968 resultados para Pharmacology
Resumo:
La diminution des doses administres ou mme la cessation complte d'un traitement chimiothrapeutique est souvent la consquence de la rduction du nombre de neutrophiles, qui sont les globules blancs les plus frquents dans le sang. Cette rduction dans le nombre absolu des neutrophiles, aussi connue sous le nom de mylosuppression, est prcipite par les effets ltaux non spcifiques des mdicaments anti-cancreux, qui, paralllement leur effet thrapeutique, produisent aussi des effets toxiques sur les cellules saines. Dans le but d'attnuer cet impact mylosuppresseur, on administre aux patients un facteur de stimulation des colonies de granulocytes recombinant humain (rhG-CSF), une forme exogne du G-CSF, l'hormone responsable de la stimulation de la production des neutrophiles et de leurs libration dans la circulation sanguine. Bien que les bienfaits d'un traitement prophylactique avec le G-CSF pendant la chimiothrapie soient bien tablis, les protocoles d'administration demeurent mal dfinis et sont frquemment dtermins ad libitum par les cliniciens. Avec l'optique d'amliorer le dosage thrapeutique et rationaliser l'utilisation du rhG-CSF pendant le traitement chimiothrapeutique, nous avons dvelopp un modle physiologique du processus de granulopose, qui incorpore les connaissances actuelles de pointe relatives la production des neutrophiles des cellules souches hmatopotiques dans la moelle osseuse. ce modle physiologique, nous avons intgr des modles pharmacocintiques/pharmacodynamiques (PK/PD) de deux mdicaments: le PM00104 (Zalypsis), un mdicament anti-cancreux, et le rhG-CSF (filgrastim). En se servant des principes fondamentaux sous-jacents la physiologie, nous avons estim les paramtres de manire exhaustive sans devoir recourir l'ajustement des donnes, ce qui nous a permis de prdire des donnes cliniques provenant de 172 patients soumis au protocol CHOP14 (6 cycles de chimiothrapie avec une priode de 14 jours o l'administration du rhG-CSF se fait du jour 4 au jour 13 post-chimiothrapie). En utilisant ce modle physio-PK/PD, nous avons dmontr que le nombre d'administrations du rhG-CSF pourrait tre rduit de dix (pratique actuelle) quatre ou mme trois administrations, condition de retarder le dbut du traitement prophylactique par le rhG-CSF. Dans un souci d'applicabilit clinique de notre approche de modlisation, nous avons investigu l'impact de la variabilit PK prsente dans une population de patients, sur les prdictions du modle, en intgrant des modles PK de population (Pop-PK) des deux mdicaments. En considrant des cohortes de 500 patients in silico pour chacun des cinq scnarios de variabilit plausibles et en utilisant trois marqueurs cliniques, soient le temps au nadir des neutrophiles, la valeur du nadir, ainsi que l'aire sous la courbe concentration-effet, nous avons tabli qu'il n'y avait aucune diffrence significative dans les prdictions du modle entre le patient-type et la population. Ceci dmontre la robustesse de l'approche que nous avons dveloppe et qui s'apparente une approche de pharmacologie quantitative des systmes (QSP). Motivs par l'utilisation du rhG-CSF dans le traitement d'autres maladies, comme des pathologies priodiques telles que la neutropnie cyclique, nous avons ensuite soumis l'tude du modle au contexte des maladies dynamiques. En mettant en vidence la non validit du paradigme de la rtroaction des cytokines pour l'administration exogne des mimtiques du G-CSF, nous avons dvelopp un modle physiologique PK/PD novateur comprenant les concentrations libres et lies du G-CSF. Ce nouveau modle PK a aussi ncessit des changements dans le modle PD puisquil nous a permis de retracer les concentrations du G-CSF li aux neutrophiles. Nous avons dmontr que l'hypothse sous-jacente de l'quilibre entre la concentration libre et lie, selon la loi d'action de masse, n'est plus valide pour le G-CSF aux concentrations endognes et mnerait en fait la surestimation de la clairance rnale du mdicament. En procdant ainsi, nous avons russi reproduire des donnes cliniques obtenues dans diverses conditions (l'administration exogne du G-CSF, l'administration du PM00104, CHOP14). Nous avons aussi fourni une explication logique des mcanismes responsables de la rponse physiologique aux deux mdicaments. Finalement, afin de mettre en exergue lapproche intgrative en pharmacologie adopte dans cette thse, nous avons dmontr sa valeur inestimable pour la mise en lumire et la reconstruction des systmes vivants complexes, en faisant le parallle avec dautres disciplines scientifiques telles que la palontologie et la forensique, o une approche semblable a largement fait ses preuves. Nous avons aussi discut du potentiel de la pharmacologie quantitative des systmes appliques au dveloppement du mdicament et la mdecine translationnelle, en se servant du modle physio-PK/PD que nous avons mis au point.
Resumo:
G protein-coupled receptors (GPCRs) are seven-pass integral membrane proteins that act as transducers of extracellular signals across the lipid bilayer. Their location and involvement in basic and pathological physiological processes has secured their role as key targets for pharmaceutical intervention. GPCRs are targeted by many of the best-selling drugs on the market and there are a substantial number of GPCRs that are yet to be characterised; these could offer interest for therapeutic targeting. GPR35 is one such receptor that, as a result of gene knockout and genome wide association studies, has attracted interest through its association with cardiovascular and gastrointestinal disease. Elucidation of the basic physiological function of GPR35 has, however, been difficult due a paucity of potent and selective ligands in addition to a lack of consensus on the endogenous ligand. Herein, a focussed drug discovery effort was carried out to identify agonists of GPR35. Various in vitro cellular assays were employed in conjunction with N- or C-terminally manipulated forms of the receptor to investigate GPR35s signalling profile and to provide an assay format suitable for the characterisation of newly identified ligands. Although GPR35 associates with both Gi/o and G13 families of small heterotrimeric G proteins, the G protein-independent -arrestin-2 recruitment format was found to be the most suited to drug screening efforts. Small molecule compound screening, carried out in conjunction with the Medical Research Council Technology, identified compound 1 as the most potent ligand of human GPR35 reported at that time. However, the lower efficacy and potency of compound 1 at the rodent species orthologues of GPR35 prevented its use in in vivo studies. A subsequent effort, carried out with Novartis, focused on mast cell stabilisers as putative agonists of GPR35, revealed lodoxamide and bufrolin as highly potent agonists that activated human and rat GPR35 with equal potency. This finding offeredfor the first timethe opportunity to employ the same GPR35 ligand between species at a similar concentration, an important factor to consider when translating rodent in vivo functional studies to those in man. Additionally, using molecular modelling and site directed mutagenesis studies, these newly identified compounds were used to aid characterisation of the ligand binding pockets of human and rat GPR35 to reveal the molecular basis of species selectivity at this receptor. In summary, this research effort presents GPR35 tool compounds that can now be used to dissect the basic biology of GPR35 and investigate its contribution to disease.
Resumo:
La diminution des doses administres ou mme la cessation complte d'un traitement chimiothrapeutique est souvent la consquence de la rduction du nombre de neutrophiles, qui sont les globules blancs les plus frquents dans le sang. Cette rduction dans le nombre absolu des neutrophiles, aussi connue sous le nom de mylosuppression, est prcipite par les effets ltaux non spcifiques des mdicaments anti-cancreux, qui, paralllement leur effet thrapeutique, produisent aussi des effets toxiques sur les cellules saines. Dans le but d'attnuer cet impact mylosuppresseur, on administre aux patients un facteur de stimulation des colonies de granulocytes recombinant humain (rhG-CSF), une forme exogne du G-CSF, l'hormone responsable de la stimulation de la production des neutrophiles et de leurs libration dans la circulation sanguine. Bien que les bienfaits d'un traitement prophylactique avec le G-CSF pendant la chimiothrapie soient bien tablis, les protocoles d'administration demeurent mal dfinis et sont frquemment dtermins ad libitum par les cliniciens. Avec l'optique d'amliorer le dosage thrapeutique et rationaliser l'utilisation du rhG-CSF pendant le traitement chimiothrapeutique, nous avons dvelopp un modle physiologique du processus de granulopose, qui incorpore les connaissances actuelles de pointe relatives la production des neutrophiles des cellules souches hmatopotiques dans la moelle osseuse. ce modle physiologique, nous avons intgr des modles pharmacocintiques/pharmacodynamiques (PK/PD) de deux mdicaments: le PM00104 (Zalypsis), un mdicament anti-cancreux, et le rhG-CSF (filgrastim). En se servant des principes fondamentaux sous-jacents la physiologie, nous avons estim les paramtres de manire exhaustive sans devoir recourir l'ajustement des donnes, ce qui nous a permis de prdire des donnes cliniques provenant de 172 patients soumis au protocol CHOP14 (6 cycles de chimiothrapie avec une priode de 14 jours o l'administration du rhG-CSF se fait du jour 4 au jour 13 post-chimiothrapie). En utilisant ce modle physio-PK/PD, nous avons dmontr que le nombre d'administrations du rhG-CSF pourrait tre rduit de dix (pratique actuelle) quatre ou mme trois administrations, condition de retarder le dbut du traitement prophylactique par le rhG-CSF. Dans un souci d'applicabilit clinique de notre approche de modlisation, nous avons investigu l'impact de la variabilit PK prsente dans une population de patients, sur les prdictions du modle, en intgrant des modles PK de population (Pop-PK) des deux mdicaments. En considrant des cohortes de 500 patients in silico pour chacun des cinq scnarios de variabilit plausibles et en utilisant trois marqueurs cliniques, soient le temps au nadir des neutrophiles, la valeur du nadir, ainsi que l'aire sous la courbe concentration-effet, nous avons tabli qu'il n'y avait aucune diffrence significative dans les prdictions du modle entre le patient-type et la population. Ceci dmontre la robustesse de l'approche que nous avons dveloppe et qui s'apparente une approche de pharmacologie quantitative des systmes (QSP). Motivs par l'utilisation du rhG-CSF dans le traitement d'autres maladies, comme des pathologies priodiques telles que la neutropnie cyclique, nous avons ensuite soumis l'tude du modle au contexte des maladies dynamiques. En mettant en vidence la non validit du paradigme de la rtroaction des cytokines pour l'administration exogne des mimtiques du G-CSF, nous avons dvelopp un modle physiologique PK/PD novateur comprenant les concentrations libres et lies du G-CSF. Ce nouveau modle PK a aussi ncessit des changements dans le modle PD puisquil nous a permis de retracer les concentrations du G-CSF li aux neutrophiles. Nous avons dmontr que l'hypothse sous-jacente de l'quilibre entre la concentration libre et lie, selon la loi d'action de masse, n'est plus valide pour le G-CSF aux concentrations endognes et mnerait en fait la surestimation de la clairance rnale du mdicament. En procdant ainsi, nous avons russi reproduire des donnes cliniques obtenues dans diverses conditions (l'administration exogne du G-CSF, l'administration du PM00104, CHOP14). Nous avons aussi fourni une explication logique des mcanismes responsables de la rponse physiologique aux deux mdicaments. Finalement, afin de mettre en exergue lapproche intgrative en pharmacologie adopte dans cette thse, nous avons dmontr sa valeur inestimable pour la mise en lumire et la reconstruction des systmes vivants complexes, en faisant le parallle avec dautres disciplines scientifiques telles que la palontologie et la forensique, o une approche semblable a largement fait ses preuves. Nous avons aussi discut du potentiel de la pharmacologie quantitative des systmes appliques au dveloppement du mdicament et la mdecine translationnelle, en se servant du modle physio-PK/PD que nous avons mis au point.
Resumo:
Objective Structured Clinical Examinations (OSCE) improved communication skills of student of Pharmacology in Medicine and Podiatry degree. Bellido I, Blanco E, Gomez-Luque A. D. Pharmacology and Clinical Therapeutic. Medicine School. University of Malaga. IBIMA. Malaga, Spain. Objective Structured Clinical Examinations (OSCEs) are versatile multipurpose evaluative tools that can be utilized to assess health care professionals in a clinical setting including communication skills and ability to handle unpredictable patient behavior, which usually are not included in the traditional clinical exam. To designee and perform OSCEs by student is a novelty that really like to the students and may improve their arguing and planning capacities and their communication skills. Aim: To evaluate the impact of designing, developing and presenting Objective Structured Clinical Examinations (OSCE) by student in the communication skills development and in the learning of medicines in Medicine and Podiatry undergraduate students. Methods: A one-year study in which students were invited to voluntarily form groups (4 students maximum). Each group has to design and perform an OSCE (10 min maximum) showing a clinical situation/problem in which medicines use was needed. A clinical history, camera, a mobile-phone's video editor, photos, actors, dolls, simulators or whatever they may use was allowed. The job of each group was supervised and helped by a teacher. The students were invited to present their work to the rest of the class. After each OSCE performance the students were encouraged to ask questions if they wanted to do it. After all the OSCEs performances the students voluntarily answered a satisfaction survey. Results: Students of Pharmacology of Medicine degree and Podiatry degree, N=80, 53.75% female, 212.3 years old were enrolled. 26 OSCEs showing a clinical situation or clinical problem were made. The average time spent by students in making the OSCE was 21.59 h. The percentage of students which were satisfied with this way of presentation of the OSCE was 89.7%. Conclusion: Objective Structured Clinical Examinations (OSCE) designed and performed by student of Pharmacology of the Medicine and Podiatry Degree improved their communication skills.
Resumo:
Single nucleotide polymorphisms (SNPs) are unique genetic differences between individuals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of samples for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable individualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.
Resumo:
Heparan sulfate mimetics, which we have called the PG500 series, have been developed to target the inhibition of both angiogenesis and heparanase activity. This series extends the technology underpinning PI-88, a mixture of highly sulfated oligosaccharides which reached Phase III clinical development for hepatocellular carcinoma. Advances in the chemistry of the PG500 series provide numerous advantages over PI-88. These new compounds are fully sulfated, single entity oligosaccharides attached to a lipophilic moiety, which have been optimized for drug development. The rational design of these compounds has led to vast improvements in potency compared to PI-88, based on in vitro angiogenesis assays and in vivo tumor models. Based on these and other data, PG545 has been selected as the lead clinical candidate for oncology and is currently undergoing formal preclinical development as a novel treatment for advanced cancer.
Resumo:
Methamphetamine (MA) use is associated with hostility, aggression, and positive psychotic symptoms. However, little is known of the processes or mechanisms that underlie this relationship. The present research was designed to investigate putative mediating and moderating variables between MA dependence and hostility in a sample of injecting MA users (N=237). Both positive symptoms of psychosis and higher levels of impulsivity functioned as mediators and moderators of this relationship. This pattern of findings suggests that MA use leads to greater hostility by increasing positive psychotic symptoms that contribute to a perception of the environment as a hostile and threatening place as well as by increasing impulsivity. Those who were high in positive symptoms and high in impulsivity were the most hostile. Individual differences in impulsivity and positive psychotic symptoms should be taken into account in the assessment and management of MA dependence.
Ghrelin gene-related peptides : multifunctional endocrine/autocrine modulators in health and disease
Resumo:
Ghrelin is a multi-functional peptide hormone which affects various processes including growth hormone and insulin release, appetite regulation, gut motility, metabolism and cancer cell proliferation. Ghrelin is produced in the stomach and in other normal and pathological cell types. It may act as an endocrine or autocrine/paracrine factor. The ghrelin gene encodes a precursor protein, preproghrelin, from which ghrelin and other potentially active peptides are derived by alternative mRNA splicing and/or proteolytic processing. The metabolic role of the peptide obestatin, derived from the preproghrelin C-terminal region, is controversial. However, it has direct effects on cancer cell proliferation. The regulation of ghrelin expression and the mechanisms through which the peptide products arise are unclear. We have recently re-examined the organisation of the ghrelin gene and identified several novel exons and transcripts. One transcript, which lacks the ghrelin-coding region of preproghrelin, contains the coding sequence of obestatin. Furthermore, we have identified an overlapping gene on the antisense strand of ghrelin, GHRLOS, which generates transcripts that may function as non-coding regulatory RNAs or code for novel, short bioactive peptides. The identification of these novel ghrelin-gene related transcripts and peptides raises critical questions regarding their physiological function and their role in obesity, diabetes and cancer.
Resumo:
Rationale: Piper methysticum (Kava) has been withdrawn in European, British, and Canadian markets due to concerns over hepatotoxic reactions. The WHO recently recommended research into aqueous extracts of Kava. Objective: The objective of this study was to conduct the first documented human clinical trial assessing the anxiolytic and antidepressant efficacy of an aqueous extract of Kava. Design and participants: The Kava Anxiety Depression Spectrum Study was a 3-week placebo-controlled, double-blind crossover trial that recruited 60 adult participants with 1 month or more of elevated generalized anxiety. Five Kava tablets per day were prescribed containing 250 mg of kavalactones/day. Results: The aqueous extract of Kava reduced participants' Hamilton Anxiety Scale score in the first controlled phase by 9.9 (CI = 7.1, 12.7) vs. 0.8 (CI = 2.7, 4.3) for placebo and in the second controlled phase by 10.3 (CI = 5.8, 14.7) vs. +3.3 (CI = 6.8, 0.2). The pooled effect of Kava vs. placebo across phases was highly significant (p < 0.0001), with a substantial effect size (d = 2.24, [sub]p[sub] = 0.428). Pooled analyses also revealed highly significant relative reductions in Beck Anxiety Inventory and MontgomeryAsberg Depression Rating Scale scores. The aqueous extract was found to be safe, with no serious adverse effects and no clinical hepatotoxicity. Conclusions: The aqueous Kava preparation produced significant anxiolytic and antidepressant activity and raised no safety concerns at the dose and duration studied. Kava appears equally effective in cases where anxiety is accompanied by depression. This should encourage further study and consideration of globally reintroducing aqueous rootstock extracts of Kava for the management of anxiety.
Resumo:
Although there has been considerable research into the adverse effects of cannabis, less attention has been directed toward subjective effects that may be associated with ongoing cannabis use. Examination of self-reported cannabis effects is an important issue in understanding the widespread use of cannabis. While reviews have identified euphoria as a primary factor in maintaining cannabis use, relaxation is the effect reported most commonly in naturalistic studies of cannabis users, irrespective of the method used. Self-reported effects in 12 naturalistic and 18 laboratory studies were compared. Regardless of methodology there was considerable variation in the effects experienced. Variation has been reported in terms of opposite effects being experienced by different individuals, variation of effects by individuals within a single occasion and between occasions of use. Factors that might explain this variation are outlined. Limitations of the available literature and suggested directions for future research are discussed.
Resumo:
Despite the severe challenges which are posed by the loss of a close friend or relative, bereavement has a relatively benign outcome in most cases. While the majority of patients cope with bereavement, a significant minority develop problems. A behavioural approach may help the bereaved avoid adverse grief reactions.
Resumo:
It is known that adenosine 5'-triphosphate (ATP) is a cotransmitter in the heart. Additionally, ATP is released from ischemic and hypoxic myocytes. Therefore, cardiac-derived sources of ATP have the potential to modify cardiac function. ATP activates P2X(1-7) and P2Y(1-14) receptors; however, the presence of P2X and P2Y receptor subtypes in strategic cardiac locations such as the sinoatrial node has not been determined. An understanding of P2X and P2Y receptor localization would facilitate investigation of purine receptor function in the heart. Therefore, we used quantitative PCR and in situ hybridization to measure the expression of mRNA of all known purine receptors in rat left ventricle, right atrium and sinoatrial node (SAN), and human right atrium and SAN. Expression of mRNA for all the cloned P2 receptors was observed in the ventricles, atria, and SAN of the rat. However, their abundance varied in different regions of the heart. P2X(5) was the most abundant of the P2X receptors in all three regions of the rat heart. In rat left ventricle, P2Y(1), P2Y(2), and P2Y(14) mRNA levels were highest for P2Y receptors, while in right atrium and SAN, P2Y(2) and P2Y(14) levels were highest, respectively. We extended these studies to investigate P2X(4) receptor mRNA in heart from rats with coronary artery ligation-induced heart failure. P2X(4) receptor mRNA was upregulated by 93% in SAN (P < 0.05), while a trend towards an increase was also observed in the right atrium and left ventricle (not significant). Thus, P2X(4)-mediated effects might be modulated in heart failure. mRNA for P2X(4-7) and P2Y(1,2,4,6,12-14), but not P2X(2,3) and P2Y(11), was detected in human right atrium and SAN. In addition, mRNA for P2X(1) was detected in human SAN but not human right atrium. In human right atrium and SAN, P2X(4) and P2X(7) mRNA was the highest for P2X receptors. P2Y(1) and P2Y(2) mRNA were the most abundant for P2Y receptors in the right atrium, while P2Y(1), P2Y(2), and P2Y(14) were the most abundant P2Y receptor subtypes in human SAN. This study shows a widespread distribution of P2 receptor mRNA in rat heart tissues but a more restricted presence and distribution of P2 receptor mRNA in human atrium and SAN. This study provides further direction for the elucidation of P2 receptor modulation of heart rate and contractility.
Resumo:
Orlistat and sibutramine only cause modest reductions in body weight. Rimonabant, a cannabinoid receptor 1 antagonist, is a new approach to weight reduction, but is it safe, efficacious, and better than the existing agents?
Resumo:
Background : Postmenopausal osteoporosis is common and is associated with stooped posture, loss of height, back pain and fractures. Objectives/methods : This evaluation is of clinical outcome trials with tibolone (Long-Term Intervention of Fractures with Tibolone) and strontium ranelate (Spinal Osteoporosis Therapeutic Intervention) in postmenopausal osteoporosis. Results : Although the Long-Term Intervention of Fractures with Tibolone trial established that tibolone decreased the incidence of vertebral and non-vertebral fractures in postmenopausal osteoporosis, it also showed that tibolone caused a small increase in the incidence of stoke. The Spinal Osteoporosis Therapeutic Intervention trial established that strontium ranelate decreased the incidence of vertebral fractures, but had little effect on the incidence of non-vertebral fractures. Conclusions : As some of the bisphosphonates (alendronate, risedronate, zoledronic acid) have been shown to prevent hip fractures without increasing the incidence of stroke, they should be preferred to tibolone and strontium in the treatment of postmenopausal osteoporosis.
Resumo:
Background : Migraine is a common cause of disability. Many subjects (30 40%) do not respond to the 5-HT 1B/1D agonists (the triptans) commonly used in the treatment of migraine attacks. Calcitonin gene-related protein (CGRP) receptor antagonism is a new approach to the treatment of migraine attacks. Objectives/methods : This evaluation is of a Phase III clinical trial comparing telcagepant, an orally active CGRP receptor antagonist, with zolmitriptan in subjects during an attack of migraine. Results : Telcagepant 300 mg has a similar efficacy to zolmitriptan in relieving pain, phonophobia, photophobia, and nausea. Telcagepant was better tolerated than zolmitriptan. Conclusions : The initial Phase III clinical trial results with telcagepant are promising but several further clinical trials are needed to determine the place of telcagepant in the treatment of migraine attacks
