Characterization of COR627 and COR628, two novel positive allosteric modulators of the GABA(B) receptor

The potential efficacy of GABA(B) receptor agonists in the treatment of pain, drug addiction, epilepsy, cognitive dysfunctions, and anxiety disorders is supported by extensive preclinical and clinical evidence. However, the numerous side effects produced by the GABA(B) receptor agonist baclofen considerably limit the therapeutic use of this compound. The identification of positive allosteric modulators (PAMs) of the GABA(B) receptor may constitute a novel approach in the pharmacological manipulation of the GABA(B) receptor, leading to fewer side effects. The present study reports the identification of two novel compounds, methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), which act as GABA(B) PAMs in 1) rat cortical membranes and 2) in vivo assay. Both compounds potentiated GABA- and baclofen-stimulated guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding to native GABA(B) receptors, while producing no effect when given alone. GABA concentration-response curves in the presence of fixed concentrations of COR627 and COR628 revealed an increase of potency of GABA rather than its maximal efficacy. In radioligand binding experiments [displacement of the GABA(B) receptor antagonist, 3-N-[1-((S)-3,4dichlorophenyl)-ethylaminol]-2-(S)hydroxypropyl cyclo-hexylmethyl phosphinic acid ([(3)H]CGP54626)], both COR627 and COR628 increased the affinity of high- and low-affinity binding sites for GABA, producing no effect when administered alone up to a concentration of 1 mM. In vivo experiments indicated that pretreatment with per se ineffective doses of COR627 and COR628 potentiated the sedative/hypnotic effect of baclofen. In conclusion, COR627 and COR628 may represent two additional tools for use in investigating the roles and functions of positive allosteric modulatory binding sites of the GABA(B) receptor.     

Multiple drug delivery hydrogel system for spinal cord injury repair strategies

The multifactorial pathological progress of spinal cord injury (SCI) is probably the main reason behind the absence of efficient therapeutic approaches. Hence, very recent highlights suggest the use of new multidrug delivery systems capable of local controlled release of therapeutic agents. In this work, a biocompatible hydrogel-based system was developed as multiple drug delivery tool, specifically designed for SCI repair strategies. Multiple release profiles were achieved by loading gel with a combination of low and high steric hindrance molecules. In vitro, in vivo and ex vivo release studies showed an independent combination of fast diffusion-controlled kinetics for smaller molecules together with slow diffusion-controlled kinetics for bigger ones. A preserved functionality of loaded substances was always achieved, confirming the absence of any chemical stable interactions between gel matrix and loaded molecules. Moreover, the relevant effect of the cerebrospinal fluid flux dynamics on the drug diffusion in the spinal cord tissue was here revealed for the first time: an oriented delivery of the released molecules in the spinal cord tract caudally to the gel site is demonstrated, thus suggesting a more efficient gel positioning rostrally to the lesion.     

Proton pump inhibitors prescribing following the introduction of generic drugs

Eur J Clin Invest 2012; 42 (10): 1068-1078 ABSTRACT: Background In many countries, the introduction of generic proton pump inhibitors (PPIs) onto the pharmaceutical market increased the phenomenon of therapeutic substitution in acid-related disorders (ARDs). Aim To investigate the treatment of ARDs in an Italian primary care setting from 2005 to 2008 by verifying: (i) dynamics of PPI prescribing; (ii) predictors of PPI switching; and (iii) healthcare resource consumption costs. Methods This was a retrospective cohort study of 102 general practitioners (GPs) who managed an average of 150?000 inhabitants in Naples. Multilevel logistic regression was used to assess the potential predictors of both PPI switching and termination. Primary care costs were expressed as the cost of ARD management per PPI user year. Results The percentage of PPI users with ARD increased from 5·5% (2005) to 7·0% (2008) (P?相似文献   

Microscopic endoluminal tumorectomy

PURPOSE: We herein report our experience with transanal endoscopic microsurgery. The new technique combines an endoscopic view and access of the rectum under gas insufflationviaa stereoscopic telescope with all conventional surgical maneuvers such as tissue preparation, coagulation and control of bleeding, irrigation, suction, and, finally, suturing of the parietal defect. METHODS: The main indication for transanal endoscopic microsurgery is the removal of broad-based sessile polyps and excision of early rectal cancers. We performed local excision of pT2, G1-2 adenocarcinomas and excision of advanced rectal cancer in high-risk patients. The reported series includes 35 consecutive patients, who have been enrolled in a prospective clinical trial. Five patients were excluded for different reasons. The patients were submitted to 29 total wall excisions with or without perirectal fat and one mucosectomy. RESULTS: Postoperative histologic examination showed 9 adenomas and 21 adenocarcinomas. Morbidity included 2 (5.6 percent) perioperative and 2 (5.6 percent) late complications. There was no operative mortality and the mean postoperative hospital course was six days. All patients are in follow-up observation with a mean time of 10.3 months. In the group of adenomas and adenocarcinomas, we did not observe local recurrence. CONCLUSIONS: Considering our experience with the overall results reported by other authors, we believe that transanal endoscopic microsurgery is the procedure of choice for the treatment of rectal polyps and early rectal cancers provided strict patient selection criteria are met.     

Validity of Clinically Derived Cumulative Somatosensory Impairment Index

Deshpande N, Metter EJ, Ferrucci L. Validity of clinically derived Cumulative Somatosensory Impairment Index.

Objective

To develop a Cumulative Somatosensory Impairment Index for the lower limbs and evaluate its construct validity for discriminating relevant groups and predictive validity for predicting global postural control over time.

Design

Prospective cohort study.

Setting

Population-based cohort.

Participants

InCHIANTI (“Invecchiare in Chianti” or aging in the Chianti area) study participants (N=960; age, 21-91y, 51.8% women).

Interventions

Not applicable.

Main Outcome Measures

The Cumulative Somatosensory Impairment Index was derived from baseline performance on clinical tests of pressure sensitivity, vibration sensitivity, proprioception, and graphesthesia. Global postural control was assessed using Frailty and Injuries Cooperative Studies of Intervention Techniques (FICSIT) balance test, time to complete 5 repeated chair stands, and fast walking speed, at baseline and at 3-year follow-up.

Results

In participants without neurologic conditions (n=799), the Cumulative Somatosensory Impairment Index was significantly different in age groups classified by decades (P<.001). Compared with participants without prevalent conditions, the Cumulative Somatosensory Impairment Index was significantly higher in persons with diabetes (P=.017), peripheral arterial disease (P=.006), and a history of stroke (P<.001). In the overall population (N=960), in the fully adjusted multiple regression models, the Cumulative Somatosensory Impairment Index independently predicted deterioration in FICSIT scores (P=.002), time for 5 repeated chair stands (P<.001), and fast gait speed (P=.003) at 3-year follow-up.

Conclusions

The Cumulative Somatosensory Impairment Index is a valid measure that detects relevant group differences in lower limb somatosensory impairment and is an independent predictor of decline in postural control over 3 years.     

Has hyperglycemia a different prognostic role in STEMI patients with or without diabetes?

Background and aimsHyperglycemia at hospital admission is a common finding in patients with STEMI. However, whether elevated acute glycemia in these patients may have a direct impact on worsening prognosis or is just a marker of a greater neurohormonal activation in response to the infarction is still unsettled.We sought to investigate the prognostic impact of hyperglycemia at hospital admission in patients undergoing primary PCI (pPCI) for STEMI, and the influence of the presence of diabetes mellitus (DM) on its prognostic impact.Methodsand Results, We enrolled 2958 consecutive STEMI patients treated by pPCI. Hyperglycemia was defined as plasma glucose >198 mg/dL (or >11 mmol/L). Patients with hyperglycemia showed a greater risk-profile; they also experienced a higher mortality both at univariable (17.6% vs 5.2%, p < 0.001) and multivariable (HR 1.9, 95%IC 1.5–2.9, p = 0.001) analysis. However, after stratification for DM presence, hyperglycemia resulted as an independent predictor of mortality only in patients without DM (HR 2, 95%IC 1.2–3.4, p = 0.01).ConclusionHyperglycemia in the setting of myocardial infarction treated with primary PCI in an independent predictor of all-cause mortality in patients without diabetes; in patients with diabetes, its prognostic impact seems attenuated.     

Carbohydrate-antigen-125 levels predict hospital stay duration and adverse events at long-term follow-up in Takotsubo cardiomyopathy

The aim of this study is to evaluate the possible role of carbohydrate-antigen(CA)-125 as prognostic marker at short- and long-term follow-up, in subjects with Takotsubo cardiomyopathy (TTC). Sixty-three consecutive subjects with TTC were enrolled in the study and followed for a median 139 days. Circulating levels of CA-125, NT-proBNP, and left ventricular ejection fraction (LVEF) were evaluated at admission. Duration of hospital stay, incidence of death, re-hospitalization and recurrence of TTC during follow-up were recorded. The mean hospital stay was 8.3 days, adverse events occurred during follow up in 17 % of cases. CA-125 levels at admission are inversely related to LVEF (r ?0.30, p < 0.05) and directly related to hospital stay (r 0.29, p < 0.05). CA-125 levels at admission are higher in subjects with adverse events at follow-up (88.9 ± 200.0 vs 20.9 ± 30.0 U/mL, p < 0.05). Rates of incidence of adverse events are proportionally increased with CA-125 tertiles (0, 6, 11 % respectively, p for trend <0.01), at survival analysis (Log Rank p < 0.05) and after correction for age, gender, LVEF and NT-proBNP levels in multivariable Cox analysis (p < 0.05). CA-125 levels <10 U/ml are predictors of adverse events at follow up with 91 % sensitivity, 52 % specificity, 29 % positive predictive power, and 96 % negative predictive power. Increased CA-125 admission levels are associated with a longer hospital stay, a lower LVEF, and a higher risk of adverse events during follow up. CA-125 might be useful for early risk stratification of subjects with TTC.