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1.  Bioavailability of ibuprofen following oral administration of standard ibuprofen, sodium ibuprofen or ibuprofen acid incorporating poloxamer in healthy volunteers 
Background
The aim of this study was to compare the pharmacokinetic properties of sodium ibuprofen and ibuprofen acid incorporating poloxamer with standard ibuprofen acid tablets.
Methods
Twenty-two healthy volunteers were enrolled into this randomised, single-dose, 3-way crossover, open-label, single-centre, pharmacokinetic study. After 14 hours' fasting, participants received a single dose of 2 × 200 mg ibuprofen acid tablets (standard ibuprofen), 2 × 256 mg ibuprofen sodium dihydrate tablets (sodium ibuprofen; each equivalent to 200 mg ibuprofen acid) and 2 × 200 mg ibuprofen acid incorporating 60 mg poloxamer 407 (ibuprofen/poloxamer). A washout period of 2-7 days separated consecutive dosing days. On each of the 3 treatment days, blood samples were collected post dose for pharmacokinetic analyses and any adverse events recorded. Plasma concentration of ibuprofen was assessed using a liquid chromatographic-mass spectrometry procedure in negative ion mode. A standard statistical ANOVA model, appropriate for bioequivalence studies, was used and ratios of 90% confidence intervals (CIs) were calculated.
Results
Tmax for sodium ibuprofen was less than half that of standard ibuprofen (median 35 min vs 90 min, respectively; P = 0.0002) and Cmax was significantly higher (41.47 μg/mL vs 31.88 μg/mL; ratio test/reference = 130.06%, 90% CI 118.86-142.32%). Ibuprofen/poloxamer was bioequivalent to the standard ibuprofen formulation, despite its Tmax being on average 20 minutes shorter than standard ibuprofen (median 75 mins vs 90 mins, respectively; P = 0.1913), as the ratio of test/reference = 110.48% (CI 100.96-120.89%), which fell within the 80-125% limit of the CPMP and FDA guidelines for bioequivalence. The overall extent of absorption was similar for the three formulations, which were all well tolerated.
Conclusion
In terms of Tmax, ibuprofen formulated as a sodium salt was absorbed twice as quickly as from standard ibuprofen acid. The addition of poloxamer to ibuprofen acid did not significantly affect absorption.
doi:10.1186/1472-6904-9-19
PMCID: PMC2796637  PMID: 19961574
2.  In vivo administration of BL-3050: highly stable engineered PON1-HDL complexes 
Background
Serum paraoxonase (PON1) is a high density lipoprotein (HDL)-associated enzyme involved in organophosphate (OP) degradation and prevention of atherosclerosis. PON1 comprises a potential candidate for in vivo therapeutics, as an anti-atherogenic agent, and for detoxification of pesticides and nerve agents. Because human PON1 exhibits limited stability, engineered, recombinant PON1 (rePON1) variants that were designed for higher reactivity, solubility, stability, and bacterial expression, are candidates for treatment. This work addresses the feasibility of in vivo administration of rePON1, and its HDL complex, as a potentially therapeutic agent dubbed BL-3050.
Methods
For stability studies we applied different challenges related to the in vivo disfunctionalization of HDL and PON1 and tested for inactivation of PON1's activity. We applied acute, repetitive administrations of BL-3050 in mice to assess its toxicity and adverse immune responses. The in vivo efficacy of recombinant PON1 and BL-3050 were tested with an animal model of chlorpyrifos-oxon poisoning.
Results
Inactivation studies show significantly improved in vitro lifespan of the engineered rePON1 relative to human PON1. Significant sequence changes relative to human PON1 might hamper the in vivo applicability of BL-3050 due to adverse immune responses. However, we observed no toxic effects in mice subjected to repetitive administration of BL-3050, suggesting that BL-3050 could be safely used. To further evaluate the activity of BL-3050 in vivo, we applied an animal model that mimics human organophosphate poisoning. In these studies, a significant advantages of rePON1 and BL-3050 (>87.5% survival versus <37.5% in the control groups) was observed. Furthermore, BL-3050 and rePON1 were superior to the conventional treatment of atropine-2-PAM as a prophylactic treatment for OP poisoning.
Conclusion
In vitro and in vivo data described here demonstrate the potential advantages of rePON1 and BL-3050 for treatment of OP toxicity and chronic cardiovascular diseases like atherosclerosis. The in vivo data also suggest that rePON1 and BL-3050 are stable and safe, and could be used for acute, and possibly repeated treatments, with no adverse effects.
doi:10.1186/1472-6904-9-18
PMCID: PMC2785756  PMID: 19922610
3.  Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part B - Behavioral results 
Background
This study investigated the effects of oral dimercapto succinic acid (DMSA) therapy on the behavioural symptoms of children with autism spectrum disorders (ASD) ages 3-8 years.
Methods
Phase 1 involved 65 children with ASD who received one round of DMSA (3 days). Participants who had high urinary excretion of toxic metals were selected to continue on to phase 2. In phase 2, 49 participants were randomly assigned in a double-blind design to receive an additional 6 rounds of either DMSA or placebo.
Results
The groups receiving one round and seven rounds of DMSA had significant improvements on all the assessment measures. For the seven round group, the degree of improvement on the assessment measures could be partially explained by a regression analysis based on excretion of toxic metals and changes in glutathione (adjusted R2 of 0.28-0.75, p < 0.02 in all cases). One round of DMSA had nearly the same benefit as seven rounds. The assessment measures correlated reasonably with one another at the beginning of the study (r = 0.60-0.87) and even better at the end of the study (r = 0.63-0.94).
Conclusion
Overall, both one and seven rounds of DMSA therapy seems to be reasonably safe in children with ASD who have high urinary excretion of toxic metals, and possibly helpful in reducing some of the symptoms of autism in those children.
doi:10.1186/1472-6904-9-17
PMCID: PMC2770991  PMID: 19852790
4.  Safety and efficacy of oral DMSA therapy for children with autism spectrum disorders: Part A - Medical results 
Background
This study investigated the effect of oral dimercapto succinic acid (DMSA) therapy for children with autism spectrum disorders ages 3-8 years.
Methods
Phase 1 involved 65 children who received one round of DMSA (3 days). Participants who had high urinary excretion of toxic metals were selected to continue on to phase 2. In phase 2, 49 participants were randomly assigned in a double-blind design to receive an additional 6 rounds of either DMSA or placebo.
Results
DMSA greatly increased the excretion of lead, substantially increased excretion of tin and bismuth, and somewhat increased the excretion of thallium, mercury, antimony, and tungsten. There was some increase in urinary excretion of essential minerals, especially potassium and chromium. The Phase 1 single round of DMSA led to a dramatic normalization of RBC glutathione in almost all cases, and greatly improved abnormal platelet counts, suggesting a significant decrease in inflammation.
Conclusion
Overall, DMSA therapy seems to be reasonably safe, effective in removing several toxic metals (especially lead), dramatically effective in normalizing RBC glutathione, and effective in normalizing platelet counts. Only 1 round (3 days) was sufficient to improve glutathione and platelets. Additional rounds increased excretion of toxic metals.
doi:10.1186/1472-6904-9-16
PMCID: PMC2774660  PMID: 19852789
5.  Evaluation of risk factor management of patients treated on an internal nephrology ward: a pilot study 
Background
The objectives of this pilot study were to evaluate treatment quality for the risk factors of hypertension, diabetes and hyperlipidemia as well as the overall treatment quality for patients on an internal nephrology ward. This evaluation included the collection of data concerning the quality of therapeutic drug monitoring, drug use and potential drug-drug interactions. Establishing such baseline information highlights areas that have a need for further therapeutic intervention and creates a foundation for improving patient care, a subject that could be addressed in future clinical pharmacy research projects.
Methods
Medical charts of patients treated on a single internal nephrology ward were retrospectively evaluated using a predefined data collection form. Assessment of further need for therapeutic intervention was performed.
Results
For 76.5% (n = 78) of the total study population (n = 102), there was either a possibility (39.2%, n = 40) or a need (37.3%, n = 38) for further intervention based on the overall assessment. For the risk factors of hypertension, diabetes and hyperlipidemia, the proportions of patients that require further intervention were 78.8% (n = 71), 90.6% (n = 58) and 87.9% (n = 58), respectively. Patients with diabetes or hyperlipidemia were less likely to have optimal risk factor control. The number of drugs prescribed and the number of potential drug-drug interactions were significantly higher after in-hospital treatment.
Conclusion
Risk factor treatment needs optimisation. Risk factor management, systematic medication reviews, and screening for and management of potential drug-drug interactions deserve great attention. Clinical pharmacy services could help in the achievement of treatment goals.
doi:10.1186/1472-6904-9-15
PMCID: PMC2744655  PMID: 19732465
6.  Perceptions of doctors to adverse drug reaction reporting in a teaching hospital in Lagos, Nigeria 
Background
Spontaneous adverse drug reaction (ADR) reporting is the cornerstone of pharmacovigilance. ADR reporting with Yellow Cards has tremendously improved pharmacovigilance of drugs in many developed countries and its use is advocated by the World Health Organization (WHO). This study was aimed at investigating the knowledge and attitude of doctors in a teaching hospital in Lagos, Nigeria on spontaneous ADR reporting and to suggest possible ways of improving this method of reporting.
Methods
A total of 120 doctors working at the Lagos State University Teaching Hospital (LASUTH), in Nigeria were evaluated with a questionnaire for their knowledge and attitudes to ADR reporting. The questionnaire sought the demographics of the doctors, their knowledge and attitudes to ADR reporting, the factors that they perceived may influence ADR reporting, and their levels of education and training on ADR reporting. Provision was also made for suggestions on the possible ways to improve ADR reporting.
Results
The response rate was 82.5%. A majority of the respondents (89, 89.9%) considered doctors as the most qualified health professionals to report ADRs. Forty (40.4%) of the respondents knew about the existence of National Pharmacovigilance Centre (NPC) in Nigeria. Thirty-two (32.3%) respondents were aware of the Yellow Card reporting scheme but only two had ever reported ADRs to the NPC. About half (48.5%) of the respondents felt that all serious ADRs could be identified after drug marketing. There was a significant difference between the proportion of respondents who felt that ADR reporting should be either compulsory or voluntary (χ2 = 38.9, P < 0.001). ADR reporting was encouraged if the reaction was serious (77, 77.8%) and unusual (70, 70.7%). Education and training was the most recognised means of improving ADR reporting.
Conclusion
The knowledge of ADRs and how to report them are inadequate among doctors working in a teaching hospital in Lagos, Nigeria. More awareness should be created on the Yellow Card reporting scheme. Continuous medical education, training and integration of ADR reporting into the clinical activities of the doctors would likely improve reporting.
doi:10.1186/1472-6904-9-14
PMCID: PMC2731723  PMID: 19671176
7.  A Phase 1 Trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion 
Background
The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours.
Methods
Twelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained.
Results
Selegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline.
Conclusion
No pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions.
doi:10.1186/1472-6904-9-13
PMCID: PMC2731040  PMID: 19646280
8.  Effect of buspirone on thermal sensory and pain thresholds in human volunteers 
Background
Buspirone is a partial 5-HT1A receptor agonist. Animal studies have shown that modulation of serotoninergic transmission at the 5-HT1A receptor can induce analgesia in acute pain models. However, no studies have been published so far on the effects of serotonin receptor agonists on pain perception in humans.
Methods
The effects of buspirone (30 mg p.o.) on thermal sensory and pain thresholds were investigated in twelve female volunteers (26 ± 2 yrs) in a prospective, randomized, double-blind, double-dummy, placebo-controlled study with morphine (10 mg i.v.) as positive control.
Results
Morphine significantly increased the heat pain detection threshold (ΔT: placebo 1.0°C and 1.3°C, p < 0.05) at 60 minutes. Buspirone caused mild sedation in six participants at 60 minutes, but was without effect on any of the measured parameters.
Conclusion
Buspirone in the maximal recommended dose was without significant effect on thermal pain. However, as it is only a partial agonist at the 5-HT1A receptor and also acts on other receptor types, the negative results of the present study do not rule out a possible analgesic effect of more specific 5-HT1A receptor agonists.
doi:10.1186/1472-6904-9-12
PMCID: PMC2698897  PMID: 19480657
9.  Dispensed drugs and multiple medications in the Swedish population: an individual-based register study 
Background
Multiple medications is a well-known potential risk factor in terms of patient's health. The aim of the present study was to estimate the prevalence of dispensed drugs and multiple medications in an entire national population, by using individual based data on dispensed drugs.
Methods
Analyses of all dispensed out-patient prescriptions in 2006 from the Swedish prescribed drug register. As a cut-off for multiple medications, we applied five or more different drugs dispensed (DP ≥ 5) at Swedish pharmacies for a single individual during a 3-month, a 6-month, and a 12-month study period. For comparison, results were also calculated with certain drug groups excluded.
Results
6.2 million individuals received at least one dispensed drug (DP ≥ 1) during 12 months in 2006 corresponding to a prevalence of 67.4%; 75.6% for females and 59.3% for males. Individuals received on average 4.7 dispensed drugs per individual (median 3, Q1–Q3 2–6); females 5.0 (median 3, Q1–Q3 2–7), males 4.3 (median 3, Q1–Q3 1–6).
The prevalence of multiple medications (DP ≥ 5) was 24.4% for the entire population. The prevalence increased with age. For elderly 70–79, 80–89, and 90-years, the prevalence of DP ≥ 5 was 62.4, 75.1, and 77.7% in the respective age groups. 82.8% of all individuals with DP ≥ 1 and 64.9% of all individuals with DP ≥ 5 were < 70 years.
Multiple medications was more frequent for females (29.6%) than for males (19.2%). For individuals 10 to 39 years, DP ≥ 5 was twice as common among females compared to males. Sex hormones and modulators of the genital system excluded, reduced the relative risk (RR) for females vs. males for DP ≥ 5 from 1.5 to 1.4.
The prevalence of DP ≥ 1 increased from 45.1 to 56.2 and 67.4%, respectively, when the study period was 3, 6, and 12 respectively months and the corresponding prevalence of DP ≥ 5 was 11.3, 17.2, and 24.4% respectively.
Conclusion
The prevalence of dispensed drugs and multiple medications were extensive in all age groups and were higher for females than for males. Multiple medications should be regarded as a risk in terms of potential drug-drug interactions and adverse drug reactions in all age groups.
doi:10.1186/1472-6904-9-11
PMCID: PMC2696422  PMID: 19473486
10.  Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial 
Background
HX575 is a human recombinant epoetin alfa that was approved for use in Europe in 2007 under the European Medicines Agency biosimilar approval pathway. Therefore, in order to demonstrate the bioequivalence of HX575 to an existing epoetin alfa, the pharmacokinetic and pharmacodynamic response to steady state circulating concentrations of HX575 and a comparator epoetin alfa were compared following multiple intravenous administrations.
Methods
An open, randomised, parallel group study was conducted in 80 healthy adult males. Subjects were randomised to multiple intravenous doses of 100 IU/kg body weight of HX575 or of the comparator epoetin alfa three-times-weekly for four weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratio of haematological characteristics were used as surrogate parameters for efficacy evaluation.
Results
The haematological profiles of both treatments were similar, as determined from their population mean curves and the AUECHb ratio and 90% confidence interval (99.9% [98.5–101.2%]), the primary pharmacodynamic endpoint of this study. The pharmacokinetic parameters after the treatments showed minor differences after single dosing, but not at steady state doses. After multiple doses, HX575 was bioequivalent to the comparator with respect to the rate and extent of exposure of exogenous epoetin (AUCτ ratio and 90% confidence interval: 89.2% [82.5–96.2%]). Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected.
Conclusion
HX575 and the comparator epoetin alfa were bioequivalent at steady state circulating drug concentrations with respect to their pharmacokinetic profile and pharmacodynamic action. This supports the conclusion that HX575 and the comparator epoetin alfa, when administered intraveneously, will be equally efficacious and may be interchangeable as therapy.
doi:10.1186/1472-6904-9-10
PMCID: PMC2695417  PMID: 19463151
11.  Errors and omissions in hospital prescriptions: a survey of prescription writing in a hospital 
Background
The frequency of drug prescription errors is high. Excluding errors in decision making, the remaining are mainly due to order ambiguity, non standard nomenclature and writing illegibility. The aim of this study is to analyse, as a part of a continuous quality improvement program, the quality of prescriptions writing for antibiotics, in an Italian University Hospital as a risk factor for prescription errors.
Methods
The point prevalence survey, carried out in May 26–30 2008, involved 41 inpatient Units. Every parenteral or oral antibiotic prescription was analysed for legibility (generic or brand drug name, dose, frequency of administration) and completeness (generic or brand name, dose, frequency of administration, route of administration, date of prescription and signature of the prescriber). Eight doctors (residents in Hygiene and Preventive Medicine) and two pharmacists performed the survey by reviewing the clinical records of medical, surgical or intensive care section inpatients. The antibiotics drug category was chosen because its use is widespread in the setting considered.
Results
Out of 756 inpatients included in the study, 408 antibiotic prescriptions were found in 298 patients (mean prescriptions per patient 1.4; SD ± 0.6). Overall 92.7% (38/41) of the Units had at least one patient with antibiotic prescription. Legibility was in compliance with 78.9% of generic or brand names, 69.4% of doses, 80.1% of frequency of administration, whereas completeness was fulfilled for 95.6% of generic or brand names, 76.7% of doses, 83.6% of frequency of administration, 87% of routes of administration, 43.9% of dates of prescription and 33.3% of physician's signature. Overall 23.9% of prescriptions were illegible and 29.9% of prescriptions were incomplete. Legibility and completeness are higher in unusual drugs prescriptions.
Conclusion
The Intensive Care Section performed best as far as quality of prescription writing was concerned when compared with the Medical and Surgical Sections.
Nevertheless the overall illegibility and incompleteness (above 20%) are unacceptably high. Values need to be improved by enhancing the safety culture and in particular the awareness of the professionals on the consequences that a bad prescription writing can produce.
doi:10.1186/1472-6904-9-9
PMCID: PMC2695418  PMID: 19439066
12.  The frequency of adverse drug reaction related admissions according to method of detection, admission urgency and medical department specialty 
Background
Adverse Drug Reactions (ADRs) have been regarded as a major public health problem since they represent a sizable percentage of admissions. Unfortunately, there is a wide variation of ADR related admissions among different studies. The aim of this study was to evaluate the frequency of ADR related admissions and its dependency on reporting and method of detection, urgency of admissions and included medical departments reflecting department/hospital type within one study.
Methods
The study team of internal medicine specialists retrospectively reviewed 520 randomly selected medical records (3%) of patients treated in the medical departments of the primary city and tertiary referral governmental hospital for certain ADRs causing admissions regarding WHO causality criteria. All medical records were checked for whether the treating physicians recognised and documented ADRs causing admissions. The hospital information system was checked to ensure ADR related diagnoses were properly coded and the database of a national spontaneous reporting system was searched for patients with ADRs included in this study.
Results
The established frequency of admissions due to certain ADRs recognised by the study team and documented in medical records by the treating physicians was the same and represented 5.8% of all patients (30/520). The frequency of ADR causing admissions detected by employing a computer-assisted approach using an ICD-10 coding system was 0.2% (1/520), and no patient admitted due to ADRs was reported to the national reporting system (0/520). The recognized frequency of ADR related admissions also depends on the department's specialty (p = 0.001) and acceptance of urgently admitted patients (p = 0.001). Patients admitted due to ADRs were significantly older compared to patients without ADRs (p = 0.025). Gastrointestinal bleeding due to NSAID, acetylsalicylic acid and warfarin was the most common ADR that resulted in admission and represented 40% of all certain ADRs (12/30) according to WHO causality criteria.
Conclusion
ADRs cause 5.8% of admissions in medical departments in the primary city and tertiary referral hospital. The physicians recognise certain ADR related admissions according to WHO causality criteria and note them in medical records, but they rarely code and report ADRs. The established frequency of ADR related admissions depends on the detection method, department specialty and frequency of urgently admitted patients.
doi:10.1186/1472-6904-9-8
PMCID: PMC2680808  PMID: 19409112
13.  Fatal drug poisonings in a Swedish general population 
Background
Pharmaceutical drug poisonings have previously been reported using single sources of information, either hospital data or forensic data, which might not reveal the true incidence. We therefore aimed to estimate the incidence of suspected fatal drug poisonings, defined as poisonings by pharmaceutical agents, by using all relevant case records from various sources in a Swedish population.
Methods
Every seventh randomly selected deceased in three counties in southeastern Sweden during a one-year period was identified in the Cause of Death Register. Relevant case records (death certificates, files from hospitals and/or primary care centres and medico-legal files) were reviewed for all study subjects.
Results
Of 1574 deceased study subjects, 12 cases were classified as pharmaceutical drug poisonings according to the death certificates and 10 according to the medico-legal files. When reviewing all available data sources, 9 subjects (0.57%; 95% confidence interval: 0.20–0.94%) were classified as drug poisonings, corresponding to an incidence of 6.5 (95% confidence interval: 2.3–10.7) per 100 000 person-years in the general population. The drug groups most often implicated were benzodiazepines (33%), antihistamines (33%) and analgesics (22%).
Conclusion
Fatal drug poisonings is a relatively common cause of death in Sweden. By using multiple sources of information when investigating the proportion of fatal poisonings in a population, more accurate estimates may be obtained.
doi:10.1186/1472-6904-9-7
PMCID: PMC2679715  PMID: 19397805
14.  Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomized placebo-controlled trial in 20,536 high-risk people 
Background
Simvastatin reduces cardiovascular mortality and morbidity but, as with other HMG-CoA reductase inhibitors, can cause significant muscle toxicity and has been associated with elevations of liver transaminases.
Methods
Muscle and liver adverse effects of simvastatin 40 mg daily were evaluated in a randomized placebo-controlled trial involving 20,536 UK patients with vascular disease or diabetes (in which a substantial reduction of cardiovascular mortality and morbidity has previously been demonstrated).
Results
The excess incidence of myopathy in the simvastatin group was < 0.1% over the 5 years of the trial, and there were no significant differences between the treatment groups in the incidence of serious hepatobiliary disease.
Conclusion
Among the many different types of high-risk patient studied (including women, older individuals and those with low cholesterol levels), there was a very low incidence (< 0.1%) of myopathy during 5 years treatment with simvastatin 40 mg daily. The risk of hepatitis, if any, was undetectable even in this very large long-term trial. Routine monitoring of liver function tests during treatment with simvastatin 40 mg is not useful.
Trial Registration
ISRCTN48489393
doi:10.1186/1472-6904-9-6
PMCID: PMC2676245  PMID: 19442259
15.  Methanol poisoning and long term sequelae – a six years follow-up after a large methanol outbreak 
Background
Mass poisonings with methanol are rare but occur regularly both in developed and in developing countries. Data from the poisoning episodes are often published, but follow-up-data is scarce. We therefore conducted a six year follow-up study after the large methanol outbreak in Estonia in September 2001.
Methods
Surviving victims from the outbreak were contacted and invited to an interview and a clinical evaluation by an ophthalmologist and a physician. The patients that failed to respond were searched for in the Estonian Register of Population and through their General Practitioner.
Results
During the outbreak in 2001, 86/111 hospitalized patients survived: 66 without sequelae (Group I) and 20 with sequelae (Group II). Six years later, 26/86 were dead, 33/86 could not be tracked down, and so only 27/86 of these were followed up and examined: 22/66 of the patients in Group I, and 5/20 in Group II were found and examined. From Group I, 8/22 were identified with new neurological impairment and 8/22 with new visual disturbances after discharge. From Group II, visual disturbances (n = 4) and neurological impairment (n = 3) were still present in all patients. Among the 26 dead, 19 were from Group I, and seven were from Group II. Alcohol intoxication was the most frequent cause of death (7/26).
Conclusion
All sequelae were still present six years after the initial poisoning suggesting that these were irreversible damages. On follow-up, apparently new neurological and visual complications were identified in 36% and 36%, respectively. 35% of the patients initially discharged with sequelae and 29% discharged without were dead six years later; 27% of them from alcohol intoxication.
doi:10.1186/1472-6904-9-5
PMCID: PMC2667428  PMID: 19327138
16.  Information about ADRs explored by pharmacovigilance approaches: a qualitative review of studies on antibiotics, SSRIs and NSAIDs 
Background
Despite surveillance efforts, unexpected and serious adverse drug reactions (ADRs) repeatedly occur after marketing. The aim of this article is to analyse ADRs reported by available ADR signal detection approaches and to explore which information about new and unexpected ADRs these approaches have detected.
Methods
We selected three therapeutic cases for the review: antibiotics for systemic use, non-steroidal anti-inflammatory medicines (NSAID) and selective serotonin re-uptake inhibitors (SSRI). These groups are widely used and represent different therapeutic classes of medicines. The ADR studies were identified through literature search in Medline and Embase. The search was conducted in July 2007. For each therapeutic case, we analysed the time of publication, the strengths of the evidence of safety in the different approaches, reported ADRs and whether the studies have produced new information about ADRs compared to the information available at the time of marketing.
Results
79 studies were eligible for inclusion in the analysis: 23 antibiotics studies, 35 NSAID studies, 20 SSRI studies. Studies were mainly published from the end of the 1990s and onwards. Although the drugs were launched in different decades, both analytical and observational approaches to ADR studies were similar for all three therapeutic cases: antibiotics, NSAIDs and SSRIs. The studies primarily dealt with analyses of ADRs of the type A and B and to a lesser extent C and D, cf. Rawlins' classification system. The therapeutic cases provided similar results with regard to detecting information about new ADRs despite different time periods and organs attacked. Approaches ranging higher in the evidence hierarchy provided information about risks of already known or expected ADRs, while information about new and previously unknown ADRs was only detected by case reports, the lowest ranking approach in the evidence hierarchy.
Conclusion
Although the medicines were launched in different decades, approaches to the ADR studies were similar for all three therapeutic cases: antibiotics, NSAIDs and SSRIs. Both descriptive and analytical designs were applied. Despite the fact that analytical studies rank higher in the evidence hierarchy, only the lower ranking descriptive case reports/spontaneous reports provided information about new and previously undetected ADRs. This review underscores the importance of systems for spontaneous reporting of ADRs. Therefore, spontaneous reporting should be encouraged further and the information in ADR databases should continuously be subjected to systematic analysis.
doi:10.1186/1472-6904-9-4
PMCID: PMC2656469  PMID: 19254390
17.  Clinical outcomes and kinetics of propanil following acute self-poisoning: a prospective case series 
Background
Propanil is an important cause of death from acute pesticide poisoning, of which methaemoglobinaemia is an important manifestation. However, there is limited information about the clinical toxicity and kinetics. The objective of this study is to describe the clinical outcomes and kinetics of propanil following acute intentional self-poisoning.
Methods
431 patients with a history of propanil poisoning were admitted from 2002 until 2007 in a large, multi-centre prospective cohort study in rural hospitals in Sri Lanka. 40 of these patients ingested propanil with at least one other poison and were not considered further. The remaining 391 patients were classified using a simple grading system on the basis of clinical outcomes; methaemoglobinaemia could not be quantified due to limited resources. Blood samples were obtained on admission and a subset of patients provided multiple samples for kinetic analysis of propanil and the metabolite 3,4-dichloroaniline (DCA).
Results
There were 42 deaths (median time to death 1.5 days) giving a case fatality of 10.7%. Death occurred despite treatment in the context of cyanosis, sedation, hypotension and severe lactic acidosis consistent with methaemoglobinaemia. Treatment consisted primarily of methylene blue (1 mg/kg for one or two doses), exchange transfusion and supportive care when methaemoglobinaemia was diagnosed clinically. Admission plasma concentrations of propanil and DCA reflected the clinical outcome. The elimination half-life of propanil was 3.2 hours (95% confidence interval 2.6 to 4.1 hours) and the concentration of DCA was generally higher, more persistent and more variable than propanil.
Conclusion
Propanil is the most lethal herbicide in Sri Lanka after paraquat. Methylene blue was largely prescribed in low doses and administered as intermittent boluses which are expected to be suboptimal given the kinetics of methylene blue, propanil and the DCA metabolite. But in the absence of controlled studies the efficacy of these and other treatments is poorly defined. More research is required into the optimal management of acute propanil poisoning.
doi:10.1186/1472-6904-9-3
PMCID: PMC2656468  PMID: 19220887
18.  A glycosylated recombinant human granulocyte colony stimulating factor produced in a novel protein production system (AVI-014) in healthy subjects: a first-in human, single dose, controlled study 
Background
AVI-014 is an egg white-derived, recombinant, human granulocyte colony-stimulating factor (G-CSF). This healthy volunteer study is the first human investigation of AVI-014.
Methods
24 male and female subjects received a single subcutaneous injection of AVI-014 at 4 or 8 mcg/kg. 16 control subjects received 4 or 8 mcg/kg of filgrastim (Neupogen, Amgen) in a partially blinded, parallel fashion.
Results
The Geometric Mean Ratio (GMR) (90% CI) of 4 mcg/kg AVI-014/filgrastim AUC(0–72 hr) was 1.00 (0.76, 1.31) and Cmax was 0.86 (0.66, 1.13). At the 8 mcg/kg dose, the AUC(0–72) GMR was 0.89 (0.69, 1.14) and Cmax was 0.76 (0.58, 0.98). A priori pharmacokinetic bioequivalence was defined as the 90% CI of the GMR bounded by 0.8–1.25. Both the white blood cell and absolute neutrophil count area under the % increase curve AUC(0–9 days) and Cmax (maximal % increase from baseline)GMR at 4 and 8 mcg/kg fell within the 0.5–2.0 a priori bound set for pharmacodynamic bioequivalence. The CD 34+ % increase curve AUC(0–9 days) and Cmax GMR for both doses was ~1, but 90% confidence intervals were large due to inherent variance, and this measure did not meet pharmacodynamic bioequivalence. AVI-014 demonstrated a side effect profile similar to that of filgrastim.
Conclusion
AVI-014 has safety, pharmacokinetic, and pharmacodynamic properties comparable to filgrastim at an equal dose in healthy volunteers. These findings support further investigation in AVI-014.
doi:10.1186/1472-6904-9-2
PMCID: PMC2639539  PMID: 19175929
19.  Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics 
Background
Demonstration of equivalent amounts of the same active pharmaceutical ingredient (API) between generic and innovator products (pharmaceutical equivalence) is a basic requirement of regulatory agencies for intravenous generic drugs prior to clinical use, and constitutes the pivotal point to assume therapeutic equivalence. Physicochemical methods are preferred instead of biological assays to determine concentration of drugs in biological fluids, but it does not permit direct quantification of potency. Here, we report a microbiological assay using large plates designed to determine potency and concentration of pharmaceutical-grade antibiotics for injection and a statistical method to assess the in vitro equivalence of generic products with respect to the innovator.
Methods
The assay is based on the concentration-dependent variation of the inhibitory effect of antibiotics on reference bacteria (B. subtilis ATCC 6633, S. aureus ATCC 6538p and S. epidermidis ATCC 12228) in a seeded agar (Difco™ Antibiotic Media), producing a concentration-response linear relationship with two parameters: y-intercept (concentration) and slope (potency). We compared the parameters of 22 generic products (amikacin 4, gentamicin 15, and vancomycin 3 products) against the innovator and the reference powder by Overall Test for Coincidence of the Regression Lines (Graphpad Prism 5.0).
Results
The validation method yielded excellent results for linearity (r2 ≥ 0.98), precision (intra-assay variation ≤ 11%; inter-assay variation ≤ 10%), accuracy, and specificity tests according to international pharmacopoeial requirements. Except for one generic of vancomycin that had 25% more API (Py-intercept = 0.001), the pharmaceutical equivalence was demonstrated in 21 generics with undistinguishable slopes and intercepts (P > 0.66). Potency estimates were 99.8 to 100.5, 99.7 to 100.2 and 98.5 to 99.9% for generic products of amikacin, gentamicin and vancomycin, respectively.
Conclusion
The proposed method allows rapid, cost-saving, precise, and accurate determination of pharmaceutical equivalence of drugs in pharmaceutical dosage-form, and may be used as a technique for testing generic antibiotics prior to their approval for human use.
doi:10.1186/1472-6904-9-1
PMCID: PMC2640365  PMID: 19149891

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