A COMPARISON OF THE EFFECTS OF CLOMIPHENE AND TAMOXIFEN TREATMENT ON THE CONCENTRATIONS OF OESTRADIOL AND PROGESTERONE IN THE PERIPHERAL PLASMA OF INFERTILE WOMEN

The effects of clomiphene and tamoxifen treatment on the concentrations of oestradiol and progesterone in plasma were compared in the same infertile women. Nine patients, three with anovulation and six with suspected luteal phase deficiency, were given clomiphene during 2 months and tamoxifen during 2 months. Placebo treatment was given in the month before the first drug and during a month between drug treatments. The concentrations of oestradiol and progesterone were determined by radioimmunoassay in three samples collected each month between days 6 and 8, 11 and 13, and 18 and 20. The mean concentration of oestradiol at the time of the expected pre-ovulatory rise was 0.82 nmol/l with placebo treatment, 1.20 nmol/l following tamoxifen treatment and 5.00 nmol/l after clomiphene treatment (normal menstrual cycle maximum, 2.0 nmol/l). The mean concentration of progesterone in the luteal phases reached maxima of 41 nmol/l, 47 nmol/l and >72 nmol/l, respectively (normal menstrual cycle maximum, 60 nmol/l). When the frequency distributions of hormone concentrations were examined for each treatment, clomiphene and tamoxifen were both found to alter the distribution from that of placebo treatment (Chi-square analysis), giving a larger proportion of high concentrations. In the six patients with suspected luteal phase deficiency clomiphene treatment was followed by biochemical evidence of ovarian hyperstimulation. There was no evidence of this when any of these patients were treated with tamoxifen, nor in anovulatory patients treated with clomiphene.     

PLASMA L-TRYPTOPHAN CONCENTRATIONS IN CHRONIC RHEUMATIC DISEASES AND THE EFFECTS OF SOME ANTIRHEUMATIC DRUGS ON THE BINDING OF THE AMINO-ACID TO PLASMA PROTEINS IN VIVO AND IN VITRO

L-TRYPTOPHAN may be used as a model endogenous molecule to studythe binding characteristics of the plasma proteins of patientswith connective-tissue diseases. A drug's ability to displaceL-tryptophan from binding to human serum albumin may also representa new in-vitro assay for screening drugs for potential anti-inflammatoryactivity. In patients with rheumatoid arthritis, ankylosingspondylitis, and psoriatic arthritis, antirheumatic drugs displaceL-tryptophan from plasma proteins in vivo, whereas withdrawalof such therapy is associated with excessive binding of theamino-acid to plasma proteins. In children with Still's disease,virtually all plasma tryptophan exists in the protein-boundform, and protein-bound tryptophan is less easily displacedfrom Still's disease plasma than from healthy children's plasmaby antirheumatic drugs in vitro. Results obtained with the novelin-vitro assay described indicate its greater sensitivity thanthe Mizushima test for screening antirheumatic agents. ^*Based on a paper presented at a combined meeting of the BritishAssociation for Rheumatology and Rehabilitation with the RoyalSociety of Medicine, Section of Rheumatology and Rehabilitation,Cardiff, September 1973.     

EFFECTS OF ARTIFICIAL MENOPAUSE ON PLASMA AND URINE CALCIUM AND PHOSPHATE

Plasma and urine calcium and phosphate were determined in nine patients before and after oophorectomy and in eleven patients before and after simple hysterectomy. Oophorectomy was followed by a significant rise in the mean plasma and fasting urine calcium, and a mean rise of 37 mg in the 24 hr calcium which, however, was not significant. Hysterectomy alone caused no significant change in plasma or urine calcium. In both groups only small changes were observed in plasma and urine phosphate and these did not reach the level of significance. The mean urine hydroxyproline/creatinine ratio rose significantly in six patients after oophorectomy but did not change after hysterectomy. It is suggested the rise in plasma and urine calcium following oophorectomy is due to increased bone resorption which does not occur after simple hysterectomy.     

外源性同型半胱氨酸对肾小球系膜细胞的影响

目的：研究外源性同型半胱氨酸对体外培养的肾小球系膜细胞增殖,表型转化和产生细胞外基质的影响。方法：采用放射性同位素测定＾３Ｈ－ＴｄＲ掺入和细胞外信号调节激酶活性,流式细胞仪分析细胞周期,Ｗｅｓｔｅｒｎ ｂｌｏｔ方法进行α－平滑肌肌动蛋白检测,ＥＬＩＳＡ方法检测细胞上清液中细胞外基质含量。结果：不同浓度的同型半胱氨酸（０．００５,０．０５,０．５和１．０ｍｍｏｌ／Ｌ）不同作用时间（８,１６和２４ｈ）     

血浆儿茶酚胺对嗜铬细胞瘤诊断标准的探讨

根据37例嗜铬细胞瘤患者血浆和肿瘤组织几茶酚胺值,提出了诊断标准:静息卧位时血浆去甲肾上腺素>2ng/ml及(或)肾上腺素>1ng/ml。其阳性率为94.6％。并对一些传统概念进行了探讨。     

PLASMA CONCENTRATIONS OF UNBOUND VALPROATE AND THE MANAGEMENT OF EPILEPSY

Abstract The range of protein binding of valproate and the use of unbound and total plasma concentrations of the drug were studied in an outpatient population of 70 epileptics. The unbound fraction of plasma valproate ranged from 4.2% to 11.7% with a median of 7.1%. A non-linear relationship was found between unbound and total plasma valproate concentrations and was best described by a cubic regression (r²= 0.88). This concentration dependent protein binding was also demonstrated by a linear relationship between total plasma valproate concentration and unbound fraction (r= 0.46). As expected, there was no correlation across the patient population between plasma concentrations of valproate and seizure frequency. In an individual patient, however, plasma valproate levels usually correlated with change in clinical status, although this correlation was no better for unbound levels than total levels. There were only three patients in whom unbound valproate levels correlated better with clinical effect than total levels, whereas there were six patients in whom total levels correlated better than unbound levels. It is therefore concluded that monitoring sodium valproate therapy with unbound concentrations is rarely helpful and the routine use of unbound valproate levels cannot be advocated.     

PLASMA STEROID CONCENTRATIONS IN PATIENTS WITH HYPOPITUITARISM AND KALLMAN''S SYNDROME: EFFECTS OF TESTOSTERONE REPLACEMENT THERAPY

To determine the adrenal contribution to plasma concentrations of steroids potentially derived from both the adrenal and the testes, plasma levels of pregnenolone (Δ⁵P), progesterone (P), dehydroepiandrosterone and its sulphate (DHA and DHAS) and androstenedione (Δ⁴A) were measured in four men with isolated gonadotrophin deficiency and anosmia (Kallman's syndrome). A comparison of these levels with those seen in ten patients with both adrenal and testicular failure (hypopituitarism) and in sixteen normal age-matched men was made. As expected, the basal plasma levels of most steroids were low in patients with hypopituitarism. An exception was the normal Δ⁵P levels in most patients. In the patients with Kallman's syndrome both DHA and Δ⁵P were elevated whereas Δ⁴A and P were low. When expressed as ratios, Δ⁵P/P was increased in both groups. DHA/Δ⁴A was increased in Kallman's syndrome but not in hypopituitarism. Following ACTH infusion, no significant changes in these ratios were observed. To determine whether testosterone deficiency was in part responsible for the abnormal Δ⁵/Δ⁴ ratios, three patients with hypopituitarism and two with Kallman's syndrome were treated for 3 months with intramuscular testosterone. A decrease in the DHA/Δ⁴A ratio was seen in all patients and a decrease in Δ⁵P/P in all but one patient. In most cases these changes were produced by a fall in the Δ⁵ steroids as well as an increase in Δ⁴ steroids. These findings suggest that a defect in the metabolism of Δ⁵ steroids exists in patients with hypopituitarism and Kallman's syndrome. In hypopituitarism the defect involves the metabolism of Δ⁵P to both DHA and P. In Kallman's syndrome only the metabolism of Δ⁵P to P is defective. Testosterone therapy alone or in combination with other appropriate hormonal replacement increases the metabolism of Δ⁵ to Δ⁴ steroids.     

THE EFFECTS OF CHRONIC SMOKING ON THE FIBRINOLYTIC POTENTIAL OF PLASMA AND PLATELETS

We studied tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) in healthy individuals divided by smoking habit into current smokers, former smokers and non-smokers (who had never smoked). Plasma PAI-1 antigen was significantly higher in smokers than in non-smokers with intermediate levels in former smokers. A similar trend was observed for plasma PAI activity but this did not reach statistical significance. Platelet PAI-1 and plasma t-PA were not significantly different when comparing the three groups. After venous occlusion t-PA rose significantly in all groups; no significant change in plasma PAI-1 was observed. The ratio of t-PA to PAI-1 in plasma was similar in non-smokers and former smokers but lower in smokers, suggesting that there is at least partial restoration of plasma fibrinolytic potential after smoking cessation. Plasma PAI-1 antigen and PAI activity correlated with estimated pack-years of cigarettes smoked among smokers and former smokers. When all subjects were studied collectively, plasma PAI-1 correlated strongly with plasma t-PA and triglycerides; plasma t-PA also correlated strongly with triglycerdes.
We conclude that chronic smoking is associated with impaired fibrinolysis in plasma and that this largely reflects elevated plasma PAI-1 in smokers. Smoking does not appear to affect the response to venous occlusion. The postulated effect of chronic smoking on plasma PAI-1 may be mediated by the influence of smoking on triglycerides and insulin resistance. Stopping smoking appears to return impaired fibrinolysis towards normal. Smoking does not quantitatively affect the platelet pool of PAI-1. Smoking habit should be controlled for in clinical analyses of PAI-1 and t-PA.     

THE EFFECTS OF EXOGENOUS MELATONIN ON ENDOCRINE FUNCTION IN MAN

At two different times of year (spring and autumn) an oral preparation of the pineal neurohormone melatonin, or placebo, was administered to 12 healthy volunteers (10 men and two women in spring: the same group minus one man in autumn) daily at 1700 h for 1 month (spring), or 3 weeks (autumn) using a double-blind cross-over protocol. The daily dose was 2 mg melatonin in 5 ml corn-oil, and placebo consisted of the vehicle only. In spring the anterior pituitary hormones LH, PRL, GH together with T4, cortisol, testosterone and melatonin were measured at 1- to 6-h intervals for 24 h in plasma on the day following the last dose. In autumn PRL, cortisol and melatonin levels were measured on the last day of treatment. Subjective fatigue, mood and sleep records were kept throughout the studies. Melatonin increased early evening fatigue and actual sleep, but had no effect on mood: these results are reported in full elsewhere. Melatonin administration had no effect on the levels or 24-h rhythm of LH, GH, T4, testosterone or cortisol. An earlier fall in the nocturnal PRL was observed on both occasions. Overall PRL levels were higher in spring than in autumn. In five of the subjects, the secretion of endogenous melatonin was advanced by 1-3 h in the presence of exogenous melatonin. These observations suggest that the potential therapeutic use of melatonin as a hypnotic or in the treatment of jet lag is unlikely to be complicated by undesirable endocrine effects.     

心血管应激和芬太尼对血浆心钠素水平的影响

本实验探讨全麻气管插管心血管应激及芬太尼作用对血浆心纳素水平的影响。结果显示，实验组气管插管心血管应激反应明显，血浆心钠素水平伴随升高，且与血压心率的增加呈高度正相关关系。而对照组在给予６μ８·ｋｇ（－１）芬太尼抑制气管插管应激反应时，插管期间循环兴奋性明显减弱，血浆心钠素水平亦未见升高。因此说明：①血浆心钠素水平与气管插管心血管应激程度密切相关，是气管插管应激指标之一；②芬太尼不参与人类血浆心钠素水平的调节。     

THE EFFECT OF PAIN ON PLASMA ARGININE VASOPRESSIN CONCENTRATIONS IN MAN

The effect of pain on plasma AVP concentration in man has previously been studied only during major surgery with general anaesthesia. Plasma AVP concentration (pAVP) and plasma osmolality (pOsm) were measured in thirty-six patients seen in a surgical emergency department complaining of pain and in fifty-one control subjects. No significant difference in pOsm was found, but pAVP was significantly higher in the emergency room patients in pain (M +/- SEM = 4.94 +/- 0.98 pmol/1 compared to 2.31 +/- 0.32 pmol/1 in control subjects, P less than 0.01). In the control subjects, age was found to have a low but significant inverse correlation with pAVP (r = 0.37, P less than 0.01). Chronic smoking was associated with significant elevation of pAVP (3.81 +/- 0.99 pmol/1 in smokers vs. 1.89 +/- 0.28 pmol/1 in non-smokers, P less than 0.02). Neither smoking nor age could account for the difference in pAVP between the pain and control groups. Thus, pain is a non-osmolar factor capable of elevating AVP in conscious man.     

运动时补液对老年人血液流变学的影响

目的观察不同持续时间运动时服用不同液体对老年人血液流变学各指标的影响。方法分别检测各组运动前后的血液流变学各指标。结果运动前后对比:1)A20组血液流变各指标差别无显著性,B20组基本保持不变,而C20组的低切全血粘度与红细胞聚集指数有显著性下降(P<0.05),红细胞变形指数有升高趋势(P>0.05);2)A40组的红细胞聚集指数(L/H)和低切全血液粘度出现显著性升高(P<0.05),B40组和B60组运动后即刻除红细胞变形指数略有下降外,其余均有轻度升高(P>0.05),而C40组除红细胞变形指数略有升高外,其余均有轻度下降(P>0.05);3)A60组除红细胞变形指数显著性下降外其余均显著性升高(P<0.05),而C60组血液粘度仍略有下降(P>0.05)。结论长时间的持续运动可能会引起老人血液流变的不良变化,但是运动中补充饮料特别是含电解质的饮料对这种不良影响可产生改善作用。     

从血浆促肾上腺皮质素释放素样生物活性和神经递质类药物的作用探讨Cushing病病因

用大鼠垂体细胞灌流技术和ACTH直接法放射免疫测定研究了正常人、Cushing病患者和其他下丘脑-垂体-肾上腺轴疾病患者血浆中的促肾上腺皮质素释放素样生物活性,结合Cushing病患者对神经递质类药物的反应所作观察提出如下假设:绝大多数Cushing病原发于垂体,在发病过程中,高皮质醇血症损害海马,削弱其对下丘脑-垂体-肾上腺轴的抑制作用是一个重要环节。     

EFFECT OF A CALCIUM ENTRY BLOCKER ON BLOOD PRESSURE, PLASMA RENIN ACTIVITY, ALDOSTERONE AND CATECHOLAMINES IN NORMOTENSIVE SUBJECTS

The effects of the calcium entry blocker nifedipine on blood pressure, heart rate, plasma renin activity, aldosterone, noradrenaline and adrenaline were studied in 23 normotensive subjects in the supine and upright positions. Nifedipine, 10 mg administered sublingually, lowered mean blood pressure and increased heart rate, plasma noradrenaline and renin activity without increasing plasma aldosterone in the supine position. The increase in plasma aldosterone in response to upright posture was inhibited by nifedipine, whereas the rise in plasma noradrenaline was augmented. These results suggest that intracellular calcium is important as a regulator of aldosterone secretion as well as of vascular tone in normotensive subjects.     

ENDOSCOPIC EVALUATION OF THE COMPARATIVE EFFECTS OF ACETYLSALICYCLIC ACID AND CHOLINE MAGNESIUM TRISALICYLATE ON HUMAN GASTRIC AND DUODENAL MUCOSA

A new salicylate product, choline magnesium trisalicylate (Trilisate^®tablets), and acetylsalicylic acid were compared for their localeffects in equipotent doses on the gastroduodenal mucosa ina randomized, double-blind, cross-over study, using 10 healthyvolunteers. After five-day periods of administration, gastroduodenoscopywas performed and photographs were obtained. All subjects givenacetylsalicylic acid developed multiple mucosal lesions, butin only four subjects given choline magnesum trisalicylate wereslight mucosal changes noted. Mean serum salicylate levels weresimilar in the two groups. Our date suggest that the risk ofdeveloping mucosal lesions is much less during treatment withcholine magnesium trisalicylate than with acetylsalicylic acid. KEY WORDS: Aspirin, Choline magnesium trisalicylate, Endoscopic evaluation     

INFUSION OF GRADED CONCENTRATIONS OF SOMATOSTATIN IN MAN: PHARMACOKINETICS AND DIFFERENTIAL INHIBITORY EFFECTS ON PITUITARY AND ISLET HORMONES

The present study was undertaken to determine the plasma levels of somatostatin-like immunoreactivity (SLI) during constant infusion of graded concentrations of synthetic somatostatin-14 (S-14); to determine the half-life (t1/2) and metabolic clearance rate (MCR) of SLI; to correlate the plasma SLI levels with the degree of inhibition of pituitary and islet hormone secretion and to establish whether the plasma SLI levels capable of inhibiting pituitary and islet hormone secretion fall into the physiological range. Four normal subjects on separate occasions were each infused with saline or S-14 (25,50 and 75 micrograms/h) at a constant rate for 2 1/2 h. Thirty min following the infusions, TRH (200 micrograms) and arginine (0.5 g/kg) were given i.v. Blood samples were drawn every 15 min for measurement of GH, TSH, insulin, glucagon and SLI (by RIA of acid-ethanol extracted plasma) and at rapid intervals for 10 min after stopping the infusions for measurement of SLI disappearance. During S-14 infusions, plasma SLI rose rapidly, reached a plateau from 15-150 min and declined rapidly on cessation of the infusions with a mean t 1/2 of 2.72 +/- 0.45 min. Mean plateau SLI levels were: 149 +/- 3 pg/ml (25 micrograms/h), 465 +/- 35 pg/ml (50 micrograms/h), and 1244 +/- 71 pg/ml (75 micrograms/h). SLI was cleared rapidly but the MCR exhibited a dose-dependent decrease from 3225 +/- 699 ml/min for the 25 micrograms infusion to 1249 +/- 241 ml/min for the 75 micrograms/h infusion (P less than 0.05). The 25 micrograms/h infusion dose produced near-maximal suppression of GH secretion and inhibited insulin secretion but not TSH or glucagon secretion. The intermediate dose significantly inhibited GH, TSH, and insulin but not glucagon whereas the 75 micrograms/h infusion suppressed all four hormones. In six normal subjects endogenous plasma SLI rose from a basal value of 32.5 +/- 4.9 pg/ml to 75.5 +/- 9.0 pg/ml following ingestion of a mixed meal. This level was 50% of that resulting from the 25 micrograms/h infusion and which suppressed GH almost completely. We concluded that: Infused S-14 is cleared rapidly and decays with a short t 1/2; S-14 inhibits its own MCR; The somatotrophs are the most sensitive to S-14 inhibition, followed by the thyrotrophs and the B-cells (approximately equally) followed by the A-cells; Fluctuations in plasma SLI occurring physiologically may influence GH and possibly other S-14 sensitive cells by an endocrine mechanism.     

扑热息痛致急性肝功能衰竭狗肝脏血流动力学和血浆儿茶酚胺的变化

本实验通过建立扑热息痛致狗急性肝功能衰竭模型,观察了肝脏血流动力学改变和外周及内脏血管床血浆儿茶酚胺浓度的变化。结果为:急性肝功能衰竭时门静脉阻力明显增加,肝动脉血管阻力下降;门静脉血流量明显减少,总肝血流量亦明显降低,肝动脉血流量、门静脉压力及嵌塞静脉压力均无明显变化;门静脉、肝静脉、腹主动脉、下腔静脉血浆去甲肾上腺素浓度均明显增加。后者可能收缩门脉血管床,增加门静脉阻力、参与和/或加重肝循环障碍,本研究支持用酚妥拉明等α受体阻滞剂治疗急性肝功能衰竭时肝脏血流动力学障碍。     

STUDIES OF DIURNAL CHANGES IN PLASMA RENIN ACTIVITY, AND PLASMA NORADRENALINE, ALDOSTERONE AND CORTISOL CONCENTRATIONS IN MAN

Diurnal studies were performed on ten normal volunteers taking a normal sodium diet. Half-hourly blood samples were taken throughout 25 h and assayed for plasma renin activity (PRA) and the plasma concentrations of noradrenaline, aldosterone and cortisol. Sleep was recorded polygraphically and scored by standard criteria. Circadian rhythms were demonstrated for plasma cortisol, aldosterone and noradrenaline concentrations, but not for plasma renin activity. The nadir of the rhythm for the noradrenaline concentration appeared to be related to sleep itself rather than to any chronological index. Only PRA was effected by the stage of sleep, falling sharply during periods of REM sleep. Plasma cortisol and aldosterone concentrations showed a positive correlation over the 24 h. There was, however, no correlation between PRA and plasma aldosterone concentrations, except when the subjects arose after their night's recumbency. Plasma noradrenaline concentration did not correlate with the concentration of any of the other hormones measured.     

EFFECTS OF HIGH-DOSE AND LOW-DOSE NALOXONE ON PLASMA ACTH IN PATIENTS WITH ACTH HYPERSECRETION

The effect of a high (5.4 mg/h) and a low (0.8 mg/h) dose of naloxone (i.v. over a period of 90 min) on ACTH secretion was compared with placebo in patients with Addison's disease, congenital adrenal hyperplasia, Cushing's disease or Nelson's syndrome. In seven patients with primary adrenal insufficiency the high dose of naloxone provoked a significant increase of plasma ACTH concentrations (P less than 0.02) whereas the low dose of naloxone failed to influence ACTH secretion. In six patients with ACTH dependent Cushing's disease or Nelson's syndrome both doses failed to alter plasma ACTH levels. These results support the concept of inhibitory delta- or kappa-opiate receptors in the regulation of ACTH secretion. In patients with Cushing's disease or Nelson's syndrome ACTH secretion is insensitive to naloxone, presumably because of an autonomous pituitary adenoma or hypothalamic derangement.     

原发性高血压左室肥厚、心律失常与血浆儿茶酚胺关系的研究

本文观察了超声心动图高血压病左室肥厚患者心律失常的发生及其与血浆儿茶酚胺的关系。结果表明,高血压性左室肥厚患者室性心律失常的发生率较单纯高血压组显著增加;血浆去甲肾上腺素与左室后壁厚度及左室重量指数显著正相关;肾上腺素与左室重量指数显著正相关;24 h室性早搏总数与血浆去甲肾上腺素及肾上腺素均显著正相关。这提示,交感—肾上腺素系统活性增强是导致高血压病心肌肥厚及室性心律失常的重要因素之一。