3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo1,5-d1,2,4triazine (MRK-016) is a pyrazolotriazine with an affinity of between 0.8 and 1.5 nM for the ...benzodiazepine binding site of native rat brain and recombinant human alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors. It has inverse agonist efficacy selective for the alpha5 subtype, and this alpha5 inverse agonism is greater than that of the prototypic alpha5-selective compound 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-hdyl)methyloxy-1,2,4-triazolo3,4-aphthalazine (alpha5IA). Consistent with its greater alpha5 inverse agonism, MRK-016 increased long-term potentiation in mouse hippocampal slices to a greater extent than alpha5IA. MRK-016 gave good receptor occupancy after oral dosing in rats, with the dose required to produce 50% occupancy being 0.39 mg/kg and a corresponding rat plasma EC(50) value of 15 ng/ml that was similar to the rhesus monkey plasma EC(50) value of 21 ng/ml obtained using (11)Cflumazenil positron emission tomography. In normal rats, MRK-016 enhanced cognitive performance in the delayed matching-to-position version of the Morris water maze but was not anxiogenic, and in mice it was not proconvulsant and did not produce kindling. MRK-016 had a short half-life in rat, dog, and rhesus monkey (0.3-0.5 h) but had a much lower rate of turnover in human compared with rat, dog, or rhesus monkey hepatocytes. Accordingly, in human, MRK-016 had a longer half-life than in preclinical species ( approximately 3.5 h). Although it was well tolerated in young males, with a maximal tolerated single dose of 5 mg corresponding to an estimated occupancy in the region of 75%, MRK-016 was poorly tolerated in elderly subjects, even at a dose of 0.5 mg, which, along with its variable human pharmacokinetics, precluded its further development.
A Pulmonary Lesion Which Is More Than Meets the Eye Gunaratnam, Cedric; Murphy, Desmond; Razak, Albiruni Ryan Abdul ...
Clinical pulmonary medicine,
2004-January, 2004-01-00, Volume:
11, Issue:
1
Journal Article
A 69-year-old female smoker presented with dyspnea, anorexia, weight loss, and bone pain. Chest radiography showed a large pulmonary mass. Initial clinical investigations suggested probable ...metastatic bronchogenic carcinoma, but biopsy revealed that the lesion represented primary pulmonary lymphoma. The pathogenesis of primary pulmonary parenchymal lymphoma is discussed, and differential diagnosis of this entity is reviewed.
Adverse reaction to prescription medications, over the counter medications and complementary medicines, are an important cause of liver toxicity.
To highlight the importance of drug induced liver ...toxicity in patients presenting with abnormal liver function tests.
In patients who present with symptoms of liver dysfunction such as anorexia, itch or Jaundice and in whom liver function tests are abnormal, the possibility of an adverse reaction to medications should be considered. A detailed history of all medications taken in the past few months, including complementary medicines, should be obtained. After exclusion of other causes of liver disease such a viral hepatitis or gallstones, the cessation of the offending medication and the normalisation of liver tests is usually sufficient to establish a diagnosis. Occasionally, referral to a specialist and liver biopsy may be required.
Chadwick et al comment on the scientific evidence in the trial of Louise Woodward for the murder of 8-month-old Matthew Eappen. The shaken baby syndrome is a well-documented clinical entity with ...diagnostic features.
We report on the design, assembly and evaluation of a dual frequency mechanically scanned transducer for ultrasound bubble manipulation and real time high frequency imaging applications. A low ...frequency 2 MHz annulus was designed to fit on the outside of a commercially available 30 MHz, 100% bandwidth single element fixed focus transducer such that the axial axes of each transducer would be substantially aligned. The acoustic pressure and beam characteristics of the low frequency transducer were characterized as a function of transmit center frequency and drive voltage. The focal depths of the low and high frequencies were measured to be 11.8-12.1 mm and 12.7 mm for transmit pulses of 2-3 MHz and 30 MHz respectively. The probe was integrated into a commercially available Visualsonics RMV Scanhead and could achieve a frame rate of 20 fps. The dual frequency probe provided an average of >12 dB enhancement of contrast to tissue ratios in rat kidney and rat xenograft Fibrosarcoma models.
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