[Pharmacotherapy for degenerative dementias]. / Pharmacothérapie des démences dégénératives.

Alzheimer disease is the most frequent type of dementia. The pathophysiology is now better understood and new drugs or therapeutic tools have been developed. Anticholinesterase and antiglutamatergic drugs are used for a few years but these drugs have a modest therapeutic efficacy, which is purely symptomatic. New drugs are in development, including neuroprotection and prevention. Taking into account the experience of these last years, several aspects have to be discussed or improved: ethical aspects, risk evaluation and cost of the treatments, biological markers of pre-symptomatic phase, well conducted clinical trials and comparative studies between different drugs, evaluation of the effective clinical results of the studies.

[Peripheral multineuritis pointing at systemic sarcoidosis]. / Multineuritis periférica reveladora de una sarcoidosis sistémica.

We report a patient with a peripheral neuropathy as the first symptom of sarcoidosis. The systemic illness was proved by the presence of typic granulomes in the bone marrow. The fact that sarcoidosis is the cause for the neuropathy is supported by the temporary relation and by the good response of all clinical picture to the corticosteroid therapy.Sarcoid neuropathy can rarely be the presenting feature of sarcoidosis.

Chronic treatment with certain antipsychotic drugs preserves upregulation of regulator of G-protein signalling 2 mRNA in rat striatum as opposed to c-fos mRNA.

Quantitative in situ hybridization on rat coronal brain sections with radiolabelled oligonucleotide probes was performed to investigate the effects of antipsychotic drugs on mRNA levels of regulator of G-protein signalling (RGS) 2 and c-fos. This study demonstrated a similar increase of RGS2 mRNA level in the striatum upon both a single and a 21-day treatment with either haloperidol (2 mg/kg) or risperidone (7.5 mg/kg) in contrast to clozapine (20 mg/kg). Otherwise, the acute c-fos mRNA induction in the striatum was abolished by 74 to 89% upon chronic treatment with either haloperidol or risperidone. In conclusion, the induction of RGS2 mRNA in the striatum, in contrast to the immediate early gene c-fos mRNA, is preserved upon chronic treatment with haloperidol and risperidone.

Modulation of the neuronal dopamine transporter activity by the metabotropic glutamate receptor mGluR5 in rat striatal synaptosomes through phosphorylation mediated processes.

There is considerable evidence that the activity of the neuronal dopamine transporter (DAT) is dynamically regulated and a putative implication of its phosphorylation in this process has been proposed. However, there is little information available regarding the nature of physiological stimuli that contribute to the endogenous control of the DAT function. Based on the close relationship between glutamatergic and dopaminergic systems in the striatum, we investigated the modulation of the DAT activity by metabotropic glutamate receptors (mGluRs). Short-term incubations of rat striatal synaptosomes with micromolar concentrations of the group I mGluR selective agonist (S)-3,5-dihydroxyphenylglycine were found to significantly decrease the DAT capacity and efficiency. This alteration was completely prevented by a highly selective mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). The effect of (S)-3,5-dihydroxyphenylglycine was also inhibited by staurosporine and by selective inhibitors of protein kinase C and calcium calmodulin-dependent protein kinase II. Co-application of okadaic acid prolonged the transient effect of the agonist, supporting a critical role for phosphorylation in the modulation of the DAT activity by mGluRs. In conclusion, we propose that striatal mGluR5 contribute to the control of the DAT activity through concomitant activation of both protein kinase C and calcium calmodulin-dependent protein kinase II.

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.

Increased dopamine uptake in striatal synaptosomes after treatment of rats with amantadine.

The aim of the present study was to investigate the effect of short- and long-term treatments with amantadine on the activity of the neuronal dopamine transporter (DAT) in the rat striatum. For this purpose, the [3H]dopamine uptake was measured in striatal synaptosomes prepared from rats treated for 2, 7 and 14 days with amantadine (40 mg/kg; i.p.). After 7 days of treatment, amantadine increased the apparent V(max) by 30% without modification of the apparent K(m) of dopamine uptake whereas no change in these parameters was observed after 2 and 14 days treatment. Binding assays conducted with [3H]GBR-12935 on membranes prepared from animals treated with amantadine revealed no difference in the density and the affinity of striatal DAT binding sites as compared to control. This indicates that the increased dopamine uptake was not reflecting a modification at the level of the DAT expression. The activity of the DAT is regulated by phosphorylation and one may propose that ionotropic glutamate receptors present on presynaptic terminals directly modulate this phosphorylation. An indirect mechanism would involve presynaptic dopamine receptors that control the activity of the DAT in response to the increased dopamine concentration in the synaptic cleft.

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.

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: 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.

Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]-ryanodine binding in rat striatum.

Dopamine nigrostriatal neurons are important for motor control and may contain a particularly dense population of ryanodine receptors involved in the control of dopamine release. To test this hypothesis, we used a classical model of unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine (6-OHDA) injection into the substantia nigra. Binding of [3H]-GBR 12935, used as a presynaptic marker since it labels specifically the dopamine uptake complex, was dramatically decreased by 83-100% in striatum homogenates after 6-OHDA lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The present data indicate that [3H]-ryanodine binding sites present in rat striatum are not preferentially localized in dopaminergic terminals.

Selective destruction of nigrostriatal dopaminergic neurons does not alter [3H]-ryanodine binding in rat striatum

Dopamine nigrostriatal neurons are important for motor control and may contain a particularly dense population of ryanodine receptors involved in the control of dopamine release. To test this hypothesis, we used a classical model of unilateral selective lesion of these neurons in rats based on 6-hydroxydopamine (6-OHDA) injection into the substantia nigra. Binding of [3H]-GBR 12935, used as a presynaptic marker since it labels specifically the dopamine uptake complex, was dramatically decreased by 83-100 percent in striatum homogenates after 6-OHDA lesion. On the contrary, no reduction of [3H]-ryanodine binding was observed. The present data indicate that [3H]-ryanodine binding sites present in rat striatum are not preferentially localized in dopaminergic terminals

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.

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.

Dopamine receptor-modulated [35S]GTPgammaS binding in striatum of 6-hydroxydopamine-lesioned rats.

The role of dopamine receptor-G protein coupling in the development of striatal dopamine receptor supersensitivity was studied in rats with a 6-hydroxydopamine (6-OHDA)-induced unilateral lesion of the nigrostriatal pathway. This coupling was assessed by the measurement of dopamine agonist-induced guanosine 5'-O-(gamma[35S]thio)triphosphate ([35S]GTP-gammaS) binding in striatal membranes, at different periods of time (1-5 weeks) following the microinjection of the neurotoxin. From the first to the fifth week following the lesion, basal and dopamine-stimulated [35S]GTPgammaS-specific binding were found to be enhanced in the denervated striata as compared to their control counterpart. D2 dopamine receptors were clearly demonstrated to be involved in this supersensitivity, as assessed by measuring N-propylnorapomorphine (NPA)-, quinpirole- and bromocriptine-induced [35S]GTPgammaS-specific binding. The involvement of D1 dopamine receptors was indirectly studied by the combination of dopamine with a saturating concentration of the selective and potent D2 antagonist domperidone. In these conditions, the remaining response to dopamine was also found to be significantly increased following the lesion. These results are consistent with the hypothesis that, in addition to D2 dopamine receptor upregulation, modulation of dopamine receptor-G protein interaction is involved in the hypersensitivity accompanying striatal dopamine depletion.

Assessment of striatal D1 and D2 dopamine receptor-G protein coupling by agonist-induced [35S]GTP gamma S binding.

The dopamine receptor-mediated modulation of guanosine 5'-O-(gamma-[35S]thio)triphosphate ([35S]GTP gamma S) binding has been characterized in rat striatal membranes. In optimized experimental conditions, the potency of dopamine was 4.47 microM [3.02-6.61 microM] and a maximal response representing 54.8 +/- 4.5% increase above basal level was observed. Data obtained with different agonists and antagonists clearly revealed that the most important fraction of this response was reflecting D2 receptor activation. Further analysis with specific antagonists also supported evidence for the involvement of D1 dopamine receptors. The potencies of compounds interacting with D1 and D2 receptors were deduced from [35S]GTP gamma S binding experiments and compared with their binding affinities for these receptors measured in similar experimental conditions. A good correlation between these parameters was observed, supporting the applicability of this technique for the study of dopamine receptors in the central nervous system.

Enhanced striatal dopamine D(2) receptor-induced [35S]GTPgammaS binding after haloperidol treatment.

Dopamine receptor-G protein coupling and dopamine D(2) receptor density were assessed in rats treated for 3 weeks with either haloperidol (2 mg/kg; i.p.) or vehicle. After 3 days of withdrawal, agonist-induced guanosine 5'-O-(gamma-[35S]thio)triphosphate ([35S]GTPgammaS) and [3H]spiperone binding were determined in striatal homogenates. Maximal [3H]spiperone binding was increased (24.8%, P<0.01) following haloperidol treatment. The efficacy of dopamine and the dopamine D(2) receptor agonist R(-)-10, 11-dihydroxy-N-n-propylnorapomorphine (NPA) to induce [35S]GTPgammaS binding were found to be increased by 24.1% (P<0.01) and 44.6% (P<0. 001), respectively. When measured in the presence of a saturating concentration of a dopamine D(2) receptor antagonist, the response to dopamine was not significantly affected by haloperidol treatment. In addition, the measurement of haloperidol-induced catalepsy confirmed that the efficient dopamine receptor blockade was followed by a progressive development of dopaminergic supersensitivity. Taken together, these results indicate that a functional pool of dopamine D(2) receptors is increased after prolonged haloperidol administration.

How epileptogenic are the recent antibiotics?

OBJECTIVE: To review the clinical and experimental data concerning the serious neurologic adverse events, and more particularly seizures, which could be related to the administration of recent antibiotics, with special reference to cephalosporins, monobactams, carbapenems, and fluoroquinolones. DATA SOURCES: We have searched in the MEDLINE database over the years 1966-1998 the pertinent publications dealing with antibiotics related neurotoxicity. We used the thesaurus function and the following key words: antibiotics, neurotoxicity, seizures. Additional references were found in the articles sorted by the MEDLINE search. DATA SYNTHESIS: Neurotoxic manifestations following antibiotics administration are infrequently encountered under usual conditions. Experimental studies are helpful to demonstrate that these compounds might interact with a major component of the neurotransmission, the gamma aminobutyric acid (GABA) receptor complex. Structure-toxicity relationships can be described. For the clinician, the recognition of some predisposing factors related either to the patient (age, previous central nervous system disorder ...) or to the drug metabolism (reduced renal clearance, drug interactions ...) may help to minimise the risk of adverse neurologic manifestations. Several factors have to be taken into account before assessing causality: delay from administration, evolution, origin of the adverse event (risk factors, other drugs, non pharmacological origin), possibility of rechallenge, confirmation by biological testing or in vitro experiments....

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.

Mechanisms of regulation of neurotensin receptors.

Since its discovery in 1973, the neuropeptide neurotensin has been demonstrated to be involved in the control of a broad variety of physiological activities in both the central nervous system and in the periphery. Pharmacological studies have shown that the biological effects elicited by neurotensin result from its specific binding to cell membrane neurotensin receptors that have been characterized in various tissue and in cell preparations. In addition, it is now well documented that most of these responses are subject to rapid desensitization. Such desensitization results in transient responses to sustained peptide applications, or to tachyphylaxis during successive stimulations in the same conditions. More recently, desensitization of neurotensin signalling was investigated at the cellular and molecular levels. In cultured cells, regulation at the second messenger level, receptor internalization, and receptor down-regulation processes have been reported. These are proposed to play a critical role in the control of cell responsiveness to neurotensin. This review aims to compile recent data on the different biochemical processes involved in the regulation of the neurotensin receptor and to discuss the physiological consequences of this regulation in vivo.