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 (AUC? 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.

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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.

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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 (?T: 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.

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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 RegistrationISRCTN48489393

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