Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors

We disclose optimization efforts based on the novel non-nucleoside adenosine deaminase (ADA) inhibitor, 4 (K(i) = 680 nM). Structure-based drug design utilizing the crystal structure of the 4/ADA complex led to discovery of 5 (K(i) = 11 nM, BA = 30% in rats). Furthermore, from metabolic considerations, we discovered two inhibitors with improved oral bioavailability [6 (K(i) = 13 nM, BA = 44%) and 7 (K(i) = 9.8 nM, BA = 42%)]. 6 demonstrated in vivo efficacy in models of inflammation and lymphoma.     

The link between contraceptive methods andChlamydia trachomatis infection

The effect of various contraceptive methods onChlamydia trachomatis (CT) infection was examined in a group of 158 women, with a mean age of 26.9 years, patients of a family planning clinic. Their symptoms were mild abdominal pain or vaginal discharge. Antibodies to CT were examined by an indirect immunoperoxidase assay, with a commercial kit. From each patient a vaginal smear was collected for bacteriologic and mycologic study.In group I, consisting of 30 married women with a mean age of 31 years, 5 (16.7%) IUD users had a positive test for CT antibodies. In group II, comprising 57 women, with a mean age of 23.3 years, 22 (38.6%) oral contraceptive (OC) users, of whom 94.7% were unmarried, had positive tests for CT antibodies. The difference between these two groups was statistically significant (p<0.05).In group III, comprising 71 women with a mean age of 28.1 years, 62% unmarried and using other contraceptive methods, 15 (21.1%) had a positive test for CT antibodies. The incidence of CT infection was not different in the 3 groups under study, when the factors of age and marital status were taken into consideration (p>0.30). Bacterial vaginal infection was found in 43.3% of the IUD users, compared with only 14% of the OC users (p<0.01).In contrast, in the OC users, candidiasis was predominant, the difference from the other groups being statistically significant (p<0.001). The women with positive antibodies also more frequently had colonies of bacterial and mycological vaginal infection. CT infection is a sexually transmitted disease (STD) related to a specific and non-monogamous sexual life style. The unmarried women in the group of OC users are the most at risk, taking into consideration that they begin sexual life at an early age and that they often change their partners.

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Resumen El efecto de varios métodos anticonceptivos en la infección porChlamydia trachomatis (CT), fué examinado en un grupo de 159 pacientes con 26,9 años de edad media, en una clinica de planificación familiar. Sus síntomas fueron: dolor leve abdominal o flujo vaginal. Se examinaron los anticuerpos a CT mediante una prueba comercial de immunoperoxidase indirecta. Se obtuvo un extendido vaginal de eada paciente para un estudio bacteriológico y micológico.En el grupo I, constituido por 30 mujeres casadas con 31 años de edad media, 5 (16,7%) usuarias de DIU tuvieron una prueba de anticuerpos positiva a CT. En el grupo II, constituido por 57 mujeres con 23.3 aflos de edad media, siendo usuarias de anticonceptivos orales (OC) y 94,7% solteras, 22 (38,6%) tuvieron resultados positivos a anticuerpos de CT. La diferencia entre estos dos grupos fue estadísticamente significativa (p<0,05).En el grupo III, constituido por 71 mujeres con 28,1 años de edad media, siendo 62% solteras y usando otros métodos anticonceptivos, 15 (21,1%) tuvieron una prucba de anticuerpos CT positiva. La incidencia de infección de CT no fue diferente en los 3 grupos de estudio cuando se tuvieron en consideracion los factores de edad y estado civil (p>0,30). Se encontró infección bacteriana vaginal en 43,3% de las usuarias de DIU, comparado con 14% de OC (p<0,01).A diferencia, en usuarias de OC predominó la candidiasis, siendo estadísticamente significativa (p<0,001) con otros grupos. Las mujeres con anticuerpos CT positivos, mas frecuentemente tuvieron colonias de infección bacteriana y micológica. La infección CT es una enfermedad transmitida sexualmente (STD), relacionada con un grupo especifico, no monógamo de vida sexual. Las solteras en este grupo de usuarias de OC, son las que tienen el mayor riesgo considerando que empiezan su vida sexual a edad mas temprana y que cambian de pareja con frecuencia.

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Resumé L'effet de diverses méthodes contraceptives sur l'infection par laChlamydia trachomatis (CT) a été examiné sur un groupe de 158 femmes dont l'âge moyen était de 26,9 ans qui fréquentaient un clinique de planning familial. Elles présentaient comme symptômes des douleurs abdominales légères et des pertes vaginales. Les anticorps à la CT ont été examinés par un essai indirect à l'immunoperoxydase effectué au moyen d'un matériel commercial. On a procédé à un frottis vaginal sur chaque patiente aux fins d'une étude bactériologique et mycologique.Dans le groupe I, comprenant 30 femmes mariées âgées en moyenne de 31 ans, l'essai sur les anticorps à la CT, chez les 5 utilisatrices de DIU (16,7%), a donné des résultats positifs. Dans le groupe II, comptant 57 femmes d'un âge moyen de 23,3 ans, les utilisatrices de contraceptifs oraux, dont 94,7% étaient célibataires, 22 (38,6%) ont produit des résultate positifs à l'essai sur les anticorps à la CT. La différence entre ces deux groupes était significative du point de vue statistique (p<0.05).Quant au groupe III, composé de 71 femmes âgées en moyenne de 28,1 ans, dont 62% n'étaient pas mariées et faisaient appel à d'autres méthodes contraceptives, les résultats de l'essai sur les anticorps à la CT ont été positifs dans 15 cas. L'lneidence de l'infection par la CT ne différait pas dans les trois groupes étudiés lorsqu'on a tenu compte des facteurs d'âge et de statut matrimonial (p>0.30). L'infection bactérienne vaginale a été retrouvéc chez 43.3% des utilisatrices de DIU, alors qu'elle était de 14% chez les femmes qui prenaient des contraceptifs oraux (p<0.01). Par contre, chez ces dernières, la candidose était prédominante, révélant une différence statistiquement signifieative avae les autres groupes (p<0.001). En outre, les femmes ayant des anticorps positifs à la CT présentaient plus souvent des colonies d'infection vaginale bactériennes et mycologiques. L'infection par la CT est une maladie sexuellement transmissible (MST) liéc à une activité sexuelle spécifique et non monogame. Les femmes célibataires du groupe des utilisatrices de contraceptifs oraux sont les plus exposées à ces risques, compte tenu du fait que leur activité sexuelle commence tôt et qu'elles changent souvent de partenaires.

     

A randomized trial of 72- versus 24-hour intravenous tubing set changes in newborns receiving lipid therapy.

OBJECTIVE: To compare the microbial contamination rate of infusate in the intravenous tubing of newborns receiving lipid therapy, replacing the intravenous delivery system at 72-hour versus 24-hour intervals. DESIGN: Infants requiring intravenous lipid therapy were randomly assigned to have intravenous sets changed on a 72- or a 24-hour schedule, in a 3:1 ratio, in order to compare the infusate contamination rates in an equivalent number of tubing sets. SETTING: A 35-bed, teaching, referral, neonatal intensive-care unit (NICU). PARTICIPANTS: All neonates admitted to the NICU for whom intravenous lipid was ordered. METHODS: Patients were randomized in pharmacy, on receipt of the order for intravenous lipid therapy, to either 72- or 24-hour administration set changes, and followed until 1 week after discontinuation of lipids or discharge from the NICU. Microbial contamination of the infusate was assessed in both groups at the time of administration set changes. Contamination rates were analyzed separately for the lipid and amino acid-glucose tubing sets. Patient charts were reviewed for clinical and epidemiological data, including birth weight, gestational age, gender, age at start of lipid therapy, duration of parenteral nutrition, and type of intravenous access. RESULTS: During the study period, 1,101 and 1,112 sets were sampled in the 72- and 24-hour groups, respectively. Microbial contamination rates were higher in the 72-hour group than the 24-hour group for lipid infusions (39/1,101 [3.54%] vs 15/1,112 [1.35%]; P=.001) and for amino acid infusions (12/1,093 [1.10%] vs 4/1,103 [0.36%]; P=.076). Logistic regression analysis controlling for birth weight, gestational age, and type of venous access showed that only the tubing change interval was significantly associated with lipid set contaminations (odds ratio, 2.69; P=.0013). The rate of blood cultures ordered was higher in the 72- versus the 24-hour group (6.11 vs 4.99 per 100 patient days of total parenteral nutrition; P=.017), and a higher proportion of infants randomized to the 72-hour group died (8% vs 4%; P=.05), although the excess deaths could not clearly be attributed to bacteremia. CONCLUSION: Microbial contamination of infusion sets is significantly more frequent with 72- than with 24-hour set changes in neonates receiving lipid solutions. This may be associated with an increased mortality rate.     

Patient and family physician preferences for care and communication in the eventuality of anthrax terrorism

BACKGROUND: The threat of bioterrorism consequent to the September 11, 2001 attack in the USA generated suggestions for improved medical response mainly through hospital preparedness. OBJECTIVES: The aim of the present study was to investigate the impact of this period of tension on patients' first choice for care and for receiving relevant information, and on primary care doctors' feelings of responsibility in the eventuality of an anthrax attack. METHODS: During October 11-31, 2001, 500 patients from 30 clinics throughout Israel were asked to complete a questionnaire on their awareness of the anthrax threat, measures taken to prepare for it, and preferred sources of care and information. Their 30 physicians, and an additional 20, completed a questionnaire on knowledge about anthrax and anthrax-related patient behaviours and clinic visits. RESULTS: The outstanding finding was the low rate (30%) of patients who chose the hospital emergency department as their first choice for care or information if they were worried about an anthrax attack or the media communicated that an attack was in progress. The other two-thirds preferred their family doctor or the health authorities. Most of the physicians (89%) felt it was their responsibility to treat anthrax-infected patients and that they should therefore be supplied with appropriate guidelines. CONCLUSION: This study suggests that in Israel, a country with a high degree of awareness of civil defence aspects, both patients and primary care doctors believe that family physicians should have a major role in the case of bioterrorist attacks. This must be seriously considered during formulation of relevant health services programmes.     

Substance P-immunoreactive neurons in the neocortex of the rat: a subset of the glutamic acid decarboxylase-immunoreactive neurons

Substance P-immunoreactive (SP-IR) neurons are found throughout the layers of the rat neocortex. Within the somatosensory (SI) cortex these cells make up about 2% of all neurons and within area 17 about 3%. Colocalization studies reveal that the SP-IR neurons are a subset of the population immunoreactive for glutamic acid decarboxylase.     

Increased renal threshold of bicarbonate due to carbon dioxide retention associated with proximal renal tubular acidosis

We report a neonate who manifested type II (proximal) renal tubular acidosis (RTA). Hypoventilation secondary to hypothalamic dysfunction led to carbon dioxide retention. The consequent changes in acid base regulation are detailed and discussed.