Rapid profiling of enteric coated drug delivery spheres via broadband acoustic resonance dissolution spectroscopy (BARDS).

There is an increased trend towards the use of drug and enteric coated sugar spheres for controlled oral delivery of active pharmaceutical ingredients (API). This trend is driven by increased efficacy and ease of formulation of different dosage levels. However, difficulties exist in determining the thickness of drug and enteric coatings in a time efficient manner during manufacture, quality assurance and stability testing. The thickness of the coating determines the dosage of the API and the thickness of the enteric coating determines the release rate of the drug in the gastro-intestinal tract. Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS) offers a rapid new approach to characterising the enteric coating thickness and the raw materials used in their manufacture. BARDS applications are based on reproducible changes in the compressibility of a solvent during dissolution which is monitored acoustically due to associated changes in the speed of sound in solution. It is demonstrated how core delivery sugar spheres have unique acoustic spectra attributable to the mean size distribution of the spheres. A steady state acoustic lag time is associated with the disintegration of the enteric coating, in basic solution. This lag time can be manipulated by varying the concentration of the base which affects the rate at which the coating dissolves. It is anticipated that the thickness/loading of the spheres can be estimated from the lag time.

Phenylalkylamine abuse among opiate addicts attending a methadone treatment programme in the Republic of Ireland.

Since the early 1990s ring-substituted derivatives of amphetamine have been abused widely in the Republic of Ireland. The main ring-substituted amphetamines being abused include methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA) and methylenedioxyethamphetamine (MDEA). A newer illicit synthetic analogue, which has been seized to a lesser extent by Irish police, is N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB). The work presented here involved the determination of the type of ring-substituted amphetamines being abused by a group of recovering opiate abusers participating in a methadone maintenance programme in a Dublin Drug Rehabilitation Centre. Urine samples which tested positive for amphetamines and ring-substituted amphetamines via EMIT immunoassay were subjected to further analysis using GC-MS with MBTFA flash derivatization. It was found that the methylenedioxypropanamines were being abused, as was amphetamine itself. However, no abuse of methylenedioxybutanamines or thioamphetamines was observed.

Management of pulmonary aspergillosis in AIDS: an emerging clinical problem.

AIMS: To review the clinical, radiographic, and therapeutic features of 11 cases of respiratory Aspergillus infection in patients with AIDS. METHODS: All induced sputum and bronchoalveolar lavage samples obtained from HIV seropositive patients between January 1985 and March 1993 were analysed for Aspergillus species. Additionally, where appropriate, bronchial or renal biopsy specimens, or both, were taken before treatment had started. RESULTS: In 11 patients Aspergillus fumigatus was identified in alveolar samples obtained by sputum induction. This was confirmed by bronchoalveolar lavage in eight. Three patients had Aspergillus plaques in the trachea and bronchus, while a fourth patient had an aspergilloma. Risk factors for Aspergillus infection were present in all patients, including corticosteroid treatment in three cases and neutropenia in four, three of whom had received chemotherapy for Kaposi's sarcoma. Four patients had concomitant cytomegalovirus infection. Ten patients had a CD4 count of less than 50 cells/mm3 while one patient had a disseminated T cell lymphoma with a CD4 count of 242 cells/mm3. Of the three patients with samples obtained by sputum induction who did not undergo bronchoscopy, two had a normal chest x ray picture and the third had a right lobar pneumonia complicating an aggressive lymphoma. All three were treated with itraconazole 200 mg twice a day without further investigation. Survival from the time of diagnosis of Aspergillus infection was short: seven patients died within six weeks, although only one death was directly attributed to pulmonary aspergillosis. At six monthly follow up, one patient, who initially had a positive Aspergillus culture from bronchial washings and a normal chest radiograph, developed a renal aspergilloma despite the disappearance of Aspergillus sp from the sputum. CONCLUSION: Pulmonary aspergillosis is an important clinical problem in patients with AIDS with a CD4 count of less than 50 cells/mm. Furthermore, patients with Aspergillus sp in sputum induction or bronchial washings may develop disseminated disease despite adequate treatment of the primary infection.

Non-surgical approaches to stones in the biliary tree.

Medical treatment of cholesterol gall stones aims to dissolve the stones leaving the biliary tract stone-free and the gall bladder in situ. The introduction of extracorporeal shock wave lithotripsy and contact solvent therapy with methyl tert butyl ether have revolutionised the medical management of both gall bladder stones and bile duct stones which are too large to be treated by sphincterotomy. Both approaches represent a major advance over cheno- and ursodeoxycholic acid which are effective in less than 30% of cases and require prolonged therapy. All medical treatments require a functioning gall bladder and suffer from relapse rates in the order of 10% per annum. Secondary prophylaxis is expensive and the rate of compliance and long term safety have yet to be established.

Enhanced secretion of prostaglandin E2 by tissue-fixed macrophages in colonic carcinoma.

Prostaglandin E2 (PGE2) secretion by peripheral blood and tissue-fixed macrophages from patients with colorectal carcinoma was assessed. There was no significant difference between PGE2 production by peripheral blood mononuclear cells between patients with colorectal carcinoma and normal controls. However, secretion of PGE2 by tissue-fixed macrophages from within the colorectal carcinomata in response to opsonised zymosan was significantly higher than in the uninvolved colonic tissue. PGE2 production by tissue-fixed macrophages from within colonic polyps was found to be normal. These results could not be explained on the basis of increased availability of substrate arachidonic acid since addition of excess arachidonic acid resulted in similar findings. The enhanced production of PGE2 correlated with Dukes staging but not the level of differentiation. The production of PGE2 from epithelial cells in response to ionophore A23187 was not significantly enhanced. Leukotriene B4 secretion by intestinal macrophages in response to opsonised zymosan was not significantly elevated in the colonic tumour tissue. Modulation of levels of prostaglandin production within colonic tumours may play a role in the rate of growth and vascularity of these tumours and in the regulation of the local immune response to malignancy.

Dietary intakes and adipose tissue levels of linoleic acid in peptic ulcer disease.

Adipose tissue levels of linoleic acid were determined from biopsies of subcutaneous abdominal fat of normal healthy controls (n 40) and from two patient groups with endoscopically evaluated non-ulcer dyspepsia (n 40) or peptic ulcer disease (n 38). The level (g/100 g) of adipose tissue linoleic acid in the normal healthy controls (15.0 (SD 4.1] was significantly (P less than 0.05) greater than that in patients with non-ulcer dyspepsia (12.8 (SD 3.5] and in patients with peptic ulcer disease (11.7 (SD 2.7]. A dietary history revealed a lower intake of linoleic acid and a significantly (P less than 0.05) lower intake of dietary fibre (g/d) for both the non-ulcer dyspepsia (15.9 (SD 6.2] and peptic ulcer disease (15.2 (SD 7.8] patients compared with normal healthy controls (20.2 (SD 11.2]. Adipose tissue linoleic acid tended to increase with indices of increasing socioeconomic status, although the differences between patient and controls were not confounded by socioeconomic status. Patients with dyspepsia reported more foods causing symptoms (onion, fried foods, alcohol, citrus fruits and spices) and more foods giving relief (milk, bread) compared with control orthopaedic patients.

A prospective randomised controlled trial of tamoxifen and cyproterone acetate in pancreatic carcinoma.

In a prospective controlled clinical trial, 108 patients with pancreatic adenocarcinoma were randomly allocated to receive tamoxifen 20 mg b.d., cyproteron acetate 100 mg t.d.s. or no active treatment. The median survival of those receiving tamoxifen was longer than either of the other two groups (5.25 compared to 4.25 and 3 months, respectively) but this difference did not achieve statistical significance. Cox regression analysis of 12 clinical and biochemical features showed that, for the entire group of patients, survival was significantly longer in younger patients, those undergoing surgical bypass and those with better initial performance status. However, even when adjustment was made to allow for the distribution of these prognostic variables within the three groups, the difference in survival still did not achieve statistical significance. No side-effects attributable to treatment was observed.

Prostaglandin E2 and leukotriene B4 synthesis by peripheral leucocytes in alcoholics.

Alcohol inhibits phospholipase (PL) activity in a number of animal models. We have therefore measured prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), liberated by stimulated peripheral blood mononuclear cells (PBMC) and neutrophils respectively in chronic alcoholics and in control subjects. Peripheral blood mononuclear cells from alcoholics produced less PGE2 (p less than 0.01) and neutrophils produced less LTB4 (p less than 0.025). Reduced PGE2 production by PBMC of alcoholics was corrected by the addition of exogenous arachidonic acid (p less than 0.005) whilst neutrophil LTB4 production remained lower in the alcoholics (p less than 0.01). Percutaneous liver biopsies were undertaken in the 20 alcoholics having abnormal liver function tests. Prostaglandin E2 biosynthesis was lower in PBMC from patients with alcoholic hepatitis than with alcoholic cirrhosis (p less than 0.05). Analysis of PBMC fatty acid composition demonstrated that endogenous arachidonate and linoleate contents were not significantly different in alcoholics and controls. Cells from controls and alcoholics were incubated with 0, 50 and 150 mmol/l ethanol for two hours but there was no alteration in PGE2 or LTB4 biosynthesis. In summary, we found reduced eicosanoid production by peripheral leucocytes in alcoholics, supporting the hypothesis that chronic alcohol consumption either inhibits membrane bound phospholipase activity or enhances, alternatively, catabolism of eicosanoids. This phenomenon is more marked in alcoholic patients with hepatitis than in those with cirrhosis alone.

Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal.

Forty-seven patients with autoimmune chronic active hepatitis in remission on azathioprine and/or prednisolone were entered into a randomized controlled trial to assess the value of azathioprine alone in maintenance of remission. The trial design involved administering azathioprine at a dose of 2 mg per kg to one-half of the patients, in whom prednisolone was then gradually withdrawn, whereas the remaining patients, the "control" group, were maintained on the conventional combination regimen of azathioprine (1 mg per kg) with prednisolone. At 1 year there was no significant difference in respect of standard liver function tests or histological appearances between the two groups. Two patients in the azathioprine group required dosage reduction because of myelosuppression and both subsequently relapsed. Following withdrawal of corticosteroids Cushingoid features were lost with a return of weight and blood pressure to normality. In 75% of the patients, corticosteroid withdrawal was marked by arthralgias and myalgias which lasted for up to 12 months: no other major side effects of corticosteroid withdrawal were noted. Thus in the majority of cases, remissions in autoimmune chronic active hepatitis which are induced by corticosteroids can be maintained with azathioprine alone.

Hyperthyroxinaemia in hepatocellular carcinoma: relation to thyroid binding globulin in the clinical and preclinical stages of the disease.

Serum thyroxine was significantly higher in 59 patients with hepatocellular carcinoma than in normal subjects, patients with uncomplicated cirrhosis (48), or other primary tumours with or without hepatic metastases (50). Elevated thyroxine levels appeared attributable to high levels of thyroxine binding globulin which showed a positive linear correlation with serum thyroxine in all groups studied. Despite this hyperthyroxinaemia all patients appeared clinically euthyroid and, consistent with this, T3 was elevated in only one patient and the free thyroxine index was normal in all. Amongst a group of 25 cirrhotic patients who were followed-up for between 12 and 72 months, there was a striking dissociation between the TBG values of those destined to develop HCC and those who did not. In the former group TBG rose steadily with time whereas in the latter group levels remained stable, or, more often, fell. The rises in TBG occurred prior to any clinical signs of tumour development and may be one of the earliest serological changes to occur during carcinogenesis in the cirrhotic liver.

Influence of aetiology, clinical and histological features on survival in chronic active hepatitis: an analysis of 204 patients.

To determine which clinical and laboratory features may influence survival in patients with chronic active hepatitis, we undertook a retrospective study of 204 patients seen on this unit over a 15-year period and applied logistic regression analysis. One hundred and six patients had autoimmune chronic active hepatitis, 69 'cryptogenic' chronic active hepatitis (no autoimmune markers or other aetiological factors identified), and 29 were HBsAg-seropositive. Variceal haemorrhage, encephalopathy and ascites were common presenting features in the cryptogenic group while the presence of jaundice and other immunopathic diseases did not differ between the groups. Cirrhosis was more common at presentation in the cryptogenic group. Remission was induced with corticosteroids and azathioprine in 82 per cent of patients with autoimmune chronic active hepatis and in 77 per cent of patients with cryptogenic chronic active hepatitis and the annual relapse rate was similar in the autoimmune and cryptogenic groups. Five-year survival was 87 per cent in the autoimmune group, 65 per cent in the cryptogenic group, and 80 per cent in those with HBsAg-positive disease, and on logistic regression analysis, the presence of cirrhosis at presentation was the only independent factor which adversely affected survival. Overall survival in the cirrhotic patients at five and 12 years was 63 and 48 per cent respectively compared with 95 and 92 per cent in those without cirrhosis.

Clinical course of cirrhosis in young adults and therapeutic potential of liver transplantation.

The lack of information on survival in young adults with cirrhosis and the increasing use of liver transplantation in this age group have led us to carry out a retrospective analysis of the clinical course and survival in 83 young adults aged between 15 and 30 years presenting to the Liver Unit between 1970 and 1983. Fifty four (65%) patients had cirrhosis at initial presentation and in the remaining 29 (35%) this developed within the study period. The overall five year survival of the group, excluding 14 cases treated by transplantation, was 70%. When considered according to aetiological groups this was 83% in those with chronic active hepatitis, 60% in those with cryptogenic cirrhosis and 37% in Wilson's disease. When considered in relation to Child's grading, only three deaths occurred in the 45 patients with well-compensated liver disease (Child's grade A and B). Of the 38 patients with Child's grade C, 20 (83%) of the 24 patients not undergoing transplantation have died, whereas eight (57%) of the 14 receiving liver grafts are alive and well.