Life after sequencing.
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Genetic Therapy↗
Biomedical subjects
G Emilien
Publications and source records attributed to G Emilien.
Alzheimer disease: mouse models pave the way for therapeutic opportunities.
Research into the molecular mechanisms of Alzheimer disease (AD) continues to clarify important issues in aberrant protein processing while seeking to identify therapeutic targets. Mutations of genes on chromosomes 1, 14 (presenilins 1 and 2), and 21 (the amyloid-beta [Abeta] amyloid precursor protein [APP]) cause the familial forms of AD that often begin before age 65. An allelic polymorphism on chromosome 19 (apolipoprotein E ) affects the age of onset of the more common forms of sporadic AD. Multiple studies in transgenic mice provide strong evidence to support the view that Abeta amyloid formation is an early and critical pathogenic event: mice expressing pathogenic human APP mutations develop Abeta deposits; coexpression of mutant presenilin genes accelerates the rate of Abeta deposition; and apolipoprotein E plays a role in this process. Thus, the 3 established genetic causes or risk factors for AD affect Abeta deposition. The fact that elevation of the Abeta42/Abeta40 ratio (differing only in 2 amino acids in length) is also linked to amyloid deposition in the APP mice and is temporally linked to cognitive impairment suggests that Abeta42 may be a principal inducing factor of AD. The exact sequence of events is still unknown, but the transgenic models generated so far have shown their usefulness in clarifying this complex part of the pathology. The continuing progress in elucidation of the molecular pathogenesis of AD suggests a range of rational pharmacological interventions for this disorder. The most promising strategy involves the development of approaches to retard, halt, or prevent Abeta-mediated disease progression, and these can now be tested in transgenic animals.
Alzheimer Disease↗
Prospects for pharmacological intervention in Alzheimer disease.
Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Abeta deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Abeta drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.
Alzheimer Disease↗
Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. The Zaleplon Clinical Investigator Study Group.
Insomnia is a frequent complaint in the elderly population. Hypnotic agents, including benzodiazepines, with longer pharmacological half-lives have been associated with side effects, including residual sedation, memory impairment, and discontinuation effects. Zaleplon is a short-acting (elimination half-life of 1 hour), non-benzodiazepine hypnotic that acts on the benzodiazepine type 1 site of the gamma-aminobutyric acid type A (GABA(A)) receptor complex. The pharmacology and pharmacokinetics of Zaleplon suggest a safety profile that is improved over other hypnotics. The objective of this placebo-controlled study was to evaluate the efficacy and safety of Zaleplon (5 and 10 mg) in elderly (> or =65 years) outpatients with primary insomnia. This was a multicenter, double-blind, randomised, placebo-controlled 2-week outpatient study. Postsleep questionnaires were used to record subjective sleep variables: sleep latency, sleep duration, number of awakenings, and sleep quality. Zaleplon significantly reduced subjective sleep latency during both weeks of the study with both 5- and 10-mg doses. Subjective sleep quality was improved for significantly more patients treated with zaleplon 10 mg than those treated with placebo during both weeks of treatment. There was a weak indication of rebound insomnia after discontinuation of treatment with the 10-mg dose, but no significant difference in common treatment-emergent adverse events across treatment groups. Zaleplon is an effective and safe hypnotic for the treatment of insomnia in the elderly.
Acetamides↗
The dose-response relationship in phase I clinical trials and beyond: use, meaning, and assessment.
Knowledge of the relationships among dose, drug concentration in blood, and clinical response is important for the safe and effective use of drugs in individual patients. Recently, pharmacokinetic-pharmacodynamic modeling has been taking an increasingly important place in clinical pharmacology because of its role in the determination of the optimal dosage of a new drug. Its primary objective is also to identify the characterization and prediction of the time course of drug effects under physiological and pathological conditions. Dose-response studies are useful in Phase I for assessing drug tolerance and safety, and invaluable in Phase II for characterizing drug efficacy. Apart from the confirmation of efficacy, the acquired information may help to investigate the shape and location of the dose-response curve, the choice of an appropriate therapeutic starting dose, the identification of optimal strategies for individual dose adjustments, and the determination of a maximal dose beyond which additional benefit is unlikely to be obtained. Recent development of pharmacodynamic models such as the mechanism-based indirect effect model may permit the identification of the physiological component of drug action that is affected by disease, other medications, gender, and other variables. Assessment of dose response should be an integral component of drug development, with studies designed to assess dose response an inherent part of establishing the safety and efficacy of the drug. Drug development can be enhanced with a good understanding of dose-response characteristics and ultimately the benefit/risk ratio of a drug.
Animals↗
Haemophilias: advances towards genetic engineering replacement therapy.
Both haemophilia A and B are X-linked recessive disorders and therefore occur almost exclusively in males. The genes for both factors VIII and IX have been mapped to the distal end of the long arm of the X chromosome, bands Xq28 and Xq27.1, respectively. The Factor VIII gene comprises 186 kb DNA with 9 kb of exon of DNA which encodes an mRNA of nearly 9 kb. The Factor IX gene is 34 kb in length and the essential genetic information is present in eight exons which encode 1.6 kb mRNA. In gene therapy, genetic modification of the target cells can be either ex vivo or in vivo. The advantage of the ex vivo approach is that the genetic modification is strictly limited to the isolated cells. In the in vivo approach, the integrity of the target tissue is maintained but the major challenge is to deliver the gene to the target tissue. The use of improved retroviral and adenovirus-based vectors for gene therapy has produced clinically relevant levels of human factor VIII in mice and haemophilic dogs. If further improvements can increase the persistence of expression and decrease the immunological responses, phase I clinical trials in patients can be considered.
Animals↗
Impact of genomics on drug discovery and clinical medicine.
Genomics, particularly high-throughput sequencing and characterization of expressed human genes, has created new opportunities for drug discovery. Knowledge of all the human genes and their functions may allow effective preventive measures, and change drug research strategy and drug discovery development processes. Pharmacogenomics is the application of genomic technologies such as gene sequencing, statistical genetics, and gene expression analysis to drugs in clinical development and on the market. It applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism, or disease pathways. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to genetic and specific individual markers, selecting medications and dosages that are optimized for individual patients. The possibility of defining patient populations genetically may improve outcomes by predicting individual responses to drugs, and could improve safety and efficacy in therapeutic areas such as neuropsychiatry, cardiovascular medicine, endocrinology (diabetes and obesity) and oncology. Ethical questions need to be addressed and guidelines established for the use of genomics in clinical research and clinical medicine. Significant achievements are possible with an interdisciplinary approach that includes genetic, technological and therapeutic measures.
Alzheimer Disease↗
Pharmacological management of diabetes: recent progress and future perspective in daily drug treatment.
Glycaemic control in Type 1 diabetes has been proven efficient in preventing microvascular and neurological complications. The assumption that good control of hyperglycaemia may also have significant impact on alleviation of complications in Type 2 diabetes has gained growing support in recent years. Measures such as body weight reduction and exercise improve the metabolic defects, but pharmacological therapy is most frequently used. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase glucose disposal and decrease hepatic glucose output without causing hypoglycaemia. Acarbose helps to spread the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological treatments can improve blood glucose regulation in Type 2 diabetes patients. However, the key to strict glycaemic control with use of exogenous insulin lies in the creation of delivery methods that emulate physiologic insulin secretion. Insulin lispro, a recombinant insulin analogue, is identical to human insulin except for the transposition of proline and lysine at positions 28 and 29 in the C-terminus of the B chain. Evidence suggests that patients perceive their quality of life to be improved with insulin lispro when compared with regular human insulin, and that satisfaction with treatment is greater with the insulin analogue. Numerous new pharmacological approaches are under active investigation, with the aim of promoting insulin secretion, improving the action of insulin, or slowing carbohydrate absorption. With respect to continuous subcutaneous insulin infusion therapy and implantable pumps, despite that this approach is not widely utilised, it appears to bring us as close to achieving glycaemic control as is feasible with current treatment approaches. However, general application of such technology requires significant improvements in several areas, such as improvement of patency of catheter, pump failures due to early battery depletion incidents, and pump miniaturisation. Future perspective resides on insulin analogues with longer half-lives that would provide better basal insulin coverage in association with fast-acting analogues.
Diabetes Mellitus↗
Dopamine receptors--physiological understanding to therapeutic intervention potential.
There are two families of dopamine (DA) receptors, called D1 and D2, respectively. The D1 family consists of D1- and D5-receptor subtypes and the D2 family consists of D2-, D3-, and D4-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a large superfamily of receptors with seven transmembrane domains, which are coupled to their intracellular signal transduction systems by G-proteins. The implications of DA receptors in neuropsychiatry and cardiovascular and renal diseases are discussed. Neuropsychiatry indications include Parkinson's disease, schizophrenia, migraine, drug dependence, mania and depression, and Gilles de la Tourette syndrome. The underlying dysfunction of dopaminergic systems and the potential benefits of dopaminergic therapy in these different indications are critically examined. With respect to the pharmacological treatment of Parkinson's disease, a range of DA agonists are in various stages of preclinical and clinical development. D2-receptor agonist activity is predominant in most effective antiparkinsonian DA agonists. However, in practice, it is difficult to treat patients for several years with DA agonists alone; therapeutic benefit is not sustained. Rather, the use of a combination of DA agonists and levodopa is considered preferable. Reports of the efficacy of DA partial agonists await confirmation, and recent clinical investigations also suggest the potential of D1 receptor agonists as antiparkinson drugs. Regarding migraine pathogenesis, clinical and pharmacological evidence suggests that DA is involved in this disorder. Most prodromal and accompanying symptoms may be related to dopaminergic activation. Several drugs acting on DA receptors are effective in migraine treatment. Furthermore, migraine patients show a higher incidence of dopaminergic symptoms following acute DA agonist administration, when compared with normal controls. In cardiology, the therapeutic benefits of DA agonists are noted in the treatment of heart failure. Low doses of DA are widely used for its specific dopaminergic effects on renal function, which are suggested to be beneficial, and for its alpha- and beta-adrenergic-mediated responses that occur with higher doses. However, studies have been unable to demonstrate that DA can prevent acute renal failure or reduce mortality. It appears that the significant progress that is being made in the molecular understanding of DA receptors will continue to have a tremendous impact in the pharmacological treatment of neuropsychiatric, cardiovascular, and renal diseases.
Animals↗
Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. Zaleplon Clinical Study Group.
BACKGROUND: Zaleplon is a short-acting pyrazolopyrimidine hypnotic with a rapid onset of action. This multicenter study compared the efficacy and safety of 3 doses of zaleplon with those of placebo in outpatients with DSM-III-R insomnia. Zolpidem, 10 mg, was used as an active comparator. METHOD: After a 7-night placebo (baseline) period, 615 adult patients were randomly assigned to receive, in double-blind fashion, I of 5 treatments (zaleplon, 5, 10, or 20 mg; zolpidem, 10 mg; or placebo) for 28 nights, followed by placebo treatment for 3 nights. Sleep latency, sleep maintenance, and sleep quality were determined from sleep questionnaires that patients completed each morning. The occurrence of rebound insomnia and withdrawal effects on discontinuation of treatment was also assessed. All levels of significance were p < or = .05. RESULTS: Median sleep latency was significantly lower with zaleplon, 10 and 20 mg, than with placebo during all 4 weeks of treatment and with zaleplon, 5 mg, for the first 3 weeks. Zaleplon, 20 mg, also significantly increased sleep duration compared with placebo in all but week 3 of the study. There was no evidence of rebound insomnia or withdrawal symptoms after discontinuation of 4 weeks of zaleplon treatment. Zolpidem, 10 mg, significantly decreased sleep latency, increased sleep duration, and improved sleep quality at most timepoints compared with placebo; however, after discontinuation of zolpidem treatment, the incidence of withdrawal symptoms was significantly greater than that with placebo and there was an indication of significant rebound insomnia for some patients in the zolpidem group compared with those in the placebo group. The frequency of adverse events in the active treatment groups did not differ significantly from that in the placebo group. CONCLUSION: Zaleplon is effective in the treatment of insomnia. In addition, zaleplon appears to provide a favorable safety profile, as indicated by the absence of rebound insomnia and withdrawal symptoms once treatment was discontinued.
Acetamides↗
Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists.
Beta-adrenoceptors are members of a large family of hormone and neurotransmitter receptors that initiate their biological function by coupling to GTP-binding regulatory proteins. beta-Adrenoceptors can be subdivided into two main subgroups, designated beta1 and beta2. Atypical beta-adrenoceptors or beta3-adrenoceptors, which are present on adipocytes, have been demonstrated pharmacologically. Their function in adipose tissue is currently being investigated. Beta2-adrenoceptor agonists have played a key role in the treatment of asthma for some 30 years, being used for the relief and prophylaxis of symptoms. There is, however, no evidence that tolerance to the bronchodilator or anti-bronchoconstrictor effects of these drugs is responsible for the deleterious effects reported with the regular use of bronchodilators. In neuropsychiatry, beta-adrenoceptor antagonists have been used for the treatment of acute stress reactions and generalised anxiety, essential tremor and prophylaxis of migraine. In general, they are effective in anxiety disorders if the somatic symptoms are not extreme. For prophylactic treatment of migraine, beta-adrenoceptor antagonists such as propranolol, metoprolol, nadolol and atenolol are the drugs of first choice. In cardiology, beta-adrenoceptor antagonists are an important class for the treatment of high blood pressure, arrhythmias and angina pectoris, and for prevention of myocardial infarction. With chronic treatment, they reduce mortality in hypertension and prolong survival in patients with coronary heart disease.
Adrenergic beta-Agonists↗
Pharmacological management of epilepsy. Mechanism of action, pharmacokinetic drug interactions, and new drug discovery possibilities.
Despite recent advances in neurobiology and significant insight into the molecular dysfunction of epilepsy, about 25% of patients do not completely respond to current frontline therapeutic agents such as carbamazepine, phenytoin, valproic acid, ethosuximide, phenobarbital, and benzodiazepine. Recently, much effort has been made to discover new antiepileptic drugs effective in refractory seizures. Two major groups of drugs have emerged of which felbamate, gabapentin, lamotrigine, oxcarbazepine, and vigabatrin are among the most promising. The mechanism of action of the first group works by enhancing brain GABA activity (e.g. vigabatrin) while the second group inhibits excitatory amino acids (e.g. lamotrigine and felbamate). Oxcarbazepine acts in a similar manner to carbamazepine while gabapentin's mode of action is still unclear. The major clinical indications of these new antiepileptics are partial complex seizures. They exhibit limited drug interactions with few adverse effects. A rational approach to the drug discovery process is necessary in order to lead to novel effective therapy. Another line of research is the use of the structure-activity relationship to fine-tune the pharmacology of existing antiepileptics providing less adverse effects with the same or better efficacy. Clinical perspectives from the discovery of new drugs such as fosphenytoin and valproyl glycinamide look promising. Rapid development in molecular biologic techniques for the study of the neurophysiology of epilepsy and the neurotransmitters which are the target for the antiepileptic drugs may also provide better insight into the interactions of antiepileptics with either ion channels or brain receptors.
Animals↗
Lithium compared to valproic acid and carbamazepine in the treatment of mania: a statistical meta-analysis.
The hypothesis that lithium is the most appropriate and efficacious pharmacological treatment in the therapy of manic-depressive illness was examined in a meta-analysis. The efficacy of lithium was compared with that of the antiepileptics, carbamazepine and valproic acid. Data sources include the Medline database and relevant references from articles. Only randomised controlled clinical trials with a double-blind assessment of outcomes were included. Lithium levels were required to be within the therapeutic range of 0.4-1.5 mmol/l. The effect sizes were measured by the odds ratio using the Mantel-Haenszel method. No significant difference was observed between the treatment effect of the 3 drugs compared. While the efficacy of the 3 treatments was identical, there is a general tendency in favour of the antiepileptics in the treatment of manic depression with regard to adverse events and treatment tolerance. The impact and importance of this study seriously question the relevance of today's practice of prescribing lithium in the acute management of manic-depressive illness.
Bipolar Disorder↗
Traumatic brain injury, cognitive and emotional dysfunction. Impact of clinical neuropsychology research.
It is well established that head injury often causes brain damage leading to long term physical, cognitive and behavioural changes in the injured patients. Whereas the physical effects ranging from sensori-motor disturbances to posttraumatic epilepsy are often reported as well as cognitive sequelae, deteriorations of emotional and behavioural aspects are often neglected. Recent advances in imaging technology and clinical neuropsychology research have greatly contributed to increase our understanding of the effect of traumatic brain injury on diverse behavioural functions. After a brief review of the current status of problems facing the brain injured patients, this paper discusses the neuropsychological aspects of 3 long term brain injured patients. All 3 patients showed important behavioural and emotional distress several years after the accident. Whereas case report of patient A and C discuss the emotional and personality disturbance characterised by anxiety, depression and irritability, case report of patient C which is a case of classic frontal syndrome showed important memory impairment with emotional disturbance characterised by apathy, lack of motivation and complete indifference to his surrounding environment. Whatever the mechanisms involved, psychoaffective disturbances in the brain injured patients appear as important problems in the long term. These emotional difficulties must be considered in the treatment and rehabilitation procedures of these victims in order to help them to improve their social adjustment and quality of life aspects. Neuropsychological test data can be used to develop treatment strategies tailored for an individual's specific cognitive strengths and deficits.
Adult↗
Lithium neurotoxicity at low therapeutic doses Hypotheses for causes and mechanism of action following a retrospective analysis of published case reports.
Lithium has been the pharmacologic treatment for the management of manic-depressive illness for many years. While the therapeutic efficacy of lithium is invaluable, it can cause a variety of neurotoxicities at normal therapeutic doses or concentrations. A systematic search through the Medline database was performed. 41 Cases of neurotoxic adverse effects of lithium at low therapeutic concentrations were observed (< 65 years, 14 males & 21 females/> 65 years, 6 females). Although a higher percentage of female subjects experienced lithium neurotoxicity, no statistically significant difference between the two groups was noted (Fisher's exact test, P = 0.07). The analysis of the data shows that among case reports of lithium neurotoxicity, drug interaction effect is an important factor. More than 50% (51.2%) of the patients received at least one neuroleptic medication with their lithium treatment, 22% received concomitantly an antidepressant, 22% an antiepileptic (carbamazepine) and 17% an anxiolytic. It is our hypothesis that these drug associations are an important contributing factor to lithium neurotoxicity. The high percentage of neurotoxicity which is associated with neuroleptics warrant caution in the daily clinical practice when these two classes of medications are combined. It is hypothesised that neuroleptics, in particular the phenothiazines, might increase lithium influx in red blood cells and that the enhanced levels of lithium in the tissue may possibly be responsible for the neurotoxic effects. Concomitant administration of medications such as neuroleptics with lithium require caution with regular clinical observations and drug plasma concentration monitoring.
Adult↗
Effect of drugs acting on monoaminergic and cholinergic systems on the quantified EEG of rats.
Five different classes of drugs (clonidine: 0, 0.10, 0.30, 0.50 mg/kg; yohimbine: 0, 2, 4, 8 mg/kg; haloperidol: 0, 0.02, 0.04, 0.08 mg/kg; piracetam: 0, 150, 300, 600 mg/kg, and eserine: 0, 0.10, 0.30, 0.50 mg/kg) were studied on two cortical EEG derivations as well as a deep structure, the locus ceruleus in the rats. Each drug affected the EEG in its own particular manner. Clonidine significantly decreased frequency in the theta band (3.7-7.5 Hz) and increased it in the alpha band (7.6-13.5 Hz). A general significant increase in power was observed. Yohimbine's effects on the EEG varied according to the regions studied. There were significant modifications of power and frequency in the theta, alpha and beta bands in the three derivations studied. Notable effects of haloperidol were observed as an increase in power in all frequency bands at all doses administered particularly in the anteroparietal and posteroparietal derivations. In the locus ceruleus derivation, power was significantly increased at all doses only in the alpha and beta frequency bands. Concerning piracetam, while no significant effects were noted on the EEG frequency, this drug significantly increased EEG power in the posteroparietal and anteroparietal derivations. The most important effects are obtained at the lowest dose (150 mg/kg) administered. Finally, it was shown that eserine significantly decreased power in the delta bandwidth shortly after its administration. Afterwards, the power gradually regained its original level.
Animals↗
Future European health care: cost containment, health care reform and scientific progress in drug research.
The cost of the development of a new pharmaceutical product from its conception and synthesis through to the regulatory approval process has more than quadrupled in the last 20 years. Both clinical and total development times have increased substantially. To amortize the costs incurred, the pharmaceutical industry has taken an international dimension. The incentives for pharmaceutical firms to discover and develop new drugs depend on the length of the development and regulatory review process plus the potential market size. Recent regulatory, economic and political changes may have significant implications for the future of new drug developments in Europe. The European Union industrial policy felt that there is a need for convergence in the area of pricing. It is recommended that the policy should aim to contain growth in pharmaceutical expenses by means specific to reimbursement rather than direct price controls. By encouraging doctors to prescribe and customers to use generics, competition is enhanced to bring down drug prices. More emphasis is being laid by government in educating customers to cost-awareness and cost-benefit ratios with regard to pharmaceuticals. Concerning clinical trials, European harmonization has been achieved by significant developments: the rights and integrity of the trial subjects are protected; the credibility of the data is established; and the ethical, scientific and technical quality of the trials has improved. Future European health care forecasts a whole change in the pharmaceutical business. Important issues in cost and outcome measurement should be carefully planned and considered in drug development. Due to important mergers and acquisitions, the pharmaceutical sector will consist mainly of important multinational corporations. In this way, valuable new products may be brought to the market.
Cost Control↗
Effects of clonidine, yohimbine and eserine on the quantified EEG of rats.
The effects of three different classes of drugs were analyzed on the EEG of rats on two cortical derivations (parieto-occipital and fronto-occipital) and one deep structure, the locus coeruleus. Clonidine, an alpha 2-agonist (0, 0.10, 0.30 and 0.50 mg/kg, i.p.), yohimbine, an alpha 2-antagonist (0, 2, 4 and 8 mg/kg, i.p.) and eserine, an anticholinesterase (0, 0.10, 0.30 and 0.50 mg/kg, i.p.), affected the EEG in different significant ways. Clonidine significantly decreased frequency in the theta-band (3.7-7.5 Hz) and increased it in the alpha-band (7.6-13.5 Hz). A general significant increase in power was also observed. For yohimbine, there was a significant dose-dependent increase of power, particularly in the theta-, alpha- and beta-bandwidth. Moreover, its effects on EEG varied in accordance to the derivations analyzed. Finally, eserine significantly decreased power in the high frequency bandwidths. A synchronization, as a function of dose, with a peak at 5-6 Hz was observed shortly after its administration. The results are discussed in terms of the potentiality of the technique of quantitative pharmaco-electro-encephalography and drug interaction studies in the analysis of psychoactive substances.
Animals↗