Reviews on Recent Clinical Trials - Volume 7, Issue 2, 2012

Multiple sclerosis (MS) is a chronic and debilitating neurological disease characterized by multifocal areas of inflammation, demyelination and neurodegeneration within the brain and spinal cord. At its core MS is still a big enigma and it seems that there is clearly a gap in our knowledge about this disease [1,2]. It is hoped that the discovery of venous lesions associated with MS, the so-called chronic cerebrospinal venous insufficiency (CCSVI) [3,4] will-at least partially-fill that gap. Although it is widely accepted that MS is an autoimmune disorder, which means that the disease is caused by autoimmune attack against nervous tissue antigens, therapeutic strategies that are based on this autoimmune concept fall short of success in the long-run and cannot protect the patients from the accumulation of disability [5-8]. Over the last century alternative causes of MS were discussed, including infectious, environmental, genetic, epigenetic and-importantly-vascular factors. Vascular model of MS has recently been revived by Italian vascular surgeon, Paolo Zamboni. His group demonstrated that majority of MS patients present with obstructive vascular abnormalities in the main veins draining the central nervous system: the internal jugular veins and the azygous vein. Zamboni's venous paradigm claims for significant role of these venous blockages in neurological pathophysiology [9-11]. The idea that MS may be contributable to vascular disorders is not new and stretches much back in time then the Zamboni's discovery [12]. It actually has its roots in the first description of MS by Charcot who depicted plaques characterized by vasocentric localization [13]. However, prior to CCSVI hypothesis, MS has not been suggested to result from impaired venous outflow. It should be emphasized that this new venous model of MS is not necessarily contrary to its currently ruling autoimmune paradigm. The heterogeneity of MS and a relative lack of response to immunomodulatory treatments leads to the hypothesis that the autoimmune and venous disorders may represent two sides of the same coin, with MS being a disease triggered and exacerbated by immune and vascular [14], and possibly also other mechanisms....

Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome recently described in multiple sclerosis patients. It is characterized by abnormal venous hemodynamics resulting from numerous obstacles in the main veins draining the central nervous system, usually: the internal jugular veins and the azygous vein. Internal jugular vein is the most commonly vein affected. Most of the abnormalities in this vein are located at the level of jugular valve. The aim of this review is to give venographic and schematic descriptions of the most common valvular and perivalvular anomalies found in the lower part of internal jugular vein.

This article discusses the biophysical aspects of venous outflow from the brain in healthy individuals and in patients with chronic cerebrospinal venous insufficiency. Blood flows out of the brain differently, depending on body position. In the supine position it flows out mainly through internal jugular veins, while in the upright position it uses the vertebral veins. This phenomenon is probably not due to the active regulation of the flow but instead results from the collapse of jugular veins when the head is elevated. Such a collapse is associated with a significant increase in flow resistance, which leads to redirection of the flow towards the vertebral pathway. Theoretical calculations respecting the rules of fluid mechanics indicate that the pressure gradients necessary for moving blood from the brain toward the heart differ significantly between the supine and upright positions. The occlusion of internal jugular veins, according to fluid mechanics, should result in significant increase in the flow resistance and the restriction of cerebral flow, which is in line with clinical observations. Importantly, the biophysical analysis of cerebral venous outflow implies that the brain cannot easily compensate for increased peripheral venous resistance (namely, an occlusion of the large extracranial veins draining this organ), either by elevating the pressure gradient or by decreasing the vascular resistance through the recruitment of additional drainage pathways. This may mean that chronic cerebrospinal venous insufficiency may cause the destruction of the delicate nervous tissue of the central nervous system.

The discovery of stenoses in the azygous and internal jugular veins, the so-called chronic cerebrospinal venous insufficiency that accompanies multiple sclerosis, has enabled the reinterpretation of knowledge about this neurologic disease. Pathologic venous outflow from the central nervous system appears to lead to two main problems. Firstly, it disassembles the blood-brain barrier and may allow the penetration of nervous parenchyma by glutamate and leukocytes. Secondly, it may result in significant hypoperfusion of the brain and spinal cord. These two overlapping pathologies are likely to trigger plaques through caspase-1-driven pyroptosis of oligodendrocytes and to evoke neurodegeneration via glutamate excitotoxicity. Moreover, brain hypoperfusion may lead to chronic fatigue and other global neurologic symptoms. It is hoped that this review will help to elucidate new strategies and treatments for multiple sclerosis and will show new avenues for the research on this debilitating disease.

The role of the venous circulation has long been underestimated in clinical practice and in research into neurological diseases. In this review, we present an overview of the existing evidence that venous abnormalities can play a key role in the development and manifestation of neurological and neurodegenerative diseases. We review the history behind the role of venous diseases in multiple sclerosis and their connections with the disease landmarks, the links of chronic venous hypertension to cerebral hydrodynamics and the role of iron in MS. In addition, we highlight the role of venous abnormalities in other diseases including jugular venous reflux, developmental anomalies, hydrocephalus and cerebrospinal fluid flow. Finally, and based on the information presented throughout the whole review, we conclude with the link between chronic cerebrospinal venous insufficiency and MS and the role and power of magnetic resonance imaging in diagnosing venous anomalies.

Purpose: To study the blood flow through the internal jugular veins (IJVs) of the MS population. Materials and Methods: Two hundred MS patients and 14 normal volunteers were evaluated with magnetic resonance imaging (MRI) at 3T. Contrast-enhanced time-resolved 3D MR angiography and 2D time-of-flight imaging were performed to assess abnormalities in the extracranial vascular anatomy. Based on this assessment, the MS population was divided into subgroups of non-stenotic (NST), cervical 1 stenotic only (C1ST) and cervical 6 stenotic (C6ST) subjects. In this study, 2D phase contrast MR imaging was used to quantify blood flow through major veins and arteries in the neck and flow differences among the groups were analyzed. Results: Of the 200 MS patients, 87 (43.5%) belonged to the NST group, 50 (25%) belonged to the C1ST group and 63 (31.5%) belonged to the C6ST group. The total IJV flow normalized to the total arterial flow of the NST group was 75.12 ± 12.22 %. This was significantly higher than that of the C1ST group, 63.93 ± 16.08 % (p<0.0001), which in turn was significantly higher than that of the C6ST group, 52.13 ± 20.71 % (p = 0.001). Seventy-nine percent of the stenotic groups had a normalized subdominant IJV flow of less than 20%, a combined IJV flow of less than 5o% and/or a sub-dominant IJV flow vs. dominant IJV flow ratio of less than 1/3. Only 2% of the NST group had a combined IJV flow of less than 50%, compared to 35% of the stenotic groups. Conclusion: Blood flow through the IJVs was reduced in the MS population with stenoses compared to those without.

The transradial approach for percutaneous coronary intervention (both diagnostic and therapeutic procedures) has gained progressive acceptance in the last years. Transradial access has been shown, also, to have several advantages over transfemoral approach; the radial artery is easily compressible, thus bleeding is controllable and hemorrhagic complications are significantly reduced. Furthermore, periprocedural bleeding and vascular complications after percutaneous coronary intervention are associated with worse clinical outcomes and increased short and long - mortality. With increasing experience and availability of dedicated equipment this technique is now being increasingly used for complex catheter intervention. The main purpose of this review is to highlight the benefits, complications and problems with transradial approach compared with conventional transfemoral approach.

This review focuses on the use of family-based treatment (FBT) for adolescents with eating disorders, including anorexia nervosa (AN) and bulimia nervosa (BN). AN and BN are serious disorders with significant psychiatric and medical morbidity. Data support the use of family treatments for adolescents with eating disorders. Developed at the Maudsley Hospital, FBT is a theoretically agnostic approach that externalizes the illness from the patient and empowers families to actively work to bring about recovery in their relative with an eating disorder. FBT appears to be an effective treatment for adolescents with AN and support is developing for the treatment of adolescents with BN. Manual development is currently underway for the implementation of FBT for young adults with eating disorders, overweight adolescents, and those with subsyndromal AN. Further research is needed to determine the effectiveness of FBT with other populations. In this review, we will provide a critical overview of the literature by focusing upon empirical findings regarding FBT, with particular emphasis on studies conducted with adolescents.

Background: The primary goals of this paper are to describe the collection and evaluation of various nonpharmacological treatment options for depressive disorders and to establish a basis for the development of a standard for the treatment of patients with depressive disorders. Method: To identify evidence-based treatment elements, a comprehensive investigation of national and international guidelines was conducted. The extracted guidelines were then assessed with regard to aspects of methodological quality and evidence-based treatment elements. In a further step, specific and systematic literature searches for residual treatment elements were conducted. For the corresponding literature search, a hierarchical approach was chosen in which current guidelines were reviewed first and systematic reviews and meta-analyses second. Psychopharmacological treatments were excluded from the analysis because this is covered by specific guidelines. Results: The treatment elements with an adequate level of evidence were identified as follows: psychotherapeutic interventions, marital/couples/family therapy and counseling, inclusion of family members, psycho-education, exercise, problem solving therapy, guided self-help and behavioral activation treatments. Further evidence-based methods include diagnostic treatment elements, participative decision-making, development of the therapeutic alliance, Cognitive Behavioral Analysis System for Psychotherapy, computerized cognitive behavior therapy, psychopharmacological therapy, combined psychopharmacological and psychotherapeutic therapy, electroconvulsive therapy, phototherapy, sleep deprivation, repetitive trans-cranial magnetic stimulation (rTMS) and acupuncture. Conclusion: In summary, using a hierarchical approach, it was possible to assign different levels of evidence to the various treatment options for depression.

Cholesterol-lowering drugs are often prescribed to patients with type 2 diabetes mellitus despite uncertainty about the benefits of this treatment in the prevention of cardiovascular complications. We here systematically review (PRISMA guidelines) the results of high-quality double blind trials testing whether cholesterol-lowering drugs (statins and fibrates) reduce mortality and cardiovascular complications specifically in type 2 diabetics. Trials with premature termination without pertinent medical justification or using nonrandomized subgroups of diabetics were excluded from the review. Only four trials met our predefined inclusion criteria. Among the 3 statin trials, CARDS was discontinued 2 years before the anticipated end and in the absence of significant effect on both overall and cardiovascular mortality, suggesting that the trial should not have been prematurely stopped. The two other statin trials showed no significant effect on the primary endpoint (relative risk 0.92, 95% CI 0.77 to 1.10 in 4D and 0.90, 95% CI 0.73 to 1.12 in ASPEN) and on both cardiovascular and overall mortality. Finally, the fibrate trial (FIELD) showed no significant benefit on the primary endpoint (relative risk 0.89, 95% CI 0.75 to 1.05) and mortality (relative risk 1.11, 95% CI 0.95 to 1.29). Because of a huge medical heterogeneity between patients in the selected trials, it was consensually decided to stop the analysis at this stage. This review does not support the use of cholesterol-lowering drugs (such as statin and fibrate) to reduce mortality and cardiovascular complications in type 2 diabetics. Official guidelines should be re-examined and reformulated by experts independent from the pharmaceutical industry.

This drug utilization or prescription-monitoring study was conducted to evaluate the drug-prescribing trend of anti-asthmatic drugs in various hospitals (health care centre) of Shamli, (Prabuddha Nagar, Uttar Pradesh, India). The study was conducted in three famous hospitals of Shamli on three hundred thirty (330) patients, using a developed prescription auditing Performa. Data was recorded from the co-operating patients, attending the outpatient department using a chance random sample method for six months by interviewing and information was filled in the performa. The collected data was studied statistically for determining the most prominently prescribed medication for the treatment. The collected information suggested that β-agonist were the most frequently prescribed anti-asthmatic drugs followed by corticosteroids, Methylxanthine, anti-histaminics and leukotriene antagonist. Also the performed prescription analysis revealed that there is significant difference in the prescriptions for multiple drug therapy (90%) as compared to single drug therapy (10%). Also even after the commercial development of pulmonary targeted systems, oral dosage form like tablets (54.93%) were preferred over inhalation (31.69%). Thus, it can be concluded that the present prescribing pattern of antiasthmatics in Shamli does not completely meet standard guidelines for the asthma treatment. Hence there is a need of awareness amongst the physicians of Shamli so that they can follow the guidelines while treating asthma. Also the patients must be encouraged to use newly developed inhalational drug delivery systems for improving the treatment.

Background: S-1, an oral fluoropyrimidine, is usually given for 4 weeks (80 mg/m2/day) followed by a 2-week rest. However, compliance with this regimen is unsatisfactory because of adverse events such as leukopenia, anorexia, and nausea. To reduce adverse effects and improve compliance, we studied a “5-day on/2-day off” low-dose regimen of S-1 and evaluated pharmacokinetics in patients with non-small-cell lung cancer (NSCLC). Methods: Twelve patients with NSCLC were divided into 2 groups and received S-1 in a dose of 25 mg twice daily (level 1, n = 6) or 40 mg twice daily (level 2, n = 6) for 5 consecutive days followed by a 2-day rest (5 days on/2 days off) every week. Plasma 5-fluorouracil (5-FU) concentrations were measured. Results: The maximum concentration in plasma and the area under the plasma concentration-time curve from 0 to 9 h were respectively 55.3 ± 21.1 ng/ml and 290.2 ± 95.7 ng·hr/ml for level 1, as compared with 104.2 ± 33.5 ng/ml and 541.9 ± 232.3 ng·hr/ml for level 2. These values were similar to those previously reported for a continuous intravenous infusion of 5-FU. Adverse events were grade 1 fatigue (n ± 1 in each group) and anorexia (n ± 1 in each group). Conclusions: A “5-day on/2-day off” low-dose (40 mg twice daily) regimen of S-1 is feasible for the treatment of NSCLC, with acceptable plasma 5-FU concentrations and minimal adverse effects. A phase II or III trial of this regimen in an adjuvant setting is warranted in patients with NSCLC.