Biomedical subjects
Publications and source records attributed to K K Jain.
Innovations in biosensors have come about as a result of improvements in the biological components and the implementation of microsystems technologies. This article reports on some of the latest product developments in this area and highlights future trends.
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Proteomics is a promising approach in the identification of proteins and biochemical pathways involved in carcinogenesis. Proteomic technologies are now being incorporated in oncology in the post-genomic era. Cancer involves alterations in protein expression and provides a good model not only for detection of biomarkers but also their use in drug discovery. Proteomics has an impact on diagnostics as well as drug discovery. Genomics still remains an important approach but the value of proteomics lies in the fact that most of the diagnostics and drugs target proteins. The importance of application of proteomics in oncology is recognized by the publication of this special issue of TRCT.
Proteins are important targets for drug discovery and this applied to cancer as well because there is a defect in the protein machinery of the cell in malignancy. Proteomic technologies are now being integrated with genomic approaches for cancer drug discovery and target validation. Among the large number of proteomic technologies available for this purpose, the most important ones are 3-D protein structure determination, protein microarrays, laser capture microdissection and study of protein-protein and protein-drug interactions. Cancer biomarkers and several cell pathways are important drug targets. Several companies are involved in using proteomic technologies for drug discovery. Finally, proteomic approaches will play an important role in the discovery and development of personalized medicines.
Proteomic technologies have emerged as an important addition to the genomic and antibody-based technologies for the diagnosis of cancer. Important technologies include 2-D gel electrophoresis, mass spectrometry, laser capture microdissection, detection of molecular markers of cancer and protein patterns. For clinical applications, the most likely technologies to be used widely are protein biochips. Application of these technologies to various cancers are described. Proteomic technologies have a potential in developing molecular diagnostics and markers for the early detection of cancer. However, information from various diagnostic technologies should be integrated to obtain the optimal information required for clinical management of a patient.
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Rapid progress in molecular diagnostics is expected to fundamentally change health care. This review of some of the latest innovations covers developments in polymerase chain reaction (PCR), several nonPCR methods, and biochips and nanotechnology, which have accelerated advances in the analysis of nucleic acids and proteins. The greatest impact is likely to be in the integration of diagnosis and therapy and the development of individualized treatment.
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Cambridge Healthtech Institute's Third Annual Conference on Lab-on-a-Chip and Microarray technology covered the latest advances in this technology and applications in life sciences. Highlights of the meetings are reported briefly with emphasis on applications in genomics, drug discovery and molecular diagnostics. There was an emphasis on microfluidics because of the wide applications in laboratory and drug discovery. The lab-on-a-chip provides the facilities of a complete laboratory in a hand-held miniature device. Several microarray systems have been used for hybridisation and detection techniques. Oligonucleotide scanning arrays provide a versatile tool for the analysis of nucleic acid interactions and provide a platform for improving the array-based methods for investigation of antisense therapeutics. A method for analysing combinatorial DNA arrays using oligonucleotide-modified gold nanoparticle probes and a conventional scanner has considerable potential in molecular diagnostics. Various applications of microarray technology for high-throughput screening in drug discovery and single nucleotide polymorphisms (SNP) analysis were discussed. Protein chips have important applications in proteomics. With the considerable amount of data generated by the different technologies using microarrays, it is obvious that the reading of the information and its interpretation and management through the use of bioinformatics is essential. Various techniques for data analysis were presented. Biochip and microarray technology has an essential role to play in the evolving trends in healthcare, which integrate diagnosis with prevention/treatment and emphasise personalised medicines.
Neurogenomics, the study of the genes of the nervous system, has applications in basic research, in the pharmaceutical industry and in the management of neurological disorders. Basic research applications include molecular neuropathology, the detection of genes for neurological disorders, the study of gene expression in the CNS and creation of transgenic models of neurological disorders. Pharmaceutical applications may be in the areas of molecular neuropharmacology, the discovery of new drugs for neurological disorders, gene therapy and the development of personalised medicines based on pharmacogenomics. Clinical applications in neurology include the redefinition and reclassification of diseases, molecular diagnostics and the integration of diagnostics with therapeutics. Various methods for the study of genes and gene expression are described. Genes have been identified for only a limited number of neurological disorders so far. The discovery of genes defective in neurological disorders would facilitate drug discovery, molecular diagnostics and gene therapy diseases. There is a trend towards the integration of diagnosis, genetic screening, prevention, treatment and monitoring of therapy of neurological disorders, which will be facilitated by neurogenomics. Pharmacogenomics-based personalised medicines are anticipated to be part of medical practice by the end of the first decade of the 21st century, and neurogenomics will contribute to the development of personalised medicines for diseases of the CNS.
Historically, bacteria were used as oncolytic agents for malignant brain tumours. Advances in bacteriology and molecular biology have widened the scope of bacterial approaches to cancer therapy and various possibilities include the use of bacteria as sensitising agents for chemotherapy, as delivery agents for anticancer drugs, and as vectors for gene therapy. Bacterial toxins can be used for tumour destruction and cancer vaccines can be based on immunotoxins of bacterial origin. The most promising approaches are the use of genetically modified bacteria for selective destruction of tumours, and bacterial gene-directed enzyme prodrug therapy. Knowledge gained from study of bacterial genomes forms an important basis of use of bacteria as anticancer agents. TAPET (Tumour Amplified Protein Expression Therapy) uses a genetically altered strain of Salmonella as a bacterial vector, or vehicle, for preferentially delivering anticancer drugs to solid tumours. Verotoxin 1 (VT1) of Escherichia coli has been used for ex vivo purging of human bone marrow of cancer cells before autologous bone marrow transplant. E. coli genes and enzymes have become part of well-known prodrug approaches to cancer in which inert prodrugs can be converted in vivo to highly active species. IL-4 fused with Pseudomonas exotoxin has been administered directly into malignant brain tumours and binds with high affinity to IL-4 receptors, which do not exist on normal brain cells, thus destroying a major part of the tumour without harming the normal brain tissue. It is in Phase I/II clinical trials in patients with glioblastoma. No ideal anticancer agent of bacterial origin that is applicable to all types of cancers has been discovered yet. The most promising approach to malignant brain tumours appears to be the use of genetically engineered bacteria that destroy the tumour selectively while sparing the normal brain tissue.
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Ziconotide, the synthetic form of cone snail peptide pi-conotoxin MVIIA, is a neurone-specific N-type calcium channel blocker with an analgesic and neuroprotective effect. Intrathecal ziconotide has been recommended for approval by the FDA for the management of chronic pain. Spinally administered ziconotide produces analgesia by blocking neurotransmitter release from primary nociceptive afferents and prevents the propagation of pain signals to the brain. It has an advantage over intrathecal morphine in that there is no development of tolerance after prolonged use. Systemic toxicity is considerably reduced by administration of smaller doses intrathecally and selective delivery to the site of action in the nervous system. Nevertheless, there are neurological adverse effects due to delay in clearance of ziconotide from the neural tissues. Overall, ziconotide has a favourable risk/benefit ratio with advantages over several currently available intrathecal therapies for pain.
Parecoxib is a prodrug of valdecoxib, which is a potent and selective inhibitor of COX-2. Intravenous preparation of parecoxib is in Phase III clinical trials for the management of acute and severe post-surgical pain. It is the only COX-2 inhibitor that is available in a parenteral formulation. Clinical results compare parecoxib with ketorolac, a NSAID, which is the only non-narcotic analgesic available in parenteral formulation that can be administered for the relief of moderate to severe acute pain. Pharmacokinetic studies have shown that parecoxib is converted to valdecoxib within a short time following administration by im. or iv. injection. In clinical trials, parecoxib compares favourably with ketorolac and produces less gastric or duodenal ulcers, the predominant adverse effect, than ketorolac. Parecoxib, thus, fulfils some of the desirable characteristics of an ideal non-narcotic analgesic for severe post-surgical pain and has application in other acutely painful conditions. Parecoxib is expected to be filed for approval before the end of 2000 and is expected to be introduced in the market in 2001. It has favourable prospects for a fair share of the post-surgical pain relief market which is valued at approximately US$ 1 billion for the year 2000.
Iloperidone (Novartis' Zomariltrade mark) is an atypical antipsychotic agent for the treatment of schizophrenia. Current trends in the treatment of schizophrenia indicate that some atypical antipsychotics are being recommended as first-line therapy. Atypical antipsychotics, in addition to being dopamine (D) receptor antagonists, are all relatively potent serotonin (5-HT) receptor antagonists and are less likely than conventional dopamine antagonists to induce movement disorders. However, all of these agents differ in their receptor profiles and clinical profiles. Iloperidone, a benzisoxazole, is a mixed 5-HT(2A)/D(2)antagonist. Iloperidone was found to be more potent than its analogues when compared with haloperidol in antagonising climbing behaviour in mice. Iloperidone is extensively metabolised and the main circulating metabolite is reduced iloperidone. In patients treated with iloperidone, a low incidence of extrapyramidal symptoms and weight gain has been shown. Data from Phase II trials demonstrated efficacy in patients at doses of 8 mg/day and tolerability was good up to 32 mg/day. Phase III prospective, double-blind, randomised trials with iloperidone are in progress under the ZEUS (Zomariltrade mark Efficacy Utility and Safety) programme involving 3300 patients. Iloperidone, with a balance of activity at the dopaminergic and serotonergic receptors, has obvious advantages over clozapine and olanzapine, both of which have a similar receptor profile as they favour serotonergic over dopamine receptors. Iloperidone is likely to reach the market in 2001 and has favourable prospects in the atypical antipsychotic market for schizophrenia, which is expanding from US$ 1.5 billion in 2000 to US$ 3 billion in 2005.
The role of neuroprotection in the management of acute cerebrovascular disease is reviewed. Neuroprotection is a valuable adjunct to thrombolytic therapy in acute cerebral ischaemia. Various pharmacological approaches for neuroprotection are based on the current knowledge of molecular events in the pathophysiology of cerebral ischaemia. Reperfusion injury following restitution of circulation is also considered to be mediated by free radicals. Various strategies include free radical scavengers, anti-excitotoxic agents, apoptosis (programmed cell death) inhibitors, anti-inflammatory agents, metal ion chelators, ion channel modulatory, antisense oligonucleotides and gene therapy. The various agents aim to prevent the progression of ischaemic cascade therefore reducing brain damage and some of these intervene at more than one point in the ischaemic cascade. Neuroprotection is considered as an adjunct to therapies designed to improve cerebral circulation such as thrombolytic agents for arterial thrombosis. Clinical effectiveness of some of the strategies has not be proven in clinical trials, some of which had to be abandoned due to adverse effects outweighing the beneficial effects. Efforts to develop new neuroprotective agents continue and prospects for the introduction of an effective neuroprotective agent(s) in the next few years are good. Apart from acute cerebrovascular disease, neuroprotective therapy has a role in preventing cerebral ischaemia in high risk cardiovascular procedures as well as in neurodegenerative disorders which has some common pathomechanisms with cerebrovascular disease. Currently, the most promising agents are free radical scavengers. In the near future, gene therapy approaches are likely to prove more effective in neuroprotection.
This article evaluates rufinamide, a new anti-epileptic drug (AED) in Phase III development. This review is done against the background of therapeutic challenges of epilepsy, old established AEDs, newly introduced AEDs and AEDs in clinical development. Pharmacological properties of 12 AEDs in clinical trials (Phases I - III) are compared: ADCI, AWD 131-138, DP-VPA, ganaxolone, levetiracetam, losigamone, pregabalin, remacemide hydrochloride, retigabine, rufinamide, soretolide and TV1901. One of these, levetiracetam has been approved in the USA and is waiting approval in other countries. The protective index of rufinamide, as shown in rodent models of epilepsy, is much higher than that of most common AEDs. Features which make it a desirable AED are: (i) a broad spectrum of anti-epileptic actions including both partial and symptomatic generalised epilepsy; (ii) a statistically significant reduction in seizure frequency in clinical trials; (iii) efficacy and safety shown in a broad range of age groups including children and the elderly; (iv) rapid oral absorption enabling quick titration to effective dose and (v) a benign adverse event profile. Most of the events did not lead to discontinuation in clinical trials. These features offer considerable advantages over the existing anti-epileptic drugs. It is one of the two drugs in development which have reached Phase III and is expected to be approved by the year 2001 - 2002.
Cerebral vasospasm is a complication of subarachnoid haemorrhage and can cause cerebral ischaemia. Antivasospastic agents are used to relieve vasospasm after subarachnoid haemorrhage. A large number of agents with varying modes of action currently being investigated are reviewed. Pharmacology and clinical trials of nicaraven are discussed. The drug has been found to have both antivasospastic as well as neuroprotective effects. Clinically, the most documented efficacy of nicaraven is in the management of vasospasm associated with subarachnoid haemorrhage based on its free radical scavenging effect. Other potential areas for application are cerebral oedema associated with intracerebral haemorrhage and for neuroprotection in cerebral infarction. Nicaraven is in pre-registration by Chugai Pharma Ltd. in Japan for the treatment of vasospasm following subarachnoid haemorrhage. The regulatory atmosphere in Japan regarding the approval of neuroprotectives is reviewed and nicaraven is likely to be approved by the year 2001 when the patent on it expires.