The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing of this combination. All subjects received 800 mg of indinavir every 8 h (q8h) on day 2. In addition, subjects in group I received one dose of 800 mg of indinavir on day 1 and 800 mg of indinavir q8h on day 17. Subjects in Groups II and IV each received one dose of 600 mg of indinavir on days 1 and 17, and subjects in groups III and V each received one dose of 400 mg of indinavir on days 1 and 17. During days 3 to 17, ritonavir placebo or ritonavir at 200, 300, 300, or 400 mg q12h was given to groups I, II, III, IV, and V, respectively. Ritonavir at steady state probably inhibited the cytochrome P-450 3A metabolism of indinavir and substantially increased plasma indinavir concentrations, with the area under the plasma concentration-time curve (AUC) increasing up to 475% and the peak concentration in serum (C max) increasing up to 110%. The C max/trough concentration ratio decreased from 50 in standard q8h regimens to less than 14 when indinavir was administered with ritonavir. For a constant indinavir dose, an increase in the ritonavir dose yielded similar indinavir AUCs, C maxs, and concentrations at 12 h (C 12s). For a constant ritonavir dose, an increase in the indinavir dose resulted in approximately proportional increases in the indinavir AUC, less than proportional increases in C max, and slightly more than proportional increases inC 12. Ritonavir reduced between-subject variability in the indinavir AUC and trough concentrations and did not affect indinavir renal clearance. With the altered pharmacokinetic profile, indinavir likely could be given as a b.i.d. combination regimen with ritonavir. This could potentially improve patient compliance and thereby reduce treatment failures.
Long-term follow-up information was obtained for 39 dogs that had undergone surgical excision of nonlymphomatous, small intestinal tumors. For all dogs evaluated in this study, the median survival time was 10 months, and the one- and two-year survival rates were 40.5% and 33.1%, respectively. There was no difference in survival times between dogs with adenocarcinomas (n=23) and dogs with leiomyosarcomas (n=16). Survival times were significantly (p less than 0.0001) shorter for dogs with histological evidence of metastases at the time of surgery (median, 3.0 months) than for dogs with no histiological evidence of metastases (median, 15.0 months).
We performed detailed DNA sequencing analysis on type III collagen cDNA from 58 patients with either intracranial artery aneurysms or cervical artery dissections. The 58 patients were of seven different nationalities; among the patients were three pairs of relatives, so that 55 were unrelated, and of these, 29 had at least one blood relative with either an intracranial artery aneurysm or a cervical artery dissection. The age of the patients at the time of diagnosis ranged from 15 to 68 years (mean +/- SD = 40.3 +/- 11.0). The study group consisted of 25 males and 33 females. The analysis covered 3,232 nucleotides of significant (nonredundant) sequences per allele; therefore, we analyzed as many as 355,520 nucleotides. Mutations in the coding sequences for the triple-helical domain of type III collagen were excluded in 40 individuals with intracranial aneurysms and 18 individuals with cervical artery dissections. Direct sequencing of polymerase chain reaction products allowed mutations to be excluded with a high degree of confidence. Mutations that markedly decreased expression from one allele were also excluded in 42 of the 58 individuals, since the presence of both bases at one or more polymorphic sites in the 42 patients showed that two alleles were transcribed. The results indicated that mutations in the gene for type III procollagen (COL3A1) are not a common cause of either intracranial artery aneurysms or cervical artery dissections.
A patient with a SUNCT-like syndrome caused by severe basilar impression in association with osteogenesis imperfecta is described. Initially symptoms of both the first and second branch of the trigeminal nerve were prominent, on which carbamazepine had only a temporary and mild eVect. Progressive symptoms with prominent ipsilateral autonomic features, unexplained triggering by photostimulation, and increasing duration of pain attacks occurred with relentless progressive basilar impression associated with pontomedullary compression. Pathophysiologically a dysfunction in ephaptic transmission is hypothesised. (J Neurol Neurosurg Psychiatry 2001;70:244-246)
Decision analysis is used to assess the decision to screen for unruptured intracranial aneurysms (IAs) in two affected families, and to formulate guide-lines for similar decisions. Four strategies are compared: "no screening", "screening directly", "screening twice", and "screening later". Intravenous and intra-arterial digital subtraction angiography techniques (iv-DSA, ia-DSA) are considered. Life years lived with and without disability are computed for each strategy. Loss of life expectancy with and without discounting and quality correction is used as an outcome measure. "No screening" is the preferred strategy when population based estimates of the prevalence of IAs are used. Thus, the results of this analysis provide no justification for screening patients without a familial history. But a physician who thinks that the risk of an IA is increased may rightly decide for screening, especially when the patient is aged 40 to 60. Ia-DSA is preferable over iv-DSA. A scenario analysis suggests that screening with magnetic resonance angiography is only slightly better than with ia-DSA, because the complication rate of screening plays a minor role in the analysis.
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