Plasma level monitoring of mitotane (o,p'-DDD) and its metabolite (o,p'-DDE) during long-term treatment of cushing's disease with low doses

Summary. Mitotane (o,p'-DDD) can be used for the treatment of various adrenocortical diseases such as Cushing's syndrome, but the usual doses of 6–8 g per day are often associated with severe adverse effects.This paper reports the results of much lower doses of o,p'-DDD (0.5–2 g per day) in two patients with Cushing's disease over periods of 8 and 5 years, respectively, under concomitant monitoring of the plasma levels of the parent drug and its major metabolite, o,p'-DDE.It became apparent that o,p'-DDD and o,p'-DDE have a strong tendency to accumulate in the body due to their high lipophilicity. As a consequence, changes in dose regimens had long lag times before they were reflected in plasma levels and once an increase or decrease had started one had to be careful not to cause overshoot.Steady state plasma levels of o,p'-DDD between 5–10 g/ml appeared sufficient to induce and to maintain remission of the disease, which was accompanied with normal cortisol levels in plasma and urine. DDD-levels below 5 g/ml for several weeks may lead to relapses, whereas DDD-levels over 10 g/ml gave rise to side effects. On the other hand, o,p'-DDE seemed inactive at levels up to 4 g/ml in plasma.     

兴山五味子的质量研究

兴山五味子;;襄五脂素;;主要药理作用     

24-hour anti-ischaemic action with once daily nifedipine

Summary The ability of a fatty-alcohol matrix, slow-release tablet of nifedipine 60 mg to maintain a 24-hour antiischaemic action in the fixed dose of 60 mg once daily has been investigated in a randomised, placebo-controlled, double-blind trial.12 normotensive patients with angiographically proven coronary artery disease (stenosis of at least one major vessel 70%) were studied. The anti-ischaemic response was assessed over a period of 4 days as changes in the exercise-induced ST-segment depression 6 h and 24 h postdose, and ST segment changes in 24-h ambulatory ECGs.A measurable anti-ischaemic response was observed in 8 of the 12 patients. Exercise-induced ST-segment depression 6 h after the administration of nifedipine was reduced by 30% compared to placebo, and there was still a measurable anti-ischaemic response 24-h post-dosing. Both responses were independent of changes in exercise blood pressure. In 7 patients with ischaemic episodes in the 24-h ECGs, nifedipine treatment had only a minor effect on the intensity and duration of ischaemia.It is concluded that a significant anti-ischaemic effect lasting 24 h could be demonstrated using effort-induced ST-segment changes in patients with angiographically proven coronary heart disease, who were treated once daily with nifedipine 60 mg as a fatty-alcohol slow release tablet.     

14例大疱性表皮坏死松解型药疹治疗体会

报告14例大疱性表皮坏死松解型药疹的治疗。以磺胺类药和解热镇痛药引起者居多,各4例。皮损面积按九分法计算,皮损面积80％以上者9例,80％以上者5例,治愈9例,死亡5例,我们认为早期使用足够剂量皮质激素类药物是有效措施。病程中注意防治感染,给予足够的液体以防止水电解质失平衡,局部治疗使用本院中药“五黄油”。     

Post-operative pain and inflammatory reaction reduced by injection of a corticosteroid

Summary In a controlled crossover study, identical surgical procedures, the prophylactic removal of bilateral non-erupted 3rd molar teeth, were performed on two separate occasions in 24 healthy patients. Prior to each procedure, either betamethasone 9 mg (Celeston Chronodose^®) or placebo was administered intramuscularly, in a randomized fashion. Objective and subjective assessments were recorded for paired comparison of the post-operative course, including swelling, pain, trismus, local temperature, bleeding, wound-healing and preference for treatment. In 23 patients, less swelling occurred when betamethasone was given pre-operatively. The mean reduction on the 3rd and 6th post-operative days was 55% (p<0.001) and 69% (p<0.001), respectively. Pain assessments (visual analogue scale) were significantly lower after the corticosteroid injection; mean response: 1st evening 17 vs 56 mm, 2nd evening 5 vs 37 mm, and 3rd evening 2 vs 13 mm. No significant correlation between the steroid-induced reduction in swelling and pain could be made. This may indicate that dissociation may exist between pain and other inflammatory events like swelling. No clinically apparent infection or other disturbance of wound-healing was noted after corticosteroid administration. This treatment course was preferred by 23 of the 24 patients.     

Different inhibitory effect of adrenaline on platelet adenylate cyclase in the presence of GTP plus cholera toxin and of stable GTP analogues

Summary GTP is generally required for hormonal stimulation of adenylate cyclase. On the other hand, the presence of GTP is essential for hormone-induced inhibition of adenylate cyclase in cell-free preparations of human platelets and other cells. In order to differentiate the dual roles of GTP in hormonal stimulation and inhibition of adenylate cyclase, we have studied the effect of adrenaline on the platelet enzyme under conditions where guanine mucleotides caused marked stimulation. In the presence of GTP (1 M), which by itself had no or only a small stimulatory effect on adenylate cyclase, adrenaline inhibited the basal and prostaglandin E₁-stimulated forms of the enzyme. In contrast, the stable GTP analogues, GMP-P(NH)P and GTP--S, which caused a time-dependent, persistent activation of the enzyme, reversed or prevented the inhibitory effect of adrenaline. Cholera toxin, which activates adenylate cyclase presumably by inhibition of a specific GTPase, increased cyclase activity in platelet membranes up to 4-fold, and GTP addition (0.1–30 M) augmented this activation about 2-fold. The -adrenergic component of adrenaline (0.1–100 M), in a concentration-dependent manner, prevented the GTP-induced increase in cholera toxin-stimulated activity. The inhibition was also observed in enzyme preparations that had been fully activated by pretreatment with cholera toxin. These data suggest that -adrenergic agonists may inhibit platelet adenylate cyclase through increased inactivation of the enzyme, possibly involving a stimulation of the GTPase connected to the adenylate cyclase system.Abbreviations GMP-P(NH)P guanylyl 5-imidodiphosphate - GTP--S guanosine 5-(-thio)triphosphate - GTPase guanosine 5-triphosphatase - P_i inorganic phosphate. Parts of the data were presented in preliminary form (Jakobs and Schultz, 1978)     

Long-term treatment with β-blockers after myocardial infarction

Summary 162 patients discharged from hospital after myocardial infarction were randomly allocated to two groups, one received alprenolol 400 mg daily and the other served as the control. The period of follow-up was two years and all other treatment given was standardized. The two groups did not differ with respect to risk factors for myocardial infarction, the course of the acute infarct or treatment during follow-up. After two years one patient in the group treated with alprenolol had died suddenly as compared to nine in the control group. During the same period four fresh infarcts had occurred in the alprenolol group compared to 15 in the control group. Both these differences were statistically significant. Only four patients were obliged to discontinue -blocker treatment because of suspected side-effects. Long-term post-infarction treatment with -blockers appears to be an effective form of secondary therapy without serious side-effects.     

Assessment of efficacy of bothropic antivenom therapy on microcirculatory effects induced by Bothrops jararaca snake venom.

Intravenous administration of antibothropic antivenom (BAv) neutralises the systemic effects, but does not efficiently reverse the local symptoms elicited by the Bothrops jararaca venom (BjV). The mechanisms involved in this poor protection have not been clarified. In this work, intravital microscopy studies were carried out to determine the efficacy of different schedules of BAv treatment on local effects evoked by topical application of BjV in the microcirculatory network of the internal spermatic fascia of Wistar rats. Results demonstrated that BAv administration 15 min before, simultaneously with, or 15 min after BjV application did not totally reverse the local symptoms, represented by disturbances of coagulation, development of haemorrhage lesions, vascular permeability increase and increment on leukocyte-endothelium interactions. This lack of effectiveness neither reflects an inadequate amount of specific antibodies in the antivenom against toxins responsible for local effects nor an insufficient dose of circulating BAv during the assays. Administration of fluorescein isothiocyanate (FITC) labelled-BAv showed the dynamics of distribution of the antivenom in the microcirculatory network. Images obtained from prior and simultaneously treated animals showed that the antivenom remains at luminal side of vessels before venom application, and the latency time to antivenom leakage is coincidental to that for local effects evoked by the venom. In addition, images from posterior treatment demonstrated that the intense alterations in the microcirculatory network impair antivenom distribution at the site of injection. Together, our data show that the lack of effectiveness of antivenom therapy is due to impaired and delayed venom and antivenom interaction at the site of injury.     

The CEC behaviour of several synthetic peptides related to the activin βA–βD subunits

Abstract: The resolution of several structurally related synthetic peptides, derived from the loop 3 region of the activin β_A–β_D subunits, has been studied using capillary electrochromatography (CEC) with Hypersil n‐octadecylsilica as the sorbent. The results confirm that the CEC migration of these peptides can be varied in a charge‐state‐specific manner as the properties of the background electrolyte, such as pH, salt concentration and content of organic modifier, or temperature are systematically changed. Acidic peptides followed similar trends in retention behaviour, which was distinctly different to that shown by more basic peptides. The CEC separation of these peptides with the Hypersil n‐octadecyl‐silica involved distinguishable contributions from both electrophoretic mobility and chromatographic retention. Temperature effects were reflected as variations in both the electro‐osmotic flow and the electrophoretic mobility of the peptides. When the separation forces acting on the peptides were synergistic with the electro‐osmotic flow, as, for example, with the positively charged peptides at a particular pH and buffer electrolyte composition, their retention coefficient, κ_cec, decreased with increasing capillary temperature, whereas when the separation forces worked in opposite directions, as for example with negatively charged peptides, their κ_cec values increased slightly with increasing temperature. Moreover, when the content of organic modifier, acetonitrile, was sufficiently high, e.g. > 40% (v/v) and nonpolar interactions with the Hypersil n‐octadecyl‐silica sorbent were suppressed, mixtures of both the basic and acidic synthetic peptides could be baseline resolved under isocratic conditions by exploiting the mutual processes of electrophoretic mobility and electrostatic interaction. A linear relationship between the ln κ_cec values and the volume fractions, ψ, of the organic modifier over a limited range of ψ‐values, was established for the negatively charged peptides under these isocratic conditions. These findings thus provide useful guidelines in a more general context for the resolution and analysis of structurally related synthetic peptides using CEC methods.     

女贞子的药理作用研究状况

从十个方面概述女贞子药理作用实验研究状况。