Reviews on Recent Clinical Trials - Volume 6, Issue 3, 2011

The increase in the average lifespan and the consequent proportional growth of the elderly segment of society has furthered the interest in studying ageing processes. Ageing may be considered a multifactorial process derived from the interaction between genetic and environmental factors including lifestyle. There is ample evidence in many species that the maximum age attainable (maximum lifespan potential, MLSP) is genetically determined and several mitochondrial DNA polymorphisms are associated with longevity. This review will address the current understanding of the relationship between ageing and several factors both genetics and life style related. Firstly we focused on the most reliable and commonly shared theories which attempt to explain the phenomenon of ageing as the genetic, cellular, neuroendocrine, immunological and free-radicals related theories. Many studies have shown that most of the phenotypic characteristics observed in the aging process are the result of the occurrence, with age, of a low grade chronic pro-inflammatory status called “inflammaging”, partially under genetic control. The term indicate that aging is accompanied by a low degree of chronic inflammatory, an up-regulation of inflammatory response and that inflammatory changes are common to many age-related diseases. In this review special attention was dedicated to diseases related to age as atherosclerosis, cancer and Alzheimer disease. Despite the fact that in recent years many theories about ageing have been developed, we are still far from a full understanding of the mechanisms underlying the ageing process.

The last twenty years, the incidence of invasive fungal infections (IFI) has risen dramatically due to the prolongation of survival of patients with multiple risk factors for fungal infections. Amphotericin B was for more than 40 years the gold standard for almost all IFI, but toxicity and resistance, especially of new and emerging pathogens remained important issues. Fluconazole and itraconazole have also the same disadvantage of resistance. Voriconazole, a new triazole antifungal has offered an additional option, but the problem of resistant aspergillosis, and zygomycosis remains. Echinocandins (caspofungin, micafungin and anidulafungin) are active only against Candida and Aspergillus spp., but not against Fusarium, Scedosporium and Zygomycetes. Posaconazole is the most recently approved triazole with broad spectrum activity against Candida spp., Aspergillus spp., Cryptococcus neoformans, Zygomycetes, dermatiaceous, dimorphic, and other fungal pathogens. Interestingly, posaconazole is active against Candida spp., resistant to fluconazole and itraconazole, and Aspergillus fumigatus resistant to fluconazole itraconazole, amphotericin B, and voriconazole. The results from clinical trials of posaconazole as salvage treatment are encouraging. Multicenter clinical trials have also established its role in the prophylaxis of (IFI) in the severely immunocompromised patients such as those after hematopoietic stem cell transplantation (HSCT) who developed graft versus host disease (GVHD), as well as the neutropenic patients with an acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after myeloablative chemotherapy. Posaconazole has pharmacokinetic advantages and low side effect profile, which are very important, especially in the seriously ill population.

The objective of this study was to examine the drug-induced sex differences in corrected QT (QTc) interval by re-analyzing the data collected in thorough QT studies submitted to the US Food and Drug Administration (FDA). We examined 64 studies available in the FDA database by performing a time-matched, baseline adjusted ANCOVA on the QTc response stratified by sex. We used several summaries to capture the differences between males and females in drug response QTc effects. They included sample means, upper confidence intervals, and areas under the curves. At baseline, females tend to have a higher QTc response than males. After treatment, various summaries suggest that females tend to have a higher QTc effect than males. However, the magnitude of the difference is small and is often not statistically significant. Several limitations can be raised about these available data: 1) available QT studies were not designed to examine the sex differences in QTc effects, 2) the findings were undermined by large variations seen in QT data, and 3) our summary statistics are descriptive in nature and are not for inferential purposes. Nonetheless, the results suggest that females tend to have a higher QTc effect than males, although the difference tends to be small. Further research is needed to formally address the question.

Background: The impact of treatment with vasodilators on the survival of patients with pulmonary arterial hypertension (PAH) remains uncertain. Despite several clinical trials have been carried out in the last 15 years, their primary objective was not to assess mortality but the changes on surrogate end points. Methods and results: We reviewed the results of all clinical trials with vasodilators in PAH and the main results of different metaanalysis. Clinical trials and systematic reviews confirm that vasodilator therapies in patients with PAH who are non-vasoreactive produce a consistent, statistically significant but a marginal effect on exercise capacity assessed by the six-minute walk test. The weighted mean difference (95% CI) achieved with epoprostenol (EPO) or other prostacyclin analogues (PCA), endothelin receptor antagonists (ETRA) and phosphodiesterase-type-5 inhibitors (PDE5-I) was 35.4 m (17.3-53.5), 46.1 m (38.1-54.2) and 33.8 m (24.8-42.7), respectively. When considering the cumulative effects within each drug family, no class of drug produced a statistically significant reduction in all cause mortality. The relative risk rates (95% CI) conferred by EPO or PCA, ETRA and PDE5-I were 0.66 (0.36-1.21), 0.48 (0.19-1.23) and 0.65 (0.16-2.67), respectively. Interpretation: Further trials utilizing similar classes of drugs, and following similar trial designs are unlikely to yield different results or offer any more clinical benefits. Given that PAH is a fatal disease this raises concerns about whether they are ethical to conduct or not. Future trials will need to utilize clinical endpoints rather than the ones that are easy to administer and will need to include longer durations of study and other strategies to test the durability of effect.

MRSA infections, especially pneumonia have been associated with considerable morbidity and mortality and the management of MRSA infections is considered as an issue of high priority for scientific societies. Many studies which have been published during the last 10 years have provided evidence for MRSA pneumonia epidemiology, diagnosis and treatment. The main regime of antibiotic treatment recommended for MRSA pneumonia is either vancomycin or linezolid. Despite its pK/pD superiority over vancomycin, linezolid has to date failed to show clear advantage over vancomycin in recent clinical trials.

The surgical treatment of prostate cancer has evolved rapidly, driven by technological advances that have made minimally-invasive prostatectomy feasible. The contemporary surgical approaches are laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic radical prostatectomy (RALP). These are now considered standard modalities of treatment in urology departments across North America, Europe and centres of excellence world-wide. However, despite the widespread adoption of minimally-invasive approaches there are only a handful of robust studies directly comparing the results of these techniques with the gold standard approach of open radical prostatectomy (ORP). Of note, uncertainty remains over exactly which men with localised prostate cancer will benefit from radical treatment and the reduction of surgical side-effects is paramount in optimising outcomes. This systematic review examines the current status of minimally- invasive prostatectomy focussing on peri-operative, oncological and urogenital functional outcomes.

According to published data, sugammadex, rapidly reverses (2-5 min) shallow and profound NM block induced by rocuronium and vecuronium, without being connected with serious adverse events. It is accepted that in order to reverse shallow block, the suggested dose of sugammadex comes up to 2 mg/kg. Profound level of NM block demands 4 mg/kg in order to defy few responses at the post titanic count. Doses of sugammadex lower than 1 mg/kg may lead to rebound of rocuronium's effect. Higher doses of sugammadex (12 - 16 mg/g) are used in rescue reversal. In children and adolescents the 2 mg/kg dose is both effective and well tolerated, while, to date, data regarding infants are scarce. In patients with renal failure, 2 mg/kg of sugammadex resulted in a mean time to recovery of TOF ratio to 0.9 in 2 min, which was quicker than the time of reversal by acetylcholinesterase inhibitors. Investigations in cardiac patients undergoing noncardiac surgery suggest that 2 and 4 mg/kg of sugammadex are both safe and effective. Compared with neostigmine, sugammadex has no need to use muscarinic antagonists and therefore is not associated with variations in heart rate. Trials indicate that sugammadex acts faster than edrophonium and neostigmine. Sugammadex is a promising, well tolerated agent that enables fast reversal in different depths of NM block -shallow and profound- and in different patients’ populations. After completion of trial probation and settlement of issues concerning estimated cost and cost impact, it is believed to play a leading part in future anesthesiology.

The natural course of multiple sclerosis is characterized by a high variability of pattern, relapse rate and different progression indices. They also present a dramatic impact on the interpretation of treatment trials. Reports, based on uncontrolled observations are therefore of little value. Currently it is generally accepted that a proper treatment trial should be double blinded and, although probably controversial, that it should be compared with a group of MS patients treated with placebo. Currently MS is considered as a generalized degenerative disease. The lesions are persistent, which is the reason why immunomodulatory treatment has to be started as early as possible. An alternative approach, somewhat suggestive for the use of placebo trials, seems to be a comparison of proposed new drug therapy group with a group of patients treated with a generally accepted reference drug.

Clinical management of patients with malignant tumors has dramatically changed over the last years with the introduction of novel therapeutics, such as receptor-targeted therapies, downstream effectors and antiangiogenic compounds. This has created a need to re-evaluate the existing criteria used to assess treatment response. Emerging diagnostic techniques, combining functional and structural data may play a relevant role in planning new treatment strategies in individual cancer patients. In the new scenario where biological treatment results in stable disease, standard Response Evaluation Criteria in Solid Tumors (RECIST) and RECIST 1.1 criteria have limitations. Moreover, functional 18- fluorodeoxyglucose (18FDG)-positron emission tomography (PET) imaging provides an additional tool to assess tumor activity, particularly consistent in some settings, such as Gastro Intestinal Solid Tumors (GIST), hepatocarcinoma, nonsmall lung cancer, and colorectal cancer. The integration of 18FDG-PET and computed tomography (CT) enhances the evaluation of oncologic patients treated with molecularly targeted drugs, and accelerates drug development in many types of tumors.

EIPL (extensive intra-operative peritoneal lavage) therapy was developed as a prophylactic strategy for peritoneal recurrence, with the goal of improving the quality of life and survival span for advanced gastric cancer patients with peritoneal free cancer cells. The purpose of this article is to review the therapy's contribution to a remarkable improvement in the 5-year survival for patients with positive lavage cytology on prospective randomized controlled clinical trials. We also advocate for the adoption of the EIPL as the optimal treatment protocol for advanced gastric cancer.

Antimitotic chemotherapy remains the most effective approach to treat a variety of human neoplasms. Since the discovery of tubulin-targeting agents, vinca alkaloids and the taxanes including paclitaxel and docetaxel are used clinically to treat several solid tumors of the head and neck, breast, lung, ovary, and bladder. Despite the preclinical and clinical success of tubulin-targeting agents, the ability of tumors to develop an acquired resistance to drugs used for treatment and neurotoxicity severely limited their long-term effectiveness to cancer cure. Lately, advances in antimitotic treatments led to the identification of novel mitosis-specific agents that are expected to show higher selectivity and less cytotoxicity compared to known antimitotics. This review focuses on the progress of kinesin motor inhibitors that target proteins that function predominantly in mitosis.