 days of quinolone administration. The crude rate of palpitation did not change significantly over that time for ciprofloxacin, ofloxacin and norfloxacin: CRR 0.83 (95% CI 0.02 to 6.86), 2.00 (95% CI 0.19 to 12.20) and 4.99 (95% CI 0.06 to 391.94), respectively. Syncope and tachycardia were also reported for ofloxacin [CRR 9.99 (95% CI 0.52 to 589.49 for both events)] and ciprofloxacin [1.0 (95% CI 0.02, 8.92)] and 2.50 (95% CI 0.04, 47.96) for syncope and tachycardia, respectively]. CONCLUSION: It cannot be ruled out that some rare hepatic and dysrhythmic events associated with quinolones may be drug related. The primary purpose of PEM is signal generation. Compared with the other quinolones, ciprofloxacin was associated with the highest number of reports of dysrhythmic cardiovascular events occurring within 42 days of administration. This requires further investigation by other types of epidemiological study.

The safety of valsartan: results of a postmarketing surveillance study on 12881 patients in England.

Valsartan is a second class of angiotensin II receptor antagonist, indicated for the treatment of hypertension. The objective of the study was to monitor the safety of valsartan using the technique of prescription event monitoring (PEM), in patients who were prescribed this drug by general practitioners (GPs) in England. PEM is a noninterventional observation cohort technique. Exposure data were obtained from dispensed prescriptions issued between December 1996 and November 1998. Outcome data were obtained by sending questionnaires to prescribing GPs. The cohort comprised 12881 patients. Events most frequently reported as suspected adverse drug reactions were malaise/lassitude (37; 0.3% of total cohort), dizziness (19; 0.1%), and unspecified side effects (57; 0.4%). Events with the highest incidence density (ID(1) per 1000 patient-months of treatment) in the first month of treatment were malaise/lassitude (15.6), dizziness (11.8), and headache/migraine (10.9). Most frequent reasons for stopping valsartan were not effective (847; 6.6% of total cohort), malaise/lassitude (265; 21%), and dizziness (146; 1.1%). No unexpected serious adverse events were identified. Other events assessed as possibly related to valsartan use were impotence (37), dizziness (19), cough (9), facial oedema (5), hyperkalaemia (3), and angioneurotic oedema (1). There were four reports of exposure during pregnancy and 203 deaths (1.5%) in this cohort. In conclusion, this study monitored the safety profile of valsartan in a large cohort of patients in general practice in England. No untoward features other than dizziness were identified that were not mentioned in the prescribing guidance.

Adverse effects associated with the use of donepezil in general practice in England.

Donepezil is an acetylcholinesterase inhibitor indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is reported to have a relatively favourable side-effect profile. We report here on a pharmacovigilance study carried out post-marketing in England. An observational cohort study using the technique of Prescription-Event Monitoring was carried out. Some 1762 patients (mean age 72.9 years; 42% male) were followed up for 6 months minimum. The commonest adverse events were nausea, diarrhoea, malaise, dizziness and insomnia. Aggression, agitation and abnormal dreams were uncommonly associated with the drug. There were no cardiac rhythm disturbances or liver disorders causally associated. The commonest adverse drug reactions are already reported in the product information. Given the relatively small size of this cohort, the signals of abnormal dreams and psychiatric disturbance as possible adverse drug reactions need further investigation in carefully planned studies.