Reviews on Recent Clinical Trials - Volume 5, Issue 3, 2010

Vascular calcification is associated with poor prognosis in hemodialysis (HD) patients. It can be assessed with computed tomography (CT) but simple in-office techniques may provide useful information. We compared the results obtained with a simple non-invasive technique with those obtained using multi-detector CT (MDCT) for aortic arch calcification volume (AoACV) in chronic HD patients. The aortic arch calcification score (AoACS) estimated by chest X-ray was highly correlated with AoACV. In another cohort study, during a follow-up period of 4.0 years, the patients with and without AoAC, 11.3% and 6.6% of cardiovascular diseases, respectively were studied. Kaplan-Meier analysis showed that cardiovascular mortality was significantly greater in patients with AoAC compared with those without it. Multivariate Cox proportional hazards analysis found that the presence of AoAC was significantly associated with increased cardiovascular mortality (hazard ratio, 2.556; 95% confidence interval, 1.006 to 6.490; P<0.05) after the adjustment for age, presence of diabetes, body mass index, diastolic blood pressure, and serum albumin level. Finally, we found that nonprogressors were significantly younger than the progressors (p=0.0419) in changes in AoACS (ΔAoACS). The prescribed dose of 1α-hydroxy vitamin D3 was significantly higher in the non-progressors than progressors. Multiple regression analysis revealed prescribed dose of 1α-hydroxy vitamin D3 to be significant independent determinant of ΔAoACS. In conclusion, the evaluation of AoACS on chest radiography is a very simple tool for the detection of AoAC in HD patients. Active vitamin D therapy seems to protect patients from developing vascular calcification in chronic HD patients.

Although self monitoring of blood glucose is accepted to be effective in lowering Hb A1c levels in insulin-treated diabetic patients, any benefit in non-insulin-treated patients remains controversial. Observational studies cannot answer this question because of either patient self selection (individuals with healthier life styles chose to perform more SMBG) or physician self selection (patients in poorer control are asked to perform SMBG). Only randomized controlled trials (RCTs) can provide the answer. Of the 14 published bona fide RCTs, nine show no benefit in lowering Hb A1c levels. In four of the five positive ones, the SMBG group received more intensive education and/or treatment than the control group. In the one in which patients in both groups were followed similarly, over 500 patients were required to produce a statistically significant difference of 0.2% favoring SMBG, the clinical significance of which is debatable. Thus, there is scant evidence that very expensive SMBG in non-insulin-treated patients is effective in lowering Hb A1c levels. This lack of benefit argues for redirecting these resources into areas of diabetes care where strong evidence exists for improving diabetes outcomes.

Background: Chronic pelvic pain (CPP) is a complex clinical scenario, which affects 15% of women. The published literature lacks a consistent definition of CPP. However according to Vercillini et al., CPP is defined by the duration and type of pelvic pain [1]. CPP is present if the pelvic pain persists for more than 3 months duration and is constant or intermittent, cyclical or noncyclical in nature. Four types of pelvic pain have also been described and these include: cyclical pain during menstruation (dysmenorrhoea), deep dyspareunia, dyschezia and noncyclical pelvic pain. Therefore for the purposes of this study, CPP will be defined by these aforementioned types of pelvic pain and duration. Methods: Multi-centre randomised controlled trial comparing Mirena IUS versus expectant management in women with CPP and/or dysmenorrhoea who undergo laparoscopic surgery. All women aged 18 - 45 years with CPP scheduled for laparoscopy will be eligible for inclusion. Women with a non-gynecological cause of pelvic pain, contraindications to the use of Mirena IUS, previous hysterectomy, contraindications to laparoscopy and/or general anesthesia, use of hormonal treatment in the preceding three months, underlying gynaecological malignancies or known ovarian cysts other than endometriomata will be excluded. Importantly, all randomised women with endometriosis noted at the time of surgery will have the disease excised laparoscopically. Routine excision of endometriosis at laparoscopy will be performed according to the anatomical location and type (superficial or deep infiltrating endometriosis (DIE)). Women will be followed for up to 24 months after laparoscopic surgery. Results: The primary outcome measure is improvement of pelvic pain and/or of dysmenorrhoea post-laparoscopic surgery for women. Assuming a 30% reduction in pain for the expectantly managed group in order to detect a reduction in pain in the study group of 50% with an alpha of 0.05 and a beta of 0.20, the sample size was estimated at a minimum of 103 women per trial arm. Discussion: This trial will provide evidence to validate the effectiveness or otherwise of progestogen-releasing IUS in treating women with CPP who undergo laparoscopy surgery. The pros and cons of both trial arms will offer guidance to clinicians in making the right treatment choice.

Recent experimental and clinical studies have shown that chronic hepatitis C virus (HCV) infection causes insulin resistance. Since insulin resistance decreases response to antiviral treatments, promotes inflammatory and fibrogenic reactions and increases a risk of hepatocellular carcinoma (HCC), amelioration of insulin resistance may be a novel therapeutic target, which could improve the prognosis in patients with HCV-related chronic liver disease. Despite the increased awareness of health risk of insulin resistance, there is no common therapeutic strategy for HCV-associated insulin resistance. Indeed, treatments with exogenous insulin or sulfonylureas may be rather harmful because these treatments are associated with the development of HCC in patients with HCV infection. Meanwhile, we, along with others, have found distinctive treatments which improve HCV-associated insulin resistance. Administration of branched-chain amino acids (BCAA), especially as a late evening snack, improves glucose metabolism by improving insulin-signal cascades in insulin resistance patients with HCV infection. In this paper, we discuss the pathogenesis and complications for HCV-associated insulin resistance and further review a recent clinical therapeutic strategy using these agents for the treatment of this devastating disorder. We also discuss therapeutic potentialities of incretin-based therapies, new anti-diabetic agents for HCV-associated insulin resistance and the significance of insulin resistance in the era of new anti-viral treatments.

Hepatitis C virus (HCV) infection affects millions of people world-wide, and chronic infection can result in end-stage liver disease and hepatocellular carcinoma. Conventional therapy to date has involved combination antiviral therapy including alpha-interferon and ribavirin; response rates with these drugs are variable based on both viral and host factors, such as HCV viral load, HCV genotype, HIV co-infection, host genetic polymorphisms (such as those in the IL28B region), and other factors. Recent advances in HCV treatment have included pegylated forms of alpha-interferon and, more recently, the development of specifically targeted antiviral therapy for HCV (STAT-C) with novel HCV protease inhibitors (PIs) for genotype 1 HCV. Although unlikely to be administered as monotherapy due to the potential for development of HCV PI drug resistance mutations, results of phase II trials of two PIs in development have recently been reported, demonstrating promising therapeutic efficacy of HCV PIs in combination with established conventional treatment. This review outlines the advances and the challenges in the development of these HCV PIs as effective HCV antiviral agents and their role in clinical practice.

Objectives: Gabapentin was initially developed as an antiepileptic drug but was later discovered to be an effective treatment of neuropathic pain. Gabapentin has been successfully used for the treatment of multiple neuropathic pain syndromes such as diabetic neuropathy and postherpetic neuralgia. However, limited data exist about its efficacy for other pain syndromes. The objective of the current review is to describe, from the literature, the role of gabapentin for the treatment of cancer-related pain syndromes. Methods: Studies were identified by searching the PubMed electronic databases. Additional review articles and article reference lists were used to identify other studies. Results: Recent studies showed effectiveness of gabapentin in improving the pain control in patients with neuropathic cancer pain, already treated with opiates. Moreover, gabapentin appeared promising in reducing the need for high total doses of opioids and avoiding unplanned treatment interruptions for patients with head and neck malignancies treated with radiotherapy or concurrent chemoradiotherapy. Furthermore, the combination of gabapentin and morphine has been shown to effect better pain relief at lower doses of each drug when compared with gabapentin or morphine alone in patients with painful diabetic neuropathy or postherpetic neuralgia. The combination of both drugs was associated with a beneficial effect on pain-related interference with daily activity, mood, sleep and quality of life. Conclusions: Given the significant benefits of gabapentin and the combination of gabapentin with opioids for the treatment of neuropathic pain, randomized clinical trials are needed to establish the role of these analgesic regimens for the treatment of neuropathic cancer pain.

Disease modifying therapy (DMT) first became available for relapsing-remitting multiple sclerosis (RRMS) fifteen years ago with the development of the moderately effective injectable agents interferon (IFN)-β and glatiramer acetate (GA). The subsequent licensure of mitoxantrone (MX) and natalizumab (NZ) has allowed for better control of refractory disease at the expense of potentially life-threatening side effects in a minority of patients. This dichotomy between DMT potency and safety also characterizes the next generation of DMTs. Five oral medications (fingolimod, cladribine, teriflunomide, laquinimod and fumarate) are at various stages of phase III trials and it is anticipated that at least some of these will be on the market within the next year. The development of oral agents would be a tremendous advance with respect to convenience and it is anticipated that this would dramatically increase the number of patients on therapy. In parallel with oral therapies, powerful immunosuppressive monoclonal antibodies (alemtuzumab, rituximab/ocrelizumab, daclizumab) are also being evaluated. Enthusiasm for the next generation of therapies is tempered by safety concerns. Serious and occasionally fatal complications have occurred with the emerging monoclonal therapies and rigorous patient selection will be required for these agents. Moreover, some of the oral DMTs that are most eagerly awaited by patients have also been associated with serious side-effects in the trials to date. It is unclear how oral agents will be incorporated into future treatment algorithms given the need to weigh the ease of oral administration against the relative inconvenience but long-term safety of current first-line injectable therapies.

Progress has been made towards the development of agents targeting tyrosine kinase receptors and other molecules involved in signalling pathways important for cell proliferation, motility, and apoptosis. Inhibitor molecules designed to be highly specific with the aim of decreasing toxicity have proven to be generally well tolerated. However, the efficacy of targeted agents may be impacted by cross-talk between pathways and downregulation of negative feed-back loops. That is the case of the IGF-IR/PI3K/Akt/mTOR pathway. This issue raises the question of how these targeted agents could be combined to prevent or delay resistance without significantly increasing toxicity. Several mTOR inhibitors have been approved for cancer therapy, and late-stage clinical trials of IGF-IR inhibitors are underway. The outcome of ongoing clinical studies of IGF-IR, PI3K, Akt and mTOR inhibitors as well as further testing of the combination of these agents will be key for the development of therapeutic options in a wide range of oncology indications.

Due to an oversight on the part of the author, unfortunately the manuscript entitled “A critical reappraisal of off-label indications for topical photodynamic therapy with aminolevulinic acid and methylaminolevulinate” submitted for publication in the journal Reviews on Recent Clinical Trials- Volume 5, Issue 2 (pg. 112-116) has been published with names in a reverse order (first names are mentioned before the surname). The printed names appear as Calzavara-Pinton Piergiacomo, Arisi Mariachiara, Sereni Elena and Ortel Bernhard, however the correct names of authors are Piergiacomo Calzavara-Pinton, Mariachiara Arisi, Elena Sereni and Bernhard Ortel.