Therapeutic attempts with anti-fibrotic drugs are still at an experimental stage. The clinical efficacies of most agents listed in Table II have not been proved. Some potential agents, such as colchicine, analogues of PGE, gamma-interferon, inhibitors of prolyl hydroxylase, malotilate, and PUL, must be further evaluated in controlled clinical trials. In addition, almost all anti-fibrotic agents, except HOE 077, are neither liver-nor fibrosis-specific. Some site-directed (targeted) drug delivery systems, drug-loaded vesicle carrier systems, like liposomes and erythrocyte ghosts, which selectively affect the extracellular matrix-producing cells, may improve efficacy and reduce adverse effects if they can be carriers for anti-fibrotic agents. Developments in biochemistry, immunohistochemistry, and molecular biology have considerably advanced our understanding of pathogenic mechanisms of hepatic fibrosis. With the development of available pathologic and serologic markers for ongoing fibrogenesis, experimental and clinical anti-fibrotic trials have become more active. Some therapeutic strategies have chosen targets for interference in collagen metabolism. In vivo inhibition of Ito cell activation has been a focus for the anti-fibrotic studies (70). In the present review an update of pharmacologic intervention in the process of metabolic pathways of collagen, the main extracellular matrices in both interstitium and basement membrane, has been summarized. Several drugs or biochemical agents that act on different steps of collagen synthesis, crosslinking, and breakdown are listed and discussed briefly. Moreover, agents that inhibit other matrix components are also involved in the review.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives. To describe the evolution of nutritional and neurological complications in a Swedish population of patients with familial amyloidotic polyneuropathy, and to identify prognostic factors and useful tests for monitoring the progress of the disease.Design. Prospective and retrospective study of patients with familial amyloidotic polyneuropathy.Setting. Tertiary referral centre.Subjects. Twenty-seven patients with familial amyloidotic polyneuropathy, and a symptomatic onset before the age of 50.Main outcome measures. Age at onset, duration of disease before death, serum albumin, body mass index (BMI), duration and grade of peripheral neuropathy and gastrointestinal disturbances. Faecal fat, xylose test and (75)selenohomocholic acid-taurine (SeHCAT) test were used for assessment of malabsorption.Results. Thirteen patients died during the study period after a disease duration of between 9 and 18 years (mean 13). A short time interval between the onset of neurological and of gastrointestinal symptoms had greater impact on survival than age at onset in this selected group of patients (r = 0.65; P = 0.017). Malnutrition was evaluated by multiplying the [body weight (kg)/height(2) (m)] with the serum albumin to compensate for oedema. This modified body mass index (mBMI) was significantly correlated to the number of years before death (r = 0.89; P < 0.0005) and to the duration of gastrointestinal symptoms (r = -0.66; P < 0.0005), but not to duration of disease (r = -0.2; P = 0.20). Polyneuropathy was graded according to functional capacity from I to IV (PND score) and was correlated to the number of years before death and mBMI, but not to serum albumin. The SeHCAT test for bile acid malabsorption was significantly correlated to the duration of gastrointestinal symptoms and to mBMI (r = -0.67; P = 0.0003 and r = -0.62; P = 0.003, respectively).Conclusion. The investigation disclosed that a short time interval between the onset of neurological and of gastrointestinal symptoms is associated with a decreased survival time. The mBMI was closely related to time before death, duration of gastrointestinal disturbances, malabsorption and functional capacity. The mBMI appears to be well suited to monitoring disease progress and gives prognostic information.

Gastrointestinal dysfunction due to autonomous neuropathy is a complication described in various diseases such as diabetes mellitus, multiple sclerosis, and familial amyloidosis with polyneuropathy. We present the results of a prospective investigation of bile acid malabsorption in 17 patients with familial amyloidosis by means of Se-75-labelled homocholic-tauro acid (SeHCAT). The diagnosis was in all cases verified by the DNA test for mutation of transthyretin in position 30. Small-intestinal biopsy specimens were examined for deposits of amyloid, and the presence of gastric retention was evaluated by gastroscopy. In addition, the patients were investigated for bacterial overgrowth by means of the bile acid breath test (BABT). A high frequency of abnormal BABT results (44%) was encountered. However, 65% also had abnormal low SeHCAT values, indicating bile acid malabsorption. Only two patients had abnormal BABT and normal SeHCAT results, indicating bacterial contamination of the small intestine. Bile acid losses increased with the duration of gastrointestinal symptoms. Significantly lower SeHCAT values were encountered in patients with gastric retention, whereas the occurrence of amyloid deposits in small-intestinal biopsy specimens was without effect on SeHCAT retention. Bile acid malabsorption is frequently encountered in familial amyloidosis with polyneuropathy and seems to be more closely associated with gastrointestinal motility dysfunction than with amyloid deposits in the intestinal mucosa.

The occurrence of chronic diarrhoea was evaluated in 173 consecutive patients previously treated with radiation for gynaecological cancer. A survey of gastrointestinal symptoms showed a high frequency of diarrhoea; 13% of the patients had 21 or more bowel movements a week and 3% had 28 or more. Significantly more patients who had a cholecystectomy were in the group with diarrhoea (chi 2 = 6.26; p less than 0.02). Twenty patients with chronic or intermittent diarrhoea were subject to extended gastrointestinal investigation. Bile acid malabsorption was evaluated by the 75Selenahomocholic acid-taurine test (SeHCAT). Bile acid malabsorption was found in 13 (65%) of the 20 patients further investigated, of whom seven had extremely low whole body retention values, which is consistent with severe malabsorption. The results suggest that bile acid malabsorption is a common cause of diarrhoea after radiation treatment for gynaecological cancer. Bacterial contamination was diagnosed in nine patients (45%) by the [14C]-D-xylose breath test or by the cholyl-[14C]-glycine breath test in combination with a normal test for bile acid malabsorption. All patients with vitamin B-12 deficiency, who were tested for bile acid malabsorption, had low retention times for the SeHCAT (p = 0.05). A significant decline in the frequency of diarrhoea was found after treatment with antibiotics or bile acid sequestrants, or both, in combination with a reduced fat diet.

Seventeen patients were operated on with intestinal shunts for morbid obesity, in eight a biliointestinal bypass (BI) was constructed and in the rest a conventional jejunoileal (JI)-shunt. The reduction in weight was similar in both groups, and so was malabsorption of fat, but the BI-group had significantly less bowel motions with less watery diarrhoea. Bile acid malabsorption was measured both chemically by estimating the total amount of faecal bile acids excreted, as well as indirectly by using a 75Se-labelled synthetic bile acid (SeHCAT). Both techniques revealed a substantial loss of bile acid after both types of operation, but patients with BI bypass surgery had significantly lower elimination time of the bile acid than those with JI-shunts. There was a significant negative correlation between SeHCAT retention and total faecal bile acids. However, some patients with low SeHCAT retention had normal or even reduced output of faecal bile acids. Estimation of faecal bile acids may display false negative results when the bile acid pool is decreased. The SeHCAT-test seems to be a better technique for measuring bile acid losses. The study suggests that BI bypass surgery for obesity seems to be advantageous over the JI shunt in reducing the postoperative loss of bile acids and choleretic diarrhoea, without influencing the weight loss.

Minute pieces of rat parotid gland were used in studies of adrenergic regulation of K+ efflux using 86Rb+ as a probe for K+. Noradrenaline induced a concentration-dependent RB+ efflux, whereas the beta 1-selective agonist prenalterol was without effect. On the other hand, the beta 2-selective drug, terbutaline, at high concentrations displayed a small enhancement of Rb+-secretion. The selective alpha 1-adrenoceptor drug, phenylephrine, was as potent as noradrenaline, whereas the alpha 2-agonist clonidine had only a small effect. The noradrenaline-induced Rb+-efflux was effectively inhibited in the presence of prazosin, an alpha 1-blocker, whereas the alpha 2-antagonist, yohimbine, was roughly 50 times less potent. The results suggest that catecholamine-induced K+-secretion from the rat parotid gland is mediated via activation of post-synaptic alpha-adrenoceptors of the alpha 1-subtype.

The intestinal absorption and hepatic metabolism of vitamin D were studied in a woman with icteric primary biliary cirrhosis (PBC) complicated by pronounced bone pain and muscle weakness due to vitamin-D deficiency. The patient had a markedly reduced intestinal absorption of vitamin D, while the 25-hydroxylation of this vitamin was found to be normal despite the presence of longstanding icterus. The malabsorption of fat-soluble compounds secondary to the cholestasis was probably further impaired by several years of cholestyramine treatment. Administration of 1.25-(OH)2D3 increased intestinal calcium absorption, normalized serum calcium and increased bone mineral content of the proximal tibia. Furthermore, drastic improvement of muscle weakness and relief of bone pain were observed. It is recommended that repeated measurements of serum 25-(OH)D should be carried out in patients with PBC, and especially in those treated with cholestyramine. In certain vitamin D deficient patients, studies using radio-labelled vitamin D may provide clinically valuable information as to the exact site of the underlying disturbances.

The activity of platelet monoamine oxidase was found to be lower in latelet-rich plasma from alcoholics than from controls. This was found for both males and females, and for all three substrates tested (tyramine, tryptamine, and β-phenethylamine). This lower monoamine oxidase activity was not due to liver damage produced by chronic alcoholism, since patients with chronic nonalcoholic liver disease showed an increased platelet monoamine oxidase activity with respect to controls. Furthermore, there was no significant change in the monoamine oxidase activity for the alcoholics after 3 weeks of abstinence, although there was a significant improvement in the livers as measured by a variety of plasma tests for liver damage. The Km value of the monoamine oxidase toward tryptamine was the same for controls, alcoholics, and patients with liver disease.

Forty-Five consecutive patients with chronic peptic ulcer disease completed a double-blind controlled trial in which they were given cimetidine 0.8 g daily or placebo, in order to evaluate the preventative effect of the drug on ulcer recurrence. On entering the trial all patients had endoscopically healed ulcers. Endoscopy was performed again at 6 and 15 months, or if there were severe epigastric pains. The period of medication was 15 months, and the patients still in remission at that time were observed for a further 9 months. During the course of the study 11 out of 23 patients (47.8%) in the placebo group developed re-ulceration, whereas 4 out of 22 (18.2%) patients relapsed while on cimetidine (p<0.05). There were significantly fewer weeks of dyspepsia and better general well-being in the cimetidine group as compared to the placebo group. No early ulcer recurrence or increased rebound acid secretion was noted after cessation of the cimetidine treatment. Viamin B12 absorption was not affected by the 15-month cimetidine treatment. Two men developed gynaecomastia, one died of myocardial infarction and one had transient sinus bradycardia during cimetidine medication. Cimetidine improves the symptomatic state and postpones ulcer recurrence as long as treatment is maintained.

Fifty patients with active peptic ulcers on endoscopy were randomly allocated for treatment with placebo or cimetidine (1.0 g daily) over a period of four weeks. All patients had free access to antacids to relieve epigastric pain. In the cimetidine group a significantly higher proportion of the ulcers had healed (82.6% of the patients) compared with the placebo group (48.0%). There was poor correlation between the healing of the ulcer and dyspeptic symptoms in the placebo group. The results suggest that the presence of endoscopic duodenitis is to a great extent responsible for the dyspepsia. Cimetidine treatment, besides healing the ulcers, also improved the endoscopic duodenitis and the symptomatic state more than placebo treatment. No significant clinical side effects were observed. Chemical abnormalities were only noted with respect to serum creatinine. In the cimetidine group there was a statistically significant rise in serum creatinine, which was most apparent after two weeks of treatment. However, the increase was slight and not significant among the males, whereas in the case of the females there was a large and highly significant rise. The reason for this sex difference is at present unknown.

Thirteen patients with essential hyperlipoproteinaemia were treated over periods of 2--29 months with hydrophilic colloid made from Psyllium. Reduction of the increased serum cholesterol levels averaged 16.9 per cent, and the corresponding figure for the increased triglyceride levels was 52.0 per cent. The reduction of cholesterol and triglyceride was statistically significant (p less than 0.0025 and p less than 0.0005 respectively). No significant change in normal blood lipid levels was observed on administration of the Psyllium colloid.