Evaluation of analgesic efficacy,gastrotoxicity and nephrotoxicity of fixed-dose combinations of nonselective,preferential and selective cyclooxgenase inhibitors with paracetamol in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) are combined with paracetamol (PCM) with a view to enhance analgesic efficacy and reduce gastric toxicity. However, there are reports of enhanced nephrotoxicity with nonselective NSAID with PCM combinations. The present study investigated the analgesic efficacy, gastrotoxicity and nephrotoxicity of nonselective, preferential and selective cyclooxgenase inhibitors and their combination with PCM in rats.Graded doses of ibuprofen, meloxicam and celecoxib alone and their combination with fixed dose of PCM were administered to the rats by gavage for 14 days. The results showed that PCM potentiated the analgesic effect of all three classes of NSAIDs significantly as evidenced by increase in tail-flick latency in radiant heat method. Dose-dependent gastromucosal damage was produced by all the drugs, which was augmented significantly with PCM in the form of decreased total carbohydrate/protein ratio of mucin and increased gastric ulcer index. It was further confirmed by histopathology of rat’s stomach. The renal histopathology was conducted to evaluate inflammation, tubular damage, papillary necrosis, and interstitial changes. Increased nephrotoxicity was observed with all NSAIDs in dose-dependent manner and in combination with PCM.Our study revealed the augmented analgesia as well as enhanced gastrotoxicity and nephrotoxicity with all three major NSAIDs classes when combined with PCM. These findings highlighted the need for large pharmacoepidemiological studies to evaluate the magnitude of gastrotoxicity and nephrotoxicity in population who are on long-term treatment with NSAID combinations.     

Role of fine‐needle aspiration cytology in tuberculosis of bone

This study was designed to evaluate the role of fine‐needle aspiration cytology (FNAC) in diagnosis of skeletal tuberculosis (TB). In this retrospective study, 20 cases were retrieved over a 10‐year period in which a cytologic diagnosis of osseous TB was rendered. The aspirations were performed with a 22‐gauge needle attached on a 20‐ml syringe after taking into consideration the radiological findings. The cytologic findings were subdivided into the following categories—epithelioid cell granulomas with necrosis, epithelioid cell granulomas without necrosis, and necrosis only. These cases were either with or without AFB positivity. The smears showed epithelioid cell granulomas in 23 cases (85.2%), multinucleate and Langhans' giant cells in 15 cases (55.6%), and inflammatory cells were noted in the background in 15 cases (55.6%). AFB was positive in six cases (22.7%). FNA provides a simple and safe outpatient procedure for the diagnosis of osseous TB and obviates the need of an open biopsy. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

Intensive care management of patients with acute intermittent porphyria: Clinical report of four cases and review of literature

Acute intermittent porphyria (AIP), the most common and the most severe form of acute hepatic porphyria, is an autosomal dominant condition. It results from lower-than-normal levels (less than 50%) of porphobilinogen (PBG) deaminase. Patients may present commonly with gastrointestinal complaints and neuropsychiatric manifestations. Diagnosis may be confirmed with the presence of intermediary metabolites of haem synthesis, amino levulinic acid (ALA) and PBG in urine or with specific enzyme assays. Abdominal pain is the most common symptom (90%). Peripheral polyneuropathy, primarily motor with flaccid paresis of proximal musculature, with or without autonomic involvement, is characteristic. Respiratory failure necessitates ventilator and intensive care support. Avoidance of precipitating factors and the use of haem preparations and intravenous dextrose form the basis of management. Gabapentin and propofol, rather than the conventional antiepileptics appear to be the appropriate choice for seizure control. Here, we present intensive care management of four cases of AIP with varying clinical presentation.     

The double-stranded RNA-activated protein kinase mediates radiation resistance in mouse embryo fibroblasts through nuclear factor kappaB and Akt activation.

PURPOSE: Activation of the double-stranded RNA-activated protein kinase (PKR) leads to the induction of various pathways including the down-regulation of translation through phosphorylation of the eukaryotic translation initiation factor 2alpha (eIF-2alpha). There have been no reports to date about the role of PKR in radiation sensitivity. EXPERIMENTAL DESIGN: A clonogenic survival assay was used to investigate the sensitivity of PKR mouse embryo fibroblasts (MEF) to radiation therapy. 2-Aminopurine (2-AP), a chemical inhibitor of PKR, was used to inhibit PKR activation. Nuclear factor-kappaB (NF-kappaB) activation was assessed by electrophoretic mobility shift assay (EMSA). Expression of PKR and downstream targets was examined by Western blot analysis and immunofluorescence. RESULTS: Ionizing radiation leads to dose- and time-dependent increases in PKR expression and function that contributes to increased cellular radiation resistance as shown by clonogenic survival and terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) apoptosis assays. Specific inhibition of PKR with the chemical inhibitor 2-AP restores radiation sensitivity. Plasmid transfection of the PKR wild-type (wt) gene into PKR(-/-) MEFs leads to increased radiation resistance. The protective effect of PKR to radiation may be mediated in part through NF-kappaB and Akt because both NF-kappaB and Akt are activated after ionizing radiation in PKR+/+ but not PKR-/- cells. CONCLUSIONS: We suggest a novel role for PKR as a mediator of radiation resistance modulated in part through the protective effects of NF-kappaB and Akt activation. The modification of PKR activity may be a novel strategy in the future to overcome radiation resistance.     

Hemodynamically significant PDA: An echocardiographic and clinical assessment of incidence,natural history,and outcome in very low birth weight infants maintained in negative fluid balance

Summary Fifty very low birth weight (VLBW) infants (750–1500 g, 27–33 weeks gestational age) were assigned at random to one of two groups of negative fluid balance and underwent prospective clinical and echocardiographic examinations during the first month of life. The purpose was to determine: (a) the effect of fluid restriction on the incidence of ductal shunting, (b) the reliability of the physical examination in diagnosing significant ductal shunting, and (c) the relationship between significant ductal shunting and outcome in such infants. None of the infants had manipulations to close the ductus during the first week of life. Using routine structural and functional echocardiographic indices as criteria for the diagnosis of hemodynamically significant ductal shunting (hsPDA), we found that the two fluid-balance groups (8%–10% weight loss vs 13%–15% weight loss) did not significantly differ in incidence of hsPDA, duration of ventilation, or development of BPD. These two groups were then combined for further analysis: 32 (64%) of 50 VLBW infants had hsPDA during the first week of life. The group of infants with hsPDA did not differ significantly from that without hsPDA in birth weight or gestational age, but had a significantly lower Apgar score (P<0.04) and was significantly more likely to require ventilator support for RDS (P<0.01). Although when present a typical ductal murmur was specific for the development of significant ductal shunting, no murmur was heard in 21 (66%) of 32 infants with early hsPDA. Of the infants requiring ventilator support for RDS, the group with early hsPDA needed ventilation for 13.8±9.4 days, significantly longer than the group without early hsPDA (3.2±2.6 days,P<0.001), and had a higher incidence of BPD and death than the group without early hsPDA (P<0.04). In our study of a large group of prospectively identified VLBW infants, we did not find that significant ductal shunting was altered by more stringent fluid restriction, but we did find that such shunting was frequently inapparent clinically, and was associated with significantly increased morbidity and mortality.This research was supported in part by Children's Hospital Research Foundation; DHHS-USPHS, MCH grant 000174; American Heart Association, SWOC; and by DRR CLINFO grant RR00068-18-52, General Clinical Research Center.     

Antitumor and Radiosensitizing Effects of Withaferin a on Mouse Ehrlich Ascites Carcinoma in vivo

The antitumor and radiosensitizing effects of withaferin A (WA), a steroidal lactone from Withania somnifera, was studied on Ehrlich ascites carcinoma in vivo. The acute LD₅₀₍₁₄₎ for WA in Swiss mice was ∼ 80 mg/kg. Twenty-four hours after i.p. inoculation of 10⁶ tumor cells, WA was injected i.p. at different dose fractions (5 or 7.5 mg/kg × 8, 10 mg/kg × 5, 20 or 30 mg/kg × 2) with or without abdominal gamma irradiation (RT, 7.5 Gy) after the first drug dose. Increase in life span and tumor-free survival were studied up to 120 days. The drug inhibited tumor growth and increased survival, which was dependent on the WA dose per fraction rather than the total dose. Combination of RT with all the drug schedules increased tumor cure and tumor-free survival, the best effect seen after 2 fractions of 30 mg/kg each. In another experiment WA was given as 2 (40 mg/kg × 2), 3 (30 mg/ kg × 3) or 4 (20 mg/kg × 4) fractions at 5, 7 or 10 days after tumor inoculation with or without RT after the first drug dose. At 7 and 10 days after inoculation the drug was effective only at 40 mg/kg × 2, but with RT 30 mg/kg × 3 produced an equal effect (20% survival) on 7 day old tumors.     

Isolation and evaluation of diagnostic value of two major secreted proteins of Mycobacterium tuberculosis

Two secreted antigens of Mycobacterium tuberculosis, namely the antigen 85 complex (30/31) and 38kDa antigens, were purified from the whole culture filtrate by using two dimensional preparative electrophoresis and anion exchange chromatography, respectively. Individual components of the antigen 85 complex namely, antigen 85A, 85B and 85C, were separated using hydrophobic interaction chromatography. The humoral antibody activity to these antigens in sputum positive cases of active pulmonary tuberculosis and normal healthy volunteers was determined by enzyme linked immunosorbent assay (ELISA) and immunoblot. Recombinant 38kDa and antigen 6 were used as reference antigens for the assay. None of the healthy volunteers reacted with the 38kDa antigen, while 52% of the TB sera reacted with it. Of the three components of the antigen 85 complex, 85B gave the highest positivity of 40 per cent. The results of combination of 38kDa with antigen 6 offered better results with 76% positivity.