Clinical Rebound Research Articles

Efficacy of isosorbide mononrtrate in angina pectoris

The rapid development of tolerance has limited the applicability of oral and transdermal nitrates in the long-term management of patients with chronic stable angina pectoris. Recent well-controlled trials have demonstrated that asymmetrical, or eccentric, dosing of oral isosorbide mononitrate, in which 20-mg doses are taken at 8 a.m. and 3 p.m., provides at least 12 hours of antianginal coverage. There is no evidence for the development of tolerance with this schedule, which allows for a 17-hour nitrate withdrawal period. Likewise, the asymmetrical 20-mg twice daily regimen has not been associated with the zero-hour effect that has been reported with higher oral doses of isosorbide mononitrate and with intermittent nitroglycerin patch therapy. This approach also avoids the development of a clinical rebound phenomenon, as measured by increased episodes of angina and nitroglycerin consumption, compared with the pretreatment period, during the nitrate-free interval at night and the early hours of the morning.

Automatic scoring of polygraphic sleep recordings: midazolam in insomniacs.

Midazolam in doses of 0.21-0.46 mg/kg was given to four insomniacs for 27 days, and to a fifth insomniac for an additional 124 days, to assess its short, intermediate, long-term and long-standing efficacy. Automatic analysis of the polygraphic sleep recordings was carried out employing real-time signal processing (based on linear prediction), and an off-line sequential fuzzy clustering. Total sleep length did not vary significantly during medication, whereas other efficacy parameters such as sleep onset latency, wake time after sleep onset and number of nightly awakenings decreased significantly throughout the period of active medication. In one patient, midazolam was still effective after 151 days of administration. The ultrashort action (probably 3-4 h) of midazolam could be demonstrated by the distribution of the efficacy parameters, dividing the night into 2-h periods, by the unchanged total sleep length during medication compared with baseline and by the lack of any subjective clinical symptoms of hangover. The quantitative analysis of the signals showed that, although a decrease in the total amount of slow-wave sleep during long-term medication and withdrawal was detected, the total relative power in the delta band increased during drug administration. This was interpreted as redistribution of the delta activity during active medication. A lengthening of REM sleep was found during active medication probably attributable to intranight rebound. This was not followed by any clinical symptom of clinical REM rebound.(ABSTRACT TRUNCATED AT 250 WORDS)

EFFECT OF AMINOGLUTETHIMIDE ON URINARY CORTISOL AND CORTISOL METABOLITES IN ADOLESCENTS WITH CUSHING'S SYNDROME

The effect of aminoglutethimide (AG) 4 X 250 mg (670 mg/m2 daily by mouth) on the excretion of the free cortisol (radio-immunoassay) and of its metabolites THE, THF-allo THF, cortolone and beta-cortolone (gas chromatography on capillary column) was studied monthly during 3-5 months in four adolescents (one girl, three boys) aged 15.9-18 years with Cushing's syndrome due to bilateral adrenal hyperplasia, but without evidence of a pituitary tumour. Under AG, all compounds decreased to a minimum after 1-2 months. The decrease of THE- THF-allo THF was most marked, followed by cortolone-beta-cortolone and free cortisol. The sum of the conjugated metabolites was normalized, but free cortisol remained high. A rebound was noted after 3-5 months of continued treatment. This was associated with clinical relapse (weight gain, increasing blood pressure). With AG, a non-steroidal peak appeared on the chromatograms. It is concluded that: (1) AG is only temporarily effective in diminishing the excretion of cortisol and its metabolites; (2) paradoxical increments of 17-ketosteroids as reported from colorimetric analysis are non-specific and are probably due to the non-steroidal peak; and (3) AG appears to modify steroid catabolizing liver enzymes (inhibition of 5beta-reductase and/or 3alpha-dehydrogenase, possibly stimulation of 20alpha- and 20beta-dehydrogenases). This could increase the biological half-life of cortisol and contribute to the clinical rebound, which is due to increased ACTH-secretion. Because of its excellent short-term effects, AG appears to be useful to prepare patients for bilateral adrenalectomy.

The Duration of Activity in Acute Rheumatic Fever

In 265 children and adolescents with rheumatic fever who were followed into and beyond the convalescent period, the average duration of acute inflammatory activity was 109 ±57 days. The average duration was significantly longer in patients who had valvular involvement (124 days) than in those who did not (89 days). In patients who received a relatively short course of anti-inflammatory treatment and who then had a posttherapeutic clinical rebound which was allowed to subside spontaneously, the total duration of rheumatic activity was almost identical to that found in patients whose entire attack had been untreated. These results suggest that the duration of rheumatic activity is prolonged by prolonged therapy but is unaffected when the original course of treatment is shorter than the natural course of the acute inflammation.