Recent Controlled Clinical Trials Research Articles

Cognitive Safety is Largely Ignored in Clinical Drug Trials: A Study of Registered Study Protocols.

The number of reports on suspected drug-induced memory impairment submitted to the US Food and Drug Administration increased 30-fold from 2000 to 2022. Drugs are the most common cause of reversible dementia. However, there is very little research on drug-induced cognitive impairment. The aim of this study was to investigate if and how an assessment of cognitive safety was included in recent, registered, controlled, clinical drug trials. The clinical trials registry ( www. gov ) was searched for randomized controlled clinical trials with available study protocols. After excluding irrelevant trials such as surgical procedures, local or short-term treatment, and dietary supplements, 803 trials were included in this study. The protocols were manually reviewed for information on if, and how, cognitive safety had been assessed. Trial drugs were categorized into those targeting the central nervous system or not, as well as older and newer drugs. Methods used for the assessment of cognitive function were categorized into questionnaires, screening instruments, and neuropsychological tests. If the trial results were published, we examined whether the publication contained any data on cognitive safety that had emerged from the trial. The start dates of the screened trials ranged from 31 July, 2009, to 4 April, 2021. Out of the 803 trials, 52 (6.5%) actively assessed cognitive safety. The remaining trials relied solely on spontaneous reporting. Of 429 trials studying a new drug, 32 (7.5%) actively assessed cognitive safety. One hundred and fifty-eight trials examined drugs intended to, or known to have, pharmacological effects on the central nervous system. Of these, 21 (13.5%) assessed cognitive safety. Most of the trials that assessed cognitive safety used either crude screening tools or questionnaires. Cognitive safety is largely ignored by recent controlled clinical trials. This applies even to trials assessing new drugs and trials assessing central nervous system drugs. There is an urgent need for drug manufacturers, regulatory authorities, and the medical profession to address the cognitive safety of drugs.

#3827 BICARBONATE PROFILING IN HEMODIALYSIS: MATHEMATICAL MODELING OF DATA FROM A CLINICAL TRIAL

Abstract Background and Aims During hemodialysis (HD), bicarbonate and other bases are added to the dialysis fluid to correct chronic acidosis that may develop in kidney-impaired patients, increasing plasma bicarbonate concentration to physiological levels. Previous studies have shown that both exceedingly high and low post-dialysis bicarbonate concentrations are associated with adverse clinical outcomes; however, no clear guidelines for the prescription of bicarbonate concentration in the dialysis fluid are available. Data from a recent controlled clinical trial, carried out at the Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw (Poland), were used to identify transport parameters of a mathematical model of acid-base homeostasis in HD patients, as the first step in the implementation of a tool to optimize bicarbonate profiling during HD. Method The study was carried out in 20 chronic patients, undergoing thrice weekly 4-hr HD. The patients underwent three treatment regimens: A) constant dialysis fluid bicarbonate concentration (HCO3,D) equal to 35 mEq/L; B) HCO3,D decreasing from 35 to 30 mEq/L after 2 hrs; C) HCO3,D increasing from 30 to 35 mEq/L after 2 hrs. The patients were divided in two cohorts: for the first (n = 11) treatment schedule was: treatment A during the first and third week, B during the second week and C during the fourth week. For the second cohort (n = 9) treatment C was carried out during the second week and treatment B during the fourth. Data were collected only during the second and third sessions of the week, and acid-base composition was determined using a blood gas analyzer. The mathematical model describes the transport of bicarbonate and dissolved CO2 from dialysis fluid to the patient and can predict changes in the acid-base equilibrium of arterial and venous plasma and erythrocytes, interstitial fluid, and tissue cells, using mass transport equations. The dialysances for bicarbonate (KHCO3) and dissolved CO2 (KCO2) were estimated via least square minimization. Results No significant difference was found comparing patients in the two cohorts, or comparing sessions of the same week. Pre-dialysis plasma bicarbonate, pH, or CO2 partial pressure (PCO2) were significantly lower for treatment B compared to treatment A. Average plasma bicarbonate concentrations for the different treatments are shown in Figure 1 for data and model simulations. Table 1 reports the average values of the estimated parameters for week. No statistically significant difference was found between sessions, cohorts, or treatments. The model fitted bicarbonate data with an average error of 2.5 ± 1.4%, and PCO2 with an error of 4.5 ± 3.6%. Simulations of mixed-venous blood, interstitial fluid, and tissue cells concentrations showed a similar response to different treatments as in arterial blood. Conclusion The model accurately describes plasma bicarbonate data with high accuracy regardless of the treatment conditions. The parameters estimated showed considerable variability between treatments (less so between the sessions of the same week), but without statistical significance. The model can be used to simulate the effect of dialysate bicarbonate profiling on acid-base equilibrium in HD patients.

GLP-1 Agonists and Blood Pressure: A Review of the Evidence.

Type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular disease. The presence of concomitant hypertension in diabetics is a major driver of excess cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1a) act on numerous pathways that intersect glycemic, weight, and blood pressure (BP) control. BP-lowering effects have been observed in mouse models of hypertension with a variety of GLP-1a. Acute administration of GLP-1a in humans has been shown to no effects and sometimes increased BP in humans. Chronic administration of GLP-1a, however, reduces clinic systolic BP (≈2mmHg) at least when evaluated as a secondary end point in glycemia-lowering studies while simultaneously increasing heart rate. BP lowering has not been consistently observed in two recent double-blind controlled clinical trials evaluating ambulatory BP as the primary end point. While a number of mechanisms including vascular, myocardial, renal, and central nervous system pathways have been suggested in animal studies, these mechanistic pathways have not been sufficiently detailed in humans and it is unclear if the same pathways are operational. Further studies need to be conducted to unravel the full spectrum of effects of this drug class. An understanding of their effects on BP may help provide an explanation for the ability of GLP-1a to influence cardiovascular (CV) events in ongoing event-driven CV trials.

Invasive Aspergillosis: Epidemiology, Clinical Aspects, and Treatment.

Invasive aspergillosis remains an often fatal, difficult-to treat infection in immunocompromised patients. Patients not classically defined as immunocompromised, especially those in an intensive care unit setting, also develop invasive aspergillosis. Clinical clues suggesting angioinvasion and radiographic modalities, especially computed tomographic scans, combined with newer non-culture-based diagnostic techniques, have allowed earlier recognition of invasive aspergillosis. Although mortality remains high, it has greatly decreased over the past 15 years. Voriconazole has supplanted amphotericin B, with its various toxicities, as primary treatment for invasive aspergillosis. Combination therapy with voriconazole and an echinocandin for initial therapy, based on results from a recent controlled clinical trial, could become the standard of care in high-risk patients.

Los Antagonistas de los Receptores Opioides en el Tratamiento del Alcoholismo

On the basis of the recent advances in drug therapy of alcoholism, we conducted a review on opioid receptor antagonist drugs with approved indication for the treatment of alcoholism, such as naltrexone and nalmefene. We reviewed over 100 publications on peptides and opioid receptors, as well as studies conducted in experimental animals and in humans on the effect of opioid receptor antagonists on alcohol consumption in the treatment of alcoholism. We also reviewed the pharmacological characteristics of naltrexone and nalmefene, and the usefulness of these drugs in clinical practice. Much evidence has demonstrated the efficacy of naltrexone and nalmefene for the reduction of alcohol consumption, in experimental animals as well as in humans examined under experimental bar conditions; however, due to its different receptor profile, nalmefene has been associated with higher efficacy levels in reducing alcohol consumption in alcohol-dependent rats. In addition, a great number of controlled clinical trials have demonstrated the efficacy of naltrexone for relapse prevention in patients with an alcohol dependence disorder. Recent controlled clinical trials have demonstrated the efficacy of nalmefene "as-needed" in the reduction of alcohol consumption in subjects with mild alcohol dependence. Both naltrexone and nalmefene have proved to be safe, well tolerated, easy to manage, and efficient drugs for the treatment of alcohol dependence disorder (currently known as alcohol use disorder). On the basis of recent controlled clinical trials, nalmefene has been shown to result in a significant reduction of alcohol consumption, thereby representing a new objective that extends the therapeutic possibilities for those patients who do not wish for a continuous abstinence, but rather a reduction of alcohol consumption.

New and treatment-relevant risk stratification for thrombosis in essential thrombocythemia and polycythemia vera.

New and treatment-relevant risk stratification for thrombosis in essential thrombocythemia and polycythemia vera.

Large-scale international study enhances understanding of an emerging acne population: adult females.

Acne vulgaris is increasingly recognized in adult women; however, few studies have formally evaluated the clinical presentation and factors associated with acne in this population. This prospective, observational international study evaluated the clinical characteristics and lifestyle correlates of acne in adults (≥25 years) at a dermatology visit for acne. Investigators conducted a detailed clinical examination and administered a validated questionnaire that covered medical history, disease evolution, lifestyle habits, previous treatments, skin care and quality of life. In this study (n = 374), acne was mild or clear/almost clear in 47.3% of subjects; however, the study visit was not required to be an initial consultation for acne and as such, many patients were already on treatment. Most women (89.8%) had acne involving multiple facial zones (cheeks, forehead, mandibular area, temples) with a spectrum of facial acne severity similar to adolescents. Mixed facial acne (both inflammatory and non-inflammatory lesions present) was the most common presentation; 6.4% of women had inflammatory acne only (no non-inflammatory lesions reported) and 17.1% had comedonal acne with no inflammatory lesions. Truncal acne was present in 48.4% of patients. A small subset (11.2%) had acne localized only to the mandibular area. Compared to the women without localized acne, those with mandibular acne were more likely to be employed (90.5% vs. 78.6%), reported greater daily stress levels (5.8 vs. 5.1), and were more likely to say their jobs were psychologically stressful (71.4% vs. 57.5%). Women with mandibular acne alone were significantly less likely to have a global acne severity rating of moderate or higher (7.1% vs. 50.1%), truncal acne (19.0% vs. 51.9%), post-inflammatory hyperpigmentation (23.8% vs. 51.9%) and erythema (19.0% vs. 48.4%). At the completion of the study visit, this group was also more likely to receive a prescription for an anti-androgen (16.7% vs. 7.7%). This study represents the first objective assessment of the facial distribution of acne lesions in adult women presenting to the dermatology office. The data surprisingly indicate that the acne distribution in almost 90% of cases is similar to that seen in adolescent acne. The stereotype of adult female acne being due to hormonal disturbances presenting as inflammatory acne localized only to the mandibular area was not found in the majority of this large group. The large majority (93.7%) of women had facial comedones. We recommend that the general treatment approach for adult acne should include agents that target each of the acne lesion subtypes. Subgroup analyses of recent large-scale controlled clinical trials have shown that many adult women respond well to standard first-line acne therapy.

NEWS FROM THE ANNUAL CONGRESS OF EUROPEAN SOCIETY OF CARDIOLOGY (BARCELONA 2014): REALIZED AND UNREALIZED EXPECTATIONS

News from Congress of the European Society of Cardiology (Barcelona, 2014) is highlighted. Results of recent controlled clinical trials, new clinical recommendations and registers data that were presented at the Congress are discussed.

Gastroesophageal reflux disease and childhood asthma

Gastroesophageal reflux disease (GERD) is common in children with asthma and may be present with or without symptoms. Clinicians, influenced by position statements in national guidelines, have routinely treated children with poorly controlled asthma with various anti-GERD medications. This practice is based on the pervasive but unproven belief that GERD is an important determinant of poor asthma control. Clinical studies show that GERD is highly prevalent in children with asthma, with estimates as high as 80%, but nearly half of the children are asymptomatic. However, there is no conclusive evidence per se that asymptomatic GERD informs asthma control, and treatment of GERD in the few controlled trials available for review does not substantively improve asthma outcomes. In a recent large controlled clinical trial, treatment with a proton-pump inhibitor (PPI) was not only ineffective, but adverse effects were common, including an increased prevalence of symptomatic respiratory infections. Current evidence does not support the routine use of anti-GERD medications in the treatment of poorly controlled asthma of childhood. However large controlled trials of children symptomatic of both GERD and asthma have not been conducted, and in this case the benefits of treatment, although unproven, might outweigh the risks.

Advances in Therapeutic Options for Gait and Balance in Parkinson’s Disease

There is a need to explore non-dopaminergic approaches to treating balance and gait problems in Parkinson's disease (PD). There is emerging evidence on the role of cholinergic denervation of the pedunculopontine nucleus (PPN) thalamus system and falls in PD. Preliminary clinical trial data suggest that the subgroup of PD patients with frequent falls may be suitable candidates for future cholinergic augmentation clinical trials. Recent controlled clinical trials using methylphenidate have been unable to confirm earlier reports of improved gait in PD. Although progressive deterioration of axial motor symptoms occur with deep brain stimulation of the subthalamic nucleus or globus pallidus interna, new preliminary research suggests that other surgical stimulation sites, such as the PPN, may have a potential benefit on gait and balance impairments in PD. Continuing vigorous exercise and physical fitness should be highly encouraged to patients with PD who are at risk of physical deconditioning and fear of falling, but effective antifall physical therapy interventions remain an unmet clinical need.

Prevention of Hospital-Acquired Infections by Selective Digestive Decontamination

Selective decontamination of the digestive tract (SDD) has been advocated to prevent ventilator-associated pneumonia (VAP) and possibly other nosocomial infections. However, its incorporation into standard health care practices has been limited. Comprehensive literature search using www.pubmed.gov and derivative cross-references. The abundance of basic science and clinical literature largely supports the concept that the incidence of VAP declines after the introduction of SDD, although there are some controversial aspects. Several meta-analyses and recent controlled clinical trials have supported the benefit of SDD. A few years ago, the Institute for Healthcare Improvement introduced the "ventilator bundle," a set of simple evidence-based measures designed to reduce the incidence of pneumonia. These measures have been implemented rapidly throughout the country. Of the four initial measures (elevation of the head of the bed, daily "sedation vacations" with assessment of readiness for endotracheal extubation, prophylaxis against stress-related gastric mucosal hemorrhage, and deep venous thrombosis prophylaxis), only the first two affect the development of VAP either directly or indirectly. The evidence supporting SDD as a prevention measure for VAP is at least as good as that supporting the ventilator bundle, if not better. At many centers, a topical oral antiseptic (e.g., chlorhexidine) has been incorporated as a fifth element of the ventilator bundle.

Advances in Therapeutic Options for Gait and Balance in Parkinson's Disease.

There is a need to explore non-dopaminergic approaches to treating balance and gait problems in PD. There is emerging evidence on the role of cholinergic denervation of the PPN-thalamus system and falls in PD. Preliminary clinical trial data suggest that the subgroup of PD patients with frequent falls may be suitable candidates for future cholinergic augmentation clinical trials. Recent controlled clinical trials using methylphenidate have been unable to confirm earlier reports of improved gait in PD. Although progressive deterioration of axial motor symptoms occur with DBS of the STN or GPi, new preliminary research suggests that other surgical stimulation sites, such as the PPN, may have a potential benefit on gait and balance impairments in PD. Ongoing vigorous exercise and physical fitness should be highly encouraged to patients with PD who are at risk of physical deconditioning and fear of falling but effective anti-fall physical therapy interventions remain an unmet clinical need.

Terapia biológica dirigida contra los linfocitos B en el lupus eritematoso sistémico

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. Autoantibody production plays a critical role in its pathogenic pathways. Thus, B-cell directed biologic therapy is a logical option. The present article reviews the latest advances in the development of B-cell directed biological agents in the treatment of SLE. Rituximab has been studied in a number of open series of patients that suggest efficacy but two recent controlled clinical trials have failed to show efficacy versus placebo. In contrast, a recent placebo-controlled, double-blind, randomized trial has reported that belimumab has statistically significant efficacy versus placebo. Atacicept, a fusion protein that blocks cytokines that play a critical role in the differentiation and survival of B-cells and plasma cells, markedly reduces autoantibody levels but could increase the risk of infection. Further studies are needed to establish the role of B-cell directed biologic therapy in SLE.

Amantadine use associated with impulse control disorders in Parkinson disease in cross‐sectional study

A recent controlled clinical trial suggested a role for amantadine as a treatment for pathological gambling in patients with Parkinson disease (PD). Analyzing data from a large cross-sectional study of impulse control disorders (ICDs) in PD, amantadine use (n = 728), vs no amantadine use (n = 2,357), was positively associated with a diagnosis of any ICD (17.6% vs 12.4%, p < 0.001) and compulsive gambling specifically (7.4% vs 4.2%, p < 0.001). This amantadine association remained after controlling for covariates of amantadine use, including both dopamine agonist use and levodopa dosage. Further research, including larger clinical trials, is needed to assess the role of amantadine in the development and treatment of ICDs in PD.

Electrical neuromuscular stimulation in dysphagia: current status

To assess current information regarding the physiological effects of transcutaneous electrical stimulation (TES) on the neck and current evidence regarding the clinical effects of adding TES to dysphagia rehabilitation. Physiological studies have demonstrated that when electrical stimulation is applied on the throat it will lower the hyo-laryngeal complex and resist elevation needed for airway protection during swallowing. Submental TES has not been found to effectively elevate the hyo-laryngeal complex. Recent controlled clinical trials have had mixed results. Most indicate that TES is beneficial in the treatment of dysphagia; however, studies differ on whether these effects are greater than, equal to, or less than traditional therapy alone for the rehabilitation of swallowing. Currently TES for dysphagia is one of several tools available to the clinician for the rehabilitation of dysphagia. The two controlled clinical trials demonstrate that use of TES in dysphagia therapy is equivalent to traditional dysphagia therapy and of greater benefit only on one of several measures in one study. TES should be used only in patients who can overcome the resistive lowering of the hyo-laryngeal complex induced by TES which could place severely affected patients at greater risk of penetration.

Current concepts on cytomegalovirus infection after liver transplantation

Cytomegalovirus (CMV) is the most common viral pathogen that negatively impacts on the outcome of liver transplantation. CMV cause febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted allograft. In addition, CMV has been significantly associated with an increased predisposition to allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV on outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is regarded as an essential component to the medical management of liver transplant patients. Two recent guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and at least in one study, such occurrence of late-onset primary CMV disease was significantly associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention are needed, and aggressive treatment of CMV infection and disease should be pursued. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, one should also reduce the degree of immunosuppression. In one recent controlled clinical trial, valganciclovir was found to be as effective and safe as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. In this article, the authors review the current state and the future perspectives of prevention and treatment of CMV disease after liver transplantation.

Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials.

Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycaemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. In the past two decades several medical treatments that exert their effects despite hyperglycaemia have been derived from the experimental pathogenetic concepts of diabetic neuropathy. Such compounds have been designed to improve or slow the progression of the neuropathic process and are being evaluated in clinical trials, but with the exception of alpha-lipoic acid (thioctic acid) which is available in Germany, none of these drugs is currently available in clinical practice. Here we review the current evidence from the clinical trials that assessed the therapeutic efficacy and safety of thioctic acid in diabetic polyneuropathy. Thus far, 15 clinical trials have been completed using different study designs, durations of treatment, doses, sample sizes, and patient populations. Within this variety of clinical trials, those with beneficial effects of thioctic acid on either neuropathic symptoms and deficits due to polyneuropathy or reduced heart rate variability resulting from cardiac autonomic neuropathy used doses of at least 600 mg per day. The following conclusions can be drawn from the recent controlled clinical trials. 1.) Short-term treatment for 3 weeks using 600 mg of thioctic acid i.v. per day appears to reduce the chief symptoms of diabetic polyneuropathy. A 3-week pilot study of 1800 mg per day given orally indicates that the therapeutic effect may be independent of the route of administration, but this needs to be confirmed in a larger sample size. 2.) The effect on symptoms is accompanied by an improvement of neuropathic deficits. 3.) Oral treatment for 4-7 months tends to reduce neuropathic deficits and improves cardiac autonomic neuropathy. 4.) Preliminary data over 2 years indicate possible long-term improvement in motor and sensory nerve conduction in the lower limbs. 5.) Clinical and postmarketing surveillance studies have revealed a highly favourable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I Study) is being conducted in North America and Europe aimed at slowing the progression of diabetic polyneuropathy using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment.

Pneumatic compression in the treatment of chronic ulcers

Objective: To review existing literature that examines physiological mechanisms and clinical effects of different types of pneumatic compression (PC) therapy in the treatment of chronic wounds.Methods: Electronic databases were searched using intermittent, sequential, cardiosynchronous, pneumatic, compression, ulcer, wound, healing, and treatment as key words. All clinical studies were included provided the study subjects had chronic wounds, the treatment included PC, and wound healing was a measured outcome. Original clinical reports investigating the physiological effects of PC were also retrieved and reviewed.Results: There is a strong physiological basis behind the use of PC for improving venous and arterial circulation. Six randomised controlled trials (RCTs) have compared the effect of PC to compression therapy or standard wound care on the healing of venous ulcers. However, these RCTs have produced conflicting results. One recent controlled clinical trial reported significantly improved healing and reduced amputation rate of people with chronic arterial ulcers. A well designed RCT also demonstrated greater oedema reduction and faster healing of diabetic foot ulcers compared to sham controls. Research is emerging to delineate optimal treatment protocols.Conclusion: PC may be a valuable adjunct to aid in the treatment of individuals with venous, arterial, and diabetic ulcers. It should be considered for those people who are not compliant with compression bandaging or those at risk of limb amputation.

Neurologic Complications of Cancer, 2nd ed.

Neurologic Complications of Cancer, 2nd ed.

Fish oil in the treatment of dyslipidemia

The recent availability of a concentrated prescription omega-3 fatty acid preparation provides physicians with an additional anti-dyslipidemic agent at a time when limitations of statin therapy in dyslipidemic high-risk patients are recognized. This review examines the evidence supporting the use of omega-3 fatty acid treatment in dyslipidemic states. There is now considerable evidence that omega-3 fatty acid treatment at the prescription strength of 4 g/day effectively and safely lowers triglyceride levels and increases low-density lipoprotein size, as well as affecting high-density lipoprotein metabolism. Similar effects have been noted in patients treated with statins, and add-on prescription omega-3 fatty acid therapy significantly increases the proportion of statin-treated dyslipidemic patients reaching their non-high-density lipoprotein cholesterol goals. In addition to past studies showing a cardioprotective effect of low-dose omega-3 fatty acid treatment against sudden death, a recent controlled clinical trial showed that 1.8 g of omega-3 fatty acid in statin-treated patients reduced major coronary events by 19% compared with statin plus placebo treatment. Omega-3 fatty acid treatment should be considered in patients with severe hypertriglyceridemia as well as in high-risk patients with an atherogenic lipoprotein phenotype.