Angiotensin-II receptor antagonists: their place in therapy.
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Angiotensin-II receptor antagonists (or blockers) are a newer class of antihypertensive agents. These drugs are selective for angiotensin II (type 1 receptor); unlike angiotensin-converting enzyme inhibitors, they do not inhibit bradykinin metabolism or enhance prostaglandin synthesis. Angiotensin-II receptor antagonists are well tolerated. Cough occurs much less often with these agents than with angiotensin-converting enzyme inhibitors, and they do not adversely affect lipid profiles or cause rebound hypertension after discontinuation. Clinical trials indicate that angiotensin-II receptor antagonists are effective and safe in the treatment of hypertension. Their use in congestive heart failure and renal disease is under investigation. (+info)
Gemcitabine: single-agent and combination therapy in non-small cell lung cancer.
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With the advent of several newer agents with single-agent response rates greater than 20% and approximately 30%-40% in combination therapy, non-small cell lung cancer (NSCLC) may now be considered a malignancy that is moderately sensitive to chemotherapy. Examples of these agents include the taxanes, paclitaxel and docetaxel; vinorelbine, a new vinca alkaloid, and the camptothecins, of which CPT-11 is the most actively studied agent. Another new and exciting agent is gemcitabine, a nucleoside analogue structurally related to cytosine arabinoside. Gemcitabine's mechanism of action is activated by deoxycytidine kinase to dFdCMP, dFdCDP and dFdCTP. The latter two compounds, when incorporated into DNA, result in chain termination. Phase I studies using a short infusion schedule given weekly for three weeks followed by one week off established 1,000-1,250 mg/m2/week as the maximum tolerated dose. Single-agent gemcitabine has been extensively studied in patients with chemotherapy-naive advanced NSCLC with response rates of approximately 20%. Response rates for the combination of gemcitabine plus cisplatin are approximately 28%-54% in phase II trials. Recently, this combination has been studied in randomized phase II and III trials revealing improvements in response rates, time to progression and, in the phase III trial, survival. Current and future studies are evaluating gemcitabine in non-cisplatin combinations (i.e., taxanes). (+info)
Ethical aspects of neural tissue transplantation.
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The method of neural grafting is considered to be a very promising therapeutic strategy for the treatment of certain neurodegenerative disorders such as Parkinson's disease or Huntington's disease. During the last 15 years, clinical transplantation studies have been carried out worldwide in several hundreds of patients with Parkinson's disease. In these studies, primarily fetal mesencephalic tissue derived from aborted human fetuses has been used for implantation. Neural tissue transplantation gives rise to ethical issues in two different areas that need careful examination: the first, ethical problems linked to the use of tissue from aborted human fetuses; and the second, ethical issues concerning the graft recipients in clinical trials, i.e., his or her well-being, personality, and personal identity. (+info)
The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.
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Cognitive function is markedly impaired in most patients with schizophrenia. Antecedents of this impairment are evident in childhood. The cognitive disability is nearly fully developed at the first episode of psychosis in most patients. The contribution of cognitive impairment to outcome in schizophrenia, especially work function, has been established. Preliminary results indicate that cognitive function, along with disorganization symptoms, discriminate schizophrenia patients who are able to work full-time from those who are not. Typical neuroleptic drugs lack the ability to improve the various domains of cognitive function impaired in schizophrenia. Atypical antipsychotic drugs pharmacologically related to clozapine-quetiapine, olanzapine, risperidone, sertindole, and ziprasidone--share the ability to produce fewer extrapyramidal symptoms than typical neuroleptic drugs and more potent antagonism of serotonin2a relative to dopamine2 receptors. However, they have a number of different clinical effects. We have identified all the studies of clozapine, olanzapine, and risperidone that provide data on their effects on cognition in schizophrenia. Data for each drug are reviewed separately in order to identify differences among them in their effects on cognition. Twelve studies that report cognitive effects of clozapine are reviewed. These studies provide (1) strong evidence that clozapine improves attention and verbal fluency and (2) moderate evidence that clozapine improves some types of executive function. However, results of the effects of clozapine on working memory and secondary verbal and spatial memory were inconclusive. Risperidone has relatively consistent positive effects on working memory, executive functioning, and attention, whereas improvement in verbal learning and memory was inconsistent. Preliminary evidence presented here suggests that olanzapine improves verbal learning and memory, verbal fluency, and executive function, but not attention, working memory, or visual learning and memory. Thus, atypical antipsychotic drugs as a group appear to be superior to typical neuroleptics with regard to cognitive function. However, available data suggest that these drugs produce significant differences in specific cognitive functions. These differences may be valuable adjunctive guides for their use in clinical practice if cognitive improvements reach clinical significance. The effects of the atypical antipsychotic drugs on cholinergic and 5-HT2a-mediated neurotransmission as the possible basis for their ability to improve cognition are discussed. It is suggested that the development of drugs for schizophrenia should focus on improving the key cognitive deficits in schizophrenia: executive function, verbal fluency, working memory, verbal and visual learning and memory, and attention. (+info)
Clinical trials design: structure modifying agents for osteoarthritis. Future guidelines: areas for development.
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Clinical trials guidelines should offer evidence-based recommendations, and, where evidence is lacking or absent, should reflect the considered opinion of experts in the field. Recent OsteoArthritis Research Society International (OARSI) guidelines encompass these principles and are the result of a Task Force Workshop involving representatives from academia, regulatory authorities and industry. Areas for continued development for trials of Structure Modifying Osteoarthritis Drugs (STMOAD) include patient selection, study duration, sample size estimation, outcome assessment, imaging, response definition and pharmoeconomics. As developments occur in these and related areas, guideline documents will require revision to reflect this evolution. Notwithstanding these issues, there is opportunity to identify STMOAD class agents using current methodologies. (+info)
Serotonin and drug-induced therapeutic responses in major depression, obsessive-compulsive and panic disorders.
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The therapeutic effectiveness of antidepressant drugs in major depression was discovered by pure serendipity. It took over 20 years before the neurobiological modifications that could mediate the antidepressive response were put into evidence. Indeed, whereas the immediate biochemical effects of these drugs had been well documented, their antidepressant action generally does not become apparent before 2 to 3 weeks of treatment. The different classes of antidepressant treatments were subsequently shown to enhance serotonin neurotransmission albeit via different pre- and postsynaptic mechanisms. Clinical trials based on this hypothesis led to the development of treatment strategies producing greater efficacy and more rapid onset of antidepressant action; that, is lithium addition and pindolol combination, respectively. It is expected that the better understanding recently obtained of the mechanism of action of certain antidepressant drugs in obsessive-compulsive and panic disorders will also lead to more effective treatment strategies for those disorders. (+info)
Patterns of care and survival for children with acute lymphoblastic leukaemia diagnosed between 1980 and 1994.
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AIMS: To document survival rates after acute lymphoblastic leukaemia (ALL) during the era of modern chemotherapy, to assess effects of prognostic factors at presentation, and to investigate the relation of survival to patterns of organisation of care. PATIENTS: From a population based series of 5078 children diagnosed in the UK during 1980-94, 4988 remained for analysis after exclusion of nine children ascertained from death certificates alone and 81 who received no antileukaemia treatment. MAIN OUTCOME MEASURES: Actuarial survival rates. RESULTS: Between 1980-84 and 1990-94, the proportion of children treated at paediatric oncology centres rose from 77% to 89%, and the proportion entered into national trials rose from 59% to 82%. Each of age, sex, white blood count, immunophenotype, and Down's syndrome status had a highly significant effect on survival. Five year survival improved from 67% in 1980-84 to 81% in 1990-94, a 42% reduction in the risk of death within five years of diagnosis. Survival did not differ significantly between hospitals with different numbers of new patients per year or between paediatric oncology centres and other hospitals. Children who were entered into national trials had higher survival and this difference became greater in recent years; five year survival rates for children diagnosed during 1980-84 were 70% and 64% for trial and non-trial patients, respectively; in 1990-94 the rates were 84% and 68% for trial and non-trial patients, respectively. CONCLUSIONS: Survival after ALL continues to improve. Nearly 50 children/year diagnosed during 1990-94 survived who would have died a decade before. Survival does not vary systematically with place of treatment but is higher for children entered into national trials. (+info)
Efficient retrovirus-mediated transfer of cell-cycle control genes to transformed cells.
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The use of gene therapy continues to be a promising, yet elusive, alternative for the treatment of cancer. The origins of cancer must be well understood so that the therapeutic gene can be chosen with the highest chance of successful tumor regression. The gene delivery system must be tailored for optimum transfer of the therapeutic gene to the target tissue. In order to accomplish this, we study models of G1 cell-cycle control in both normal and transformed cells in order to understand the reasons for uncontrolled cellular proliferation. We then use this information to choose the gene to be delivered to the cells. We have chosen to study p16, p21, p53 and pRb gene transfer using the pCL-retrovirus. Described here are some general concepts and specific results of our work that indicate continued hope for the development of genetically based cancer treatments. (+info)