Selective kinase inhibition with daily imatinib intensifies toxicity of chemotherapy in patients with solid tumours

The aim of this study was to determine the safety and maximum-tolerated doses of imatinib combined with cytotoxic chemotherapy (either gemcitabine or doxorubicin). Patients with advanced solid tumours were enrolled separately in two different combinations of imatinib with chemotherapy (imatinib + gemcitabine or imatinib + doxorubicin). A standard modified Fibonacci inter-cohort dose escalation was planned for each combination. Sixteen patients were accrued. Seven patients received gemcitabine and imatinib. A separate cohort of nine patients received imatinib and doxorubicin. In both groups, dose-limiting toxicity (DLT) was observed at the initial dose level requiring dose reductions for subsequent cohorts. Further DLTs were observed necessitating closure of the protocol. Daily dosing of imatinib with concurrent administration of cytotoxic chemotherapy (either gemcitabine or doxorubicin) at standard doses was associated with toxicity that was clinically unacceptable. It remains unclear whether addition of growth factors might improve tolerability for imatininb in combination with cytotoxic chemotherapy.     

P53, COX-2, iNOS protein expression changes and their relationship with anti-oxidant enzymes in surgically and multi-modality treated esophageal carcinoma patients

Esophageal carcinoma has a high incidence in India but its etiology remains unknown. In the present study the correlation between apoptosis regulatory proteins and anti-oxidant enzymes in 40 esophageal carcinoma patients was examined. Patients in one group were operated by transhiatal esophagectomy and in the second group were administered cisplatin (30 mg/m2/day) and 5-fluorouracil (5-FU) (750 mg/m2/day) daily for three days followed by surgery after four weeks of neo-adjuvant therapy (NAT). Complete pathological response was achieved in 15% of patients. Results obtained by Western blot analysis showed over-expressed p53 and COX-2 protein levels in the tumor tissues as compared to the adjoining tissue and its paired normal mucosa in both groups of patients. Immunohistochemical studies showed heterogenous p53 staining pattern with sections showing both nuclear and cytoplasmic staining with 36.8% mild, 10.5% moderate and 52.6% intense p53 immunoreactivity. Both COX-2 and iNOS immunostaining revealed 25% negative and 75% mild to strongly positive immunoreactivity. Correlation studies demonstrated a positive relationship between p53 and COX-2 (P=0.030; r = +0.70) in surgically treated patients. The association of COX-2 and p53 with various anti-oxidant enzymes showed a significantly positive correlation between COX-2 expression and catalase activity and an inverse correlation between p53 expression and superoxide dismutase and catalase activity in the tumor tissue of patients given NAT. In addition, we observed a negative trend between p53 expression levels and GPx enzyme levels in both the adjoining and tumor tissue of patients having undergone surgery as main mode of treatment.     

Design and synthesis of the first generation of dithiolane thiazolidinedione- and phenylacetic acid-based PPARgamma agonists

A series of novel derivatives of potent antioxidant vitamin, alpha-lipoic acid, and related analogues were designed, synthesized, and evaluated for their PPARgamma agonist activities. Compounds 9a and the water soluble analogue11e were found to be potent PPARgamma agonists. Compound 9a appeared to have a significant role in improving insulin sensitivity and reducing triglyceride levels in fa/fa rats as well as inhibited proliferation of a variety of normal and neoplastic cultured human cell types. These novel compounds may prove efficacious not only in the treatment of Type 2 diabetes, but also atherosclerosis, prevention of vascular restenosis, and inflammatory skin diseases.     

Methylphenidate and cocaine: a placebo-controlled drug interaction study

Up to thirty percent of cocaine addicted individuals may meet diagnostic criteria for Attention-Deficit/Hyperactivity Disorder (ADHD). Methylphenidate (MPH) is a highly effective and commonly used treatment for ADHD but, like cocaine, is a cardiovascular and central nervous system stimulant with the potential to cause toxicity at high doses. The present study was undertaken to investigate the likelihood of a toxic reaction in individuals who use cocaine while concurrently taking MPH. Seven non-treatment seeking cocaine-dependent individuals completed this placebo-controlled, crossover study with two factors: Medication (placebo, 60 mg MPH, 90 mg MPH) and Infusion (saline, 20 mg cocaine, 40 mg cocaine). Physiological measures included vital signs, adverse events, and electrocardiogram. Subjective response was measured with visual analog scale (VAS) ratings of craving and drug effect. Cocaine pharmacokinetic parameters were calculated for each participant at each drug combination, using a non-compartmental model. MPH was well tolerated, did not have a clinically significant impact on cocaine's physiological effects, and decreased some of the positive subjective effects of cocaine. MPH did not significantly alter the pharmacokinetics of cocaine. The study results suggest that MPH at the doses studied can likely be used safely in an outpatient setting with active cocaine users.     

A clinical sign to predict difficult tracheal intubation: a prospective study

It has been suggested that the size of the base of the tongue is an important factor determining the degree of difficulty of direct laryngoscopy. A relatively simple grading system which involves preoperative ability to visualize the faucial pillars, soft palate and base of uvula was designed as a means of predicting the degree of difficulty in laryngeal exposure. The system was evaluated in 210 patients. The degree of difficulty in visualizing these three structures was an accurate predictor of difficulty with direct laryngoscopy (p less than 0.001).     

Peritoneal dialysis in obstructive jaundice: an experimental study

Rats were subjected to common bile duct ligation, after which intermittent peritoneal dialysis with a buffered solution containing rat plasma proteins was carried out in an attempt to reduce plasma bilirubin levels. Plasma bilirubin increased significantly (P less than 0.01) on the seventh day and was still rising 12 days after ligation of the common bile duct. Dialysis was performed during the second postoperative week. Provided that rat plasma protein was present in the dialysing fluid, dialysis significantly reduced (P less than 0.01) the levels of total plasma bilirubin, conjugated bilirubin and serum GPT in the experimental animals.     

Solid state polymerization of a nitrophenoxy disubstituted diacetylene

The solid state polymerization of the disubstituted diacetylene 1,6-bis(2,4-dinitrophenoxy)-2,4-hexadiyne by thermal annealing at 130°C to yield high quality polymer single crystals is reported. This compound is unique in that it polymerizes by thermal annealing but not under ordinary x-ray conditions, thus allowing determination of the crystal structures of both the monomer and polymer by x-ray diffraction. The conditions for solid state polymerization and the structural changes during polymerization were investigated. In addition, the kinetics of polymerization were studied by differential scanning calorimetry. An induction period with activation energy E_A(slow) = 139,7 ± 3 kJ/mol (33,4 ± 0,7 kcal/mol) is followed by a rapid polymerization regime with activation energy E_A(fast) = 132,2 ± 6 kJ/mol (31,6 ± 1,5 kcal/mol) during which first order kinetics are obeyed. The total heat of polymerization is ? ΔH_p = 134,7 ± 6 kJ/mol (32,2 ± 1,5 kcal/mol). After polymerization, a disordering phase change takes place with continued isothermal annealing which becomes clearly evident at isothermal annealing temperatures higher than 130°C.     

Seminal fructose, citric acid and phosphatase levels and their relation to the sperm count in man

Seminal fructose, citric acid and phosphatase levels were estimated in 60 normal adults and compared with 60 oligospermic and 24 azoospermic Indian subjects. In normal group, the seminal plasma fructose level and acid phosphatase activity showed a fall as the sperm count increased. As compared to normals, significantly higher mean values for fructose and acid phosphatase activity were observed in oligospermic and azoospermic groups. Seminal alkaline phosphatase activity did not show any relationship with sperm count. Similarity in changes observed in seminal fructose and acid phosphatase levels with respect to seminal citric acid content and sperm concentration suggests that both these parameters are probably regulated by similar physiological mechanism.