Synthesis and anti-HIV-1 activity of a series of 1-alkoxy-5-alkyl-6-(arylthio)uracils.

A series of 1-alkoxy-5-alkyl-6-(arylthio)uracils was synthesized and tested for their ability to inhibit HIV-1 replication. Treatment of 2-alkyl-3,3-bis(methylthio)acryloyl chlorides (5a-e) with AgOCN in benzene followed by reaction of the resulting isocyanates 6a-e with an appropriate alkoxyamine gave N-alkoxy-N'-((2-alkyl-3,3-bis(methylthio)acryloyl)ureas (10a-z) in good to excellent yields. Cyclization of 10a-z in AcOH containing a catalytic amount of p-TsOH produced 1-alkoxy-5-alkyl-6-(methylthio)uracils (11a-z). Oxidation of 11a-z with 3-chloroperoxybenzoic acid in CH2Cl2 resulted in high yields of 1-alkoxy-5-alkyl-6-(methylsulfonyl)uracils (12a-x and 12z) and 1-(benzyloxy)-6-(methylsulfinyl)thymine (12y), which were subsequently reacted with an appropriate arenethiol in ethanolic NaOH solution to afford 1-alkoxy-5-alkyl-6-(arylthio)uracils (14-49). Substitution at the 3- and 5-positions of the C-6-(phenylthio) ring by two methyl groups significantly increased its original anti-HIV-1 activity (EC50: 6-((3,5-dimethylphenyl)thio)-5-isopropyl-1-propoxyuracil (18), 0.064 microM; 6-((3,5-dimethylphenyl)thio)-1-(3-hydroxypropoxy)-5-isopropyluracil++ + (23), 0.19 microM). Among the various alkoxy substituents at the N-1, the propoxy group was the most beneficial for improving the anti-HIV-1 activity. The 1-propoxy derivative 18 proved to be the most potent inhibitor of HIV-1 replication, followed by the 1-(3-hydroxypropoxy) derivative 23. Introduction of an isopropyl group at C-5 of the uracil base also remarkably enhanced the activity. When compound 18 was incubated with a rat liver homogenate preparation, no metabolite was observed, thus confirming the metabolic stability of the N-O bond in these 1-alkoxyuracils.

Synthesis and antitumor activity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes.

The synthesis, physical properties, antitumor activity, structure-activity relationships, and nephrotoxicity of a series of [2-substituted-4,5-bis(aminomethyl)-1,3-dioxolane]platinum(II) complexes are described. The 42 platinum(II) complexes having a seven-membered ring structure in this series have been prepared and characterized by 1H NMR, 13C NMR, IR, FAB-MS, and elemental analysis. All members of the series were designed to have a 1,3-dioxolane ring moiety in their carrier ligands to increase water solubility. The solubility of platinum complexes was related to the nature of leaving ligands and 2-substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane carrier ligands. In general, compounds having two different R1 and R2 substituents in the 4,5-bis(aminomethyl)-1,3-dioxolane moiety were more water-soluble than those having the same substituents. Most members of this series showed the excellent antitumor activity against murine L1210 leukemia cells transplanted in mice and were superior to cisplatin and carboplatin. The (4R,5R)-stereoisomer 1a-h exhibited the higher antitumor activity than the corresponding (4S,5S)-stereoisomer 2a-h in the (1,1-cyclobutanedicarboxylato)platinum(II) complexes. The (glycolato)-platinum(II) complexes were highly cytotoxic toward four human stomach cancer cell lines, SNU-1, SNU-5, SNU-16, and NCI-N87, and among them, complexes 3d-g were even more cytotoxic than cisplatin. The (malonato)platinum(II) complex 1m and the (glycolato)platinum(II) complexes 3d-g were selected for further studies based on the greater in vivo and in vitro antitumor activity and desirable physical properties. The complexes 3e-g were almost equally cytotoxic to cisplatin toward human stomach cancer cell lines, KATO-III and MKN-45, and a human non-small cell lung cancer cell line, PC14. In contrast with cisplatin and carboplatin, five complexes selected significantly increased in life span in mice transplanted with cisplatin-resistant L1210 cells. Nephrotoxicity studies in ICR mice indicated that serum BUN and creatinine levels were not elevated when five complexes were given at a dose equal to 1.5 times the optimal dose determined in the in vivo L1210 screening system.

[AIDS with apoplectic onset]. / AIDS med apoplektiform debut.

Four cases with an apoplectic debut of AIDS are reported. Two of the patients had not earlier been identified as being HIV-positive. In three patients, the underlying cause was probably cerebral toxoplasmosis. It is important to consider AIDS in the differential diagnosis of stroke, particularly in young adults.

Effects of chronic alcoholism on hemispheric functioning: an examination of gender differences for cognitive and dichotic listening tasks.

A pattern of intact verbal abilities and impaired visuospatial abilities has led to a hypothesis of alcohol-induced right-hemisphere dysfunction in male chronic alcoholics. The applicability of this hypothesis to chronic female alcoholics was examined by administering the WAIS-R, Stark Paired Associates Tasks, and dichotic listening tasks to 15 male and 10 female alcoholics and 15 male and 10 female controls of similar age and education. Alcoholics had significantly lower Full Scale IQ scores on the WAIS-R but neither sex had a Verbal-Performance IQ difference indicative of right-hemisphere dysfunction. Male alcoholics showed deficits on both the Verbal and Visuospatial Stark Tasks, the deficit being greater on the Visuospatial Task. Male alcoholics showed an increased right-ear superiority on the verbal dichotic listening task and a decreased left-ear superiority on the musical dichotic listening task, both indicative of right-hemisphere dysfunction. The results, except for the WAIS-R, support the hypothesis that male but not female chronic alcoholics exhibit right-hemisphere dysfunction. Females, alcoholic or not, appear to be less lateralized in function.

Silent infarction in acute stroke patients. Prevalence, localization, risk factors, and clinical significance: the Copenhagen Stroke Study.

BACKGROUND AND PURPOSE: Our objective was to study age-specific prevalence, computed tomographic (CT) characteristics, risk factors, and the prognostic influence on stroke outcome of silent infarction in acute stroke patients. METHODS: The study was prospective and community-based and included 801 acute stroke patients, of whom 587 had first-ever stroke. A CT scan was performed in 500 (85%) of the 587 patients with first-ever stroke. CT was reviewed blindly, and infarcts were classified according to patient history as silent or symptomatic. Patients were evaluated initially with the Mini-Mental State Examination (MMSE) and weekly with both the Scandinavian Stroke Scale (SSS) and the Barthel Index (BI) from the onset of stroke to completion of rehabilitation. CT characteristics, risk factors, and stroke outcome were compared in stroke patients with and without silent infarction. RESULTS: The prevalence of silent infarction in patients with first-ever stroke and recurrent strokes was similar, at 29% (group aged 0 to 54 years, 16%; 55 to 64 years, 22%; 65 to 74 years, 30%; 75 years or older, 33%). Silent infarcts were small and subcortical. Independent risk factors were increasing age (odds ratio [OR], 1.95 per 25 years; confidence interval [CI], 1.19 to 3.15), hypertension (OR, 1.75; CI, 1.13 to 2.70), claudication (OR, 1.74; CI, 1.01 to 3.00), and male sex (OR, 1.72; CI, 1.12 to 2.64); other stroke risk factors such as atrial fibrillation and former transient ischemic attack were not independent risk factors. Patients with and without silent infarction did not differ in frequency of prestroke home care (P = .2). MMSE (P = .56), initial BI (P = .62) and SSS score (P = .08), BI (P = .85) and SSS score (P = .75) after completion of rehabilitation, or in the speed of recovery (P = .85). Length of hospital stay, mortality rate, and discharge rate to nursing home also did not differ between the two groups. CONCLUSIONS: This community-based study shows that silent infarction in stroke patients is more related to certain stroke risk factors than others and that silent infarction does not seem to influence the prognosis of stroke.

Alteplase therapy in acute ischemic stroke: a Danish pilot study.OFF.

In the period from October 1990 to December 1991, 23 patients with acute ischemic stroke were treated with recombinant tissue plasminogen activator (rt-PA) at a median of 205 min (range 78-355 min) after symptom onset. In this open pilot study rt-PA was given intravenously after an acute CT scan had not shown acute changes. In 12 patients regional cerebral blood flow was measured intravenously using 99mTc-HMPAO before and within 24 h after thrombolytic therapy. Reperfusion of the ischemic area was obtained in 10 patients. In these patients clinical improvement was greater the shorter the delay from symptom onset to initiation of treatment. Three of the 23 patients died, one of a parenchymatous hematoma, one of a large middle cerebral artery infarct, and one of acute myocardial infarction.

Thrombolytic therapy in acute ischemic stroke. A Danish pilot study.

BACKGROUND AND PURPOSE: In a feasibility and safety study of thrombolytic therapy in acute ischemic stroke, we explored the usefulness of measurements of regional cerebral blood flow. METHODS: Twenty-three patients with acute ischemic stroke were treated with 100 mg recombinant tissue plasminogen activator infused intravenously over 1 hour. Thrombolytic therapy was initiated 78 to 355 minutes after onset of symptoms. RESULTS: Angiography 16 to 24 hours after treatment in 17 patients showed patient intracranial arteries in 12, partial occlusion of the middle cerebral artery in 3, and total occlusion of the middle cerebral artery in 2. rCBF with 99mTc-hexamethylpropyleneamine oxime intravenously was measured 5 minutes before and within 24 hours after thrombolytic therapy in 12 patients. 10 of the 12 patients showed brain tissue reperfusion and 2, with angiographically documented middle cerebral artery occlusion, showed no reperfusion, thus documenting a relationship between reperfusion measured by regional cerebral blood flow and angiographic patency (P = .015). Three patients died. Patients who were reperfused within 24 hours (documented by repeated regional cerebral blood flow measurements) showed greater clinical improvement on the Scandinavian Stroke Scale the sooner their thrombolytic therapy was started and the more severe their neurological deficits. CONCLUSIONS: Acute cerebral ischemia can be documented by rCBF measurements without delay of thrombolytic therapy, and repeated rCBF measurements can reveal whether cerebral reperfusion has occurred. In our study, early reperfusion was associated with clinical improvement.