Clinical Trials In People Research Articles

Systematic Review and Meta‐Analysis: Do Clinical Trials Testing Antimuscarinic Agents for Overactive Bladder Adequately Measure Central Nervous System Adverse Events?

Experimental studies in healthy volunteers suggest that some antimuscarinic agents confer a risk of cognitive impairment, yet clinical trials of people with overactive bladder report only rare central nervous system (CNS) side effects. A lack of systematic measurement and reporting of CNS outcomes in clinical trials may partially explain this discrepancy. The purpose of this review and meta-analysis was to ascertain the reporting bias associated with adverse CNS events in clinical drug trials of younger and older adults with overactive bladder. Articles were identified from MEDLINE and EMBASE databases until 2010 using the search terms "clinical trial" AND (one of) "oxybutynin, tolterodine, fesoterodine, propiverine, solifenacin, darifenacin, and trospium." Eligibility criteria included original randomized trials involving adults with overactive bladder; standard doses of medication; reports of confusion, somnolence, sedation, dizziness, drowsiness, asthenia, insomnia, and vertigo; no evidence of dementia at baseline; and trials in English. Seventy-seven percent (242/314) of eligible trials identified in the search neither measured nor reported CNS outcomes. Of the remaining 23%, it was difficult to distinguish whether CNS adverse events were systematically measured or spontaneously reported. Only one of 72 trials that were retained objectively measured changes in cognitive performance (Mini-Mental State Examination). Dizziness was the most frequently reported side effect, in 3% of oxybutynin, 3.2% of propiverine, and 1.8% of tolterodine users, compared with 1.6% with placebo. Confusion was reported in fewer than 1% of cases. Age-stratified analyses of CNS outcomes from trials in adults aged 65 and older with overactive bladder were found in only eight publications. Meta-analyses were conducted with 33 randomized, double-blind, placebo-controlled trials to determine the effect of each drug and dose on different CNS outcomes. Study heterogeneity, dosing inconsistency, and reporting bias limited interpretation of the findings from the meta-analyses. More-detailed standardized measurement of age-stratified CNS outcomes in clinical trials is required to better inform patients and clinicians about CNS risks associated with antimuscarinic agents.

Melanotropic peptides: more than just ‘Barbie drugs’ and ‘sun-tan jabs’?

While ultraviolet radiation (UVR) is a major cause of skin ageing and carcinogenesis, public pursuit of a novel tanning strategy circumventing the need for UVR is increasingly reported in the media and scientific press. This involves the subcutaneous self-administration of unregulated products labelled as melanotan I and/or II, synthetic analogues of α-melanocyte stimulating hormone (α-MSH), as obtained via the internet, tanning salons and gyms. The Medicines and Healthcare products Regulatory Authority has recently raised awareness of the public health risk of transmission of blood-borne viruses from the needle sharing that may occur, and of the potential impurity of these products. Dermatologists should also be aware that these agents can complicate the clinical presentation of patients with pigmented lesions; their use may be suspected in unexpectedly tanned individuals with rapidly pigmenting naevi. Meanwhile, the regulated α-MSH analogue afamelanotide (Clinuvel Pharmaceuticals Ltd, Melbourne, Australia) is showing promise for its photoprotective potential, and is undergoing phase II and III clinical trials in people with photosensitivity disorders and those prone to nonmelanoma skin cancer. The photoprotective and other biological effects of α-MSH analogues await full determination.

Predictors of general quality of life and the mediating role of health related quality of life in patients with schizophrenia

The concept 'quality of life' (QoL) has become increasingly important as an outcome measure in the evaluation of services and in clinical trials of people with schizophrenia. This study examines the mediating role of health related quality of life (HRQoL) in the prediction of general quality of life (GQoL). QoL and other patient- and illness characteristics (psychopathology, overall functioning, illness history, self-esteem and social integration) were measured in a group of 143 outpatients with schizophrenia. GQoL was measured by the Lancashire Quality of Life Profile and HRQoL was measured by the MOS SF-36. To test the temporal stability of our findings, assessments were performed twice with an 18-month interval. We found that patient's GQoL is predicted mainly by anxiety and depression and self-esteem and to a lesser extent by global functioning and social integration. At both time intervals HRQoL appeared to be a significant mediator of the relationship between anxiety and depression and self esteem versus patient's GQoL. The results of this study are important for mental health professionals, as these provide more insight in the mechanisms by which they could improve the GQoL of their patients with schizophrenia. The results confirm that diagnosis and treatment of anxiety and depression in outpatients with schizophrenia deserves careful attention of clinicians. Also strategies and specific interventions to improve self-esteem of patients with schizophrenia are very important to maximise patient's QoL.

Rescue treatment and prevention of asthma using magnesium throat lozenges: Hypothesis for a mouth–lung biologically closed electric circuit

In the rescue treatment of acute asthma, injected and inhalant magnesium are relatively weak having demonstrated value only in severe illness, although theoretical and laboratory considerations suggest that magnesium should be strongly effective as an asthma rescue agent. It was hypothesized that a mouth-lung biologically closed electric circuit (BCEC) exists capable of nearly instantly transporting positively charged magnesium ions from the mouth and throat into the lungs. One hundred milligram magnesium (magnesium chloride) 4-g throat lozenges producing 100+ mM magnesium ion concentration in saliva were tested to determine if they had beneficial effects in asthma rescue and prevention. Subjects were selected based solely on need for asthma rescue, and lozenges were used as needed. Case histories are presented showing the nearly immediate effect of magnesium chloride throat lozenges in terminating and preventing asthma attacks. Throat lozenges containing magnesium chloride produced much more rapid and stronger benefits than has been reported for inhaled and injected magnesium. An added benefit from magnesium chloride lozenge treatment of asthma was relaxation. In this first report of its kind, magnesium chloride throat lozenges appeared to provide rescue benefits in the treatment of asthma equivalent to pharmaceutical asthma drugs. Countering these benefits, strong ionic magnesium solutions greatly increase rhinovirus, herpesvirus and Candida albicans in vitro, and appear to worsen these infections in humans. Magnesium lozenges releasing concentrated magnesium ions appear contraindicated during common colds, oral herpes infections, chronic rhinosinusitis, oral and respiratory infections in general, and their use must immediately be terminated if respiratory or oral symptoms worsen. Double-blind, placebo-controlled, clinical trials in people without respiratory or oral infections are needed to determine magnesium lozenge safety, and the extent by which drug treatment of asthma can be reduced.

Inclusion of albuminuria in hypertension and heart guidelines

The current recommendations by all United States guideline committees, including the American Diabetes Association and the JNC 7, include screening for microalbuminuria in those with diabetes or evidence of kidney disease, but not the general population. Internationally, both the Canadian and European Guidelines have concurred with this approach. This recommendation is due in part to the findings from long-term outcome studies that measurement of microalbuminuria, while a strong predictor of cardiovascular risk, fails to shows change in CV events if reduced. Unfortunately, this conclusion may be wrong because no randomized trial has examined the question of whether a reduction in microalbuminuria does correlate with a reduction in CV events. Thus, we don't know the answer to this question. Additionally, a recent cost-effective analysis was just published, suggesting it is not worth measuring urinary albumin because it is too expensive for the information obtained. Unfortunately, these conclusions were based on the same faulty logic that relates changes in microalbuminuria to cardiovascular events. It is clear that microalbuminuria is a cardiovascular risk factor, acknowledged by both the JNC 7 and the European Guidelines. Moreover, presence of microalbuminuria correlates strongly with elevated levels of C-reactive protein and abnormal vascular responsiveness to vasodilating stimuli. Thus, its presence indicates abnormal responses by vascular tissue, perhaps due to underlying inflammatory responses. Every clinical trial that has assessed changes in albuminuria as a secondary end point with clinical outcomes has shown a strongly positive correlation between reduction in albuminuria and greater protection of a given end organ; this effect is, in part, independent of blood pressure reduction. Thus, what is needed is a clinical trial in people at high cardiovascular risk, such as those in the INVEST or ALLHAT trials where the primary end point is change in albuminuria and its relationship to cardiovascular outcomes. Likewise, a cardiovascular primary end point could relate to the secondary end point of changes in microalbuminuria, and the latter powered appropriately to make stronger statements about albuminuria and cardiovascular outcomes. With this data, guidelines can then make much strong statements about intervention on this marker of risk.

Exenatide: NMR/CD evaluation of the medium dependence of conformation and aggregation state.

Exenatide, synthetic exendin-4, is the first member of the incretin mimetic class of potential therapeutic agents. It has been the subject of extensive clinical trials in people with Type 2 diabetes. Results to date indicate that exenatide decreases postmeal blood glucose concentrations and that this effect is associated with weight loss. Prior NMR studies of exendin-4 utilized 30% trifluoroethanol because this medium affords sharp, high-resolution NMR spectra. These studies defined its three-dimensional structure in this medium. The NMR-derived ensemble included a novel tertiary structure motif that has subsequently been optimized, yielding water-soluble Trp-cage miniproteins. Prior to the present study, the structuring propensities (and aggregation/association state) of exendin-4 in strictly aqueous media had not been established. Studies of exendin-4 and N-terminally truncated analogs of exendin have established that the structuring propensities of these species are highly medium dependent. This study extends knowledge of the medium dependence of exendin structure to DMSO-water mixtures and to aqueous media mimicking the formulation conditions for this investigational drug. Exenatide retains a substantial helical propensity from residues 9-27 even in 98% DMSO. The addition of water leads to the appearance of NMR diagnostics of the Trp-cage formation. In strictly aqueous media (pH 4-4.4), exenatide is monomeric only at <10 microM peptide concentrations. Under these conditions the Trp cage is partially formed. NMR and CD data indicate that higher concentrations lead to helix bundle formation and that the helix/helix interactions involve residues 11-26. Both the N- and C-termini of the helix bundle state display rapid segmental motion.

Effects of sodium hyaluronate on tendon healing and adhesion formation in horses

SUMMARY Sodium hyaluronate reduces adhesions after tendon repair in rodents and dogs, and has been used in limited clinical trials in people. To evaluate its effect on tendon healing and adhesion formation in horses and to compare these effects with those of a compound of similar viscoelastic properties, a study was performed in horses, using a model of collagenase injection in the flexor tendons within the digital sheath. Eight clinically normal horses were randomly allotted to 2 groups. Adhesion formation between the deep digital flexor tendon and the tendon sheath at the pastern region was induced in the forelimbs of all horses. Using tenoscopic control, a 20-gauge needle was inserted into the deep digital flexor tendon of horses under general anesthesia and 0.2 ml of collagenase (2.5 mg/ml) was injected. The procedure was repeated proximally at 2 other sites, spaced 1.5 cm apart. A biopsy forceps was introduced, and a 5-mm tendon defect was created at each injection site. Group-A horses had 120 mg of sodium hyaluronate (NaHA) gel injected into the tendon sheath of one limb. Group-B horses had methylcellulose gel injected at the same sites. The contralateral limbs of horses in both groups served as surgical, but noninjected, controls. Horses were euthanatized after 8 weeks of stall rest. Ultrasonographic evaluation revealed improved tendon healing after NaHa injection, but no difference in peritendinous adhesion formation. Tendon sheath fluid volume and hyaluronic acid (ha) content were greater in NaHA-treated limbs. Gross pathologic examination revealed considerably fewer and smaller adhesions when limbs were treated with NaHA. However, significant difference in pull-out strengths was not evident between NaHA-treated and control limbs. Histologically, the deep digital flexor tendon from the NaHA-treated limbs had reduced inflammatory cell infiltration, improved tendon structure, and less intratendinous hemorrhage. Treatmerit with methylcullulose had no significant effect on tendon healing, adhesion size, quantity, or strength or on the volume and composition of the tendon sheath fluid. Sodium hyaluronate, administered intrathecally, appears to have a pharmaceutically beneficial action in this collagenase-induced tendinitis and adhesion model in horses.