Pulmonary protective efficacy of S-2[2-aminoethylamino] ethyl phenyl sulphide (DRDE-07) and its analogues against sulfur mustard induced toxicity in mice.

Our previous study showed that percutaneous sulfur mustard (SM) exposure induced pulmonary toxicity, which was attenuated by DRDE-07 (S-2[2-aminoethylamino] ethyl phenyl sulphide) pretreatment. The present study aimed to evaluate the protective efficacy of DRDE-07 and its analogues viz., DRDE-30 (S-2(2-aminoethyl amino)ethyl propyl sulphide) and DRDE-35 (S-2(2-aminoethyl amino)ethyl butyl sulphide) against SM. Thirty minutes before percutaneous SM (0.8 LD50) exposure, female Swiss mice were orally gavaged with DRDE-07 and its analogues(0.2 LD50). Animals were sacrificed on day 3 and 7, BAL fluid (BALF) and lung tissue were collected for biochemical, histopathological studies. As results, DRDE-07 and its analogues were beneficial in reducing the number of BALF inflammatory cells, protein level, lactate dehydrogenase (LDH) activity, myeloperoxidase (MPO) and ß-glucuronidase activity, while content of BALF and lung reduced glutathione level (GSH) were significantly protected. The pretreatment of DRDE-07 and its analogues inhibited the recruitment of inflammatory cells into the lung. The beneficial effects of DRDE-07 and its analogues were attributed to their antioxidant and anti-inflammatory activity. Among the analogues, DRDE-30 exhibited significant beneficial effects as compared to the other two compounds. These analogues may be considered as prototype candidate molecules as there is no effective antidote for SM toxicity.

Prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) against sulfur mustard induced lung toxicity in mice.

OBJECTIVE: The present study was planned to investigate the prophylactic efficacy of S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07), against topically applied SM induced pulmonary toxicity in mouse. MATERIALS AND METHODS: Animals were pretreated with S-2(2-aminoethylamino)ethyl phenyl sulfide (DRDE-07) (249.4 mg/kg by oral gavage) 30 minutes before SM exposure. The SM (6.48 mg/kg) was applied on hair clipped dorsocaudal region (percutaneous) of the animal. The animals were sacrificed on day 1, 3, 5 and 7. The biochemical changes those were observed in the bronchoalveolar lavage (BAL) fluid and lung tissue included protein, LDH, MPO, ß-glucuronidase, MMP-2, MMP-9, activated macrophages, reduced glutathione and lipid peroxidation level. RESULTS AND DISCUSSION: Pretreatment with DRDE-07 (0.2 LD50) attenuated SM-induced changes at all time point tested. BAL fluid biochemical endpoints indicated epithelial and endothelial cell damages as evidenced by increase in BAL protein, LDH level and increased number of activated macrophages. The increased myeloperoxidase activity and ß-glucuronidase level exhibited the degranulation of neutrophils due to SM toxicity in lung. The zymogrphy analysis of BAL fluid showed a significant increase in matrix metalloproteases (MMP) activity due to inflammatory cells accumulation. CONCLUSION: Thirty minutes pretreatment with DRDE-07 decreased vascular permeability reduced the inflammation and oxidative stress, hence may be recommended as a potential prophylactic agent for SM intoxication.

Predischarge non-invasive risk assessment for prediction of significant hyperbilirubinemia in term and late preterm neonates.

OBJECTIVE: To evaluate efficacy of predischarge transcutaneous bilirubin (TcB) measurement and clinical risk assessment in predicting hyperbilirubinemia needing treatment. STUDY DESIGN: A diagnostic test was performed in a prospective cohort study conducted at a teaching hospital in North India. Subjects included healthy neonates with a gestation period of ≥35 weeks or birth weight ≥2000 g. Maternal, neonatal and delivery risk factors for hyperbilirubinemia were prospectively collected. TcB was measured in all enrolled neonates at 24±6, 72 to 96 and 96 to 144 h of postnatal age and when indicated clinically. Neonates were followed up during hospital stay and after discharge till completion of the 7th postnatal day. The key outcome was significant hyperbilirubinemia defined as need of phototherapy on the basis of modified American Academy of Pediatrics guidelines. In neonates born at ≥38 weeks of gestation and in neonates born at ≤37 completed weeks of gestation, middle line and lower line of phototherapy thresholds were used to initiate phototherapy, respectively. Variables observed to be significantly associated with significant hyperbilirubinemia on multivariate analysis were used for construction of a clinical risk assessment tool. Predictive ability of the risk assessment tool was assessed by calculating sensitivity, specificity, positive predictive value and negative predictive value, by plotting receiver-operating characteristics curve and calculating c-statistic. RESULT: A total of 997 neonates (birth weight: 2627±536 g, gestation: 37.8±1.5 weeks) were enrolled in the study, of which 931 completed follow-up. Among enrolled neonates, 344 (34.5%) were low birth weight. Overall, a total of 199 (20%) neonates developed significant hyperbilirubinemia. On stepwise logistic regression analysis, predischarge TcB percentile and gestation were significantly found to be associated with significant hyperbilirubinemia. A risk assessment graph was constructed to predict subsequent development of significant hyperbilirubinemia. Area under curve for this risk assessment strategy was 0.75. CONCLUSION: A risk assessment graphical tool consisting of TcB and gestation accurately predicted subsequent need of phototherapy. Further studies are needed to validate performance of this risk assessment tool.

Common reasons for hospitalization among adult patients with diabetes in a private medical college in Kathmandu.

Diabetes Mellitus is one of the important non communicable disease affecting the adult populations around the world. Incidence of diabetes increasing in South Asia. Nepal is also experiencing increasing in diabetes disease burden. Diabetes mellitus is one of the important causes of hospital admission in the western world. In this study we evaluated the causes of hospital admission amongst diabetic population. Most common cause is of diagnosis is some forms of infections commonest (20%) being urinary tract infections. Ten out of total 69 patients had septicemia. Six patients out of 69 had sputum positive pulmonary tuberculosis only one patient presented with metabolic complications of diabetes i.e. diabetic ketoacidosis. Coronary artery disease with heart failure was present in 14 patients. Five patients had diabetic nephropathy and 3 had retinopathy. This shows that infections is the major cause of hospital admission for diabetics followed by heart failure. Tuberculosis is important diagnosis in person with diabetes. This study shows more female patients get admitted and amongst admitted patents glycemic control is poor. This signify that women had more complications than male counter parts.

Profile of ascites patient admitted in Nepal Medical College Teaching Hospital.

Ascites is one of the frequently encountered problems in internal medicine. Common causes of ascites are portal hypertension including cirrhosis of liver and congestive heart failure, hypoalbuminemia associated with nephrotic syndrome, intra-abdominal malignancy and abdominal tuberculosis. We evaluated 43 patients presented with ascites in Nepal Medical College Teaching Hospital (NMCTH). After history taking, clinical examination, imaging studies and laboratory evaluation alcoholic liver disease and abdominal tuberculosis were diagnosed in 19 and 5 patients restively. Constrictive pericarditis was diagnosed in 2 patients and 2 patients were suffering from HCV related liver disease. Present study revealed alcoholic liver disease as the commonest cause of ascites.

Evaluation of analogues of DRDE-07 as prophylactic agents against the lethality and toxicity of sulfur mustard administered through percutaneous route.

Sulfur mustard (SM), chemically bis (2-chloroethyl) sulfide is a bifunctional alkylating agent that causes serious blisters on contact with human skin. Although several antidotes have been reported for the systemic toxicity of SM in experimental animals none of them are approved so far and decontamination of SM immediately by physical or chemical means is recommended as the best protection. Two compounds amifostine [S-2(3-aminopropylamino) ethyl phosphorothioate] and DRDE-07 [S-2(2-aminoethylamino) ethyl phenyl sulfide] gave very good protection as an oral prophylactic agent against SM the in mouse model, but in the rat model the protection was only moderate. In the search for more effective and less toxic compounds, a number of analogues of DRDE-07 were synthesised and their protective efficacy was evaluated in mouse and rat models. The LD50 of S-aryl substitution was between 1 and 2 g kg(-1) and S-alkyl substitution was more than 2 g kg(-1). In the mouse model, DRDE-07, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 gave about 20 fold protection, and DRDE-23 and DRDE-38 gave less protection of 4.8 and 9.0 fold respectively, against percutaneously administered SM. In the rat model, DRDE-07, DRDE-09, DRDE-10 and DRDE-21 gave about two fold protection. Percutaneously administered SM (19.33 mg kg(-1)) significantly depleted the hepatic GSH content in mice. Pretreatment with DRDE-21 significantly elevated the levels. A 4.4 fold increase in % DNA fragmentation was observed 7 days after SM administration (19.33 mg kg(-1)) in mice. Pretreatment with DRDE-07, DRDE-09, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 significantly protected the mice from SM induced DNA damage. The histopathological lesions in liver and spleen induced by percutaneously administered SM was reduced by pretreatment with DRDE-07, DRDE-09, DRDE-10 and DRDE-21. These analogues may prove as prototypes for the designing of more effective prophylactic drug for SM.

In vivo protection by amifostine and DRDE-07 against sulphur mustard toxicity.

The study was aimed at investigating the prophylactic efficacy of orally administered amifostine and a newly synthesized compound, S-2(2-amino-ethylamino)ethyl phenyl sulphide (DRDE-07), against dermally applied sulphur mustard (SM) in mice and rats. The LD50 values of amifostine and DRDE-07 were determined following oral and intraperitoneal routes and the LD50 of SM diluted in PEG-300 was determined following dermal route. Amifostine or DRDE-07 (equivalent to their 0.05 LD50, 0.10 LD50 and 0.20 LD50) dissolved in water was fed to mice and rats and, after 30 min, various doses of SM were applied to the hair-clipped area of the skin and were observed for 14 days for mortality. The protection index (PI) was calculated as a ratio of LD50 with treatment to LD50 without treatment. The estimated percutaneous LD50 of SM was found to be 8.1 and 2.4 mg/kg for female mice and male rats, respectively. A dose-related protection was observed with all the three doses of both compounds. Thirty minutes prior, the administration of amifostine in female mice offered a PI of 3.0 at the lowest pretreatment dose (52.5 mg/ kg) followed by PI of 6.7 and 9.5 at 105 and 210 mg/kg pretreatment doses, respectively. DRDE-07 offered better protection against SM in female mice, i.e., a PI of 4.8 at pretreatment dose of 62.5 mg/kg, a PI of 12.0 at the dose of 124.7 mg/kg and a PI of 27.0 at the dose of 249.4 mg/kg. In male rats, DRDE-07 gave a PI of about 3.0 at all the three pretreatment doses (80, 160 and 320 mg/kg), whilst amifostine offered a PI of 3.1 at the highest pretreatment dose (452 mg/kg). The present study showed that oral administration of both amifostine and DRDE-07 was effective as a prophylactic agent for protecting against SM toxicity, and that DRDE-07 offered better protection.

Protective effects of amifostine and its analogues on sulfur mustard toxicity in vitro and in vivo.

Sulfur mustard (bis(2-chloroethyl)sulfide, SM) is a highly reactive bifunctional alkylating agent that forms sulfonium ions in the body. SM alkylates DNA, leading to DNA strand breaks and cell death in a variety of cell types and tissues. Although several approaches have been proposed to challenge the toxic action(s) of SM, no satisfactory treatment regimen has evolved. The synthetic aminothiol amifostine, earlier known as WR-2721 (S-2-(3-aminopropylamino)ethyl phosphorothioate), has been extensively used as a chemical radioprotector for the normal tissues in cancer radiotherapy and chemotherapy. SM is known as a radiomimetic agent and this prompted us to evaluate the protective efficacy of amifostine (2.5 mM) and three of its analogues, DRDE-06 (S-2 (3-aminopropylamino) ethyl phenyl sulfide), DRDE-07 (S-2 (2-aminoethylamino) ethyl phenyl sulfide), and DRDE-08 (S-2 (4-aminobutylamino) ethyl phenyl sulfide), against SM toxicity in rat liver slices. Of the four agents tested, a 30-min pretreatment of amifostine and DRDE-07 enhanced the LC50 (a concentration producing 50% leakage of lactate dehydrogenase (LDH) or alanine aminotransferase (ALT)) of SM by 5.9- and 3.3-fold for LDH and 10.2- and 5.5-fold for ALT, respectively. Except DNA fragmentation, both these agents significantly attenuated the loss of intracellular K(+) and mitochondrial integrity (MTT assay), depletion of GSH levels, and histopathology produced by a toxic concentration (80 microM) of SM. However, when amifostine and DRDE-07 were introduced 2 h after SM, no significant protection was observed. SM (77.5 or 155 mg/kg) was also applied dermally on female albino mice and challenged by 0.20 LD50 (po) of amifostine, DRDE-06, DRDE-07, or DRDE-08 at -30 min, 0 min, or +6 h. Protection was observed only when the agents were administered at -30 min or 0 min; posttreatment (+6 h) did not offer any protection. The magnitude of in vivo protection was in the following order: DRDE-07 >or= amifostine > DRDE-08 > DRDE-06. Gas chromatographic analysis showed that there was no direct chemical interaction between SM and the antidotes. The po LD50s of amifostine, DRDE-06, DRDE-07, and DRDE-08 were 1049, 1345, 1248, and 951 mg/kg, respectively. Both in vitro and in vivo data indicate promising roles of amifostine and DRDE-07 as prophylactic agents against SM poisoning.

Synthesis and QSAR of some 3-amino-2-(substituted)aminomethyl-5,6-disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones as novel H1-receptor antagonists.

The present study describes the synthesis and quantitative structure activity relationships (QSAR) of novel 3-amino-2-(substituted)aminomethyl-5,6-disubstitutedthieno[2,3-d] pyrimidin-4(3H)-ones for their potent H1-receptor antagonist activity on the guinea pig ileum. With the IC50 values in the range of 10(-5) gms/lit, all the compounds tested were found to possess ten fold higher affinity to the H1-receptor than diphenhydramine and cetirizine, but lower than astemizole and loratidine. The sedative potential of these compounds was found to be lower than cetirizine and astemizole but comparable to loratidine. The QSAR study indicates a parabolic relationship of the biological activity mainly with the steric parameters and partly with the lipophilic parameters.

Treatment of typhoid fever: randomized trial of a three-day course of ceftriaxone versus a fourteen-day course of chloramphenicol.

To compare the efficacy of a short course of ceftriaxone with a standard course of chloramphenicol for typhoid fever, a randomized trial was conducted in 46 patients (30 adults and 16 children) who were blood culture-positive for Salmonella typhi or S. paratyphi. Ceftriaxone was given intravenously once a day for three days to 15 adults at a dose of 2 g/day and to eight children at a dose of 50 mg/kg/day. Chloramphenicol was given orally four times a day to an equal number of patients at a dose of 60 mg/kg/day until defervescence, followed by 40 mg/kg/day for a total of 14 days. Clinical cure without complications or relapse occurred in 19 patients (83%) treated with ceftriaxone and in 20 patients (87%) treated with chloramphenicol (P > 0.05). Four patients with clinical failures in the ceftriaxone group included two with fever lasting six days or more, one with altered sensorium, and one with relapse; three patients treated with chloramphenicol developed leukopenia and thrombocytopenia and were switched to amoxicillin therapy. Bacteriologically, blood cultures of all 46 patients were sterile three days after the start of treatment, and remained so through day 15 of follow-up. These results extend previous observations on the efficacy of ceftriaxone in short courses for both adults and children with typhoid fever.

Infant growth charts.

Detection and monitoring childhood growth disorders requires the correct use of growth charts. A check on the accuracy of every point plotted on Gairdner-Pearson growth charts of premature infants in a hospital paediatric department was carried out. Errors beyond set limits were recorded. Of 611 points plotted on the growth charts of 50 premature infants who were at least 1 year of age at the time of the study, there were 173 (28.5%) points plotted in error. Altogether 94.7% of the errors occurred when plotting the age along the horizontal (X) axis of the growth chart, irrespective of whether weight, length, or head circumference was being measured. There was no evidence that the errors caused appreciable changes in clinical management. Potential sources of error identified were failure to adjust for prematurity correctly, inaccuracy in calculating age, and the use of the logarithmic scale. These errors could be serious and it is important that there should be greater vigilance in using growth charts. The use of age calculators or improved chart design is recommended. Assessment of the use of other growth charts in different settings is also suggested.

Emblica officinalis Gaertn and serum cholesterol level in experimental rabbits.

Twelve albino rabbits of either sex weighing 1.0-1.25 kg were fed a standard laboratory diet of green grass and sattu (roasted Bengal gram). After a 2-week run-in period their serum cholesterol levels were estimated. All animals were now fed 0.5 g cholesterol and 1.0 g clarified butter daily and were not divided into 3 groups of 4 animals each. While all received the standard cholesterol-rich diet, Group A animals received no additional substances, animals in Group B were each fed 10 mg vitamin C daily, while those in Group C were each given 1.0 g fresh Amla (Emblica officinalis Gaertn). Mean serum cholesterol levels in all three groups rose to significantly higher levels by the end of the second week. There was a further rise by the end of the third and fourth weeks in Groups A and B. However, animals in Group C (i.e. those given Amla) showed significantly lower mean serum cholesterol levels at the end of the second week than their counterparts in Groups A and B. At the end of the third and fourth weeks the differences were even more pronounced.

Synthesis and pharmacological properties of some 4-amino-5-substituted thiazole-2(3H)-thiones and thiazolo(4,5-d)pyrimidin-7(6H)-one-2(3H)-thiones.

4-Amino-5-substituted thiazole-2(3H)-thiones and thiazolo(4,5-d)-pyrimidin-7(6H)-one-2(3H)-thiones have been synthesized and screened for antimicrobial and pharmacological activities. Significant analgesic, antiinflammatory, anticonvulsant and antimicrobial properties have been found in some of the compounds synthesized. Analgesic and antiinflammatory activities are reported for the first time in thiazole-2(3H)-thiones.

Synthesis of 3-substituted thieno [2, 3-d] pyrimidin-4(3H)-one-2-mercaptoacetic acids and their ethyl esters for pharmacological screening.

3-Substituted thieno [2, 3-d] pyrimidin-4(3H)-one-2-mercaptoacetic acids and their ethyl esters were synthesized from 2-mercaptothieno [2, 3-d] pyrimidin-4(3H]-ones, which were obtained by cyclization of thienylthioureas in acidic medium. Analgesic, anti-inflammatory, and anticonvulsant activities were found in some of these compounds. Significant antimicrobial activity was exhibited by thienylthioureas.