2-Chloro-2'-deoxyadenosine (CdA), a newly developed anticancer drug, has been tested in phase II trials in the treatment of lymphoproliferative disorders. 2-Chloro-2'-arabino-fluoro-2'-deoxyadenosine (CAFdA), an acid stable derivative of CdA with promising anti-lymphoproliferative activity, has been suggested as a potentially effective oral drug. In the present study, we investigated the metabolism of CdA and CAFdA in isolated perfused rat liver. The liver was recycled with a perfusate containing CdA or CAFdA (2-200 micrograms/ml) for 3.5 h. The elimination half-lives were concentration-dependent for both CdA and CAFdA. The elimination rate of CAFdA was slower than that of CdA, suggesting that CAFdA is more stable than CdA against deglycosylation by hepatic enzymes. The amount of 2-chloroadenine (CAde), the major metabolite of CdA and CAFdA, increased proportionally with time and dose. The first passage effect was approximately 50% both for CdA and CAFdA. Less than 1% of CdA and CAFdA were recovered as intact drug in the bile during the experiment and less than 1% of CdA and 0.1% of CAFdA were found as CAde in the bile, respectively. The structural identity of metabolites present in the perfusates was verified utilizing electrospray ionization mass spectrometry.

Adenine Nucleotides↗

PubMedDate not supplied

Metabolism of 14C-busulfan in isolated perfused rat liver.

1,4-14C Busulfan gave one main metabolite in the isolated perfused rat liver during 4 hr cyclic perfusion. The cumulative bile excretion contained about 38% of the total radioactivity. About 1% of unchanged 14C-busulfan was excreted in the bile. The metabolite was identified as gamma-glutamyl-beta-(S-tetrahydrothiophenium) alanyl-glycine (sulfonium ion of glutathione) by 252Cf-plasma desorption time-of-flight mass spectrometry. The formation of the metabolite was drastically decreased when the glutathione-S-transferase was inhibited, which indicates that the major reaction of busulfan with glutathione is enzymatic in nature. The sulfonium ion was more stable in the perfusate (t1/2 = 22.4 hr, 37 degrees C) than in the bile (t1/2 = 3.2 hr, 37 degrees C) at pH 7.4.

Animals↗

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Pharmacokinetic and metabolic studies of busulfan in rat plasma and brain.

Busulfan kinetics were studied in the rat plasma and brain after an I.P. dose of 14C-busulfan or busulfan (15 mg/kg). The distribution of busulfan to the brain was rapid and the ratio brain/plasma concentration was 0.74 during the time-course of busulfan. The elimination half-lives in plasma and brain were 3h for intact busulfan and 8h for the 14C-radioactivity. The radioactivity remaining in plasma and brain after 24h was mostly busulfan metabolites e.g. sulfolane, 3-hydroxysulfolane and tetrahydrothiophene-1-oxide as identified by gas chromatography-mass spectrometry. The protein binding to rat plasma was low (9.2 +/- 4.4%).

Animals↗

PubMedDate not supplied

The isolation and cultivation of Leishmania infantum from apparently normal skin of visceral leishmaniasis patients in northern Pakistan.

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Animals↗

PubMedDate not supplied

Novel algorithms for the optimization of molecular diversity of combinatorial libraries.

Various approaches to measuring and optimizing molecular diversity of combinatorial libraries are presented. The need for different diversity metrics for libraries consisting of discrete molecules ("cherry picking") vs libraries formed from combinatorial R-group enumeration (array-based selection) is discussed. Ideal requirements for diversity metrics applied to array-based selection are proposed, focusing, in particular, on the concept of incremental diversity, i.e., the change in diversity as redundant or nonredundant molecules are added to a compound collection or combinatorial library. Several distance and cell-based diversity functions are presented and analyzed in terms of their ability to satisfy these requirements. These diversity functions are applied to designing diverse libraries for two test cases, and the performance of the diversity functions is assessed. Issues associated with redundant molecules in the virtual library are discussed and analyzed using one of the test examples. The results are compared to reagent-based diversity optimizations, and it is shown that a product-based diversity protocol can result in significant improvements over a reagent-based scheme based on the diversity obtained for the resulting libraries.

Algorithms↗

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Combinatorial library design for diversity, cost efficiency, and drug-like character.

Most computational techniques for the design of combinatorial libraries have concentrated solely on maximizing the diversity of the selected subset or its similarity to a known target. However, such libraries can produce high-throughput screening hits with properties that make them unsuitable to take forward into medicinal chemistry. This article describes software that allows the design of library subsets to simultaneously optimize a library's diversity or similarity to a target, properties (such as drug likeness) of the library members, properties (such as cost) of the reagents required to make them, and efficiency of synthesis in arrays or mixtures. Example are given showing that libraries can be designed to contain drug-like molecules with only a small trade-off in terms of the maximum possible diversity, and that the cost of the library, in terms of the reagents required to make it, can be contained. Other examples show that libraries can be designed to minimize the deconvolution problem or to maximize the number of molecules predicted to be active while also being designed for efficiency of synthesis.

Algorithms↗

PubMedDate not supplied

Evaluation of reagent-based and product-based strategies in the design of combinatorial library subsets.

With the current and ever-growing offering of reagents along with the vast palette of organic reactions, virtual libraries accessible to combinatorial chemists have dramatically increased in size. Yet, extracting representative subsets for experimentation is an essential step in the design of combinatorial libraries. There has been some controversy whether it is necessary to consider product properties, at some computational expense, or whether sufficiently representative sets can be identified from considerations of the reagent space alone. This study compares the efficiency of reagent-based selections and that of product-based combinatorial subsetting in the identification of representative library subsets. Quantitative estimates reported herein show that the advantage of working in product space is descriptor dependent. For some descriptors, product-based approaches provide a distinct advantage, whereas for others results from reactant pools offer comparable results. Hence the behavior of descriptors, in mapping diversity from reagent space to product space, should be investigated prior to embarking into lengthy product-based considerations. Several classes of descriptors are studied including two-dimensional fingerprints (ISIS and Daylight) and physicochemical descriptors.

Benzodiazepines↗

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Use of an interactional model with survivors of incest.

Psychiatric mental health nurses are increasingly recognizing the traumatic effects of childhood incest on adult survivors. This article discusses a long-term group therapy that specifically deals with unresolved familial issues as a treatment for adult women who are survivors of incest. An interactional family model is described, as well as its use by nurse specialists who act as facilitators and surrogate parents in a long-term group process. Specific focus is on the use of the model in working through dysfunctional communication patterns and boundary and survival issues.

Family↗

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Infection-associated hemophagocytic syndrome complicated by infectious lymphoproliferation: a case report.

The case of a 7-year-old boy with virus-associated hemophagocytic syndrome (VAHS) and serologically proven parvovirus B-19 infection is described. The patient with VAHS presented with fever, hepatosplenomegaly, pancytopenia, and hyperlipidemia type IV. After induction therapy with VP-16 and prednisone, partial remission was achieved. Despite maintenance therapy, reinductions, and the addition of cyclosporine A for 3 months, several relapses occurred. The therapy was stopped because of life-threatening complications (Klebsiella sepsis, neutropenic enterocolitis, and stercoral peritonitis). The complications were treated successfully. The patient status was stabilized after splenectomy. However, hepatomegaly progressed slowly and the hyperlipidemia endured. Ten months after the diagnosis leukocytosis with absolute T lymphocytosis appeared. Reactivation of VAHS was suspected and intravenous immunoglobin and then antilymphocyte immunoglobulin ALG therapy were started. The resultant decrease in leukocytosis was prompt, but lymphopenia did not occur. Virostatic treatment with foscarnet was introduced based on human herpesvirus-6 seroconversion. Twenty-six months after the diagnosis, the patient is well, without any sign of VAHS or lymphoproliferation.

Bone Marrow↗

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Studies on the kinetics of Isopropyl Palmitate synthesis in packed bed bioreactor using immobilized lipase.

The objective of this research was to study the kinetics of synthesis of a commercially important ester - Isopropyl Palmitate (IPP) using immobilized lipase (Lipozyme IM). It was studied in a packed bed differential reactor. In order to establish the kinetics of the reaction, parameters such as linear velocity of the fluid through the reactor, particle size, substrate concentration, substrate molar ratio, temperature and water activity were studied. Operational and storage stability of the enzyme were also assessed. The reaction followed Michaelis-Menton kinetics as observed from the relationship of initial rate of the reaction as a function of substrate concentration. It was found that the optimum substrate concentration was 0.15M palmitic acid and isopropyl alcohol in 1:1 stoichiometric ratio. Inhibition by excess of isopropyl alcohol has been identified. The optimum temperature for the esterification reaction was found to be around 50 degrees C. The activation energy of this process was determined to be 43.67 kJ/mol. The optimum water content was 0.50%. The reaction rates were measured in the absence of any significant external diffusional limitations. Since internal diffusional limitations could not be eliminated, the kinetics observed is only apparent.

2-Propanol↗

PubMedDate not supplied

Efficacy of twice-daily amoxycillin/clavulanate in lower respiratory tract infections.

In this double-blind, double-dummy study, 324 patients with clinical evidence of community-acquired pneumonia (CAP) or an acute exacerbation of chronic bronchitis were randomly assigned to receive 10 days' treatment with either amoxycillin/clavulanate 875/125 mg twice daily or amoxycillin/clavulanate 500/125 mg three times daily. At the end of therapy, clinical success rates were 92.4% for the twice daily regimen and 94.2% for the three times daily regimen. There was no statistically significant difference between treatments (p = 0.647) and the 95% confidence interval around the treatment difference indicated that the two treatments were equivalent. Treatment equivalence was also confirmed at follow-up, four weeks after the end of treatment. Both regimens were well tolerated. In conclusion, amoxycillin/clavulanate 875/125 mg twice daily is as effective as amoxycillin/clavulanate 500/125 mg three times daily for the treatment of community-acquired lower respiratory tract infections and could improve patient compliance.

Adolescent↗

PubMedDate not supplied

Sites of right ventricular outflow tract obstruction in tetralogy of Fallot--a retrospective study.

Fifty one angiographically proved cases of tetralogy of Fallot (TOF) in the age group of 5-50 years were analysed retrospectively for the level(s) of right ventricular outflow tract (RVOT) obstruction. Mean age was 18.1 +/- 11 yrs. Subvalvular stenosis was found to be the commonest site of RVOT obstruction in 49 (96.1%) patients. Evidence of valvular pulmonary stenosis was seen quite commonly (42/51, 83.9% cases), mostly in association with obstruction at other sites. Supravalvular stenosis was also seen in 17 (33.3%) cases. Higher incidence of pulmonary valvular involvement in patients with TOF, in higher average age of patient population may represent valvular involvement to be an acquired phenomenon.

Adolescent↗

PubMedDate not supplied

Urinary metabolites of busulfan in the rat.

After ip administration of 15 mg/kg [1,4-14C]busulfan to rat, the urinary excretion was 70% of the total radioactivity after 72 hr. Three major metabolites were isolated and quantified by HPLC. Of the total radioactivity in the urine, unchanged busulfan was excreted as a minor amount (6%) and the following metabolites were identified as: 3-hydroxysulfolane (39%), tetrahydrothiophene 1-oxide (20%), and sulfolane (13%) using GC/MS and NMR spectroscopy. The cytotoxicity of busulfan and its major metabolites was examined using a V79 Chinese hamster cell line.

Animals↗

PubMedDate not supplied

[Combined analysis by echography and biology in bile duct dilatation. Value in etiologic diagnosis].

Fifty-five consecutive case-reports of patients with evidence of confirmed biliary tract dilatation on ultrasound imaging were reviewed retrospectively to assess value of combined indirect ultrasound signs and simple biologic data in determining etiologic diagnosis. The diagnostic value of certain groups of signs representing indicators of tumoral or nontumoral lesions was equal or superior to that of direct visualization of the occlusion.

Adult↗