IDENTIFICATION OF CLINICAL, LABORATORY AND GENETIC COVARIATES FOR PHARMACOKINETICS, EFFICACY AND TOXICITY OF SORAFENIB IN PATIENTS WITH SOLID TUMORS

The goal of this research work was to understand the clinical-pharmacology based treatment approaches for sorafenib. Treatment with sorafenib is associated with high inter-patient variability in pharmacokinetic exposures, efficacy and toxicity. We explored the demographic, laboratory, clinical and pharmacogenetic factors to elucidate the sources of variability. In addition, we examined the impact of pharmacogenetic variation in VEGFR2, an important mediator of the VEGF pathway, on risk of prostate cancer. To support these investigations, (mainly single-dose) pharmacokinetic, pharmacogenetic, efficacy and toxicity information were collected from patients with solid tumors, enrolled in five phase I / II clinical trials at National Cancer Institute. Non-compartmental analysis-general linear modeling (NCA-GLM), population pharmacokinetic analysis and several correlative studies were performed to characterize the sources of variability in pharmacokinetics and response. The role of prostate specific antigen (PSA) and ex-vivo anti-angiogenic activity as efficacy markers was evaluated, respectively, for patients with prostate cancer treated with sorafenib and patients with solid tumors treated with combination of sorafenib and bevacizumab. Sweat concentrations of sorafenib were measured to study its association with development of hand-foot skin reaction (HFSR). Only body weight was a significant covariate for volume of distribution by population pharmacokinetic analysis, while BSA, albumin and UGT1A9*3 appeared to be significant by NCA-GLM. However, the contribution of these covariates in overall exposure variability was very small; hence, these were considered clinically irrelevant. The association of sorafenib exposure with efficacy in patients with prostate cancer, colorectal cancer and combined solid tumors were not significant; exposure-efficacy relationship for lung cancer patients requires further evaluation. Sorafenib exposures appeared to be associated with incidences of rash in single agent trials and with HFSR in trials involving treatment with sorafenib and bevacizumab combination. In-vitro cell-line experiments determined that prostate specific antigen (PSA) is not a suitable marker of efficacy in patients with prostate cancer treated with sorafenib. The ex-vivo anti-angiogenic activity, measured by rat-aortic ring assay using patient serum samples, appeared to be not associated with clinical response. Sorafenib concentration in sweat, upto ≥5 ng/mL, apparently was not associated with HFSR. The VEGFR2 H472Q polymorphism was associated with progression-free survival (PFS) (with an apparent heterozygous advantage for survival) and toxicities in patients treated with drugs against the VEGF pathway. Patients who developed hypertension and HFSR on bevacizumab and sorafenib therapy, respectively, appeared to have longer PFS. Therefore, these side effects should be effectively managed to avoid/delay the treatment discontinuation. The VEGFR2 H472Q and V297I genotype were not predictive of risk of prostate cancer in Caucasian subjects

Amelioration of Paracetamol-Induced Hepatotoxicity in Rat by the Administration of Chloroform extract of Argemone mexicana

Aim: The present study was undertaken to examine the effects of Chloroform extract of Argemone mexicana using the paracetamol-induced liver damage in rats as the animal model. Materials and methods: Chloroform extract of Argemone mexicana (100 and 200 mg/kg body weight) was administered daily in experimental animals. The hepatoprotective efficacy of Chloroform extract of Argemone mexicana (100 and 200 mg/kg) was investigated against paracetamol-induced hepatotoxicity. The levels of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), serum alkaline phosphatase (ALP), bilirubin and triglycerides were estimated. Moreover, chloroform extract of Argemone mexicana -aided antioxidant defense against hepatotoxic insult of paracetamol was measured by evaluating a number of anti-oxidative biomarkers including reduced malondialdehyde (MDA) in the serum. Results: Oral administration of paracetamol (500 mg/kg b.wt.) resulted in a significant elevation of liver enzymes in serum such as SGOT, SGPT, ALP, bilirubin and triglyceride levels when compared with the results in the control group. As regards oxidative stress biomarkers, there were increased tissue levels of malondialdehyde in the group treated with paracetamol. All of these results were ameliorated by co-administration of chloroform extract of Argemone mexicana. Conclusions: These results suggest that the protective role of Chloroform extract of Argemone mexicana in the prevention of PCM-induced hepatic toxicity in rats was associated with a decrease of oxidative stress in hepatic tissues. Keywords: Antihepatotoxicity; Chloroform extract of Argemone mexicana; Paracetamo

Mitigation of adverse effects of salt stress on germination, growth, photosynthetic efficiency and yield in maize (Zea mays L.) through magnetopriming

The efficiency of magnetopriming was evaluated for mitigation of the detrimental effects of salt stress on maize germination, growth, photosynthesis, and yield of maize plants. Maize seeds were pretreated with 200 mT of static magnetic field (SMF) for 1 h to assess the impact of SMF on the germination, seedling vigor, growth of plant, photosynthetic performance, ROS content, and yield under salt stress. The seedling characteristics of maize were negatively influenced by salt stress. However, SMF-pretreated maize seeds showed relatively higher germination percentage and germination stress tolerance index as compared to untreated seeds in saline and nonsaline conditions. The detrimental effect of NaCl induced salt stress was also observed on growth, yield, and different physiological characteristic of maize plants. The results showed that SMF-pretreated seeds enhanced seedling vigor, growth parameters such as plant height, leaf area, and biomass accumulation at different concentrations of NaCl (0, 25, 50, 75, and 100 mM) as compared to untreated seeds. Photosynthetic pigments, quantum yield of PSII photochemistry (Fv/Fm), phenomenological fluxes such as electron transport per leaf CS (ETo/CSm) and density of reaction centers (RC/CSm), the performance index (PI) were high in the leaves of plants that emerged from SMF-pretreated seeds as compared to untreated seeds. This stimulatory effect of SMF treatment of seeds was also revealed in the rate of photosynthesis and stomatal conductance, which results in improved yield of maize plants under saline conditions. The leaves from plants of SMF-treated seeds showed decreased hydrogen peroxide (H2O2) when compared with untreated seeds in both conditions. SMF ameliorates the adverse effect of salt stress in maize plants, by reducing H2O2 and increasing growth, photosynthetic performance, and yield under salt stress. For improvement of salt tolerance, magnetopriming with SMF of 200 mT for 1 h to dry seeds of maize can be efficiently used as a presowing treatment

A rare case of Bochdalek diaphragmatic hernia with concomitant partial situs inversus

Congenital diaphragmatic hernias clinically presenting in adulthood are exceedingly rare lesions, mainly left-sided defect (Bochdalek). Bochdalek hernias most commonly manifest during the patient’s first few weeks of life. Diagnosis beyond the first 8 weeks of life is estimated to represent 5-25% of all Bochdalek hernias. Here we have a 32 year old female patient who presented with 10x10 cm diaphragmatic hernia with dextrocardia who was asymptomatic for years

Effectiveness of Transcutaneous Electrical Nerve Stimulation Therapy on whole Salivary Flow in Patients with Xerostomia and Healthy Adults

Objective: To evaluate and compare the effectiveness of transcutaneous electrical nerve stimulation (TENS) therapy on whole salivary flow in patients with xerostomia and healthy adults. Material and Methods:  Thirty subjects with a history of xerostomia and subjects with unstimulated salivary flow equal to or less than 0.5 ml in 5 min were included in the study group, and 30 healthy subjects were included in the control group. Low forced spitting unstimulated saliva was collected for five minutes in a test tube fitted with a funnel. Then electrode pads of the TENS unit were applied bilaterally on skin overlying the parotid glands and at optimal intensity, stimulated saliva was collected for 5 minutes with the same method in a separate graduated test tube. The salivary flow rate (per minute) was calculated by dividing the amount of collected saliva (volume in mL) by the duration of collection period (5 minutes) and the salivary flow rates prior and after electrostimulation were compared for both groups. The Student’s t-test (unpaired and paired) was performed for group-wise comparisons. Results: In study group, the mean unstimulated salivary flow rate was 0.07 ± 0.01 mL/min. There was an 85.71% increase in salivary flow (0.13 ± 0.03 mL/min) during the TENS application and the difference was highly significant (p<0.001). In control group, the mean unstimulated salivary flow rate was 0.37 ± 0.07 mL/min. There was a 21.62% increase in salivary flow (0.45 ± 0.07 mL/min) during the TENS application and the difference was highly significant (p<0.001). An increase in mean salivary flow rate both in males and females after TENS application in both groups (p<0.001) was noted. The difference between unstimulated, stimulated and mean difference in salivary flow rate between males and females was not statistically significant in both groups (p>0.05). Conclusion: TENS can be an effective therapy in increasing whole salivary flow rates in patients with xerostomia

Effectiveness of Transcutaneous Electrical Nerve Stimulation Therapy on whole Salivary Flow in Patients with Xerostomia and Healthy Adults

Objective: To evaluate and compare the effectiveness of transcutaneous electrical nerve stimulation (TENS) therapy on whole salivary flow in patients with xerostomia and healthy adults. Material and Methods:  Thirty subjects with a history of xerostomia and subjects with unstimulated salivary flow equal to or less than 0.5 ml in 5 min were included in the study group, and 30 healthy subjects were included in the control group. Low forced spitting unstimulated saliva was collected for five minutes in a test tube fitted with a funnel. Then electrode pads of the TENS unit were applied bilaterally on skin overlying the parotid glands and at optimal intensity, stimulated saliva was collected for 5 minutes with the same method in a separate graduated test tube. The salivary flow rate (per minute) was calculated by dividing the amount of collected saliva (volume in mL) by the duration of collection period (5 minutes) and the salivary flow rates prior and after electrostimulation were compared for both groups. The Student’s t-test (unpaired and paired) was performed for group-wise comparisons. Results: In study group, the mean unstimulated salivary flow rate was 0.07 ± 0.01 mL/min. There was an 85.71% increase in salivary flow (0.13 ± 0.03 mL/min) during the TENS application and the difference was highly significant (p<0.001). In control group, the mean unstimulated salivary flow rate was 0.37 ± 0.07 mL/min. There was a 21.62% increase in salivary flow (0.45 ± 0.07 mL/min) during the TENS application and the difference was highly significant (p<0.001). An increase in mean salivary flow rate both in males and females after TENS application in both groups (p<0.001) was noted. The difference between unstimulated, stimulated and mean difference in salivary flow rate between males and females was not statistically significant in both groups (p>0.05). Conclusion: TENS can be an effective therapy in increasing whole salivary flow rates in patients with xerostomia

Intramedullary nailing versus plating in shaft humerus fractures: a prospective randomized study

Introduction- The two most commonly used modalities of internal fixation in fracture shaft of humerus are Plate osteosynthesis and Intramedullary nailing. The present study aims to analyze and compare both the techniques in terms of functional and radiological outcome. Material and Methods- 43 patients with diaphyseal fracture humerus were treated with Intramedullary nailing and plating between March 2015 and March 2016. The inclusion criteria were patients with closed diaphyseal fracture humerus. Compound fractures, pathological fractures, Non-union, mal-union fractures were excluded from the study. Results- 22 (51.2%) cases were operated using the antegrade nailing technique whereas dynamic compression plating was done in 21 (48.8%) cases. The mean age was 42±4.2 years. Road traffic accident was the most common mechanism of injury with 29 (67.5%) cases. 12-A2 type of fracture pattern were most common involving 23 (53.5%) cases. The mean surgical time was 68 mins in cases where nailing was done and 115 mins in cases with plating (P<0.001). Radiological union was seen at 13±4.8 weeks and 15±3.9 weeks in the nailing and plating group respectively. There were 2 (9.09%) cases in the nailing group and 1 (4.7%) case in the plating group which had delayed union. 3 (13.6%) cases in the nailing group had post-operative shoulder stiffness. The mean ASES score at the end of one year was 31.3 in nailing andBackground: The two most commonly used modalities of internal fixation in fracture shaft of humerus are plate osteosynthesis and intramedullary nailing. The present study aims to analyze and compare both the techniques in terms of functional and radiological outcome.Methods: 43 patients with diaphyseal fracture humerus were treated with Intramedullary nailing and plating between March 2015 and March 2016. The inclusion criteria were patients with closed diaphyseal fracture humerus. Compound fractures, pathological fractures, non-union, mal-union fractures were excluded from the study.Results: 22 (51.2%) cases were operated using the antegrade nailing technique whereas dynamic compression plating was done in 21 (48.8%) cases. The mean age was 42±4.2 years. Road traffic accident was the most common mechanism of injury with 29 (67.5%) cases. 12 A2 type of fracture pattern were most common involving 23 (53.5%) cases. The mean surgical time was 68 minutes in cases where nailing was done and 115 minutes in cases with plating (P <0.001). Radiological union was seen at 13±4.8 weeks and 15±3.9 weeks in the nailing and plating group respectively. There were 2 (9.09%) cases in the nailing group and 1 (4.7%) case in the plating group which had delayed union. 3 (13.6%) cases in the nailing group had post-operative shoulder stiffness. The mean ASES score at the end of one year was 31.3 in nailing and 29.6 in plating group (P =0.327). There were 37 (86.5%) cases with excellent to good results. Conclusions: Nailing and plating have equal functional outcomes in cases with shaft humerus fracture.29.6 in plating group (P=0.327). There were 37 (86.5%) cases with excellent to good results. Conclusion- Nailing and plating have equal functional outcomes in cases with shaft humerus fracture

Recall System in Dental Practice: A Review

The patients are generally encouraged to attend their recall visits at regular intervals of six months, irrespective of the individual's risk of developing dental disease. The major important role of the dental recall has been seen as the prevention and early detection of dental caries and periodontal disease in particular. The recommendation of a six-month recall interval has become a mandatory practice in dental clinics. Thus, this paper reviews about the guidelines relating to the recall of the patients, various types of recall systems and how we can establish a recall visit. In addition, the paper focuses about the ideal recall visit as well