Application of latent growth and growth mixture modeling to identify and characterize differential responders to treatment for COPD

Objective

To explore the utility of applying growth mixture models (GMMs) in secondary analyses of clinical trials to identify sources of variability in data reported by patients with COPD.

Methods

Analyses were performed on data from two 6-month clinical trials comparing indacaterol and open-label tiotropium or blinded salmeterol and the first six months of a 12-month trial comparing indacaterol and blinded formoterol. Latent growth model (LGM) analyses were conducted to explore the response of the SGRQ Symptoms score from baseline to six months and GMM analyses were evaluated as a method to identify latent classes of differential responders.

Results

Variability in SGRQ Symptom scores was found suggesting subsets of patients with differential response to treatment. GMM analyses found subsets of non-responders in all trials. When the responders were analyzed separately from non-responders, there were increased treatment effects (e.g., symptoms score improvement over six months for whole groups: indacaterol = 8–12 units, tiotropium = 7 units, salmeterol = 9 units, formoterol = 11 units. Responder subgroup improvement: indacaterol = 9–21 units, tiotropium = 7 units, salmeterol = 10 units, formoterol = 20 units). Responders had significantly different baseline SGRQ Symptom scores, smoking history, age, and mMRC dyspnea scores than non-responders.

Conclusions

Patients with COPD represent a heterogeneous population in terms of their reporting of symptoms and response to treatment. GMM analyses are able to identify sub-groups of responders and non-responders. Application of this methodology could be of value on other endpoints in COPD and in other disease areas.     

Influence of MKP medium stored for prolonged periods on growth and morphology of Borrelia afzelii,Borrelia garinii,and Borrelia burgdorferi sensu stricto

Modified Kelly‐Pettenkofer (MKP) medium is one of the several media used for isolation and cultivation of Borrelia. The aim of the study was to assess whether particular Borrelia species (B. afzelii, B. garinii, and B. burgdorferi sensu stricto) have the ability to grow in MKP medium stored at +4 °C for periods for 1 month up to 1 year, and how prolonged storage may influences Borrelia growth and morphology. The growth of Borrelia was evaluated after 5 days of incubation at 33 °C: cell count per mL, morphology, and motility were assessed. The results of this study showed that the duration of storage of MKP medium had statistically significant influence on growth of B. afzelii (p = 0.021) and B. garinii (p = 0.004), but not on growth of B. burgdorferi sensu stricto (p = 0.204), whereas duration of storage of the medium had no impact on Borrelia morphology and motility. The results of the study indicate that medium stored for more than 1 and up to 12 months supports Borrelia growth.     

Early pregnancy angiogenic proteins levels and pregnancy related hypertensive disorders

Introduction: Normal placental vascular development depends on multiple interactions of many regulatory molecules including pro and antiangiogenic proteins. It is considered that these vascular modulators might be one of the factors responsible for development hypertensive disorders in pregnancy.

Objective: To evaluate and compare the early pregnancy (11–14 week of gestation) serum level of angiogenic proteins sFlt1, VEGF i PIGF between different types of pregnancy related hypertensive disorders.

Materials and methods: The study included 177 pregnant women between 11 and 14 weeks of gestation, divided into four study subgroups (preeclampsia group-41, gestational hypertension group-31, chronic hypertension group-32 and miscarriage group-19) and control group-54. Blood samples (serum) were taken for measuring sFlt1, VEGF i PIGF by a quantitative ELISA technique and measuring other biochemical and hematological parameters.

Results: Significantly higher levels of sFlt1 were in the subgroups with preeclampsia and miscarriages, significantly lower level of VEGF in the all study subgroups and lover level of PIGF were in miscarriage group. In the groups with chronic and gestational hypertension there were higher level of sFlt1 and lover level of VEGF than in the control group, but the differences did not reach statistical significance.

Conclusion: Early pregnancy imbalance between antiangiogenic protein sFlt1 and proangiogenic molecules VEGF and PIGF could have impact on pathophysiology of placental disorders which leads to development of pregnancy related hypertensive disorders.     

New opportunities of real-world data from clinical routine settings in life-cycle management of drugs: example of an integrative approach in multiple sclerosis

The assessment and demonstration of a positive benefit–risk balance of a drug is a life-long process and includes specific data from preclinical, clinical development and post-launch experience. However, new integrative approaches are needed to enrich evidence from clinical trials and sponsor-initiated observational studies with information from multiple additional sources, including registry information and other existing observational data and, more recently, health-related administrative claims and medical records databases. To illustrate the value of this approach, this paper exemplifies such a cross-package approach to the area of multiple sclerosis, exploring also possible analytic strategies when using these multiple sources of information.     

BPC-157,一种胃十五肽的抗焦虑作用:休克探查/埋藏试验和明暗试验(英文)

AIM: To study anxiolytic effect of a gastric pentade-capeptide, BPC-157. METHODS: In shock probe/burying test, pentadecapeptide BPC-157 (10 μg/kg, 10ng/kg, ip), diazepam (0.075, 0.0375 mg/kg, ip),and an equivolume of saline (5 mL/kg, ip) were givenat 30 min prior test. In light/dark test, the same dosageof diazepam, BPC-157, and saline were given at 45 minPrior procedure. RESULTS: Shock probe/buryingtest: rats treated with either diazepam or pentadecapeptideBPC-157 were much less afraid after the shock: almost     

KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer

The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFR-related signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04). In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment.     

Effects of pharmaceutical formulations containing thyme on carbon tetrachloride-induced liver injury in rats

Background

Herbal supplements are widely used in the treatment of various liver disases, but some of them may also induce liver injuries. Regarding the infuence of thyme and its constituents on the liver, conflicting results have been reported in the literature. The objective of this study was to examine the influence of two commonly used pharmaceutical formulations containing thyme (Thymus vulgaris L.), tincture and syrup, on carbon tetrachloride-induced acute liver injury in rats.

Methods

Chemical composition of investigated formulations of thyme was determined by gas chromatography and mass spectrometry. Activities of enzyme markers of hepatocellular damage in serum and antioxidant enzymes in the liver homogenates were measured using the kinetic spectrophotometric methods. Liver morphology was characterized by light microscopy using routine hematoxylin and eosin staining.

Results

Thymol was found to be predominant active constituent in both tincture and syrup. Investigated thyme preparations exerted antioxidant effects in liver by preventing carbon tetrachloride-induced increase of lipid peroxidation. Furthermore, co-treatment with thyme preparations reversed the activities of oxidative stress-related enzymes xanthine oxidase, catalase, peroxidase, glutathione peroxidase and glutathione reductase, towards normal values in the liver. Hepatotoxicity induced by carbon tetrachloride was reflected by a marked elevation of AST and ALT activities, and histopathologic alterations. Co-administration of thyme tincture resulted in unexpected exacerbation of AST and ALT values in serum, while thyme syrup managed to reduce activites of aminotransferases, in comparison to carbon tetrachloride-treated animals.

Conclusions

Despite demonstrated antioxidant activity, mediated through both direct free radical scavenging and activation of antioxidant defense mechanisms, thyme preparations could not ameliorate liver injury in rats. Molecular mechanisms of diverse effects of thyme preparations on chemical-induced hepatotoxicity should be more in-depth investigated.