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Ketanserin compared to nifedipine and methyldopa in patients aged above 50 years: two international multicentre studies. For the International Study Group.

The antihypertensive properties and adverse reactions of ketanserin, nifedipine and methyldopa were compared in hypertensive patients aged above 50 years in two international studies. After a placebo run-in period, patients received for 3 months, either ketanserin or nifedipine retard in study 1, and either ketanserin or methyldopa in study 2. After 1 month of monotherapy, a diuretic was added if necessary. Study 1 had 117 subjects, with 119 in study 2. The changes in systolic and diastolic blood pressure were similar for ketanserin and nifedipine although more patients switched to combination therapy in the ketanserin group. The overall response rate was comparable with ketanserin and nifedipine (96% for both drugs). The decrease in diastolic blood pressure was significantly greater in the ketanserin group compared to methyldopa and more patients responded to ketanserin (82%) than to methyldopa (65%). No rebound hypertension was observed on discontinuation of therapy with any of the drugs. The total incidence of adverse reactions in monotherapy was lower with ketanserin than with nifedipine (34 and 47%) and similar for ketanserin and methyldopa (40 and 45%). For ketanserin no consistent adverse reaction pattern was seen.

Blood Pressure↗

Insulin-induced internalization of the insulin receptor in the isolated rat adipose cell. Detection of the internalized 138-kilodalton receptor subunit using a photoaffinity 125I-insulin.

A photoactive insulin analogue (N epsilon-B29-(2-nitro-4-azidophenylacetyl)insulin) which specifically and covalently labels the 138-kDa insulin receptor subunit, is used here to examine the effect of insulin on the subcellular distribution of insulin receptors in the isolated rat adipose cell. The photolabeled 138-kDa receptor subunit in the plasma and Golgi-enriched membrane fractions was quantitated by Na dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. When intact cells are photolabeled, subsequent incubation for 30 min at 37 degrees C with saturating native insulin induces a 30% loss of the labeled receptor subunit from the plasma membrane fraction. Greater than 50% of the lost receptor subunits can be specifically recovered in the Golgi-enriched membrane fraction. Qualitatively and quantitatively similar results are obtained when the 138-kDa receptor subunit is labeled in the membrane fractions following their preparation. However, the 138-kDa receptor subunit in the Golgi-enriched membrane fraction can only be labeled when the vesicles in this fraction are made permeable to the insulin analogue by the presence of 0.01% digitonin. The appearance of the 138-kDa receptor subunit in the Golgi-enriched membrane fraction is rapid, with a half-time of 2 min, and achieves a steady state within 10 min. This effect is also insulin concentration-dependent, with half-maximal and maximal effects at 6 and 30 nM, respectively, and is markedly, but not completely, inhibited at 16 degrees C. These results suggest that insulin induces a rapid and insulin concentration- and temperature-dependent translocation of its own receptor from the plasma membrane to an intracellular membrane fraction in the isolated rat adipose cell, and that this translocation represents internalization of the insulin receptor through an endocytic like process.

Adipose Tissue↗

[The Bratislava International Eye Bank--a member of the International Federation of Eye Banks].

The International Eye Bank in Bratislava has assembled during its two-year activities 1007 corneae with a 2mm scleral margin by excision performed in the donor in situ, 11 total eye-balls and 43 sclerae. From this total number 1331 eye tissues had to be eliminated because of serum positivity (115 HBsAg, 12 HCV, 2 HIV 1,2 + HCV + HBsAg, 2 HBsAg + HCV, 2 HIV 1.2 + HBsAg). The most frequent cause of death in donors of corneae were carcinomas, injuries and cerebro- and cardiovascular diseases. Corneal grafts are stored at a temperature of +2 degrees C to +6 degrees C in Optisol GS medium. The most frequent indication for keratoplasty in Slovakia was keratopathia bullosa (28.6%), keratoconus (23.9%) and leukoma corneae (18.7%).

Antibodies, Viral↗

The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group.

BACKGROUND: Only a few small trials have compared antithrombotic therapy (antiplatelet or anticoagulant agents) versus control in acute ischaemic stroke, and none has been large enough to provide reliable evidence on safety or efficacy. METHODS: The International Stroke Trial (IST) was a large, randomised, open trial of up to 14 days of antithrombotic therapy started as soon as possible after stroke onset. The aim was to provide reliable evidence on the safety and efficacy of aspirin and of subcutaneous heparin. Half the patients were allocated unfractionated heparin (5000 or 12,500 IU bd [twice daily]), and half were allocated "avoid heparin"; and, in a factorial design, half were allocated aspirin 300 mg daily and half "avoid aspirin". The primary outcomes were death within 14 days and death or dependency at 6 months. 19,435 patients with suspected acute ischaemic stroke entering 467 hospitals in 36 countries were randomised within 48 hours of symptom onset. RESULTS: Among heparin-allocated patients, there were non-significantly fewer deaths within 14 days (876 [9.0%] heparin vs 905 [9.3%] no heparin), corresponding to 3 (SD 4) fewer deaths per 1000 patients. At 6 months the percentage dead or dependent was identical in both groups (62.9%). Patients allocated to heparin had significantly fewer recurrent ischaemic strokes within 14 days (2.9% vs 3.8%) but this was offset by a similar-sized increase in haemorrhagic strokes (1.2% vs 0.4%), so the difference in death or non-fatal recurrent stroke (11.7% vs 12.0%) was not significant. Heparin was associated with a significant excess of 9 (SD 1) transfused or fatal extracranial bleeds per 1000. Compared with 5000 IU bd heparin, 12,500 IU bd heparin was associated with significantly more transfused or fatal extracranial bleeds, more haemorrhagic strokes, and more deaths or non-fatal strokes within 14 days (12.6% vs 10.8%). Among aspirin-allocated patients there were non-significantly fewer deaths within 14 days (872 [9.0%] vs 909 [9.4%]), corresponding to 4 (SD 4) fewer deaths per 1000 patients. At 6 months there was a non-significant trend towards a smaller percentage of the aspirin group being dead or dependent (62.2% vs 63.5%, 2p = 0.07), a difference of 13 (SD 7) per 1000; after adjustment for baseline prognosis the benefit from aspirin was significant (14 [SD 6] per 1000, 2p = 0.03). Aspirin-allocated patients had significantly fewer recurrent ischaemic strokes within 14 days (2.8% vs 3.9%) with no significant excess of haemorrhagic strokes (0.9% vs 0.8%), so the reduction in death or non-fatal recurrent stroke with aspirin (11.3% vs 12.4%) was significant. Aspirin was associated with a significant excess of 5 (SD 1) transfused or fatal extracranial bleeds per 1000; in the absence of heparin the excess was 2 (SD 1) and was not significant. There was no interaction between aspirin and heparin in the main outcomes. INTERPRETATION: Neither heparin regimen offered any clinical advantage at 6 months. The results suggest that if heparin is given in routine clinical practice, the dose should not exceed 5000 IU subcutaneously twice daily. For aspirin, the IST suggests a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke; previous trials have already shown that continuation of low-dose aspirin gives protection in the longer term.

Acute Disease↗

High dose chlorambucil versus Binet's modified cyclophosphamide, doxorubicin, vincristine, and prednisone regimen in the treatment of patients with advanced B-cell chronic lymphocytic leukemia. Results of an international multicenter randomized trial. International Society for Chemo-Immunotherapy, Vienna.

BACKGROUND: In recent years, much attention has been paid to the possible efficacy of intensive chemotherapy in the treatment of advanced, progressive B-cell chronic lymphocytic leukemia (CLL) patients. For this reason, the International Society for Chemo-Immunotherapy, Chronic Lymphocytic Leukemia Cooperative Group, has begun a randomized multicenter trial comparing Binet's modified cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen with continuous high dose chlorambucil (HD-CLB). METHODS: During the period January 1987 to May 1993, 228 previously untreated CLL patients from 7 cooperative institutions were randomized to this trial. Advanced and/or progressive disease was defined by high Total Tumor Mass (TTM) score (> 9), and/or short doubling time (DT) (< 12 months), and/or bone marrow failure. The response to therapy was defined by reduction of the initial TTM score. The end points of the trial were response rate, survival, and toxicity. RESULTS: HD-CLB resulted in a higher response rate than CHOP in evaluable cases, with 89.5% overall responses (complete response+partial response) versus 75%, respectively (P < 0.001). At the time of an analysis performed in July 1995 (after a median follow-up period of 37 months), overall survival was also longer in the HD-CLB treatment arm (median survival, 68 months) than in the CHOP treatment arm (median survival, 47 months) (P < 0.005). Toxicity was acceptable and comparable in the two treatment arms. CONCLUSIONS: The current study showed that HD-CLB is an effective and well-tolerated therapeutic option for patients with advanced and/or progressive CLL. Therefore, the authors recommend its wider use, possibly in comparison with and/ or in combination with new therapeutic agents, such as purine analogues.

Aged↗

International collaborative study to evaluate a recombinant L ferritin preparation as an International Standard.

A recombinant L ferritin preparation, lyophilized in ampoules and designated 94/572, was evaluated by 18 laboratories in 9 countries for its suitability as an International Standard (IS). The preparation was assayed in a wide range of in-house and commercial immunoassays against the 2nd IS for ferritin (of spleen origin; 80/578). The immunological reactivity of the recombinant material was similar to that of the 2nd IS for ferritin in the majority of assays and demonstrated adequate stability in accelerated degradation studies. On the basis of the results presented here, the WHO Expert Committee on Biological Standardization established 94/572 as the 3rd IS for ferritin, recombinant.

Automation↗

The long-term tolerability and efficacy of oral zolmitriptan (Zomig, 311C90) in the acute treatment of migraine. An international study. The International 311C90 Long-term Study Group.

This international open-label study evaluated the tolerability and efficacy of zolmitriptan (Zomig, 311C90), a selective 5-HT1B/1D receptor agonist, in the long-term treatment of multiple migraine attacks. Patients who had previously participated in placebo-controlled zolmitriptan studies were recruited. A total of 2058 patients treated 31,579 migraine attacks (average 15 per patient), for up to 1 year. Twenty-six percent of attacks treated with a single zolmitriptan 5-mg dose were associated with at least one adverse event (24% treated with two doses). The most frequent adverse events included asthenia (14% of patients), nausea (12%), somnolence (10%), dizziness (11%), and paresthesia (11%). The rank order of the most common adverse events was not influenced by sex, age, or number of zolmitriptan doses taken and was similar between attacks 1 and 45. The majority of adverse events (59%) occurred within 2 hours of dosing, were of either mild (59%) or moderate (35%) intensity, of 4 hours' duration or less (67%), and required no further action (94%). Following an initial 5-mg dose of zolmitriptan, the 2-hour headache response rate (reduction in headache pain from moderate or severe before treatment to mild or no pain at 2 hours posttreatment) was 81% in patients treating moderate and severe attacks (19,639 of 24,161). Patients were pain-free at 2 hours in 55% of all attacks (16,510 of 29,808). The efficacy of zolmitriptan was not influenced by age, sex, weight, use of prophylactic antimigraine medication, or association of attacks with menstruation. Analysis of the overall population and a subgroup who treated 30 or more migraine attacks showed that zolmitriptan was consistently effective across attacks. Overall, 67% of patients who treated five or more attacks reported zolmitriptan to be effective in 80% to 100% of attacks. Zolmitriptan produced meaningful migraine relief and improvement in normal activity impairment in 73% and 78% of moderate and severe attacks, respectively. Patients treated recurrence of moderate or severe headache with a second zolmitriptan dose in 32% of attacks which responded to the first dose within 2 hours. Where required, a second zolmitriptan 5-mg dose for treatment of recurrence produced a headache response rate of 90% at 2 hours postdose. Thus, zolmitriptan 5 mg (plus an optional second 5-mg dose for treatment of recurrence) is well tolerated and effective in the acute treatment of multiple migraine attacks over periods up to 1 year.

Adult↗

[Failure of coronary artery bypass with the internal thoracic artery. Does extended use of the internal thoracic artery affect the patency of the coronary artery?].

OBJECTIVE: The aim of this study was to precise the circumstances of the failure of coronary artery bypass graft by internal thoracic artery (ITA). METHODS: It was a retrospective study which compared angiographic results between several techniques of ITA graft; 512 coronary artery bypass graft have been realized on 302 patients: 115 single left ITA grafts, 78 sequential left ITA grafts, 48 bilateral pedicled ITA grafts, 61 bilateral ITA Y grafts. The mean interval between operation and reangiography was 17.3 months (s = 4.1 months). Graft failures were occluded and non functioning ITA grafts (threadlike ITA). RESULTS: There were 11 occluded grafts (2%) and 19 non functionning grafts (4%). There was no difference of failure rate between the 4 techniques of ITA grafts (p > 0.05). The failure rate for right ITA grafts 13% was higher than for the left ITA grafts 4% (p < 0.001). The failure rate for obtuse marginal branch grafts 13% was higher than for left anterior descending artery grafts 3% (p < 0.001). CONCLUSION: The extended use of ITA doesn't increase the risk of graft failure rate. The patency of obtuse marginal branch ITA graft is less than the patency of left anterior descending artery or diagonal branch ITA grafts.

Coronary Angiography↗