Bikash Medhi

Bacteria in cancer therapy: a novel experimental strategy

Resistance to conventional anticancer therapies in patients with advanced solid tumors has prompted the need of alternative cancer therapies. Moreover, the success of novel cancer therapies depends on their selectivity for cancer cells with limited toxicity to normal tissues. Several decades after Coleys work a variety of natural and genetically modified non-pathogenic bacterial species are being explored as potential antitumor agents, either to provide direct tumoricidal effects or to deliver tumoricidal molecules. Live, attenuated or genetically modified non-pathogenic bacterial species are capable of multiplying selectively in tumors and inhibiting their growth. Due to their selectivity for tumor tissues, these bacteria and their spores also serve as ideal vectors for delivering therapeutic proteins to tumors. Bacterial toxins too have emerged as promising cancer treatment strategy. The most potential and promising strategy is bacteria based gene-directed enzyme prodrug therapy. Although it has shown successful results in vivo yet further investigation about the targeting mechanisms of the bacteria are required to make it a complete therapeutic approach in cancer treatment.

Role of vinpocetine in cerebrovascular diseases

A cerebrovascular accident, or stroke, is defined as the abrupt onset of a neurological deficit, which can be due to ischemia. Cerebral ischemia is caused by a reduction in blood flow that thereby decreases cerebral metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of certain types of dementia. Vinpocetine, chemically known as ethyl apovincaminate, is a vinca alkaloid that exhibits cerebral blood-flow enhancing and neuroprotective effects. Non-clinical and clinical studies have suggested multiple mechanisms responsible for the beneficial neuroprotective effects of vinpocetine. As no significant side effects related to vinpocetine treatment have been reported, it is considered to be safe for long-term use. This vasoactive alkaloid is widely marketed as a supplement for vasodilation and as a nootropic for the improvement of memory. The present review focuses on studies investigating the role of vinpocetine in cerebrovascular diseases.

Pharmacokinetic and Toxicological Profile of Artemisinin Compounds: An Update

Artemisinin has been used effectively in malaria treatment. With the emerging resistance to malaria, the optimum and judicial use of the drug has become important. The drug metabolism and toxicology can have an impact on the therapeutic profile and clinical use of this antimalarial agent. In this review, we discuss the pharmacokinetics and toxicological aspects of artemisinin and its therapeutic implications. Artemisinins have several dosing routes including oral, intramuscular, intravenous and rectal. With repeated dosing, artemisinin has propensity for autoinduction, leading to decreased plasma levels on repeated dosing. Combination with other antimalarials in most cases did not influence the pharmacokinetics of artemisinins. Interactions with cytochrome P450 inhibitors are known but these neither affect the efficacy nor the toxicity of the respective derivative. Artemisinins are generally regarded to be of low toxicity. Two major problems associated with them are neurotoxicity and reproductive toxicity. But the extent of this neurotoxicity is dependent on the nature of the compound, on the route of administration, and on the nature of the formulation. Moreover, it occurs in humans at very high doses. However, as a matter of precaution, the use of artemisinins in the first trimester of pregnancy has been contraindicated.

Challenges of drug-resistant malaria

Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia–Thailand border threatened all the previous success. This review addresses the global scenario of antimalarial resistance and factors associated with it, with the main emphasis on futuristic approaches like nanotechnology and stem cell therapy that may impede resistant malaria, along with novel medications which are preparing to enter the global antimalarial market. These novel studies are likely to escalate over the coming years and will hopefully help to reduce the burden of malaria.

Drug Therapy in Stroke: From Preclinical to Clinical Studies

Background: Stroke is one of the major challenges to health and the reason for increasing disability-adjusted life years. Despite tremendous progress in preclinical studies, none of the treatment options has proven efficacious in clinical studies. The basic aim of neuroprotection is to interfere with the events of the ischemic cascade, halt the pathological processes and prevent the death of vulnerable nerve cells in the ischemic penumbra. Summary: This review will provide a brief overview of the current understanding of stroke, including the global epidemiology of stroke, its pathophysiology, the targeting of specific pathways and the success and failure of preclinical as well as clinical studies, and it will discuss the emerging targets for novel therapeutic strategies under investigation. Key Messages: New advancing investigational drugs for the prevention and treatment of stroke are on the way and may someday give hope to neuroscientists and clinicians. A novel approach should adopt preclinical testing, advance the understanding of the pathophysiology of stroke and make it possible to translate it from bench to bedside. We should learn from the past failures and move on with more enthusiasm.

Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-β induced experimental model of Alzheimer's disease

GCSF is an endogenous neuronal hematopoietic factor that displays robust in vitro and in vivo neuroprotective activity. The present study aimed to evaluate the effect of GCSF on Aβ-induced memory loss in an Alzheimers disease model of rats. A total of 42 male adult Wistar rats weighing 200-250 g were used in the study and were divided into 7 experimental groups. Animals were subjected to intracerebroventricular (ICV) injection stereotaxically at day 0 to instill amyloid-β(1-42) (Aβ(1-42)) or PBS (sham operated group) at 10 μl (5 μl bilaterally). GCSF treatment was given from day 7 to 12 of Aβ injection. On day 21, behavioral tests (short term memory, exploratory behavior and motor coordination) in all groups were evaluated. Biochemical parameters and RNA expression were measured to ensure the efficacy of GCSF. GCSF (35 and 70 μg/kg, s.c.) showed statistically significant improvement in memory as compared to control and sham operated groups (p<0.05). Mean time spent in the platform placed quadrant was found to be significantly increased in the GCSF (70 μg/kg, s.c.) as compared to GCSF (35 μg/kg, s.c.) and GCSF (10 μg/kg, s.c.) groups (p<0.001). GCSF (35 and 70 μg/kg, s.c.) also improved motor coordination and exploratory behavior significantly as compared to naïve sham operated and GCSF (10 μg/kg, s.c.) groups (p<0.05). Improvement in memory by GCSF (35 and 70 μg/kg, s.c.) was coupled with marked reduction of lipid peroxidation, acetylcholinesterase levels and a significant increase in antioxidant enzymes as well as total RNA expression in the brain. Additionally, GCSF (35 and 70 μg/kg, s.c.) significantly increased progenitor cells (iPSCs) and surface marker CD34+ in the brain and hence induced neurogenesis. The present findings demonstrate an improvement of memory and neurobehavioral function with GCSF in Aβ-induced Alzheimers disease model in rats.

Neuroprotective effect of progesterone on acute phase changes induced by partial global cerebral ischaemia in mice

The possible neuroprotective effect of progesterone, a steroid hormone, on acute phase changes in a mouse model of cerebral ischaemia induced by bilateral common carotid artery occlusion (BCAO) was studied. A total of 72 male mice were included in the study. The BCAO model was used to induce partial global cerebral ischaemia. Morphological assessment included measurement of infarct size and brain oedema. Post‐ischaemic seizure susceptibility was assessed using a subconvulsive dose of pentylenetetrazole (30 mgkg−1 i.p.). Biochemical estimations included tumour necrosis factor α (TNF‐α) levels and enzyme parameters such as lipid peroxidation, superoxide dismutase, catalase and glutathione peroxidase, and protein estimation. BCAO induced a significant infarct size and oedema in the saline‐treated control group, along with an increase in oxidative stress, indicated by increased lipid peroxidation and decreased levels of antioxidants such as superoxide dismutase, catalase and glutathione peroxidase. Progesterone (15 mgkg−1 i.p.) administration showed a neuroprotective effect by significantly reducing the cerebral infarct size as compared with the control group. Post‐ischaemic seizure susceptibility was also reduced as the number of positive responders decreased. Brain oedema subsided, but not significantly. Progesterone significantly reduced TNF‐α levels compared with the ischaemia group. Progesterone improved levels of all the anti‐oxidants, indicating activity against oxidative stress induced by BCAO. The results demonstrate the neuroprotective effect of progesterone against ischaemic insult, suggesting a role for the steroid as a neuroprotective agent.

Drug development status for Alzheimer's disease: present scenario.

Recent advances in the understanding of Alzheimer’s disease pathogenesis have led to the development of numerous compounds that might ameliorate the disease process. Research in the field of Alzheimer’s disease therapy has been partly successful in terms of developing symptomatic treatments, but also had several failures in terms of developing disease-modifying therapies. These successes and failures have led to a debate about the potential deficiencies in our understanding of the pathogenesis of Alzheimer’s disease and potential pitfalls in diagnosis, choice of therapeutic targets, development of drug candidates, and design of clinical trials. Many clinical and experimental studies are ongoing, but we need to acknowledge that a single cure for Alzheimer’s disease is unlikely to be found and that the approach to drug development for this disorder needs to be reconsidered. Preclinical research is constantly providing us with new information on pieces of the complex Alzheimer’s disease puzzle, and an analysis of this information might reveal patterns of pharmacological interactions instead of single potential drug targets. Several promising randomized controlled trials are ongoing, and the increased collaboration between pharmaceutical companies, basic researchers, and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of Alzheimer’s disease.

Potential of metabolomics in preclinical and clinical drug development

Metabolomics is an upcoming technology system which involves detailed experimental analysis of metabolic profiles. Due to its diverse applications in preclinical and clinical research, it became an useful tool for the drug discovery and drug development process. This review covers the brief outline about the instrumentation and interpretation of metabolic profiles. The applications of metabolomics have a considerable scope in the pharmaceutical industry, almost at each step from drug discovery to clinical development. These include finding drug target, potential safety and efficacy biomarkers and mechanisms of drug action, the validation of preclinical experimental models against human disease profiles, and the discovery of clinical safety and efficacy biomarkers. As we all know, nowadays the drug discovery and development process is a very expensive, and risky business. Failures at any stage of drug discovery and development process cost millions of dollars to the companies. Some of these failures or the associated risks could be prevented or minimized if there were better ways of drug screening, drug toxicity profiling and monitoring adverse drug reactions. Metabolomics potentially offers an effective route to address all the issues associated with the drug discovery and development.

Current status of pharmacological treatment of colorectal cancer

AIM To review the clinical trials for the development in drugs for chemotherapeutic treatment of colorectal cancer (CRC). METHODS A systematic review identified randomized controlled trials (RCTs) assessing drugs for the treatment of CRC or adenomatous polyps from www.clinicaltrials.gov. Various online medical databases were searched for relevant publications. RESULTS Combination treatment regimens of standard drugs with newer agents have been shown to improve overall survival, disease-free survival, time to progression and quality of life compared to that with standard drugs alone in patients with advanced colorectal cancer. The FOLFOXIRI regimen has been associated with a significantly higher response rate, progression-free survival and overall survival compared to the FOLFIRI regimen. CONCLUSION Oxaliplatin plus intravenous bolus fluorouracil and leucovorin has been shown to be superior for disease-free survival when compared to intravenous bolus fluorouracil and leucovorin. In addition, oxaliplatin regimens were more likely to result in successful surgical resections. First line treatment with cetuximab plus fluorouracil, leucovorin and irinotecan has been found to reduce the risk of metastatic progression in patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases. The addition of bevacizumab has been shown to significantly increase overall and progression-free survival when given in combination with standard therapy.