[Liver-protective action of silymarin therapy in chronic alcoholic liver diseases]. / Silymarin kezelés májvédö hatása idült alkoholos májbetegségben.

The effects of silymarin (Legalon) therapy on liver function tests, serum procollagen III peptide level and liver histology were studied in 36 patients with chronic alcoholic liver disease in a six month double blind clinical trial. During silymarin treatment serum bilirubin, aspartate aminotransferase and alanin-aminotransferase values have been normalized, while gamma-glutamyl transferase activity and procollagen III peptid level decreased. The changes were significant, and there was a significant difference between post-treatment values of the two groups, as well. In the placebo group only gamma-glutamyl transferase values decreased significantly but to a lesser extent than that in the silymarin group. The histological alterations showed an improvement in the silymarin group, while remained unchanged in the placebo group. These results indicate that silymarin exerts hepatoprotective activity and is able to improve liver functions in alcoholic patients.

[Familial occurrence of carcinoid of the small intestine]. / Vékonybél-carcinoid familiaris elöfordulása.

The case of a 41 year old woman has been reported, whose "flush" syndrome was caused by a carcinoid tumor originated from the jejunum. The patient's father had to be operated for intestinal carcinoid tumor several times. The occurrence of different forms of carcinoid tumors, especially in the gastrointestinal tract, has been discussed in connection with the diagnostic approaches and therapeutical possibilities. The authors considered the case interesting for publications, because carcinoid is a rather rare tumor, and one cannot find its familiar occurrence in the available literature.

Dopaminergic-opioidergic interaction is reflected by changes in pituitary hormone secretion in patients with essential hypertension.

In a randomized, double-blind crossover study 13 untreated patients with mild essential hypertension were exposed to submaximal bicycle exercise. Sixty minutes before ergometry 10 mg metoclopramide or placebo, and 10 min before exercise 0.4 mg naloxone or placebo, were given intravenously. Plasma adrenocorticotrophic hormone, beta-endorphin and cortisol levels increased significantly after ergometry, whether performed after placebo, naloxone, metoclopramide or metoclopramide + naloxone treatment. However, only naloxone administration potentiated plasma adrenocorticotrophic hormone, beta-endorphin and cortisol responses to workload. Plasma levels of adrenocorticotrophic hormone, beta-endorphin and cortisol were 45 +/- 14 pg/ml, 6.2 +/- 1.2 pmol/l and 141 +/- ng/ml, respectively, after ergometry, when performed after placebo, but these values were increased to 61 +/- 10 pg/ml, 11.4 +/- 2.8 pmol/l and 207 +/- 22 ng/ml, respectively, after naloxone treatment. This naloxone-induced potentiation of hormonal release was blocked by metoclopramide pretreatment, suggesting a close interaction between dopaminergic and opioidergic mechanisms, regulating hormonal responses to physical exercise.

Life expectancy in chronic liver disease.

Life-table analysis is a suitable method for evaluating the effectiveness of therapeutical approaches to and the progression of, chronic diseases. The authors performed 324 liver biopsies in patients with liver disease between 1976 and 1986. The cumulative life-table analysis of Cutler and Ederer was applied in this retrospective study. Survival rates of different groups of patients expressed as the 7-year life expectancy were as follows: toxic hepatitis 90%, steatosis hepatitis 87%, chronic persistent hepatitis 87%, nonspecific reactive hepatitis 76%, chronic active hepatitis 72%, acute alcoholic hepatitis 66%, liver cirrhosis 40%. There seems to be a correlation between the severity of histological alteration and live expectancy. A similar correlation between the inflammatory cell infiltration and life expectancy cannot be observed. The life expectancy of patients with chronic active hepatitis has significantly improved recently. Further improvement of survival of patients with liver cirrhosis can be expected only from a reduction of alcohol consumption. The results can be regarded as a reference data for life expectancy of patients with chronic liver disease in Hungary.

Determination of the aminoterminal peptide of procollagen type III and laminin P1 in serum of patients with chronic liver disease.

Serum concentration of the aminoterminal peptide of procollagen type III (P III P) and that of the high-molecular-weight glycoprotein laminin P1 (LP1) were determined by a specific radioimmunoassay (RIA) in patients with different chronic liver diseases. Besides the routine laboratory tests, histological verification of the liver samples obtained by needle biopsy and a complex hepatitis B virus marker analysis by RIA (Biomedica-Sorin), or ELISA (Behringwerke, Marburg, FRG) kits were carried out in order to set up the correct clinical diagnosis. In normal controls, the P III P and LP1 concentrations were 7.8 +/- 1.1 ng/ml (n = 10) and 0.08 +/- 0.1 units/ml (n = 7), respectively. Patients with fatty liver (n = 25) showed a significant elevation in P III P concentration (18.6 +/- 2.7 ng/ml). Such an elevation was not unequivocally demonstrated before. In this group of patients LP1 level was also increased (1.4 +/- 0.2 units/ml, n = 10). In liver cirrhosis (n = 51) both P III P and LP1 concentrations were found to be consistently elevated.

Serum type-III-procollagen and laminin concentration after interferon therapy in chronic myeloproliferative disorders.

Serum procollagen-III-peptide (P-III-P) and laminin P 1 (LP1) concentrations were measured in 24 patients with various chronic myeloproliferative diseases, viz., essential thrombocythaemia (ET), chronic myelogenous leukaemia (CML) and myelofibrosis (MF). The highest P-III-P values were found in myelofibrosis. As compared to the controls, the serum laminin concentration was higher in all there groups of patients. No significant difference was found between the groups of patients. After three months of alpha-IFN therapy the P-III-P values became significantly higher, the laminin concentration slightly decreased in all investigated patients. Longitudinal follow-up myeloproliferative patients should be carried out in order to prove whether P-III-P and laminin determinations provide a useful test to monitor the progression of the disease and the effect of the therapy.

A prospective multicenter study of insulin and glucagon infusion therapy in acute alcoholic hepatitis.

A randomized, single-blind controlled multicenter study of insulin and glucagon infusion was carried out in 66 patients with acute alcoholic hepatitis. Thirty-three patients were treated with insulin 10 U and glucagon 1 mg in 500 ml 5% glucose in water via a peripheral vein for 2-6 h three times every day for 3 weeks. Patients in the control group received 5% glucose in an identical fashion. Fourteen control patients and five treated patients died from liver failure during the study (P less than 0.02). Clinical features of liver disease on entry into the study were similar in the two groups, but the total serum bilirubin, aspartate aminotransferase, gamma-glutamyltranspeptidase activities and prothrombin time significantly improved in the treated patients (P less than 0.05). Insulin and glucagon infusion appears to be a promising treatment of acute alcoholic hepatitis.

Serotonergic stimulation of prolactin and corticosterone secretion is mediated by different pathways from the mediobasal hypothalamus.

In previous studies we obtained evidence that serotonin release by p-chloroamphetamine (PCA) causes an increase in corticosterone secretion but that this effect is not mediated via the raphe nuclei in the midbrain. In contrast, PCA-induced prolactin secretion was abolished by dorsal raphe lesions. In the present study, posterolateral cuts which interrupted caudal inputs to the hypothalamus attenuated the effect of PCA on plasma prolactin but did not block the PCA-induced increase in plasma corticosterone levels. Large lesions of the mediobasal hypothalamus produced a significant reduction of plasma corticosterone concentration but did not completely prevent the effect of PCA on corticosterone secretion. Hypophysectomy performed 24 h before sacrifice caused a marked decrease in plasma corticosterone levels but did not completely abolish the effect of PCA. These results suggest that PCA also stimulates corticosterone secretion via a direct action on the adrenal gland. The lesions in the mediobasal hypothalamus caused an increase in plasma prolactin concentration, and in these rats, PCA suppressed rather than stimulated prolactin secretion. This suggests that the known weak dopamine agonist activity of PCA is exposed when the effects of serotonin release in the brain are eliminated.

Rapid changes in growth hormone regulation and hypothalamic somatostatin after transection of anterolateral pathways to the medial-basal hypothalamus in the rat.

Plasma and pituitary GH content, in-vitro GH release and somatostatin-like immunoreactivity (SLI) in the stalk-median eminence were studied up to 7 days after making an anterolateral cut (ALC) around the medial-basal hypothalamus. Plasma GH concentration increased within 15 min to a very high level, then fell to a high level which was unchanged for several hours. The GH concentration then steadily decreased between days 2 and 7. The SLI content in the stalk-median eminence decreased to 3.5% of the control value within 3 days. The GH content of the anterior pituitary gland was 58.8% of the control value by 1 week after the operation but the in-vitro sensitivity to somatostatin of the GH cells failed to change. Pentobarbitone injection stimulated GH release in the sham-operated controls but decreased it in the rats with an ALC. These findings suggest that transection of somatostatin-containing fibres is followed by a rapid rise and a lasting high concentration of plasma GH which slowly returns towards lower levels in parallel with a marked depletion of pituitary GH content. In rats with transected somatostatin innervation of the median eminence, sodium pentobarbitone probably decreases GH secretion by depressing the secretion of GH-releasing hormone.

Evidence that the effects of arginine-8-vasopressin (AVP) on pituitary corticotropin (ACTH) release are mediated by a novel type of receptor.

Ovine corticotropin releasing factor (oCRF-41) and AVP act synergistically to stimulate pituitary ACTH secretion. In the present study we have investigated whether the effect of AVP, either in the presence or in the absence of oCRF-41 (0.5 nmol/l), could be blocked by V1 (pressor)-antagonists. Furthermore, oxytocin, and [1-deamino,8-D-arginine] vasopressin (dDAVP) were tested for their ability to release ACTH. All experiments were carried out in vitro, using segments of rat anterior pituitary glands. The V1-antagonist [1-deamino,penicillamine(o-methyl-tyrosine)]AVP inhibited ACTH release induced by AVP or AVP + oCRF-41. However, it also had some agonistic activity which was more pronounced in the presence of oCRF-41. An equally potent V1-antagonist, [1-beta-mercapto-beta, beta-cyclopentamethyleneproprionic acid (o-methyl-tyrosine)]AVP, failed to inhibit AVP-stimulated ACTH secretion, and also had weak agonist potency. The relatively selective V2 (antidiuretic)-agonist dDAVP was 20-30 fold less potent than AVP. Oxytocin, a weak V1- and V2-agonist was only 4-8 fold less potent than AVP. These data are compatible with the suggestion that AVP receptors on pituitary corticotrope cells are neither classical V1- nor V2-receptors.

Inhibition of growth hormone and prolactin secretion by a serine proteinase inhibitor.

The action of the tripeptide aldehyde t-butyloxycarbonyl-DPhe-Pro-Arg-H (boc-fPR-H), belonging to a family of serine proteinase inhibitors, on the release of immunoreactive prolactin (iPRL) and growth hormone (iGH) has been studied. In rat anterior pituitary cell cultures and pituitary quarters 1 mM boc-fPR-H inhibited basal iPRL and iGH release. Thyroliberin-induced iPRL release by cultured cells was also markedly inhibited with a concomitant accumulation of intra-cellular iPRL. During the short- and long-term exposure of cells to boc-fPR-H there no changes in total cell protein contents and in activities of some lysosomal marker enzymes. A wide scale of unchanged parameters characteristic for cellular metabolism indicated that the tripeptide aldehyde has no cytotoxic effect. The marked inhibition of basal as well as stimulated hormone release in the presence of the enzyme inhibitor might suggest that at least a portion of the hormones is released via a proteolytic enzyme-dependent process.

Effects of arginine-8-vasopressin and 1-deamino-8-D-arginine-vasopressin on ACTH secretion in rats.

The corticotropin-releasing effect of arginine-8-vasopressin (AVP) has been compared to that of 1-deamino-8-D-arginine-vasopressin (dDAVP) in male rats of R-Amsterdam strain. AVP increased the level of ACTH and corticosterone in the peripheral blood in a dose-dependent manner. In contrast to AVP, a very potent antidiuretic agent dDAVP which is devoid of pressor activity had no effect on ACTH release and did not stimulate the secretion of corticosterone. It is concluded that CRF activity of vasopressin in vivo is related to its pressor activity. These data are in agreement with the previous findings of these authors demonstrating that dDAVP shows a very low affinity for vasopressin receptors of the cell membranes in the adenohypophysis.

Responsiveness of adenohypophysial corticotrophs to hypothalamic (SME) extract remains unchanged in rats with hypothalamic lesions inhibiting CRF release.

The corticotrophin-releasing activity of stalk-median eminence (SME) extract was studied using incubated quarters of anterior pituitary glands obtained from rats with long-term anterolateral deafferentiation or complete surgical lesion of the medial basal hypothalamus, as well as with the lesion of the paraventricular nuclei. These hypothalamic interventions are known to cause a complete or partial but significant deficiency in hypothalamic corticotrophin-releasing factor (CRF) release, however, such lesions failed to alter the sensitivity of the ACTH response from incubated pituitary segments towards the SME extract. These results suggest that the specific responsiveness of adenohypophysial corticotrophs is maintained when hypothalamic CRF supply is decreased for a long period of time.

Circadian variations in beta-endorphin concentrations in pituitary and in some brain nuclei of the adult male rat.

Using both the 'punch' microdissection and a radioimmunological technique, circadian variations in beta-endorphin concentrations can be observed in the pituitary and in some discrete brain regions of the male rat (Wistar CFY). Animals were synchronized with light from 06.00 to 18.00 h, then darkness. Water and food were available ad libitum. Very well marked circadian rhythms were in evidence in the anterior lobe of the pituitary, the septum, the pons, the medulla oblongata and the cerebellum. There crest time locations were situated between 20.00 and 24.00 h. No significant circadian rhythms but biphasic variations were observed in the intermediate lobe of the pituitary, the POA, the thalamus, the central gray and the caudatus. There crest time locations were synchronized around 08.00 and 20.00 h. The most striking finding was that, regardless of the brain area investigated so far, maximal values were observed a short time after the beginning of the activity period of rats. This fact is identical with the one which has been observed for substance P and LH-RH contents in brain areas where these peptides are mostly present in nerve terminals in high concentrations.

Further characterization of putative alpha--adrenergic receptors in brain that affect blood pressure and the secretion of ACTH, GH and renin in dogs.

To determine if alpha 1-or alpha 2-adrenergic receptors mediate the inhibition of ACTH stimulation of growth hormone secretion, decrease in blood pressure and inhibition of renin secretion produced by release of catecholamines in the brain, drugs with varying amounts of alpha 1- and alpha 2-adrenergic activity were injected directly into the third ventricle in pentobarbital anesthetized dogs. To determine whether the receptors mediating the responses to clonidine were pre- or postsynaptic, the effect of intravenous clonidine was determined 2 weeks after intraventricular 6-hydroxydopamine, and 24 h after intravenous alpha-metyl-p-tyrosine. Norepinephrine, epinephrine and clonidine, but not methoxamine and phenylephrine inhibited ACTH secretion. None of these alpha-agonists affected growth hormone secretion. Epinephrine and clonidine lowered blood pressure. Clonidine decreased plasma renin activity, but the other agonists increased it. In dogs treated with 6-hydroxydopamine, the decrease in blood pressure and ACTH and renin secretion produced by clonidine was not altered but the growth hormone response was reduced. alpha-methyl-p-tyrosine had no effect on the ACTH and growth hormone responses to clonidine. The data suggest that postsynaptic alpha-adrenergic receptors mediate inhibition of ACTH secretion and stimulation of growth hormone secretion, although in the case of growth hormone secretion, a presynaptic receptor is also involved. In addition, postsynaptic alpha 2-adrenergic receptors mediate a decrease in blood pressure, and they may mediate decreased renin secretion.

Lack of episodic growth hormone secretion in rats with anterolateral deafferentation of the medial-basal hypothalamus.

Growth hormone secretory dynamics were studied in rats sampled through chronic indwelling right atrial cannulae at time-intervals ranging from 2 days to 2 months after placing an anterolateral cut (ALC) around the medial-basal hypothalamus (MBH). The episodic secretion normally occurring in the control animals could not be seen in the rats with an ALC. Instead of the usual high bursts and low trough levels occurring between 09.00 and 13.00 h in the controls, the operated animals had fairly constant plasma GH levels with only minor fluctuations at all postoperative time-points studied. These results suggest that (1) the isolated MBH is incapable of maintaining the episodic secretion of GH and (2) the pulsatile hormone release is dependent on neural pathways entering the MBH from an anterolateral direction.

Evidence that the mediobasal hypothalamus is involved in serotonergic stimulation of renin secretion.

The effect of the serotonin-releasing drug parachloroamphetamine (PCA) on plasma renin activity was studied in rats 4 days after surgical lesions of the mediobasal hypothalamus, anterolateral deafferentation of the mediobasal hypothalamus, posterolateral deafferentation, or hypophysectomy. PCA increased plasma renin activity in sham-operated rats, but it failed to increase plasma renin activity in rats with mediobasal hypothalamic lesions or posterolateral deafferentation. The response to PCA was unaffected by anterolateral deafferentation and enhanced by hypophysectomy. There were no significant differences in plasma renin activity in lesioned, deafferented, and hypophysectomized rats injected with saline. The data indicate that the mediobasal hypothalamus is part of the pathway by which central serotonergic neurons affect renin secretion, and that the effect is not mediated via hormones of the pituitary gland.

Corticoliberin activity of rat neurohypophysis is distinct from vasopressin.

Electrical stimulation of the neural lobe of the pituitary resulted in an increase of corticosterone secretion in both normal and Brattleboro rats. Bioassaying the corticoliberin (CRF) activity of stalk-median eminence and neural lobe extracts obtained from normal and Brattleboro rats revealed that the endogenous vasopressin was not a prerequisite of ACTH-releasing potency. Arginine-8-vasopressin failed to potentiate the CRF activity of the different extracts. These data suggest that a nonvasopressin substance(s) with CRF activity can be released from the neurohypophysis of the rat, and it may contribute to activating the pituitary-adrenal axis under certain experimental conditions.