A change in the trend in dosulepin usage following the introduction of a prescribing indicator but not after two national safety warnings.

WHAT IS KNOWN AND OBJECTIVE: The tricyclic antidepressant dosulepin has been associated with an increased risk of toxicity in overdose compared with other antidepressants. In the UK, the MHRA and NICE have issued advice on the prescribing of dosulepin, and a National Prescribing Indicator (NPI) to monitor usage was introduced in Wales in 2011. The aim of this study was to assess whether trends in dosulepin usage in Wales and NE England changed following the two pieces of safety guidance and the introduction of the National Prescribing Indicator in Wales. METHODS: Primary care dosulepin usage in the 12 months prior to and following MHRA safety advice (in 2007), NICE guideline CG90 (in 2009) and the introduction of the NPI (in 2011) was obtained. Usage was measured using defined daily doses (DDDs) per 1000 prescribing units (PUs). The trends in the 12 months prior to and following the introduction of prescribing advice and the NPI were compared using an autoregressive integrated moving average (ARIMA) model. RESULTS AND DISCUSSION: In Wales, the trend in dosulepin usage did not change significantly prior to and following the MHRA advice: -0·18 and -0·43 DDDs/1000PUs per month, respectively (P = 0·07), or prior to and following NICE CG90: -0·30 and -0·49 DDDs/1000PUs per month, respectively (P = 0·35). In the 12 months prior to and following the introduction of the NPI, the trend was -0·45 and -0·98 DDDs/1000PUs per month, respectively (P = 0·001). In NE England, the trend did not alter significantly following the NICE advice or the introduction of the NPI in Wales. WHAT IS NEW AND CONCLUSION: The trend in dosulepin usage in Wales altered significantly following the introduction of the NPI, but not after the other prescribing advice. This association, coupled with the absence of a significant change in NE England over the same period, provided some evidence of the effectiveness of the NPI in prompting a change in prescribing behaviour in Wales.

Impact of anti-cancer drugs and other determinants on serum protein binding of morphine 6-glucuronide.

BACKGROUND AND THE PURPOSE OF THE STUDY: The aim of the present study was to examine factors that may influence the protein binding of morphine 6-glucuronide (M6G), the most active metabolite of morphine. METHODS: An enzyme-linked immunoabsorbent assay technique was used to measure the M6G concentration in serum of 18 healthy adults, 18 neonatal and 7 children with cancer. Total and free M6G concentrations were measured following equilibrium dialysis for 3 hrs and at physiological pH at 37°C. The influence of vincristine, methotrexate, 6-mercaptopurine, morphine, human albumin, alpha-1-acid glycoprotein, palmitic acid, oleic acid and pH on M6G protein binding was examined. RESULTS: M6G was 66.87±0.73 percent free in human serum at physiological pH and temperature. The percentage free (unbound) was increased significantly by vincristine (4.33%) and methotrexate (9.68%), but 6- mercaptopurine and morphine had no significant effect on it. Free percentages of M6G was reduced by decreasing serum albumin concentration but was unaffected by the presence of alpa-1-acid glycoprotein (AAG) or changes in serum pH. Similar results were obtained in human serum albumin (HAS) solutions. Addition of palmitic acid and oleic acid reduced protein binding significantly by 6.3% and 7.4%, respectively. MAJOR CONCLUSION: Although M6G in this study was not highly bounded, but because of its high analgesic potency, any change in its free concentration due to concurrent medication or disease caused significant changes in its effects. This dearth of evidence has been implicated in the reluctance of professionals to be cautious in prescribing them to children, particularly in the neonatal period.

Evidence of active transport involvement in morphine transport via MDCKII and MDCK-PGP cell lines.

Several transporters appear to be important in transporting various drugs. Many patients, who receive morphine as analgesic medication, also receive other medications with potency of changing morphine transport by affecting P-glycoprotein (P-GP) and oatp2 transport system. This could influence morphine pharmacokinetics and pharmacodynamics. The aim of present study was to elucidate the transport mechanisms involved in transporting morphine via MDCKII and MDCK-PGP cells. Morphine permeability was examined in the presence of various compounds with ability in inhibiting different transport systems including: digoxin, probenecid and d- glucose. The effect of morphine concentration changes on its transport was also examined. Morphine concentration was measured using HPLC with electrochemical detector. Morphine permeability via a MDCK II cells was greater than sucrose permeability, and reduced when a P-GP expressed cell line was used. Its permeability was increased significantly in the presence of a strong P-GP inhibitor. Morphine permeability decreased significantly in the presence of digoxin but not in the presence of d-glucose or probenecid. These results showed that morphine was a P-GP substrate, and digoxin related transporters such as oatp2 were involved in its transport. Morphine was not substrate for glucose or probenecid-sensitive transporters.

Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial.

OBJECTIVE: To determine the optimum duration of oral anticoagulant therapy after an episode of deep vein thrombosis or pulmonary embolism, or both. DESIGN: Multicentre, prospective, randomised study with follow-up for one year. SETTING: 46 hospitals in United Kingdom. PARTICIPANTS: Patients aged > or =18 with deep vein thrombosis or pulmonary embolism, or both. INTERVENTIONS: Three (n=369) or six months (n=380) of anticoagulation with heparin for five days accompanied and followed by warfarin, with a target international normalised ratio of 2.0-3.5. MAIN OUTCOME MEASURES: Death from deep vein thrombosis or pulmonary embolism; failure to resolve, extension, recurrence of during treatment; recurrence after treatment; and major haemorrhage during treatment. RESULTS: In the patients allocated to three months' treatment two died from deep vein thrombosis or pulmonary embolism during or after treatment, compared with three in the six month group. During treatment deep vein thrombosis or pulmonary embolism failed to resolve, extended, or recurred in six patients in the three month group without fatal consequences, compared with 10 in the six month group. After treatment there were 23 non-fatal recurrences in the three month group and 16 in the six month group. Fatal and non-fatal deep vein thrombosis or pulmonary embolism during treatment, and after treatment thus occurred in 31(8%) of those who had received three months' anticoagulation compared with 29 (8%) of those who had received six months' (P=0.80, 95% confidence interval for difference -3.1% to 4.7%). There were no fatal haemorrhages during treatment but there were eight major haemorrhages in those treated for six months and none in those treated for three months (P=0.008, -3.5% to -0.7%). Thus 31 (8%) of the patients receiving three months' anticoagulation experienced adverse outcomes as a result of deep vein thrombosis or pulmonary embolism or its treatment compared with 35 (9%) of those receiving six months' (P=0.79, -4.9% to 3.2%). CONCLUSION: For patients in the UK with deep vein thrombosis or pulmonary embolism and no known risk factors for recurrence, there seems to be little, if any, advantage in increasing the duration of anticoagulation from three to six months. Any possible advantage would be small and would need to be judged against the increased risk of haemorrhage associated with the longer duration of treatment with warfarin. TRIAL REGISTRATION: Clinical Trials NCT00365950 [ClinicalTrials.gov].

Patient reporting of suspected adverse drug reactions: a review of published literature and international experience.

AIMS: To synthesize data from published studies and international experience to identify evidence of potential benefits and drawbacks of direct patient reporting of suspected adverse drug reactions (ADRs) by patients. METHODS: Structured search of MEDLINE, CINAHL and PsycINFO supplemented by internet searches and requests for information to key contacts. RESULTS: Seven studies (eight papers) were included in the review. None of the studies concerned spontaneous reporting by patients. Information on patient reporting systems was obtained for six countries, with summary data reported by four. Patient reports identified possible new ADRs that had not previously been reported by health professionals. The quality of patient reports appears to be similar to that of health professional reports. There is some evidence that patients report an ADR when they consider their health professional has not paid attention to their concerns. Patient reports may, at least initially, be more time consuming to process. CONCLUSIONS: Overall, the evidence indicates that patient reporting of suspected ADRs has more potential benefits than drawbacks. Evaluation of patient reporting systems is needed to provide further evidence.

The effects of acute ethanol intake on isoniazid pharmacokinetics.

AIM: To assess effects of acute ethanol intake on the pharmacokinetics of isoniazid in healthy male volunteers. METHODS: Sixteen healthy male, drug-free subjects were studied. Each received in the fasting state, on two occasions separated by at least 1 week, isoniazid (200 mg orally). On one occasion (assigned randomly), subjects received ethanol 0.73 g/kg, 1 h before isoniazid, followed by 0.11 g/kg ethanol orally every hour thereafter for 7 h. Plasma isoniazid and acetylisoniazid concentrations were measured by means of high-performance liquid chromatography. Blood ethanol concentrations were measured hourly by breath analysis. Plasma concentrations of isoniazid and acetylisoniazid were analysed using TOPFIT software. RESULTS: Peak concentrations of isoniazid were reached within 90 min, in both the ethanol-treated and control groups. The ethanol dosage regimen used resulted in peak blood ethanol concentrations between 78 mg/l and 103 mg/l. There was no significant difference in area under the curve, half-life of elimination or the ratio of acetylisoniazid to isoniazid (AcINH/INH) in the sample withdrawn 3 h after isoniazid dose. Acetylator phenotype for patients was the same in both phases, whether assessed by half-life of isoniazid or the AcINH/INH ratio at 3 h. CONCLUSIONS: Acute ethanol intake at this dose is unlikely to affect results of acetylation studies in which isoniazid is used as a substrate, whether the half-life of isoniazid or the AcINH /INH ratio at 3 h is used to phenotype patients.

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.

The involvement of nurses in reporting suspected adverse drug reactions: experience with the meningococcal vaccination scheme.

AIMS: In order to aid the monitoring of the new Meningococcal serogroup C Conjugate (Men C) vaccine, the Yellow Card Scheme was extended to allow nurses for the first time to report any suspected adverse reactions associated with these vaccines. We have analysed the Yellow Cards received by the Committee on Safety of Medicines (CSM) Wales from nurses reporting a suspected reaction in association with these vaccines during the first 16 months of the programme. METHODS: CSM Wales receives Yellow Cards from healthcare professionals in Wales. Details of Yellow Cards reporting a suspected adverse reaction associated with Men C vaccines during the study period were extracted from the CSM Wales database and analysed according to health professional category [nurses, General Practitioners (GP), hospital doctors or pharmacists]. RESULTS: During the study period 534 117 doses of Men C vaccines were administered in Wales; in the same period CSM Wales received 1095 Yellow Cards containing 1952 suspected reactions. Nurses completed 529 [48.3%, 95% confidence interval (CI) 43.6, 53.1] Yellow Cards compared with 294 (26.8%, 95% CI 22.7, 30.8) from GPs, 262 (23.9%, 95% CI 20.1, 27.6) from hospital doctors and 10 (0.91%, 95% CI 0.43, 1.73) from others, which include hospital pharmacists, community pharmacists and health visitors. The proportion of Yellow Cards sent by nurses was significantly higher than those sent by GPs and hospital doctors. Ninety-five percent CIs for differences in proportions (CI diff prop) were (0.175, 0.254) and (0.204, 0.282), respectively. The majority (90.9%, 95% CI 88.7, 93.5) of the Yellow Cards from nurses reported suspected reactions children in over the age of 5 (95% CI diff prop 0.861, 0.917). The spectrum of suspected adverse drug reactions (ADRs) involved the skin and subcutaneous tissue, central nervous system, general reactions, and the gastrointestinal tract. Of the suspected reactions reported by nurses, GPs and hospital doctors, 13.4% (95% CI 10.5, 15.8), 12.9% (95% CI 9.6, 16.8) and 9.1% (95% CI 6.5, 11.8), respectively, were of serious reactions. Nurses reported 52.5% (95% CI 45.4, 60.6) of all the suspected serious reactions, which was statistically more significant than hospital doctors [chi2 = 5.864, degree of freedom (DF) = 1, P < 0.05] but not GPs (chi2 = 0.066, DF = 1, P > 0.05). CONCLUSIONS: Nurses were the health professionals who provided the largest proportion of reports of suspected ADRs and almost half of all reports during the Men C vaccination campaign. Their reports contained an equal proportion of serious suspected ADRs and the reports were documented as completely as those from GPs and hospital doctors.

Erythrocyte thiopurine methyl transferase assessment prior to azathioprine use in the UK.

BACKGROUND: Individuals with low activity of a key metabolic enzyme, thiopurine methyl transferase (TPMT), are more susceptible to azathioprine-induced myelosuppression. AIM: To determine the pattern of use of TPMT activity estimation, with respect to azathioprine use, by medical practitioners in the UK. DESIGN: Retrospective analysis of assay use. METHODS: We analysed all test results (n=3291), and patient and practitioner details, from inception of TPMT assay in 1990 to the end of December 2000, held at the Purine Research Laboratory, Guy's Hospital, London. Patient details were anonymized. Repeat analyses and requests from outside the UK were excluded. RESULTS: The male:female ratio was approximately equal and the mean age was 46.6 (range 0.5-97) years. Thirteen different medical specialities requested assays; Dermatology and Gastroenterology were the most frequent users, together accounting for 86% of requests. The numbers of centres requesting the assay varied widely both within and between different specialities. Some 80% of individuals had normal TPMT activity, 9% enzymic activity above normal, and 10% low activity. Fifteen had no detectable enzymic activity: 0.45% (1:220) of the study population. DISCUSSION: This incidence of undetectable enzyme activity is significantly higher than the previously reported level of 1:300 derived from smaller studies, and makes the economics of screening more attractive.

Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example.

AIMS: The nature and incidence of errors in prescribing and giving medicines have previously been estimated by trained observers, or by retrospective analysis of incidents in which patients have come to harm. We have examined prospectively in routine clinical practice the concentrations of intravenous infusions of a drug (acetylcysteine) which is given according to a complicated dosing schedule. METHODS: We prospectively collected samples before and, where possible, after the infusion of acetylcysteine in 66 anonymous patients requiring treatment for acetaminophen (paracetamol) overdose in four centres in the United Kingdom. We measured the concentration in each infusion bag, and deduced from the weight of the patient the percentage of the anticipated dose that had actually been given. RESULTS: The experimentally determined dose was within 10% of the anticipated dose in 68 of 184 individual bags (37%), and within 20% of the anticipated dose in 112 bags (61%). Doses in 17 bags were more than 50% from the anticipated doses. In three patients, values in all three bags appeared to be systematically wrong by 50% or more; in a further seven cases, individual bags differed by 50% or more from the anticipated value. The median difference between pre- and post-infusion samples was 0% [interquartile range -5.2% to +14.6%], but 9% showed a disparity of greater than +/- 50%. CONCLUSIONS: Our data suggest that there is large random variation in administered dosage of intravenous infusions. Systematic calculation errors occur in about 5% [95% confidence interval 2, 8%] of cases, and major errors in drawing up in a further 3% [1, 7%], with inadequate mixing in 9% [4, 14%]. While we have no evidence that patients were adversely affected, and while the regime of administration of the drug studied (acetylcysteine) is complicated, these data suggest that the delivered dose often deviates from the intended dose, and that methods of quality control are needed.

Colchicine induced rhabdomyolysis.

A case of colchicine induced rhabdomyolysis is reported. A 73 year old man with ischaemic heart disease, atrial fibrillation, chronic congestive cardiac failure, and chronic gout presented with diffuse muscle pain. He had been taking an increased dose of colchicine (1.5 mg daily) for an exacerbation of gout for six weeks before the presentation. Investigations confirmed the diagnosis of rhabdomyolysis and discontinuation of colchicine resulted in resolution of clinical and biochemical features of rhabdomyolysis. Although neuromuscular adverse effects of colchicine are well recognised, rhabdomyolysis is rare and this is only the fourth reported case of colchicine induced rhabdomyolysis in the literature.

Community exposures to chemical incidents: development and evaluation of the first environmental public health surveillance system in europe.

OBJECTIVE: To describe the frequency, nature and location of acute chemical incidents in Wales, and the morbidity in employees, emergency responders and the general public who were exposed. DESIGN: Active multi-agency community-based surveillance system. SETTING: Wales, 1993-5. MAIN OUTCOME MEASURES: Frequency, nature and location of incidents, populations potentially exposed and with symptoms. RESULTS: Most of the 402 incidents identified were not associated with sites governed by the Control of Industrial Major Accident Hazard Regulations but with smaller industrial sites and commercial premises. About two in every thousand of the estimated 236 000 members of the public considered to be at risk from exposure reported symptoms, which were mainly nausea, headaches, and irritation of the eye, skin and respiratory tract. The most commonly reported chemicals that members of the public were exposed to were smoke toxins, miscellaneous organics, toxic gases and flammable gases. A health authority was reported to be involved in only 34 (8%) of the incidents and in only 3 of the 29 incidents where more than 100 members of the public were exposed. CONCLUSION: A geographically defined, multi-agency surveillance system can identify high risk locations and types of incidents, together with the chemicals most likely to be involved. Such ongoing surveillance information is essential for appropriate policy making, emergency planning, operational management and training.

1,2-dibromoethane--a toxicological review.

DBE is transported in the UK in road tankers and there is always the possibility of an accident. The consequences could be serious, since this chemical is absorbed by all routes, rapidly penetrates clothing and there is no effective antidote. Severe cases of poisoning are difficult to treat and there is a high mortality. Prevention of exposure is therefore essential.

Spontaneous reporting of suspected adverse reactions to antihistamines: a national and international perspective.

Twenty-one sedative and five non-sedating antihistamines are presently available on the UK market. Analysis of spontaneous reports of suspected adverse drug reactions was performed for those drugs with more than 90 reported reactions on the UK ADROIT database to the period ending 31 December 1997. Thus nine antihistamines, (four sedative antihistamines and five non-sedating antihistamines) were included. For each of the four sedative agents (azatidine, chlorpheniramine, diphenhydramine and trimeprazine), reactions associated with the cardiovascular, gastrointestinal, central nervous systems, the skin, general and psychiatric reactions made up more than 70% of total reported reactions. For all four agents, fatal reactions constituted less than 2.5% of total reactions. For each of the five non-sedating agents (acrivastine, astemizole, cetirizine, loratidine and terfenadine), reactions associated with the cardiovascular, gastrointestinal central nervous systems, the skin, general and psychiatric disorders together made up more than 75% of total reported reactions. For all five non-sedating agents, fatal reactions constituted less than 1% of total reactions. However, there were 21 reports of fatality in association with terfenadine, 11 (52%) of which were either sudden deaths or those associated with a cardiac rate of rhythm reaction. Analysis of the WHO database for non-sedating drugs showed a similar pattern, with terfenadine being associated with the highest frequency of reports of potentially serious arrhythmias and of sudden death and death related to disturbances of cardiac rate and rhythm combined. Despite the limitations of spontaneous reporting systems, comparison of the benefit-risk profiles of drugs using this data within a class of drugs can provide valuable information, and pharmacovigilance of antihistamines (and all other agents) using this and other means should continue for the lifetime of their use in humans.

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.