SYNTHESIS AND BIOLOGICAL EFFICACY OF NOVEL PIPERAZINE ANALOGUES BEARING QUINOLINE AND PYRIDINE MOIETIES.

A series of novel piperazine analogues bearing quinolin-8-yloxy-butan--ones/pyridin-2-yloxy-ethanones were synthesized by a simple and convenient approach based on various substituted piperazine incorporating quinoline and pyridine moieties. The analogues were evaluated for in vitro antioxidant activity against 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and ferrous ion radical scavenging activities and anti-inflammatory activity by inhibition of Vipera russelli venom (PLA2) and gastric K+/H(+)-ATPase activities. Most of the title compounds exhibited promising activity. Best antioxidant and PLA2-inhibiting activities were found for piperazine analogues with phenyl and nitro phenyl groups, whereas methoxy group on phenyl piperazine indicated selectivity for the H+/K(+)-ATPase.

DAO-9 (2,5-di(4-aryloylaryloxymethyl)-1,3,4-oxadiazole) exhibits p53 induced apoptogenesis through caspase-3 mediated endonuclease activity in murine carcinoma.

One of the main strategies to inhibit the tumor growth is to promote the biochemical events leading to DNA degradation, which would eventually culminate in apoptosis. We have earlier reported that the 2,5-di(4-aryloylaryloxymethyl)-1,3,4-oxadiazole(DAO-9) possessed anti-cancer activity. To address the exact molecular mechanism underlying anti-cancer property, present study focused on evaluating the anti-tumor effect of the DAO-9 on murine ascites carcinoma cells using various in vivo and in vitro assays. The in vivo assays implicated a strong regression in tumor growth of ascites carcinoma after treatment which is due to apoptogenic efficacy as assessed through structural morphology of EAC cells by Giemsa, Acridine orange, Annexin V staining and FACS analysis. Nucleosomal DNA fragmentation induced by DAO-9 is due to activation of caspase-3 mediated DNAse as verified by endonuclease assays and immunoblot analysis. The caspase-3 activation mechanism is by induction of intrinsic cascade signaling molecules, such as p53, Bax, Bad and cytochrome c (cyt c) expression as verified by western blot. The results concluded that the tumor inhibiting activity of DAO-9 is due to activation of the apoptotic signaling cascade, which could be translated into targeted anti-cancer drug in the near future.

(4-Fluoro-phen-yl)(2-hy-droxy-5-methyl-phen-yl)methanone.

In the title compound, C14H11FO2, the dihedral angles beteen the central C3O ketone residue and the fluoro- and hy-droxy-substituted benzene rings are 50.44 (9) and 12.63 (10)°, respectively. The planes of the benzene rings subtend a dihedral angle of 58.88 (9)° and an intra-molecular O-H⋯O hydrogen bond closes an S(6) ring. No directional inter-actions beyond van der Waals packing contacts were identified in the crystal structure.

(4-Fluoro-phen-yl)(4-hy-droxy-3-methyl-phen-yl)methanone.

In the title compound, C14H11FO2, the two benzene rings are not coplanar, with a dihedral angle of 57.45 (12)° between their planes. In the crystal, mol-ecules are linked by an O-H⋯O hydrogen bond, forming a 21 helical chain along the b axis.

(4-Hy-droxy-3,5-di-methyl-phen-yl)(phen-yl)methanone.

In the mol-ecule of the title compound, C15H14O2, the dihedral angle between the benzene and phenyl rings is 61.27 (8)°. In the crystal, O-H⋯O and weak C-H⋯O hydrogen bonds link the mol-ecules into chains extending along the c-axis direction.

Synthesis and anti-inflammatory activity of 2-(2-aroylaroxy)-4,6-dimethoxy pyrimidines.

Reaction of 6a-f individually with 2-methylsulfonyl-4,6-dimethoxypyrimidine yielded 7a-f in excellent yield. The newly synthesized heterocycles were characterized by IR, (1)H NMR, and mass spectral data. Compounds 7a-f was screened for their anti-inflammatory activity and were compared with standard drugs. Of the compounds studied, the compound 7e showed more potent activity than the standard drugs at all doses tested.

Synthesis and crystallographic analysis of benzophenone derivatives--the potential anti-inflammatory agents.

Fries rearrangement of substituted phenyl benzoates 1a-j to substituted hydroxy benzophenones 2a-j was achieved in excellent yield. Further benzoylation of 2a-j to benzoyloxy benzophenones 4a-n, a benzophenone analogue was achieved in good yield. All the newly synthesized compounds were evaluated for their anti-inflammatory activity and were compared with standard drugs. Out of the compounds studied, the compounds 4c, 4e, 4g, 4h and 4k with chloro and methyl substituents at para position showed more potent activity than the standard drugs at all doses tested.

Improving child survival: Malnutrition Task Force and the paediatrician's responsibility.

Malnutrition (underweight) contributes to approximately 60% of all child deaths, yet health professionals, policy makers, and donor agencies often fail to recognise its relevance to child survival. There is a need for the paediatric community to champion the importance of adequate nutrition for normal growth and development, and of placing sufficient emphasis on the prevention and treatment of malnutrition. Many severely malnourished children die from inappropriate treatment. Case fatality rates of 25-30% are commonly found and in some hospitals as many as 50-70% will die. Many of these deaths are avoidable. Weaknesses in health systems, inappropriate training of doctors and nurses, inadequate supervision, and lack of support for staff all contribute to compromised quality of care. The International Union of Nutritional Sciences, with support from the International Pediatric Association, Launched a global Malnutrition Task Force in 2005. The main objective is to ensure that an integrated system of prevention and treatment of malnutrition is actively supported as a fundamental aspect of care, and becomes an integral part of all training programmes.

Studies on congenital abnormalities and related risk factors.

Congenital malformations were studied prospectively covering 11680 consecutive deliveries. The overall incidence of malformations was 2.3%. Musculoskeletal system was the most commonly involved system. The incidence of malformation was higher in still borns, premature, low birth weight babies and those with positive heredo-familial history. It was also higher in babies, born to mothers who were more than 35 years of age and gravida four and above. Consanguinity of marriage, drugs and hormone ingestion during pregnancy, antenatal complication like hydramnios, pre eclamtic toxemia, gestational diabetes was associated with high incidence of congenital malformations.

Growth, morbidity, and mortality of children in Dhaka after treatment for severe malnutrition: a prospective study.

Over 1300 severely malnourished children (< 60% of US National Center for Health Statistics weight-for-height, with edema, or both) are admitted each year to the Children's Nutrition Unit in Dhaka. Fatality during treatment is low and recovery is rapid. Our aim was to determine whether this initial success is sustained when children return home. A previous attempt to address this question was frustrated by the difficulty in tracing children after discharge because most are from slum settlements and families move frequently. This prospective study with fortnightly monitoring was therefore undertaken. The main outcomes of interest were anthropometric status, relapse, morbidity, and mortality. Children (n = 437) who had been treated for severe malnutrition when aged 12-59 mo and had reached the discharge criterion of 80% of weight-for-height, were followed for the next 12 mo. During follow-up, 7.5% were lost without trace, 0.6% relapsed, and 2.3% died. Morbidity was high, with a mean of seven episodes of diarrhea during the year. Outpatient visits for diarrhea occurred for 67% of children, and 58% had pneumonia (10% had pneumonia three times). After 12 mo, mean weight-for-height was 91% (-0.92 z score) but mean height-for-age remained at 84% (-4.14 z score). Weight gain, but not height gain, tended to be lower in children who experienced more diarrhea. Fever and cough were not associated with either weight or height gain. The high prevalence of illness highlights the need for continued accessible health care and for interventions to reduce disease acquisition.

Cost-effective treatment for severely malnourished children: what is the best approach?

UNLABELLED: In urban Bangladesh, 437 children with severe malnutrition aged 12-60 months were sequentially allocated to treat either as i) inpatients, ii) day care, or iii) domiciliary care after one week of day care. Average institutional cost (US$) to achieve 80% weight-for-height were respectively $156, $59 and $29/child. As a proportion of the overall costs, staff salaries were the largest component, followed by laboratory tests. Parental costs were highest for domiciliary care, as no food supplements were provided. Nevertheless it was the option most preferred by parents and when the institutional and parental costs were combined, domiciliary care was 1.6 times more cost-effective than day care, and 4.1 times more cost-effective than inpatient care. CONCLUSION: With careful training and an efficient referral system, domiciliary care preceded by one week of day care is the most cost-effective treatment option for severe malnutrition in this setting.

PIP: This study examines the cost effectiveness of three different approaches to treating severe malnutrition among children aged 12-60 months in Dhaka, Bangladesh. The treatment options included inpatient management, day care, and home care. Study participants were examined at the Children's Nutrition Unit of the Save the Children Fund in Dhaka, Bangladesh, during December 1990 to November 1991. Malnutrition is measured as weight-for-height under 60% of the reference median and/or edema. Children were randomly assigned to treatment groups. Critically ill, severely anemic, tuberculous, or congenitally impaired children were excluded. Cost effectiveness was measured as the total cost of institutional plus parental care in order to achieve 80% weight-for-height. Institutional costs included capital costs and operational costs such as salaries, utilities, laboratory test, medical supplies, and food. Parental costs included wage loss, transportation, and food. The opportunity cost of a mother's time was not included. The greatest cost for parents was for transportation. The Nutrition Unit admitted 1470 children, but 138 children were transferred after a few hours. 759 were ineligible due to age or illness/anemia. 70 of the 573 remaining children were excluded due to death, illness, transfusions, or discontinuation of treatment. 437 children reached 80% weight-for-height. Mortality and relapses were low in all treatment groups. There were significant differences in the median durations to achieve 80% weight-for-height. The inpatient group took 18 days, the day care group took 23 days, and the home care group took 35 days. The institutional cost of inpatient treatment was 2.6 times greater than day care and 5.3 times greater than home care. Costs were significantly different between care groups. Findings indicate that home care was 1.6 times more cost-effective than day care and 4.1 times more cost-effective than inpatient care.

Fighting malnutrition from hospital to home.

PIP: At a Children's Nutrition Unit in Bangladesh, a screening process has been developed to determine the type of care which should be provided to malnourished children. Malnourished children receive an initial period of full-time medical attention if they exhibit apathy and anorexia, dehydration, severe anemia, life-threatening infection, hypoglycemia, hypothermia, or severe Vitamin A deficiency. Also, malnourished children under 12 months old are given preference for in-patient care. Children may be hospitalized for three to five weeks until they are reasonable recovered and have reached a target weight-for-height or they may be discharged early and receive continued treatment through day care or home visits. Goals of the minimum stay (one to two weeks) should include restored appetite, treatment of clinical complications, and teaching the mother about appropriate feeding. Hospitalization and day care in the hospital may be very difficult for a family to manage. Home-based treatment, on the other hand, produces good, although slower, results and is the most cost-effective approach. Success of home care depends upon the quality of care and advice given during home visits by health personnel and an effective referral system if the children need more attention. In this program, while the provision of a Vitamin and mineral mixture is considered helpful, food supplements are not distributed. Even very poor families can adapt family foods to provide better nutrition. Less malnourished children also need attention, and their mothers must be trained to adapt family foods, give frequent meals, and continue to breast feed. Action is needed when growth begins to falter to prevent the need for later treatment. In Dhaka, the total cost to rehabilitate one child is US$29 for home-based care, US$59 for day care, and US$156 for in-patient care.^ieng

Ten steps to recovery.

PIP: Severe malnutrition in children results in severe wasting and/or edema (swollen limbs). Severely malnourished children often are very ill and have complications. Health workers need to follow 10 steps first to stabilize these children and then to move them into a rehabilitation phase. During days 1-2 of the stabilization phase, health workers need to treat and/or prevent hypoglycemia (blood sugar 3 mmol/l), hypothermia (35 degrees Celsius [underarm]), and dehydration. Children with hypoglycemia should receive 50 ml of 10% glucose solution or sugar water then be fed every 2 hours round-the-clock. Health workers should either feed or start rehydration of children with hypothermia immediately, place the child on the mother's bare chest or abdomen, and cover them. They must use a modified oral rehydration salts solution and encourage feeding to rehydrate the severely malnourished child. During days 2-14 and stopping at day 14, health workers need to give broad-spectrum antibiotics to all severely malnourished children and a measles vaccine to non-immunized children and to start cautious feeding practices whereby the frequency of feeding decreases and the volume increases. Conditions that need to be addressed throughout the stabilization and rehabilitation phases include electrolyte imbalance and micronutrient deficiencies. Health workers must never treat electrolyte imbalance with a diuretic. They should not provide iron during the stabilization phase and not until a good appetite has returned and the child begins to gain weight. Health workers need to encourage sensory stimulation (tender, loving care; structured play and physical activity; stimulating environment; and mother's involvement) throughout both phases. They must focus on rebuilding tissues (catch-up growth) and preparing for follow-up during the rehabilitation phase (weeks 2-6). Once the child's appetite has returned, health workers must make a gradual transition from starter to catch-up formula and encourage continued breast feeding if the child is breast fed. They should prepare the child and parents for discharge through education on a healthy diet and eating patterns.^ieng

Controlled trial of three approaches to the treatment of severe malnutrition.

Domiciliary treatment of severely malnourished children could have economic and practical advantages over other methods. We compared three approaches in a controlled trial. 437 children in Dhaka (< 60% weight-for-height, and/or oedema) aged 12-60 months were sequentially allocated to treatment as inpatients, to day-care, or to care at home after one week of day-care. Institutional and parental costs incurred to reach 80% weight-for-height were compared. Costs for inpatient, day-care, and at-home groups averaged 6363, 2517, and 1552 taka (60 taka = UK pound 1). Mortality was low (< 5%) in all three groups. Day-care treatment approached inpatient care for speed of recovery at less than half the cost, but it was unpopular with parents. The at-home group took significantly longer to attain 80% weight-for-height than the other groups, but did so at the lowest average cost. Parental costs were highest for the at-home group as no food supplements were provided; nevertheless this was the most popular option. We conclude that at-home management of severely malnourished children after 1 week of inpatient care is a cost-effective strategy.

Structure of leuconolam sesquihydrate.

8a-Ethyl-7,8,8a,10,11,12a-hexahydro-12a- hydroxyindolizino[8,1-ef][1]benzazonine-6,13-(5H,9H)-dione sesquihydrate, C19H22N2O3.3/2H2O, Mr = 353.42, triclinic, P1, a = 9.250 (2), b = 13.366 (3), c = 9.217 (2) A, alpha = 97.786 (3), beta = 119.590 (3), gamma = 70.726 (3) degrees, V = 934.8 A3, Z = 2, Dx = 1.255 g cm-3, Mo K alpha,lambda = 0.71073 A, mu = 0.839 cm-1, F(000) = 378, T = 293 K. The final R value is 0.061 for 1646 significant [I greater than 3 sigma(I)] reflections. The alkaloid from the leaves of Rhazia stricta is built up by a benzene ring ortho disubstituted with a 4,5-dihydro-5-hydroxy-2-oxo-pyrrol-1,4,5-triyl unit and an N(CO)R- unit forming a twelve-membered ring.

Effect of zinc supplementation on the dietary intake and weight gain of Bangladeshi children recovering from protein-energy malnutrition.

Sixty severely malnourished children aged between 5 and 60 months were studied during nutritional rehabilitation. They all received a rice-based diet ad libitum plus vitamins and iron supplementation. Thirty children received zinc supplements (10 mg/kg/d for those weighing less than 6 kg and 50 mg daily for those over 6 kg) on a random basis. Zinc was started from the 15th hospital day when they were free of infection and continued for a period of 3 weeks. Both groups had a mean energy intake of 200 kcal/kg/d, but the majority of the supplemented children had a better rate of weight gain: 66 per cent of the supplemented compared with 33 per cent of the controls gained more than 10 g/kg body weight/d. Moreover, 76 per cent of the supplemented children compared with 23 per cent of the controls were over 90 per cent of Harvard median weight for height on discharge. It appears from this study that zinc supplementation promotes growth and enhances the rate of clinical recovery from severe PEM.

Nutritional rehabilitation in Bangladesh--the importance of zinc.

Our aim was to investigate whether zinc deficiency becomes apparent during nutritional rehabilitation and limits the rate of weight gain. Twenty-five severely malnourished children, who were admitted to the Children's Nutrition Unit in Bangladesh, were alternately allocated to two groups. Their mean dietary Zn intake was 3.7 mg/d and mean caloric intake greater than 150 kcal.kg-1.d-1; one group received a daily Zn supplement of 50 mg for 2 wk. During the first week, weight gain was similar in the two groups, but during the second week, weight gain was 73% more in the Zn-supplemented group (8.83 +/- 1.56 vs 5.09 +/- 1.62 g.kg-1.d-1). The 95% confidence limits were 0.88 less to 8.36 g.kg-1.d-1 more gain in children receiving Zn supplements. The results strongly suggest that Zn supplements are beneficial to severely malnourished children during nutritional rehabilitation. Polymorphonuclear (PMN) cell Zn increased in the group receiving Zn supplements (p less than 0.001), confirming that the Zn content of PMN cells reflects available Zn.

Comparison of Edmonston-Zagreb and Schwarz strains of measles vaccine given by aerosol or subcutaneous injection.

The serological response to measles vaccine was tested in Bangladesh in groups of infants aged 4-6 months who received equal doses of Edmonston-Zagreb or Schwarz vaccine by subcutaneous injection or by aerosol. Seroconversion (as measured by the haemagglutination test) occurred in 62% of infants receiving Edmonston-Zagreb strain by injection compared with only 37% of those receiving Schwarz strain. Seroconversion occurred in 35% of those given Edmonston-Zagreb and 34% of those given Schwarz vaccine by aerosol. Edmonston-Zagreb strain appears more effective than Schwarz vaccine in this population and further studies are indicated in other populations where early measles immunisation is desirable.

Xerophthalmia in urban Bangladesh. Implications for vitamin A deficiency preventive strategies.

Eight per cent of children attending a nutrition unit in urban Bangladesh had the eye signs and symptoms of vitamin A deficiency. About 1 in 10 of children with xerophthalmia and moderate-to-severe protein-energy malnutrition (PEM) had corneal involvement (X2,X3A/B): seasonal variation in prevalence was striking. Xerophthalmia was commonest in the 2-3 years age group and was associated with gastro-enteritis and measles. Breast feeding rates were low for PEM children with or without xerophthalmia. Poverty and overall shortage of food are the common denominators for both PEM and xerophthalmia. Effective vitamin A deficiency preventive strategies in urban Bangladesh will need, therefore, to include a broad range of measures such as the present limited distribution of high potency vitamin A capsules (200 000 IU) to children aged 0-6 years, food subsidies and food fortification if the most vulnerable children in the slums are to be reached.