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Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[11C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[11C]verapamil brain uptake (expressed as whole-brain volume of distribution (VT)), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain VT approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain VT relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB. [ABSTRACT FROM AUTHOR]

BackgroundHydroxyurea is a disease-modifying medication for patients with sickle cell disease (SCD). Despite demonstrated efficacy, hydroxyurea nonadherence in clinical practice is common and results in worse health outcomes for nonadherent patients. Mobile Directly Observed Therapy (Mobile DOT) is a pilot-tested, electronic, multidimensional hydroxyurea adherence intervention for children with SCD. Mobile DOT includes sending daily text message reminders to patients to take hydroxyurea, patients recording and sending daily videos that capture their hydroxyurea administrations for the research team to review and track adherence, providing personalized feedback to patients about their adherence, and providing small monetary incentives to patients if they achieve high hydroxyurea adherence. ObjectiveThis study aimed to determine if Mobile DOT increases hydroxyurea adherence in children with SCD and to explore its impact on hematologic and clinical outcomes. MethodsThis was a single-arm, 6-month intervention study of patients with SCD on hydroxyurea who were aged ≤19 years and reported having access to an electronic device. Participants’ hydroxyurea adherence when they received Mobile DOT was compared with their adherence 6 months before and after receiving Mobile DOT. Participants’ medication possession ratio (MPR) was calculated from their pharmacy dispensing records and was used to measure adherence. Laboratory and clinical outcomes were abstracted from participants’ electronic medical records. Infrequently hospitalized patients who received at least 160 days of the intervention were considered to be engaged participants. ResultsOf 91 patients who were approached, 55 enrolled and 34 engaged with Mobile DOT. The median age of the engaged participants was 10 years (range 2-18.8 years), and 21 (62%, 21/34) participants were male, 28 (82%, 21/34) had hemoglobin SS SCD, and 19 (56%, 19/34) were prescribed hydroxyurea for at least a year before enrollment. With Mobile DOT, engaged participants’ median MPR increased from 61.7% to 84.4% (P

Provides information on a study which described the principles of nuclear forward scattering (NFS) in hedenbergite at high pressures. Discussion on NFS; Comparison of the accuracy of NFS data with transmission Mossbauer spectroscopy; Evaluation of the NFS time spectrum.

- Transurethral resection (TUR) is regarded as the treatment of choice for relief of outflow tract obstruction in the male, but bladder neck incision (BNI) is an acceptable alternative when the gland is small. Seven hundred cases of TUR/BNI have been reviewed (TUR = 388; BNI = 312). BNI was performed when the gland was less than 35 g and where there was no clinical suspicion of malignancy. The operative details of our single incision technique are given. While the patients in the BNI group were younger, catheter stay was shorter, there was less infection, a significantly reduced need for blood transfusion and a satisfactory outcome in terms of control and need for further surgery. BNI is a technically simpler procedure than TUR and is easy to teach and learn. Results show it is safe and effective for patients in acute retention as well as those treated electively and it is the operation of choice for small benign prostates. [ABSTRACT FROM AUTHOR]

A-4166, a phenylalanine derivative, is a hypoglycemic agent, whichhas been shown to improve blood glucose levels mainly due to the rapid andshort term stimulation of insulin release. Nevertheless, a possible extrapancreaticaction of A-4166 has not yet been investigated. Therefore, insulin action(euglycemic hyperinsulinemic 6.4 mU.kg[sup -1] .min[sup -1] clamp plus [sup 3] H-2-deoxyglucose tracer administration) wasstudied after 3 weeks on either standard (BD) or high fat (HF) diet in normalcontrol (C) or in hereditary insulin resistant (hHTg) rats which were givena single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement.HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemiato about 50% of C (p < 0.001). In hHTg rats, HF did not further pronouncethe pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIRneither in C, nor in the hHTg group. The estimated glucose disposal (Rd)(C-BD: 32.3 ± 1.9 vs C-HF: 25.5 ± 1.9 mg.kg[sup -1] .min[sup -1] , p < 0.001) and glucose metabolic index (Rg')in skeletal muscles (Q. femoris: C-BD: 25.6 ± 1.5 vs C-HF: 12.3 ±1.1 mmol.100 g[sup -1] .min[sup -1] , p < 0.001) werereduced by HF in control rats but were not restored by a concomitant bolusof A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166brought back their Rd (hHTg-HF: 23.5 ± 1.3 vs hHTg-HF plus A-4166:31.0 ± 3.5 p ,< 0.03) and Rg' (Soleus muscle: hHTg-HF:29.2 ± 3.2 vs hHTg-HF plus A-4166: 41.3 ± 4.0) to values ofthe control group on BD. In summary, a) a single bolus administration of A-4166to the control or to the insulin resistant hHTg rats, fed either the BD orHF diets, did not abolish the reduction of GIR required to maintain euglycemiaduring hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significantincrease of the estimat ed plasma glucose disposal (Rd) and skeletal muscleglucose metabolic index (Rg') of hHTG ra... [ABSTRACT FROM AUTHOR]

Analogues of 3-aminooxy-1-propanamine proved to be highly potent and selective inhibitors of ornithine decarboxylase (ODC). The compounds competed with ornithine for the substrate binding site of ODC, but resulted in progressive and apparently irreversible inactivation of the enzyme. Diamine oxidase was inhibited by these compounds to a lesser extent than ODC; the compounds were not metabolized by this enzyme. Several derivatives were growth-inhibitory for human T24 cells and for other mammalian cells, the most active compound being 3-aminooxy-2-fluoro-1-propanamine (AFPA). Growth-arrested cells were largely depleted of putrescine and spermidine. Cellular growth arrest could be antagonized by supplementation with spermidine. Selection for resistance against AFPA led to cells with amplified ODC genes and overexpression of the message. Some of the derivatives were tumoristatic at well-tolerated doses in mice bearing solid T24 tumours. The antiproliferative activity of these compounds appears to be mediated by polyamine depletion. [ABSTRACT FROM AUTHOR]

CGP 6809 is a water-soluble nitrosourea derivative with quite distinct chemical and biological properties as compared with the well-known representatives of this class of compounds. It is related to the antibiotic streptozotocin, from which it is distinguished in the structure of the sugar moiety and the position of the methylnitrosourea residue. CGP 6809 possesses practically the same alkylating potential as streptozotocin; however, its carbamoylating activity is comparable with that of CCNU. In contrast to other nitrosourea derivatives, CGP 6809 showed relatively little activity in murine leukemias but was markedly active in solid transplantable melanomas (Harding-Passay, B16), in the 11095 prostate carcinoma, and in a substrain of Yoshida hepatoma (AH 7974) resistant to BCNU and CCNU. In the Ehrlich and Yoshida ascitic tumors complete responses were seen with no toxic death. Dose-dependent activity was found in the human lung carcinoma MBA 9812 and almost complete growth inhibition was achieved in the human melanoma WM 47 by both the oral and parenteral routes of administration. However, mammary tumor lines (Ca 755, 2661/61, R-3230AC), the Guerin-T8 uterus epithelioma, and the Rous sarcoma/S-R proved to be relatively refractory to this drug. This was also the case for the Lewis lung carcinoma implanted i.m. or s.c. However, development of lung metastases was markedly inhibited. Combination therapy using CGP 6809 with cyclophosphamide, 5-fluorouracil, or chlorambucil in the same model led to partial responses of the primary tumor as well as almost total eradication of lung metastases. [ABSTRACT FROM AUTHOR]