BMC Clinical Pharmacology - Most viewed articles

Trends in hospital admissions for adverse drug reactions in England: analysis of national hospital episode statistics 1998–2005

2007-09-25

Background: Adverse drug reactions (ADRs) are a frequent cause of mortality and morbidity to patients worldwide, with great associated costs to the healthcare providers including the NHS in England. We examined trends in hospital admissions associated with adverse drug reaction in English hospitals and the accuracy of national reporting. Methods: Data from the Hospital Episode Statistics database (collected by the Department of Health) was obtained and analysed for all English hospital episodes (1998–2005) using ICD-10 codes with a primary (codes including the words ('drug-induced' or 'due to') or secondary diagnosis of ADR (Y40–59). More detailed analysis was performed for the year 2004–2005 Results: Between 1998 and 2005 there were 447 071 ADRs representing 0.50% of total hospital episodes and over this period the number of ADRs increased by 45%. All ADRs with an external code increased over this period. In 2005 the total number of episodes (all age groups) was 13,706,765 of which 76,692 (0.56%) were drug related. Systemic agents, which include anti-neoplastic drugs, were the most implicated class (15.7%), followed by analgesics (11.7%) and cardiovascular drugs (10.1%). There has been a 6 fold increase in nephropathy secondary to drugs and a 65% decline in drug induced extra-pyramidal side effects. 59% of cases involving adverse drug reactions involved patients above 60 years of age. Conclusion: ADRs have major public health and economic implications. Our data suggest that national Hospital Episode Statistics in England have recognised limitations and that consequently, admissions associated with adverse drug reactions continue to be under-recorded. External causes of ADR have increased at a greater rate than the increase in total hospital admissions. Improved and more detailed reporting combined with educational interventions to improve the recording of ADRs are needed to accurately monitor the morbidity caused by ADRs and to meaningfully evaluate national initiatives to reduce adverse drug reactions.

Intrathecal baclofen withdrawal syndrome- a life-threatening complication of baclofen pump: A case report

Imran Mohammed and Asif Hussain — 2004-08-09

Background: Intrathecal baclofen pump has been used effectively with increasing frequency in patients with severe spasticity, particularly for those patients who are unresponsive to conservative pharmacotherapy or develop intolerable side effects at therapeutic doses of oral baclofen. Drowsiness, nausea, headache, muscle weakness, light-headedness and return of pretreatment spasticity can be caused by intrathecal pump delivering an incorrect dose of baclofen. Intrathecal baclofen withdrawal syndrome is a very rare, potentially life-threatening complication of baclofen pump caused by an abrupt cessation of intrathecal baclofen.Case presentationA 24-year-old man with a past medical history of cerebral palsy and spastic quadriparesis developed hyperthermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure and multisystem organ failure leading to a full-blown intrathecal baclofen withdrawal syndrome. Intrathecal baclofen pump analysis revealed that it was stopped due to some programming error. He was treated effectively with supportive care, high-dose benzodiazepines and reinstitution of baclofen pump. Conclusion: The episodes of intrathecal baclofen withdrawal syndrome are mostly caused by preventable human errors or pump malfunction. Educating patients and their caregivers about the syndrome, and regular check-up of baclofen pump may decrease the incidence of intrathecal baclofen withdrawal syndrome. Oral baclofen replacement may not be an effective method to treat or prevent intrathecal baclofen withdrawal syndrome. Management includes an early recognition of syndrome, proper intensive care management, high-dose benzodiazepines and prompt analysis of intrathecal pump with reinstitution of baclofen.

Finasteride induced depression: a prospective study

Babak Rahimi-Ardabili, Ramin Pourandarjani, Peiman Habibollahi and Amir Mualeki — 2006-10-07

Background: Finasteride is a competitive inhibitor of 5 alpha-reductase enzyme, and is used for treatment of benign prostatic hyperplasia and androgenetic alopecia. Animal studies have shown that finasteride might induce behavioral changes. Additionally, some cases of finasteride-induced depression have been reported in humans. The purpose of this study was to examine whether depressive symptoms or anxiety might be induced by finasteride administration. Methods: One hundred and twenty eight men with androgenetic alopecia, who were prescribed finasteride (1 mg/day) were enrolled in this study. Information on depressed mood and anxiety was obtained by Beck Depression Inventory (BDI), and Hospital Anxiety and Depression Scale (HADS). Participants completed BDI and HADS questionnaires before beginning the treatment and also two months after it. Results: Mean age of the subjects was 25.8(± 4.4) years. At baseline, mean BDI and HADS depression scores were 12.11(± 7.50) and 4.04(± 2.51), respectively. Finasteride treatment increased both BDI (p < 0.001) and HADS depression scores significantly (p = 0.005). HADS anxiety scores were increased, but the difference was not significant (p = 0.061). Conclusion: This preliminary study suggests that finasteride might induce depressive symptoms; therefore this medication should be prescribed cautiously for patients with high risk of depression. It seems that further studies would be necessary to determine behavioral effects of this medication in higher doses and in more susceptible patients.

Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study

2008-03-31

Background: Cases of impaired renal function have been reported in patients who had been treated with both zoledronic acid and thalidomide for myeloma. Hence, we conducted a safety study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance therapy. Methods: Twenty-four patients who were enrolled in a large randomized trial of thalidomide vs no thalidomide maintenance therapy for myeloma, in which all patients also received zoledronic acid, were recruited to a pharmacokinetic and renal safety sub-study, and followed for up to 16 months. Results: No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid pharmacokinetics or renal safety for up to 16 months in patients randomized to thalidomide or not. Conclusion: In myeloma patients receiving maintenance therapy, the combination of zoledronic acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone.

Evaluation of safe and effective administration of nitrous oxide after a postgraduate training course

2008-06-11

Background: Conscious sedation is used in dentistry to improve access and quality of care in patients who have difficulty coping with treatment. The aim of this prospective study was to describe a postgraduate training course in conscious sedation for dentists, with specific evaluation of the safe and effective administration of a 50% nitrous oxide in oxygen premix. Methods: 45 practitioners were trained between 2002 and 2004. They carried out 826 sessions of inhalation sedation in 662 patients. The clinical competency of this group was compared with an expert group. Results: There was no difference between trainees and experts in ability to complete the planned dental treatment under sedation (89.6% vs 93.2%). Trainees were less successful than experts for patients with intellectual disability (87.4% vs 94.2%, p < 0.01). For both groups, the degree of cooperation improved between initial induction and each perioperative step (Wilcoxon test, p < 0.01). However, for trainees, Venham behaviour scores varied with the type of patient (Kruskal Wallis test, p < 0.001). No major adverse effects were recorded. Trainees reported more minor adverse effects than experts (13% vs. 5.3% respectively, Fisher exact test, p < 0.001) Conclusion: The trainee practitioners provided effective and safe inhalation sedation. This challenges the current French restriction of the 50% nitrous oxide in oxygen premix to the hospital setting. Further emphasis is required on the teaching of behaviour management skills for patients with intellectual disability.

Pharmacokinetics of recombinant human growth hormone administered by cool.click™ 2, a new needle-free device, compared with subcutaneous administration using a conventional syringe and needle

Chris Brearley, Anthony Priestley, James Leighton-Scott and Michel Christen — 2007-10-08

Background: Growth hormone (GH) is used to treat growth hormone deficiency (GHD, adult and paediatric), short bowel syndrome in patients on a specialized diet, HIV-associated wasting and, in children, growth failure due to a number of disorders including Turner's syndrome and chronic renal failure, and in children born small for gestational age. Different brands and generic forms of recombinant human growth hormone (r-hGH) are approved for varying indications in different countries. New ways of administering GH are required because the use of a needle and syringe or a device where a patient still has to insert the needle manually into the skin on a daily basis can lead to low adherence and sub-optimal treatment outcomes. The objective of this study was to assess the relative bioavailability of r-hGH (Saizen®, Merck Serono) administered by a new needle-free device, cool.click™ 2, and a standard needle and syringe. Methods: The study was performed with 38 healthy volunteers who underwent pituitary somatotrope cell down-regulation using somatostatin, according to a randomized, two-period, two-sequence crossover design. Following subcutaneous administration of r-hGH using cool.click™ 2 or needle and syringe, pharmacokinetic parameters were analysed by non-compartmental methods. Bioequivalence was assessed based on log-transformed AUC and Cmax values. Results: The 90% confidence intervals for test/reference mean ratio of the plasma pharmacokinetic variables Cmax and AUC0-inf were 103.7–118.3 and 97.1–110.0, respectively, which is within the accepted bioequivalence range of 80–125%. r-hGH administered by cool.click™ 2 is, therefore, bioequivalent to administration by needle and syringe with respect to the rate and extent of GH exposure. Treatment using cool.click™ 2 was found to be well tolerated. With cool.click™ 2 the tmax was less (3.0 hours) than for needle and syringe delivery (4.5 hours), p = 0.002 (Friedman test), although this is unlikely to have any clinical implications. Conclusion: These results demonstrate that cool.click™ 2 delivers subcutaneous r-hGH exposure that is bioequivalent to the conventional mode of injection. The new device has the additional advantage of being needle-free, and should help to increase patient adherence and achieve good therapeutic outcomes from r-hGH treatment.

The safety of over-the-counter niacin. A randomized placebo-controlled trial [ISRCTN18054903]

2003-11-13

Background: Niacin is widely available over the counter (OTC). We sought to determine the safety of 500 mg immediate release niacin, when healthy individuals use them as directed. Methods: 51 female and 17 male healthy volunteers (mean age 27 years SD 4.4) participated in a randomized placebo-controlled blinded trial of a single dose of an OTC, immediate-release niacin 500 mg (n = 33), or a single dose of placebo (n = 35) on an empty stomach. The outcomes measured were self-reported incidence of flushing and other adverse effects. Results: 33 volunteers on niacin (100%) and 1 volunteer on placebo (3%) flushed (relative risk 35, 95% confidence interval (CI) 6.8–194.7). Mean time to flushing on niacin was 18.2 min (95% CI: 12.7–23.6); mean duration of flushing was 75.4 min (95% CI: 62.5–88.2). Other adverse effects occurred commonly in the niacin group: chills (51.5% vs. 0%, P < .0001), generalized pruritus (75% vs. 0%, P = <.001), gastrointestinal upset (30% vs. 3%, P = .005), and cutaneous tingling (30% vs. 0%, P = <.001). Six participants did not tolerate the adverse effects of niacin and 3 required medical attention. Conclusion: Clinicians counseling patients about niacin should alert patients not only about flushing but also about gastrointestinal symptoms, the most severe in this study. They should not trust that patients would receive information about these side effects or their prevention (with aspirin) from the OTC packet insert.

Individual case safety reports in children in commonly used drug groups – signal detection

Gertrud Brunlöf, Carina Tukukino and Susanna M Wallerstedt — 2008-03-17

Background: Due to few paediatric drug safety studies, knowledge on risks of drug treatment in children is limited. The knowledge needs to be increased to make proper risk-benefit analyses possible when treating paediatric patients with drugs. The aim of the present study was to investigate drug groups commonly used in children concerning type and frequency of individual case safety reports in children. Methods: Number and type of individual case safety reports in the 30 groups of drugs (5th level ATC-code) most sold (number of defined daily doses) in outpatient treatment to children (<15 years old) during 2005 were obtained. Descriptive analyses of the adverse drug reactions reported in children were performed. Results: The number of individual case safety reports per million defined daily doses in children varied in the groups of drug between 0 and 24. The largest number was found in the drug group R03DC, the leukotriene receptor antagonist montelukast; the majority of the children being <5 years old and experiencing psychiatric adverse drug reactions. Conclusion: The number of individual case safety reports per million defined daily doses varies in different groups of drugs. A possible signal for montelukast and psychiatric adverse drug reactions was found, which should be further explored.

Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell®)

Bertrand Dautzenberg, Mitchell Nides, Jean-Luc Kienzler and Anne Callens — 2007-10-08

Background: The use of nicotine replacement therapy (NRT) can almost double the chances of success for smokers to quit. Nevertheless, there is still a considerable number of cessation attempts that are made without any treatment. This novel oral formulation, (lozenge containing nicotine bitartrate dihydrate) has been developed to enlarge the offer for efficient smoking cessation drug therapies, assuming that increasing treatment options will bring more smokers to find the support they personally need to stop smoking. Methods: Three pharmacokinetic (PK), one safety and two efficacy studies were carried out with Nicotinell lozenges. PK trials were: (1) a single-dose, three-way crossover study comparing 1 and 2 mg lozenges with 2 mg nicotine gum; (2) a multiple-dose, two-way crossover study comparing 1 mg lozenge with 2 mg gum; (3) a multiple-dose, three-way crossover study comparing 1 and 2 mg lozenges with 4 mg gum. Safety trial: (4) a single dose study to assess the safety of swallowing up to 12 lozenges containing 1 mg nicotine. Efficacy trials: two efficacy studies in (5) France and (6) the USA, including more than 900 smokers followed-up for up to one year, conducted with the 1 mg lozenge. Results: The results of the individual PK trials showed that the 1 mg Nicotinell lozenge is bioequivalent to 2 mg polacrilex gum, as demonstrated by similar blood PK parameters (tmax, Cmax, AUC). The 2 mg lozenge was found to deliver quantities of nicotine that were intermediate between those delivered by 2 and 4 mg polacrilex gum.The short-term efficacy of the 1 mg lozenge in comparison with placebo was also demonstrated with significantly more subjects continuously abstinent from smoking with active lozenges on week 6 in two different populations: moderate to heavy smokers (FTND between 4 and 7) OR = 1.72 [95% CI: 1.05–2.80]; heavy to very heavy smokers (FTND 6 and over) OR = 2.87 [95% CI: 1.18–6.97].Nicotinell lozenges were found to be safe with mainly mild and reversible adverse events. The safety of the 1 mg lozenge formulation, even when misused was also demonstrated. Conclusion: The data presented in this review demonstrate high nicotine bioavailability, excellent safety profile and proven short-term efficacy of Nicotinell lozenges. At nominal equivalent doses 1 and 2 mg Nicotinell lozenges were shown to deliver larger amounts of bioavailable nicotine compared to the nicotine polacrilex gum. According to the data developed here, the systemic exposure to nicotine could be ranked: 4 mg polacrilex gum > 2 mg Nicotinell lozenge > 1 mg Nicotinell lozenge = 2 mg polacrilex gum.Adverse events observed during the clinical trials were mild or moderate in severity, transient and completely reversible. With respect to efficacy in smoking cessation, significantly higher continuous abstinence rates were achieved with lozenge compared to placebo. In conclusion, Nicotinell lozenges offer a valuable addition to the therapeutic armamentarium available for smoking cessation.

Aspects of statin prescribing in Norwegian counties with high, average and low statin consumption – an individual-level prescription database study

2007-12-05

Background: A previous study has shown that variations in threshold and intensity (lipid goal attainment) of statins for primary prevention contribute to regional differences in overall consumption of statins in Norway. Our objective was to explore how differences in prevalences of use, dosing characteristics, choice of statin and continuity of therapy in individual patients adds new information to previous results. Methods: Data were retrieved from The Norwegian Prescription Database. We included individuals from counties with high, average, and low statin consumption, who had at least one statin prescription dispensed during 2004 (N = 40 143).1-year prevalence, prescribed daily dose (PDD), statin of choice, and continuity of therapy assessed by mean number of tablets per day. Results: The high-consumption county had higher prevalence of statin use in all age groups.Atorvastatin and simvastatin were dispensed in 79–87% of all statin users, and the proportion was significantly higher in the high-consumption county.The estimated PDDs were higher than the DDDs, up to twice the DDD for atorvastatin. The high-consumption county had the highest PDD for simvastatin (25.9 mg) and atorvastatin (21.9 mg), and more users received tablets in the upper range of available strengths. Continuity of therapy was similar in the three counties. Conclusion: Although differences in age-distribution seems to be an important source of variation in statin consumption, it cannot account for the total variation between counties in Norway. Variations in prevalences of use, and treatment intensity in terms of PDD and choice of statin also affect the total consumption. The results in this study seems to correspond to previous findings of more frequent statin use in primary prevention, and more statin users achieving lipid goal in the highest consuming county.