Open-label randomized non-inferiority trial of a fixed-dose combination of glimepiride and atorvastatin for the treatment of people whose Type 2 diabetes is uncontrolled on metformin.

AIMS: To evaluate, in a randomized, open-label study, the non-inferiority of a bioequivalent fixed-dose combination of glimepiride and atorvastatin vs. separately co-administered tablets in people with Type 2 diabetes mellitus. METHODS: Participants with HbA1c ≥ 53 to < 80 mmol/mol (≥ 7.0 to < 9.5%), average fasting blood glucose > 7.0 mmol/l, who were on metformin for ≥ 3 months, were randomized to combination (n = 215) or co-administered glimepiride and atorvastatin (n = 212) once daily for 20 weeks. Up-titration of glimepiride (1-4 mg) and atorvastatin (10-20 mg) were based on average fasting blood glucose and LDL cholesterol, respectively. Co-primary endpoints were change from baseline to week 20 in HbA1c and LDL cholesterol. RESULTS: Non-inferiority was demonstrated for both co-primary endpoints: the upper limits of 95% CIs for differences (combination-reference) were less than the prespecified margins of 3.3 mmol/mol (0.3%) for change from baseline in HbA1c [difference 0.1 mmol/mol (95% CI -1.6, 1.9); 0.01% (95% CI -0.15, 0.17)] and 6% for percentage change from baseline in LDL cholesterol [difference 0.87% (95% CI -2.47, 4.21)]. Similar proportions of participants on combination and reference had treatment-emergent adverse events (64 vs. 61%). More participants on combination had hypoglycaemia (21 vs. 13%); most events were considered by the treating physician to be unrelated to study drug. CONCLUSIONS: The combination was non-inferior to separately co-administered tablets and the safety profile was consistent with the known profiles of glimepiride and atorvastatin. The observed increase in hypoglycaemia on the combination cannot be explained, but may be attributable to non-systematic collectiof glucose readings and may have been influenced by reporting bias in this open-label trial.

Clinical studies with granisetron, a new 5-HT3 receptor antagonist for the treatment of cancer chemotherapy-induced emesis. The Granisetron Study Group.

Granisetron (BRL 43694A) is a novel, selective 5-hydroxytryptamine-3 (5-HT3) receptor antagonist developed for the prophylaxis and treatment of cytostatic drug-induced emesis. After a brief review of the preclinical evaluation of granisetron the clinical findings with this novel compound are summarised. From the data of large randomised trials one can conclude that granisetron is an active antiemetic, both as a prophylactic and an intervention agent, to an extent which is superior or at least equal to the best available antiemetic combination regimens, having a major efficacy ranging from 74 to 92%. Granisetron may be given as a single, 5-min infusion before chemotherapy and is thus more convenient to administer than many antiemetic regimens. The adverse event profile of granisetron is favourable with a wide therapeutic margin. The only consistent side-effects attributable to granisetron are headache in about 14% of the patients and constipation in about 4% of the patients. Headache induced by granisetron was generally mild and resolved spontaneously or was promptly relieved with standard analgesics. No extrapyramidal side-effects were observed with granisetron.

Postcardiac surgery low cardiac output syndrome: dopexamine or dopamine?

OBJECTIVE: To compare the efficacy and safety of dopexamine with dopamine in the treatment of low cardiac output syndrome after cardiac surgery. DESIGN: This was a multicentre, double-blind, randomised, parallel-group study conducted in intensive care units at centres in Holland and Belgium. Patients were randomised to receive dopexamine (up to 2.0 micrograms/ kg per min) or dopamine (up to 6.0 micrograms/kg per min) for 6 h after low cardiac output syndrome was confirmed. RESULTS: 70 patients were enrolled (35/group) and there was no significant differences in the operative procedures or haemodynamics at entry into the study. Clinical efficacy, defined as a cardiac index > 2.5 l/min per m2 with urine production > 0.5 ml/kg per h and stable haemodynamics for two consecutive readings 1 h apart, was achieved by 90 and 87% of patients in the dopexamine and dopamine groups, respectively. However, more patients maintained clinical efficacy over the 6-h period in the dopexamine group, which was statistically significant at 1-2 h and approached significance at all other time points. Safety was assessed by comparing the adverse events and concomitant medication. Fewer patients on dopexamine had cardiac events compared with dopamine-treated patients (25 vs 38 events), although there was no difference in the pattern of rhythm disturbance. Fewer patients in the dopexamine group required concomitant vasodilating drugs (18 vs 30). CONCLUSION: Taking the proportion of patients achieving clinical efficacy, the time to achieve it and the maintenance of it along with the adverse event profile, dopexamine was shown to be an effective and safe drug to use in the management of low cardiac output syndrome after coronary artery bypass graft surgery and may be superior to dopamine.

The visualization and characterization of two immunological forms of alpha 2 macroglobulin by immunoelectrophoretic methods.

Two peaks of alpha 2 macroglobulin (alpha 2M) were demonstrated in serum or plasma treated with trypsin using crossed immunoelectro-phoresis (CIEP). Both peaks moved the same distance in the first dimension and separated only when electrophoresed into antibody containing gel. The double peak phenomenon was shown not to be an artefact of the antiserum used and that the sample had to be fresh for both peaks to be visualised. Using the methods of staggered well CIEP and crossed thin layer gel chromatography (CTLGC) both peaks were shown to be of very similar antigenicity and molecular size. The technique of line immunoelectrophoresis (LIEP) demonstrated that the newly described lower peak was the alpha 2M/protease complex. The lowest concentration of alpha 2M/protease complexes that could be detected was 0.03 g/l. The two peaks of alpha 2M do not follow the theory of rocket immunoelectrophoresis (RIEP) and this is discussed.

[High-risk surgical patients. Who are they and how should they be treated?]. / Les patients chirurgicaux à haut risque. Qui sont-ils et comment pourraient-ils être traités?

This review addresses the currently available information that describes the identification of high risk patients undergoing surgery and how they may be treated to improve their outcome. It is clear from this data that high risk patients have a mortality rate of around 30% and that the major cause of death is due to multiple organ failure (MOF) which occurs days or in some cases weeks after the operation. The hypothesis for the onset of MOF is presented and it relates to the breakdown in gut patency which can allow the translocation of initiating inflammatory mediators which sets the MOF cascade in action. Current treatment strategies based on preclinical and clinical data to prevent MOF are discussed which includes the use of catecholamines such as dobutamine and dopexamine (Dopacard). It is concluded that the high risk surgical patient is not well defined and that the most rigorously tested criteria are those developed by Shoemaker. These criteria relate far more to the patients physiological status than the surgery that they are undergoing. The treatment of these patients is far more successful if intervention starts prior to surgery with fluids and vasoactive drugs such as Dopacard where the mortality rate has been shown to be reduced by 75%.

Angiogram negative subarachnoid haemorrhage: outcomes and the role of repeat angiography.

BACKGROUND: Angiogram negative sub-arachnoid haemorrhage (SAH) is generally considered to have a more benign course than SAH of known cause. There is also variability from centre to centre as to what proportion of angiogram negative SAH patients undergo repeat Digital Subtraction Angiography (DSA). We performed a retrospective study looking at the last four years' of SAH patients at our institution in order to ascertain the clinical course, the nature and results of repeat imaging. METHODS: Retrospective analysis of clinical records and imaging of all patients presenting to our institution with non-traumatic SAH between April 2008 and February 2012 was performed. Results were analysed for presenting grades, blood distribution, complications, outcomes, repeat imaging modalities and findings. RESULTS: 459 patients with proven non-traumatic SAH of which 50 (11%) had no vascular cause identified on their initial angiogram were identified. The blood distribution was perimesencephalic in 17, non-perimesencephalic in 23, and 10 patients were computed tomography (CT) Negative with a positive lumbar puncture. Eight (16%) patients were complicated by hydrocephalus and 2 (4%) were complicated by vasospasm. Eight patients (16%) underwent repeat cranial DSA with a high suspicion in a multi-disciplinary team setting. None of the repeat angiograms showed an underlying aetiology for the SAH. 76% of patients had a Glasgow Outcome Score of 5 at 6 months. There were no rebleeds. CONCLUSIONS: While generally more benign, angiogram negative subarachnoid haemorrhage can have a complicated clinical course. In our experience repeat DSA should be reserved for cases in which there is significant suspicion of occult vascular lesion. However, evidence-based guidelines are needed to aid the development of management protocols for angiogram-negative SAH and ensuring optimal patient outcomes.

Can genetic polymorphism of alpha-2-macroglobulin be detected by immunoelectrophoresis? A study using sera, plasma and joint fluids from patients with rheumatoid arthritis and controls.

The technique of immunoelectrophoresis (IEP) was used to examine polymorphism of the endopeptidase inhibitor alpha-2-macroglobulin (alpha 2M) by measuring its electrophoretic mobility. Examination of the variability of the method showed that a large intra- and inter-plate variation occurred (3.3 and 11.6%, respectively). It was also shown that alpha 2M from plasma moves significantly slower than that from serum and that the mobility of alpha 2M from plasma can be increased to that of serum by treatment with trypsin. Upon comparing sera, plasma and synovial fluids from a control group (normal subjects and patients with osteoarthritis) with a group of patients with rheumatoid arthritis, no difference in alpha 2M mobility could be demonstrated. It is concluded that genetic polymorphism of alpha 2M cannot be detected by the technique of IEP.

Does reducing spasticity translate into functional benefit? An exploratory meta-analysis.

BACKGROUND: Spasticity and loss of function in an affected arm are common after stroke. Although botulinum toxin is used to reduce spasticity, its functional benefits are less easily demonstrated. This paper reports an exploratory meta-analysis to investigate the relationship between reduced arm spasticity and improved arm function. METHOD: Individual data from stroke patients in two randomised controlled trials of intra-muscular botulinum toxin were pooled. The Modified Ashworth Scale (elbow, wrist, fingers) was used to calculate a "Composite Spasticity Index". Data from the arm section of the Barthel Activities of Daily Living Index (dressing, grooming, and feeding) and three subjective measures (putting arm through sleeve, cleaning palm, cutting fingernails) were summed to give a "Composite Functional Index". Change scores and the time of maximum change were also calculated. RESULTS: Maximum changes in both composite measures occurred concurrently in 47 patients. In 26 patients the improvement in spasticity preceded the improvement in function with 18 showing the reverse. There was a definite relationship between the maximum change in spasticity and the maximum change in arm function, independent of treatment (rho = -0.2822, p = 0.0008, n = 137). There was a clear relationship between the changes in spasticity and in arm function in patients treated with botulinum toxin (Dysport) at 500 or 1000 units (rho = -0.5679, p = 0.0090, n = 22; rho = -0.4430, p = 0.0018, n = 47), but not in those treated with placebo or 1500 units. CONCLUSIONS: Using a targeted meta-analytic approach, it is possible to demonstrate that reducing spasticity in the arm is associated with a significant improvement in arm function.

A double blind, randomised, parallel group study to investigate the dose equivalence of Dysport and Botox in the treatment of cervical dystonia.

OBJECTIVE: This study was designed to establish whether a ratio of three units of Dysport is equivalent to one unit of Botox for the treatment of cervical dystonia. METHODS: Patients with predominantly rotational cervical dystonia, and a minimum of four previous Botox treatments, were randomised to receive either the clinically indicated dose of Botox or three times that dose in Dysport units. Study botulinum toxin was administered in a double blind fashion, to one or more clinically indicated muscles, at one or more sites per muscle. Patients returned for assessment two, four, eight, and 12 weeks after treatment. RESULTS: A total of 73 patients (Dysport, 38; Botox, 35) were entered. The Dysport group received a mean (SD) dose of 477 (131) (range 240-720) Dysport units, and the Botox group received a mean (SD) dose of 152 (45) (range 70-240) Botox units. The mean (SEM) post-treatment Tsui scores for the Dysport group (4.8 (0.3)) and the Botox group (5.0 (0.3)) were not statistically different (p=0.66). The study had 91% power to detect a clinically significant difference of two points. Both groups showed substantial improvement in Tsui score by week 2 (mean (SD); Dysport, 46 (28)%; Botox, 37 (28)%), with a peak effect at week 4 (mean (SD); Dysport, 49 (29)%; Botox, 44 (28)%). A similar response profile was seen for other assessments of efficacy. The duration of effect, assessed by time to retreatment, was also similar (mean (SD); Dysport, 83.9 (13.6) days; Botox, 80.7 (14.4) days; p=0.85). During the study 22 of 38 (58%) Dysport patients reported 39 adverse events, and 24 of 35 (69%) Botox patients reported 56 adverse events (p=0.35). A global assessment of efficacy and safety considered that 29 of 38 (76%) Dysport patients and 23 of 35 (66%) Botox patients were treatment successes (p=0.32). CONCLUSION: Patients with predominantly rotational cervical dystonia treated with the clinically indicated dose of Botox or three times that dose in Dysport units show similar improvements and do not have significantly different safety profiles.

Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study.

OBJECTIVE: To define a safe and effective dose of Dysport for treating hip adductor spasticity. METHODS: Patients with definite or probable multiple sclerosis, and disabling spasticity affecting the hip adductor muscles of both legs, were randomised to one of four treatment groups. Dysport (500, 1000, or 1500 Units), or placebo was administered by intramuscular injection to these muscles. Patients were assessed at entry, and 2, 4 (primary analysis time-point), 8, and 12 weeks post-treatment. RESULTS: A total of 74 patients were recruited. Treatment groups were generally well matched at entry. The primary efficacy variables-passive hip abduction and distance between the knees-improved for all groups. The improvement in distance between the knees for the 1500 Unit group was significantly greater than placebo (p = 0.02). Spasm frequency was reduced in all groups, but muscle tone was reduced in the Dysport groups only. Pain was reduced in all groups, but improvements in hygiene scores were evident only in the 1000 Unit and 1500 Unit groups. Duration of benefit was significantly longer than placebo for all Dysport groups (p<0.05). Adverse events were reported by 32/58 (55%) Dysport patients, and by 10/16 (63%) placebo patients. Compared with the two lower dose groups, twice as many adverse events were reported by the 1500 Unit group (2.7/patient). The incidence of muscle weakness was higher for the 1500 Unit group (36%) than for placebo (6%). The response to treatment was considered positive by two thirds of the patients in the 500 Unit group, and by about half the patients in the other groups. CONCLUSION: Dysport reduced the degree of hip adductor spasticity associated with multiple sclerosis, and this benefit was evident despite the concomitant use of oral antispasticity medication and analgesics. Although evidence for a dose response effect was not statistically significant, there was a clear trend towards greater efficacy and duration of effect with higher doses of Dysport. Dysport treatment was well tolerated, with no major side effects seen at doses up to 1500 Units. The optimal dose for hip adductor spasticity seems to be 500-1000 Units, divided between both legs.