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961.
Nassar MN Nesarikar VV Lozano R Huang Y Palaniswamy V 《Pharmaceutical development and technology》2005,10(2):227-232
The purpose of this study was to identify two degradation products formed in the parenteral lyophilized formulation of BMS-204352, investigate the possible role of elastomeric closures in their formation, and develop a strategy to minimize/control their formation. The first degradant was identified as the hydroxymethyl derivative (formaldehyde adduct, BMS-215842) of the drug substance formed by the reaction of BMS-204352 with formaldehyde. Structure confirmation was based on liquid chromatography/mass spectroscopy (LC/MS), nuclear magnetic resonance (NMR), and chromatographic comparison to an authentic sample of the hydroxymethyl degradation product, BMS-215842. To confirm the hypothesis that formaldehyde originated from the rubber closure, migrated into the product, and reacted with BMS-204352 drug substance to form the hydroxymethyl degradant, lyophilized drug product was manufactured, the vials were stoppered with two different rubber closure formulations, and its stability was monitored. The formaldehyde adduct degradant was observed only in the drug product vials stoppered with one of the rubber closures that was evaluated. Although formaldehyde has not been detected historically as leachable and is not an added ingredient in the rubber formulation, information obtained from the stopper manufacturer indicated that the reinforcing agent used in the stopper formulation may be a potential source of formaldehyde. The second degradant was identified as the desfluoro hydroxy analog (BMS-188929) based on LC/MS, NMR, and chromatographic comparison to an authentic sample of the desfluoro hydroxy degradation product. 相似文献
962.
963.
The individualized medicine aims to identify the molecular basis of the individual's response to different therapeutic treatments. Individualized medicine is very relevant for human diseases such as cancer and it has become a major task to accomplish more efficient and specific therapeutics. An individualized response to treatment could underline therapeutic success or failure and, even more, could support the rationale for good or bad prognosis. The use of up to date genomic approaches is changing the way we understand modern medicine in terms of drug efficacy, toxicity and diagnosis. Results from genetic polymorphism studies, gene expression profiling and epigenetics illustrate how pharmacogenomic testing will contribute to the goal of individualized medicine. Antineoplastic drugs are designed to block the anomalous activity of specific molecules (therapeutic targets) that regulate cellular processes such as cell cycle. Understanding the relationship between molecular changes in therapeutic targets and enhanced antitumoral response or chemotherapeutic resistance is crucial to establish the clinical relevance of genomic approaches. The goal of this review is to discuss the basic and the clinical significance of genomic research on drug targets and its impact on the early diagnosis and treatment of cancer. We will also assess how these methodologies could contribute to individualized medicine in oncology. A special focus will be put on oncogenes and tumor suppressor genes. Aspects such as drug efficacy, side effects and the diagnostic value of antineoplastic pharmacogenomic research will be also considered. 相似文献
964.
García-Bueno B Madrigal JL Lizasoain I Moro MA Lorenzo P Leza JC 《Psychopharmacology》2005,180(3):513-522
Rationale Immobilisation stress is followed by accumulation of oxidative/nitrosative mediators in brain after the release of tumour necrosis factor-alpha (TNF) and other cytokines, nuclear factor kappa B (NFB) activation, nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) expression in the brain.Objectives This study was conducted to assess if some of the anti-inflammatory products of COX can modify the accumulation of oxidative/nitrosative species seen in brain after stress and to study the mechanisms by which this effect is achieved.Methods Young-adult male Wistar rats were subjected to a single session of immobilisation during 6 h.Results In stressed animals, brain levels of the anti-inflammatory 15d-PGJ2 increases concomitantly with COX-2 expression. Inhibition of COX-2 with NS-398 prevents stress-induced 15d-PGJ2 increase. Injection of supraphysiological doses of 15d-PGJ2 (80–120 g/kg) decreases stress-induced increase in NOS-2 activity as well as the stress-induced increase in NO metabolites. On the other hand, 15d-PGJ2 decreases stress-induced malondialdehyde (an indicator of lipid peroxidation) accumulation in cortex and prevents oxidation of the main anti-oxidant glutathione. The mechanisms involved in the anti-oxidative properties of 15d-PGJ2 in stress involve NFB blockade (by preventing stress-induced IB decrease) as well as inhibition of TNF release in stressed animals. At the doses tested, 15d-PGJ2 decreases COX-2 expression and PGE2 release during stress, suggesting an alternative mechanism for this endogenous compound.Conclusions These findings demonstrate a role for this anti-inflammatory pathway in the brain response to stress and open the possibility for preventing accumulation of oxidative/nitrosative species and subsequent brain damage. 相似文献
965.
Lahlou S Magalhães PJ de Siqueira RJ Figueiredo AF Interaminense LF Maia JG Sousa PJ 《Journal of cardiovascular pharmacology》2005,46(4):412-421
Cardiovascular effects of intravenous (i.v.) treatment with the essential oil of the bark of Aniba canelilla (EOAC) were investigated in normotensive rats. In both pentobarbital-anesthetized and conscious rats, i.v. bolus injections of EOAC (1 to 20 mg/kg) elicited similar and dose-dependent hypotension and bradycardia. Pretreatment of anesthetized rats with bilateral vagotomy significantly reduced the bradycardia without affecting the hypotension. In conscious rats, pretreatment with hexamethonium (30 mg/kg, i.v.) significantly reduced the EOAC-induced bradycardia without affecting the hypotension. The opposite effect was observed after i.v. pretreatment with the nitric oxide synthase inhibitor, N-nitro-L-arginine methyl esther (L-NAME, 20 mg/kg). However, both EOAC-induced hypotension and bradycardia were significantly reduced by pretreatment with methylatropine (1 mg/kg, i.v.). In rat endothelium-containing aorta preparations, EOAC (1-600 microg/mL) induced a concentration-dependent reduction of potassium (60 mM)-induced contraction [IC50 (geometric mean+/-95% confidence interval)=64.5 (45.6-91.2) microg/mL)], an effect that was significantly reduced by the addition of atropine (10 microM) in the perfusion medium [IC50=109.5 (72.5-165.4) microg/mL)]. Furthermore, the vasorelaxant effects of the EOAC were also but significantly reduced [IC50=139.1 (105.2-183.9) microg/mL)] by removal of the vascular endothelium. Furthermore, the CaCl2-induced contractions in calcium-free medium were reduced and even fully abolished by EOAC (100 and 600 microg/mL), respectively. However, EOAC (600 microg/mL) was without significant effect on caffeine-induced contractions in calcium-free medium. These data show that i.v. treatment of rats with EOAC induces dose-dependent hypotension and bradycardia, which occurred independently. The bradycardia appears mainly dependent upon the presence of an operational and functional parasympathetic drive to the heart. However, the hypotension is due to an active vascular relaxation rather than withdrawal of sympathetic tone. This relaxation seems partly mediated by an endothelial L-arginine/nitric oxide pathway through peripheral muscarinic receptor activation (endothelium-dependent relaxation) and predominantly through an inhibition of calcium inward current (endothelium-independent relaxation). 相似文献
966.
Costa PR Rosa R Duarte-Silva A Brotas V Sampayo MA 《Aquatic toxicology (Amsterdam, Netherlands)》2005,74(1):82-91
Domoic acid (DA) is a phycotoxin produced by some diatoms, mainly from the Pseudo-nitzschia genus, and has been detected throughout the marine food web. Although DA has been frequently found in cephalopod prey such as crustaceans and fish, little is known about DA accumulation in these molluscs. This study presents the first data showing relevant concentrations of DA detected in the common cuttlefish, Sepia officinalis, which is one of the most studied cephalopod species in the world. Domoic acid was consistently found throughout 2003 and 2004 in the digestive gland of cuttlefish reaching concentrations of 241.7 microg DA g(-1). The highest DA values were detected during spring and summer months, periods when Pseudo-nitzschia occur in the plankton. In fact, Pseudo-nitzschia blooms preceded the highest DA concentrations in cuttlefish. Evaluation of DA tissue distribution showed elevated DA concentrations in the digestive gland and branchial hearts. Further, DA isomers comprised a relevant percentage of the toxin profile, indicating degradation and biotransformation of the toxin in the branchial hearts. The common cuttlefish, like other cephalopod species, plays a central position in the food web and might be a new DA vector to top predators like marine mammals. Human intoxications are not expected since DA was only seldom detected in the mantle and even then in very low levels (max 0.7 microg DA g(-1)). However, in some countries whole juvenile animals are consumed (i.e. without evisceration) and in this case they might represent a risk to human health. This study contributes to understanding the occurrence of phycotoxins in cephalopods and reveals a new member of the marine food web able to accumulate DA. 相似文献
967.
Sierra-Johnson J Olivera-Mar A Monteón-Padilla VM Reyes PA Vallejo M 《Revista de saúde pública》2005,39(5):754-760
OBJECTIVE: To compare the epidemiological and clinical characteristics of chronic Chagas' heart disease to other dilated cardiomyopathies. METHODS: A study comprising 128 patients from a heart disease center was carried out from 1993 to 2003. Of them, 51 (40%) were Trypasonoma cruzi positive. Epidemiological data was obtained through interviews and clinical and serological data from health services. Statistic analysis was conducted using the Chi-square, Fischer, Mann-Whitney or Students' t-test as well as multivariate analysis. RESULTS: Chronic Chagas' disease patients were older (55+/-10 years old) than those patients with cardiopathy (42+/-17 years old). Most of them were born in rural areas (90% vs 68%), lived in poor (75% vs 16%), crowded households (45% vs 20%), together with domestic animals (71% vs 61%) and were aware of the Chagas' vector (73% vs 25%). Rhythm and conduction ECG abnormalities as well as permanent pacemaker were common among Chagas' patients (84% vs 55%, 78% vs 64% and 24% vs 10%, respectively). Congestive heart failure was more frequent among cardiomiopathy patients (88% vs 71%). Both groups had abnormal myocardial perfusion with normal epicardial arteries. Comorbidities were more frequent in cardiomiopathy patients than in chronic Chagas' disease patient (two cases only). CONCLUSIONS: Chagas' disease is the most common cause of dilated cardiomiopathy in the study hospital. Due to its regional distribution in Mexico, it deserves special attention and control programs proven to be effective in other countries. 相似文献
968.
Palanca Martin D Bueno Lozano AL Martin Ruiz G 《La Chirurgia degli Organi di Movimento》2005,90(4):397-401
We present a clinical case of anterior instability of the knee due to chronic rupture of the ACL; where there was also proximal deformity of the tibia, secondary to consolidation in flexion of the proximal fragment in a bifocal fracture of the tibia, treated by non-reamed intramedullary nailing, which consolidated in flexion of the proximal fractured segment, causing a marked increase in the angle of the tibial slope. The patient refers an articular instability, which prevented her from walking correctly and causing her frequent falls. We repaired under same chirurgical act, all the problems of the patient, her vicious consolidation and her articular instability. The result is perfect. 相似文献
969.
de Castro G Iribarren M Rivo E Meléndez R Nóvoa E Cañizares M Gil P 《Cirugía espa?ola》2005,77(4):230-232
Currently, acquired benign tracheoesophageal fistulas are mainly iatrogenic lesions produced by prolonged tracheal intubation. Their occurrence in intubated patients is infrequent but devastating and their therapeutic resolution is highly complex. We present the case of a patient with an extensive tracheoesophageal fistula following tracheal intubation that was surgically treated through esophageal exclusion (cervical esophagostomy and suture-stapling of the distal esophagus) and closure of the tracheal defect using the posterior esophageal wall. 相似文献
970.