Methods and findings in experimental and clinical pharmacology最新文献

Graft-versus-host disease (GVHD) remains the greatest source of morbidity-mortality in allogenic transplant patients. Although in most cases the more easily obtainable clinical and laboratory test parameters suffice to confirm the diagnosis and establish the stage of the disease biopsies of the affected organ are sometimes needed. At present there is great Interest in the study of factors allowing a prognosis of the course and type of response to treatment in patients with CVHD. In this sense, It would be necessary to objectively Identify and validate biomarkers capable of predicting biological or pathological processes in patients with cVHD. To this effect we have performed serial analyses of skin tissue using peripheral blood and tissue biomarkers in a prospective observational study conducted in three transplant centers. The still preliminary results Indicate that certain histopathological findings classically attributed to CVHD ore also seen in patients not clinically affected by the disease--this probably being related to other physiopathological phenomena occurring during transplantation. The study of these findings, combined with biomarker analysis, will allow improved understanding of the underlying etiopathogenesis, as well as the definition of new diagnostic, prognostic and response-evaluating criteria.

At this time, allogeneic transplantation should be offered only within the context of clinical trials. The likelihood of achieving prolonged complete remission with standard therapy with new drugs and autografting renders allogeneic transplantation unadvisable as first-line treatment in most patients. In this situation, the procedure must be reserved only for young patients with very poor prognostic factors or with progression of the disease offer receiving first-line treatment. After the first relapse, it should be applied to patients with an adverse cytogenetics and early relapse (< 18 months) after optimized treatment that includes new drugs and autologous transplantation. In any case, the patient should undergo transplantation with minimal disease. For the remaining patients, this procedure should not be considered the last therapeutic resort, since in this context there is a very low probability of success. On the other hand, conducting the procedure does not imply that the patient will not benefit a posteriori from other treatments, should they become necessary. Caution must be used when interpreting the available data from comparative studies. We have an obligation to continue exploring and improving this strategy which, to date, constitutes the most effective therapeutic tool available to us.

Urolithiasis, the process of formation of stones in the kidneys and urinary tract, is the major clinical manifestation of hyperoxaluria. Ethylene glycol feeding resulted in hyperoxaluria with increased renal excretion of oxalate, sodium, calcium and phosphate and a decrease in the excretion of magnesium. Supplementation with an aqueous and alcoholic extract of the leaves of Salvadora persica significantly reduced elevated urinary oxalate levels, indicating a regenerative action on endogenous oxalate synthesis. The deposition of stone-forming constituents in the kidneys of calculogenic rats was also significantly lowered by curative and preventive treatments with the aqueous and alcoholic extracts of Salvadora persica. The high serum creatinine level observed in ethylene glycol-treated rats was also reduced following treatment with the extracts. Histopathological findings showed signs of improvement after treatment with the extracts. These observations led to the conclusion that the aqueous and alcoholic extracts of the leaves of Salvadora persica are endowed with antiurolithiatic properties.

Angiotensin (AT) II plays a key role in the regulation of blood pressure and water-salt balance and modulates nociception. Peptides based on AT influence central functions through the activation of AT₁, AT₂ or AT₄ receptors. The aim of this study was to elucidate the role of AT₁ receptors in diurnal variation in nociception in spontaneously hypertensive rats (SHR). Male Wistar rats (16 weeks old) and SHR were caged individually and exposed to light from 08:00 to 20:00 h. The tail cuff method for noninvasive measurement of arterial blood pressure (ABP), paw pressure test for the determination of pain threshold and rotarod test to study motor coordination were used. Chronic treatment was administered to the SHR with the AT₁ receptor antagonist losartan (10 mg/kg/day, s.c.) for 14 days. Spontaneously hypertensive rats showed lower pain threshold and smaller day-night variations of nociception as compared to Wistar rats. Chronic losartan decreased the ABP and produced an inverted diurnal pattern of nociception in SHR, increasing the pain threshold at 03:00 h. Neither strain differences nor changes in motor coordination after losartan treatment were observed in SHR. Our results suggest that SHR have disturbances in diurnal variation in nociception and that the AT₁ receptor plays a role in the regulation of the circadian rhythm of mechanical pain threshold in SHR.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Thomson Reuters Integrity(SM), the drug discovery and development portal, http://www.thomsonreutersintegrity.com. This issue focuses on the following selection of drugs: Abatacept, Adalimumab, AdCD40L, Adefovir, Aleglitazar, Aliskiren fumarate, AM-103, Aminolevulinic acid methyl ester, Amlodipine, Anakinra, Aprepitant, Aripiprazole, Atazanavir sulfate, Axitinib; Belimumab, Bevacizumab, Bimatoprost, Bortezomib, Bupropion/naltrexone; Calcipotriol/betamethasone dipropionate, Certolizumab pegol, Ciclesonide, CYT-997; Darbepoetin alfa, Darunavir, Dasatinib, Desvenlafaxine succinate, Dexmethylphenidate hydrochloride cogramostim; Eltrombopag olamine, Emtricitabine, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus-eluting coronary stent, Exenatide, Ezetimibe; Fenretinide, Filibuvir, Fludarabine; Golimumab; Hepatitis B hyperimmunoglobulin, HEV-239, HP-802-247, HPV-16/18 AS04, HPV-6/11/16/18, Human albumin, Human gammaglobulin; Imatinib mesylate, Inotuzumab ozogamicin, Invaplex 50 vaccine; Lapatinib ditosylate, Lenalidomide, Liposomal doxorubicin, Lopinavir, Lumiliximab, LY-686017; Maraviroc, Mecasermin rinfabate; Narlaprevir; Ocrelizumab, Oral insulin, Oritavancin, Oxycodone hydrochloride/naloxone; Paclitaxel-eluting stent, Palonosetron hydrochloride, PAN-811, Paroxetine, Pazopanib hydrochloride, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Pitavastatin calcium, Posaconazole, Pregabalin, Prucalopride succinate; Raltegravir potassium, Ranibizumab, RHAMM R3 peptide, Rosuvastatin calcium; Salclobuzic acid sodium salt, SCY-635, Selenate sodium, Semapimod hydrochloride, Silodosin, Siltuximab, Silybin, Sirolimus-eluting stent, SIR-Spheres, Sunitinib malate; Tapentadol hydrochloride, Tenofovir disoproxil fumarate, Tocilizumab, Tositumomab/iodine (I131) tositumomab, Trabectedin, TransVax™ hepatitis C vaccine; Ustekinumab; V-260, Valspodar, Varenicline tartrate, VCL-IPT1, Vildagliptin, VRC-HIVADV014-00-VP, VRC-HIVDNA009-00-VP, VRC-HIVDNA016-00-VP; Yttrium 90 (90Y) ibritumomab tiuxetan, Yttrium Y90 Epratuzumab; Zibotentan, Zotarolimus-eluting stent.

Allergic rhinitis is a common airways hypersensitivity disease. Histamine and leukotrienes are involved in the pathogenesis of allergic rhinitis. Conventional treatments include topical steroids and antihistamines. Due to the adverse effects of these treatments, new drugs like leukotriene receptor antagonists are being investigated for the treatment of allergic rhinitis. A total of 90 patients suffering from allergic rhinitis were enrolled in this prospective, randomized, controlled study. Patients were divided randomly into three groups of 30 patients each. Group I was administered fluticasone nasal spray (200 μg in each nostril) once a day, Group II was administered fluticasone nasal spray (200 μg in each nostril) plus cetrizine (10 mg) orally once a day and Group III was administered fluticasone nasal spray (200 μg in each nostril) plus montelukast (10 mg) orally once a day. Efficacy was measured based on daytime and nighttime symptom scores. Safety was evaluated on the basis of psychomotor tests, laboratory investigations and subjective assessment. The present study showed that montelukast add-on therapy is as efficacious as conventional therapies in controlling total symptom score, but it is more efficacious in controlling nighttime symptoms. Furthermore, montelukast add-on therapy does not cause psychomotor impairment as observed with cetrizine.

The aim of this study was to compare the protective effects of three traditional Chinese herbal medicines (ligustrazine, kakonein and Panax notoginsenosides) on multiple organs in a rat model of severe acute pancreatitis (SAP) and to explore the underlying mechanisms. The mortality rates in all three treated groups were significantly lower than the control group (P < 0.05). All three herbal medicines significantly alleviated the pathological changes in the pancreas, liver and kidney in SAP rats, induced pancreatic acinar cell apoptosis and effectively prevented the apoptosis of cells in the liver and kidney; however, no obvious lung protection was observed. Panax notoginsenosides showed better pancreatic protection than ligustrazine and kakonein, while kakonein displayed a better role in improving liver and kidney function. The protective effects of ligustrazine were somewhat more comprehensive.

Methotrexate is a folate antagonist that is commonly used as an antitumor and antiarthritic drug. The aim of this study was to investigate the possible roles of exogenous glutamine (Glu), arginine (Arg) and proanthocyanidin (PA) on gut protection from methotrexate-induced intestinal damage in rats. Experimental rats were separated into eight groups. The first (sham) group received a 0.9% NaCl solution alone. The second group received intraperitoneal injections of methotrexate (20 mg/kg/day) administered on day 4 of the experiment and continued for 5 days. Rats in the other six groups were administered PA, Glu, Arg, Glu+PA, Arg+PA or Glu+Arg orally by gavage together with methotrexate and animals were sacrificed on day 8 of the experiment. All animals were sacrificed 4 days after methotrexate injection for histopathological analysis, tissue glutathione peroxidase, malondialdehyde and superoxide dismutase assays. Proanthocyanidin and Glu decreased the severity of intestinal injury and oxidant injury as evident by histopathology and changes in malondialdehyde levels. Histological analysis confirmed that PA and to a lesser extent Glu supplementation were more favorable than Arg for the protection of the small intestine from methotrexate-induced injury.

The effects of fluoxetine, a serotonin reuptake inhibitor, were studied in the isolated rat small intestine. Electrical field stimulation (EFS) triggered relaxant and/or contractile responses that were sensitive to tetrodotoxin and fluoxetine at 1.0-10.0 μM. In 0.1 mM hexamethonium-treated tissues, fluoxetine (1.0 μM) induced a relaxant response at 10.0 Hz, while it decreased the attenuation of the contractile responses to EFS. In PCPA pretreated rat jejunum and ileum, 1.0 μM of fluoxetine induced a greater relaxation response to EFS and significantly attenuated the contractile responses to EFS (10.0 Hz) in the duodenum. In a separate experiment, the application of reboxetine (1.0-10.0 μM), a noradrenergic reuptake inhibitor, reduced the contraction and increased the relaxation responses to EFS at 10.0 Hz in most regions. In the presence of hexamethonium (0.1 mM) the application of 10.0 μM reboxetine reduced contractile responses to ESF while enhancing the relaxant responses to EFS at 10.0 Hz. The data suggest that the effects of fluoxetine appear to be related to the selected region of the intestine and may contribute to a better understanding of the serotonergic and cholinergic transmitter mechanisms involved in ileal activity and the gastrointestinal discomfort associated with the clinical use of fluoxetine.

Several tests have been developed to obtain mechanical nociceptive withdrawal thresholds for arthritis-associated pain research in preclinical animal models, which are routinely used for testing the efficacy of antinociceptive pharmaceutical candidates. Here, we aimed to validate a recently introduced and commercially available digital pressure application measurement (PAM) device for the detection of primary mechanical hyperalgesia in a model of antigen-induced knee joint arthritis (AIA) in rats and mice. Two particular advantages of the PAM device are visual feedback control of the force increase rate and the detection of the complete threshold range. Using PAM, we were able to quantify mechanical thresholds at the knee joint in rats and mice (400 and 350 g, respectively) before and during the time course of AIA (approximately 100 g for rats and mice in the acute phase). Inter-observer agreement was generally higher when using PAM instead of an analog dynamometer. In conclusion, the digital PAM device is a suitable apparatus to detect primary mechanical hyperalgesia in experimental knee joint arthritis in rats and mice. The use of this device allows visual feedback control of the stimulus rate, thus minimizing the chances of confounding factors arising from differences in ramp speed.