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1.  Investigation of the diurnal variation in bone resorption for optimal drug delivery and efficacy in osteoporosis with oral calcitonin 
Background
Bone resorption displays marked diurnal variation. Reversible inhibition of bone resorption may result in best possible efficacy when bone resorption peaks. The aim of the study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral salmon calcitonin (sCT) and the effect of timing of drug intake.
Methods
The study was a randomized, double-blind, double-dummy, placebo-controlled, phase I study to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral sCT in healthy postmenopausal women. Totally 81 subjects were included, aimed at investigation of a morning dose given at 8:00 (n = 42), a pre-dinner dose given at 17:00 (n = 20), and an evening dose given at 22:00 (n = 19). Plasma sCT concentrations and bone resorption (C-terminal-telopeptide of collagen type I (CTX-I)) was assessed.
Results
Morning and pre-dinner dosing led to comparable concentration of sCT of 45 pg/ml, whereas there was a tendency towards lower Cmax for the evening dosing having a mean of 24 pg/ml. The maximum difference from placebo was observed 1 to 3 hours post-dose with a 40 to 50% suppression consequent to morning dose, and about 75% suppression after pre-dinner and evening dose, due to the increase bone resorption as a result of circadian variation.
Conclusion
The study suggests that orally administered 0.8 mg of salmon calcitonin was effective in suppression of serum CTX irrespective of time of dosing. The pre-dinner dosing resulted in optimum efficacy response corresponding to an overall suppression of bone resorption by 25%.
Trial registration
NCT00411125
doi:10.1186/1472-6904-8-12
PMCID: PMC2611964  PMID: 19055791
2.  Systematic review of dexketoprofen in acute and chronic pain 
Background
Dexketoprofen, an NSAID used in the management of acute and chronic pains, is licensed in several countries but has not previously been the subjected of a systematic review. We used published and unpublished information from randomised clinical trials (RCTs) of dexketoprofen in painful conditions to assess evidence on efficacy and harm.
Methods
PubMed and Cochrane Central were searched for RCTs of dexketoprofen for pain of any aetiology. Reference lists of retrieved articles and reviews were also searched. Menarini Group produced copies of published and unpublished studies (clinical trial reports). Data were abstracted into a standard form. For studies reporting results of single dose administration, the number of patients with at least 50% pain relief was derived and used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief compared with placebo.
Results
Thirty-five trials were found in acute pain and chronic pain; 6,380 patients were included, 3,381 receiving dexketoprofen. Information from 16 trials (almost half the total patients) was obtained from clinical trial reports from previously unpublished trials or abstracts. Almost all of the trials were of short duration in acute conditions or recent onset pain.
All 12 randomised trials that compared dexketoprofen (any dose) with placebo found dexketoprofen to be statistically superior. Five trials in postoperative pain yielded NNTs for 12.5 mg dexketoprofen of 3.5 (2.7 to 4.9), 25 mg dexketoprofen of 3.0 (2.4 to 3.9), and 50 mg dexketoprofen of 2.1 (1.5 to 3.5). In 29/30 active comparator trials, dexketoprofen at the dose used was at least equivalent in efficacy to comparator drugs. Adverse event withdrawal rates were low in postoperative pain and somewhat higher in trials of longer duration; no serious adverse events were reported.
Conclusion
Dexketoprofen was at least as effective as other NSAIDs and paracetamol/opioid combinations. While adverse event withdrawal was not different between dexketoprofen and comparator analgesics, the different conditions and comparators studies precluded any formal analysis. Exposure was limited, and no conclusions could be drawn about safety in terms of serious adverse events like gastrointestinal bleeding or cardiovascular events.
doi:10.1186/1472-6904-8-11
PMCID: PMC2585070  PMID: 18976451
3.  Statins but not fibrates improve the atherogenic to anti-atherogenic lipoprotein particle ratio: a randomized crossover study 
Background
Prior studies suggested low density lipoprotein particle (LDLP) size is a predictor of atherosclerosis. Knowledge of effects of lipid lowering drugs on lipoprotein subclasses is useful. We treated subjects with hyperlipidemia sequentially with statins and fibrates, the 2 main classes of lipid lowering therapy and studied changes in NMR lipoprotein subclasses.
Methods
35 subjects (21 males; 60 ± 12 y) were enrolled in a crossover study. Subjects had baseline lipid profile & apoB. Lipoprotein subclasses, particle numbers and diameters were assessed with NMR spectroscopy. Subjects were randomized to simvastatin 20 mg or fenofibrate 200 mg. Repeat testing was done at 12 weeks. After 6 week washout, subjects were started on alternate drug for 12 weeks with pre/post tests.
Results
Both therapies resulted in expected changes in lipids and apoB. Decreases in total cholesterol, LDL and apoB were greater with simvastatin. Fenofibrate led to small increase in HDL. Both therapies decreased LDLP. Reduction in LDLP was greater with simvastatin (32%, p < .001) compared to fenofibrate (17%; p = .036 vs pre; p = .027 vs simvastatin end). Fenofibrate resulted in 17% rise in large LDLP (p = .06 vs pre) and 32% drop in small LDLP (p = .007 vs pre). Simvastatin led to decrease in both LDLP fractions (19% large LDLP; p = .001 vs fenofibrate end; 34% small LDLP, p = .019 vs pre). With fenofibrate, LDLP size increased from 20.4 nm to 20.8 nm (p = .037). There was no change in LDLP size with simvastatin. There was 18% increase in HDL particle number (HDLP) with fenofibrate (p = .05). There were no changes in HDLP with simvastatin. There were no changes in HDLP size with either drug. Pre- and post-therapy LDLP/HDLP ratio was similar with fenofibrate but was reduced by simvastatin (p = .045).
Conclusion
Simvastatin reduced LDLP across all subclasses with no effect on size. Simvastatin had no effect on HDLP. Fenofibrate had weak effect on LDLP number but increased LDLP size by raising large LDLP and reducing small LDLP. Fenofibrate had weak effect on HDLP number with no change in size. Importantly, net atherogenic to antiatherogenic lipoprotein ratio (LDLP/HDLP) was reduced by simvastatin but not by fenofibrate.
doi:10.1186/1472-6904-8-10
PMCID: PMC2586010  PMID: 18957124
4.  How often do physicians review medication charts on ward rounds? 
Background
Prescribing errors are common in hospital settings. Regular review of medication charts is recommended as a way to reduce errors but it is not clear how often this happens. The aim of this study was to determine the frequency with which specialist physicians reviewed medication charts during ward rounds.
Methods
An observer noted how often consultant physicians at Auckland City Hospital reviewed medication charts during ward rounds. The physicians were not aware that they were being observed.
Results
Twenty-one physicians were observed over a 26 week period. The general physicians reviewed the medication charts on 77% of occasions (range: 45% – 100%) during routine ward rounds and 65% of the time (range: 41% – 80%) on post admission rounds. Subspecialty physicians who did not see more than 8 patients on their rounds reviewed medication charts more frequently (88%) than those specialties where more than 8 patients were seen on average (61%).
Conclusion
The physicians did not review medication charts on all ward rounds and there was considerable variation in how often they did this. There is some evidence that the frequency with which charts are reviewed decreases as the number of patients seen increases. More efforts should be made to encourage regular review of medication charts.
doi:10.1186/1472-6904-8-9
PMCID: PMC2566971  PMID: 18823561
5.  Use of and attitudes towards the prescribing guidelines booklet in primary health care doctors 
Background
In the region of Västra Götaland in Sweden, prescribing guidelines, drawn up by 24 expert groups and determined by the regional board for drugs, are since 2006 available in the form of an annually published booklet. This study investigates, for the first time, the use of and attitudes towards this publication.
Methods
A questionnaire was administered to doctors working in primary health care in the region of Västra Götaland in Sweden. Questions included characteristics of the responding doctor and use of the prescribing guidelines booklet, as well as attitude questions constructed as statements to which the responder should grade his level of agreement from 1 (total disagreement) to 6 (total agreement).
Results
Totally 603 filled-in questionnaires were returned (estimated response rate 60%). The majority of the doctors (n = 571, 97%) responded that they use the prescribing guidelines booklet, and when prescribing a drug for a new diagnosis, a drug from the booklet is chosen in most cases [median (25th – 75th percentile) 80 (75–90)]. However, at renewal of a drug prescription, active change to a drug from the prescribing guidelines booklet occurs less often [median (25th – 75th percentile) 50 (20–70)]. The booklet also includes short therapy advice sections, which 231 doctors (42%) use every day and 191 (34%) use every week. The attitudes towards the prescribing guidelines booklet were generally positive. Doctors in privately run primary health care units and doctors running their own business were generally more negative and judged themselves to be less adherent to the prescribing guidelines booklet compared with doctors in publicly run primary health care units.
Conclusion
The prescribing guidelines booklet is frequently used and is generally appreciated, though differences exist between subgroups of users.
doi:10.1186/1472-6904-8-8
PMCID: PMC2556993  PMID: 18808661
6.  Long-term platinum retention after treatment with cisplatin and oxaliplatin 
Background
The aim of this study was to evaluate long-term platinum retention in patients treated with cisplatin and oxaliplatin.
Methods
45 patients, treated 8–75 months before participating in this study, were included. Platinum levels in plasma and plasma ultrafiltrate (pUF) were determined. In addition, the reactivity of platinum species in pUF was evaluated. Relationships between platinum retention and possible determinants were evaluated.
Results
Platinum plasma concentrations ranged between 142–2.99 × 103 ng/L. Up to 24% of plasma platinum was recovered in pUF. No platinum-DNA adducts in peripheral blood mononuclear cells (PBMCs) could be detected. Ex vivo incubation of DNA with pUF of patients revealed that up to 10% of the reactivity of platinum species was retained. Protein binding proceeded during sample storage. Sodium thiosulfate (STS) appeared to release platinum from the plasma proteins. Platinum levels were related to time, dose, STS co-administration, and glomerular filtration rates (GFR).
Conclusion
Our data suggest that plasma platinum levels are related to time, age, dose, GFR, and STS use. Platinum in plasma, probably, represent platinum eliminated from regenerating tissue. Platinum species in pUF were partly present in a reactive form. The effects of the reactivity on long-term consequences of Pt-containing chemotherapy, however, remains to be established.
doi:10.1186/1472-6904-8-7
PMCID: PMC2559818  PMID: 18796166
7.  Antihypertensive drug class and impaired fasting glucose: a risk association study among Chinese patients with uncomplicated hypertension 
Background
There is a scarcity of studies addressing the factors associated with impaired fasting glucose in Chinese patients with uncomplicated hypertension. We included 1,218 patients newly prescribed a single antihypertensive drug in the public primary healthcare setting in Hong Kong, where their fasting glucose levels were measured 6–7 weeks after the first-ever antihypertensive prescription.
Methods
The odds ratios of having above borderline (≥ 6.1 mmol/l) and adverse (≥ 7.0 mmol/l) glucose levels, respectively, were studied according to patient age, gender, socioeconomic status, clinic types and antihypertensive drug classes by multivariable regression analyses.
Results
The fasting glucose levels were statistically similar (p = 0.786) among patients prescribed thiazide diuretics (5.48 mmol/l, 95%, 5.38, 5.59), calcium channel blockers (5.46 mmol/l, 95% C.I. 5.37, 5.54), β-blockers (5.42 mmol/l, 95% C.I. 5.34, 5.51) and drugs acting on the renin angiotensin system (RAS) [5.41 mmol/l, 95% C.I. 5.20, 5.61]. Multivariate analyses reported no significant associations between antihypertensive drug class and impaired fasting glucose. Elderly patients and male gender were significantly more likely to present with above borderline and adverse readings respectively.
Conclusion
Clinicians should be aware of the increased risk of impaired fasting glucose in these groups, and use of thiazides should not in itself deter its use as a first-line antihypertensive agent among ethnic Chinese patients.
doi:10.1186/1472-6904-8-6
PMCID: PMC2551584  PMID: 18783618
8.  Optimizing bioavailability of oral administration of small peptides through pharmacokinetic and pharmacodynamic parameters: The effect of water and timing of meal intake on oral delivery of Salmon Calcitonin 
Background
To investigate the influence of water intake and dose timing on the pharmacokinetic and pharmacodynamic parameters of an oral formulation of salmon calcitonin (sCT).
Methods
The study was a randomized, partially-blind, placebo-controlled, single dose, exploratory crossover phase I study. 56 healthy postmenopausal women were randomly assigned to receive five treatments. The treatments comprised a combination of study medication (SMC021 (0.8 mg sCT + 200 mg 5-CNAC), SMC021 placebo, or 200 IU Miacalcic® NS nasal spray), water volume given with the tablet (50 or 200 ml water), and time between dosing and meal (10, 30, or 60 minutes pre-meal). Plasma sCT levels and changes in the bone resorption (C-terminal telopeptide of collagen type I) was investigated. Trial regristration
Results
Oral delivery of 0.8 mg of sCT with 50 ml of water compared to that with 200 ml water resulted in a two-fold increase in maximum concentration (Cmax and AUC0–4) of plasma sCT but comparable time to reach maximum concentration (Tmax). The sCT AUC0–4 with 50 ml of water was 4-fold higher than that obtained with nasal calcitonin. The increased absorption of sCT resulted in increased efficacy demonstrated by AUC of the relative change of serum CTX-I measured in the 6 hours post dosing.
Conclusion
0.8 mg sCT with 50 ml of water taken 30 and 60 minutes prior to meal time resulted in optimal pharmacodynamic and pharmacokinetic parameters. The data suggest that this novel oral formulation may have improved absorption and reduction of bone resorption compared to that of the nasal form.
doi:10.1186/1472-6904-8-5
PMCID: PMC2551583  PMID: 18782439
9.  The Clinical Pharmacology of Intranasal l-Methamphetamine 
Background
We studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant.
Methods
12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 μg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured.
Results
Plasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 ± 56.1, 124.7 ± 106.6, and 268.1 ± 220.5 μg for ascending exposures (mean 4.2 ± 3.3 μg/inhalation). Physiological changes were minimal and not dose-dependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen.
Conclusion
Inhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant.
doi:10.1186/1472-6904-8-4
PMCID: PMC2496900  PMID: 18644153
10.  Evaluation of safe and effective administration of nitrous oxide after a postgraduate training course 
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.
doi:10.1186/1472-6904-8-3
PMCID: PMC2438323  PMID: 18547418
11.  Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study 
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.
doi:10.1186/1472-6904-8-2
PMCID: PMC2330021  PMID: 18377658
12.  Individual case safety reports in children in commonly used drug groups – signal detection 
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.
doi:10.1186/1472-6904-8-1
PMCID: PMC2279106  PMID: 18366638

Results 1-12 (12)