Modulation of cholinergic contractions of airway smooth muscle by cathinone: potential beneficial effects in airway diseases.

Infusion of khat leaves is an African traditional remedy used to treat airway diseases. The beneficial effects of khat are thought to be due to the activity of its main active component, cathinone. Cathinone inhibited electric field stimulation-induced acetylcholine release and the contractions of smooth muscle, which could be responsible for the beneficial effects seen in airway disease. The mechanism of action of this natural product appears to be via the activation of both pre-junctional alpha(2) adrenergic and 5-hydroxytryptamine 7 receptors. The present novel study describes how cathinone modulates airway tone, and may go some way to explaining the traditional use of khat as a remedy for the alleviation of respiratory disease symptoms. In conclusion, cathinone may have beneficial effects in airway diseases with heightened cholinergic tone. There is some rationale for follow-up of these observations, given previous experience of other traditional remedies being developed for therapeutic use.

Khat (Catha edulis): health aspects of khat chewing.

Catha edulis Forsk leaves (khat) are chewed daily by a high proportion of the adult population in Yemen for the mild stimulant effect. Cathinone is believed to be the main active ingredient in fresh khat leaves and is structurally related and pharmacologically similar to amphetamine. The habit of khat chewing is widespread with a deep-rooted sociocultural tradition in Yemen and as such poses a public health problem. The objective of this literature review was to examine studies on khat, particularly human studies, with special reference to its effect on the central nervous system, cardiovascular, digestive and genitourinary systems, oral-dental tissues, diabetes mellitus and cancer.

Khat [Catha edulis]: health aspects of khat chewing

Catha edulis Forsk leaves [khat] are chewed daily by a high proportion of the adult population in Yemen for the mild stimulant effect. Cathinone is believed to be the main active ingredient in fresh khat leaves and is structurally related and pharmacologically similar to amphetamine. The habit of khat chewing is widespread with a deep-rooted sociocultural tradition in Yemen and as such poses a public health problem. The objective of this literature review was to examine studies on khat, particularly human studies, with special reference to its effect on the central nervous system, cardiovascular, digestive and genitourinary systems, oral-dental tissues, diabetes mellitus and cancer

Discontinuation of pegylated interferon plus ribavirin in patients who are not responding to therapy -- patients' views of early cessation of therapy.

BACKGROUND: Current therapy for chronic hepatitis C infection involves a course of pegylated interferon and ribavirin. Patients who do not show a virological response after 12 weeks of therapy have a low probability of sustained virological response and it is therefore recommended that such patients stop treatment. AIM: To assess patients' views of early treatment cessation. METHODS: We conducted a open-labelled study in three UK centres, in which patients with biopsy-proven chronic hepatitis C requiring therapy were offered the choice of a full course of therapy with 40 kDa pegylated interferon-alpha 2a plus ribavirin (24 or 48 weeks depending on viral genotype) or early cessation if therapy had failed after 12 weeks. RESULTS: Ninety-five participants were enrolled and the majority (69%) did not wish to discontinue therapy even if it had low probability of success. In this unselected UK population, very few patients (4%) did not achieve an early virological response with the 40-kDa pegylated interferon-alpha 2a plus ribavirin and two of the four early virological non-responders decided to continue therapy. CONCLUSION: Early discontinuation of 'ineffective' anti-viral therapy may prove less popular with patients than with health care providers, and further patient-directed education regarding the cost-effectiveness of therapy will be needed if early discontinuation of unsuccessful therapy is to be accepted by patients.

CD10 immunostaining of bile canaliculi in liver biopsies: change of staining pattern with the development of cirrhosis.

AIMS: This study was prompted by published observations concerning the absence of normal bile canalicular CD10 staining in some cases of primary liver cell carcinoma. Our aim was to investigate the possibility that this loss of staining occurs prior to the development of cancer. METHODS AND RESULTS: The study comprised 164 liver biopsies, including 96 from patients with hepatitis C infection of various grades and stages including nine cases with cirrhosis, 24 other cases of cirrhosis of other aetiology, five cases of primary liver carcinoma, 12 cases of metastatic carcinoma, as well as biopsies with a variety of other liver diseases. CD10 was demonstrated in paraffin sections using the avidin-biotin immunoperoxidase technique. In hepatitis C cases, a significant loss of the canalicular pattern was seen in four out of 41 (10%) biopsies with stages 0-1 compared with 25 out of 55 (45%) with stages 2-6 (P < 0.001). There was also a significant difference (P < 0.001) between biopsies with stage 2-3 and those with stage 4-6, where marked pattern loss was seen in 9/37 (24%) and 16/18 (89%), respectively. Marked loss of the pattern was also seen in 16 out of the 24 (67%) other cirrhotic biopsies, as well as in cases with severe lobular inflammation and cholestasis and liver cell dysplasia and carcinoma. In hepatitis C biopsies, no relationship was noted between the reduction in the canalicular pattern and the necroinflammatory score. CONCLUSIONS: CD10-stained bile canalicular pattern in liver biopsies is preserved in cases with mild fibrosis and inflammation, but it becomes increasingly reduced with the advance of fibrosis or the presence of severe lobular inflammation or extensive metastases. Further investigations into the relationship between the changes in CD10 staining pattern and liver function tests may be useful in explaining test results.

The effect of khat chewing on gallbladder motility in a group of volunteers.

An increase in the prevalence of gallstones has been reported from the Middle East and the Republic of Yemen. Changing dietary habits and obesity are thought to be responsible but other local factors may contribute such as chewing the leaves of the khat plant (Catha edulis Forsk.) which is a widespread social custom in Yemen. We have studied the effects of khat chewing on gallbladder motility in a group of 10 healthy volunteers. All subjects underwent ultrasound measurements of gallbladder volume after chewing khat leaves or lettuce, which was used as the control. Results were compared after chewing for up to 2h in the fasting state and in response to a fatty meal. There was no significant change in gallbladder volume after chewing khat compared with lettuce in the fasting state (P=0.7) or in gallbladder emptying after a fatty meal (P=0.4) and we conclude that khat chewing has no clinically significant effect on gallbladder motility.

Hazardous and harmful drinking: a comparison of the AUDIT and CAGE screening questionnaires.

BACKGROUND: Hazardous and harmful use of alcohol remains a public health concern, and many general hospital admissions are alcohol-related. AIM: To compare the CAGE and Alcohol Use Disorders Identification Test (AUDIT) questionnaires in screening general medical admissions for harmful or hazardous drinking. DESIGN: Prospective questionnaire-based study. METHODS: Both questionnaires were administered, and demographic data collected. RESULTS: One hundred and three patients were included. Of these, 36% were identified by the AUDIT to be drinking hazardously or harmfully, and 22% were identified as CAGE cases. All CAGE cases were also AUDIT cases. DISCUSSION: As the CAGE and the AUDIT are designed to identify different populations, it is not surprising that significantly fewer cases were identified using the CAGE. The AUDIT identifies not just the harmful drinkers detected by the CAGE, but also hazardous drinkers, who have not yet reached that level of harm. As drinkers at an earlier stage may respond better to interventions aimed at reducing their consumption, the AUDIT is preferable in clinical practice.

Hepatic abscesses complicating injection sclerotherapy of haemorrhoids.

We report the case of a 50-year-old man who developed a febrile illness four days after injection sclerotherapy of his haemorrhoids. The patient increasingly became unwell and was eventually found to have multiple hepatic abscesses. He made a complete recovery with antibiotic therapy. The importance of educating both patients and doctors about this complication is emphasized.

The effect of Qat chewing on blood pressure and heart rate in healthy volunteers.

The leaves of the Qat plant (Catha edulis Forsk., Celastraceae) which contain amphetamine like compounds are widely chewed in Yemen and East Africa for their pleasurable stimulant properties. There are also a number of unwanted side-effects and this paper studies the effect on heart rate and blood pressure in 80 healthy volunteers. During a 3-h period of chewing fresh Qat leaves there was a significant and progressive rise in systolic and diastolic blood pressure and heart rate, and levels had not returned to baseline 1 h after chewing had ceased. Further studies are needed on possible cardiovascular morbidity associated with regular Qat chewing.

A placebo-controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection.

Adefovir dipivoxil (bis-POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co-infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double-blind, placebo-controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for > or = 6 months, with elevated hepatic transaminases and serum HBV DNA > or = 50 pg ml-1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml-1) but increased by 0.01 log10 pg ml-1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1-6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l-1 were observed in three patients during therapy (leading to protocol-specified treatment discontinuation or dose reduction) and in four patients during follow-up. On-treatment transaminase elevations were associated with HIV status, occurring in three of six HIV-uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non-HIV-infected patients. Treatment for chronic hepatitis B as a once-daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.

Intestinal capillariasis acquired in Egypt.

A 34-year-old Egyptian man presented with a 4-month history of profound weight loss, diarrhoea and abdominal pain. Extensive investigations in Egypt had failed to provide a diagnosis but subsequent stool examinations revealed ova of Capillaria philippinensis. The patient made a slow but complete recovery after treatment with albendazole. The literature on intestinal capillariasis is reviewed.

Chewing Qat leaves slows the whole gut transit time.

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Ribavirin and interferon alfa-2b in chronic hepatitis C: assessment of possible pharmacokinetic and pharmacodynamic interactions.

AIMS: The primary objective of this study was to determine whether pharmacokinetic interactions occurred between interferon alpha-2b (IFN) and ribavirin in patients with chronic hepatitis C infections. Additionally this study assessed the single and multiple-dose pharmacokinetics of ribavirin and IFN, and compared the safety, tolerability and antiviral pharmacodynamics of IFN plus ribavirin compared with either drug alone. METHODS: In this open label parallel group study, patients with chronic hepatitis C were randomized to receive IFN 3 million IU thrice weekly s.c. alone, ribavirin 600 mg twice daily p.o. alone or both drugs in combination over 6 weeks. Single and multiple dose pharmacokinetics and indices of antiviral pharmacodynamics were assessed during weeks 1 and 6, along with safety assessments during the study. RESULTS: The range of mean ribavirin terminal phase half-lives after single doses was 44-49 h. Comparison of week 1 and week 6 AUC(0,12h) values showed accumulation in plasma of approximately 6-fold. The range of mean washout half-lives after week 6 was 274-298 h, reflecting release of ribavirin from deep compartment stores. The range of single and multiple dose IFN terminal phase half-lives was 5-7 h. IFN demonstrated an increase in bioavailability (approximately 2-fold) upon multiple dose administration. Ribavirin and IFN pharmacokinetic parameters for combined ribavirin and IFN were similar to those during monotherapy with either compound, although the power of this study to detect differences was low. Serum HCV-RNA titers and ALT concentrations were reduced by IFN alone, ribavirin alone reduced ALT concentrations only, and combined IFN plus ribavirin produced numerically greater falls in both measurements than either treatment alone. Serum concentrations of neopterin and activity of 2',5'-oligoadenylate synthetase (2'5'-OAS) were increased by IFN alone and in combination with ribavirin, whereas serum 2'5'-OAS activity was decreased and neopterin concentrations unaltered by ribavirin monotherapy. IFN and ribavirin monotherapy produced characteristic changes in safety laboratory tests (IFN--reductions in white cells, neutrophils and platelets; ribavirin--reduced haemoglobin) and characteristic adverse event profiles (IFN--headache, flu-like symptoms, fatigue, anorexia, nausea, myalgia, and insomnia; ribavirin--headache, fatigue, myalgia, and pruritus). There was no additive effect of combination therapy on safety laboratory tests or reported adverse events. All changes were fully reversible upon treatment cessation. CONCLUSIONS: There was no evidence of pharmacokinetic interactions between IFN and ribavirin in this study. There were numerical trends indicating that the combination of IFN and ribavirin reduced titers of HCV-RNA to a greater extent than did either treatment alone, and the safety profile of combination therapy was similar to those of both monotherapy treatments.

Neurology and the gastrointestinal system.

Both achalasia and Hirchsprung's disease arise from defects of innervation of the oesophagus and distal large bowel respectively. Their consequences are confined to disorders of motility in the relevant part of the gastrointestinal tract. Many neurogenic and primary muscle disorders are associated with abnormalities of gut motility. Stroke, even when unilateral, is commonly associated with dysphagia. Transcranial magnetoelectric stimulation has established that the pharyngeal phase of swallowing tends to receive its innervation principally from one hemisphere. In many neurological disorders, dysphagia is only one part of the clinical picture but in some--for example, the Chiari malformation--dysphagia may be the sole or major feature. Disturbances of small and large bowel motility, when seen in neurogenic disorders, are associated with autonomic neuropathy and are particularly common in diabetes mellitus. Primary muscle disorders can lead to dysphagia (for example, with polymyositis or oculopharyngeal dystrophy) or defects of large bowel motility (for example, with Duchenne's muscular dystrophy). Primary gut disorders particularly associated with neurological disease include pernicious anaemia, nicotinamide and thiamine deficiencies, selective vitamin E deficiency, and coeliac disease. Inflammatory bowel disease is associated with thromboembolic complications which may include the CNS, inflammatory muscle disease, and abnormalities on MRI of the brain of uncertain relevance. Whipple's disease is a rare condition which sometimes is largely or entirely confined to the CNS. In such cases, a particular neurological presentation can indicate the diagnosis.

Management of chronic hepatitis C: clinical audit of biopsy based management algorithm.

OBJECTIVE: To assess the attendance, outcome, compliance with treatment, and response to interferon alfa in patients with chronic hepatitis C who attended during 1995 and were treated according to a biopsy based algorithm. DESIGN: Retrospective audit of all patients with chronic hepatitis C attending outpatient clinics over one year. SETTING: The liver unit at a London teaching hospital. SUBJECTS: 255 patients with chronic hepatitis C. MAIN OUTCOME MEASURES: Patient survival, attendance, and compliance with diagnostic and therapeutic regimens. Response to interferon alfa treatment, based on loss of viraemia three months after cessation of treatment. RESULTS: A large proportion of patients (39%) with newly diagnosed chronic hepatitis C infection do not want to undergo further investigation. Of those patients who do attend for further treatment, a large proportion with severe hepatic fibrosis (42%) do not want to undergo currently available treatment. The response rate to interferon (21%) in treated patients was similar to that previously reported in a trial setting. There was no significant difference in response rates in patients with or without severe fibrosis not amounting to cirrhosis. In patients with cirrhosis there was a high incidence of hepatocellular carcinoma (18%) over a follow up period of 20 months. CONCLUSION: Current strategies aimed at investigating and treating patients with chronic hepatitis C are not acceptable to a large proportion of patients. Many patients with cirrhosis related to hepatitis C infection develop hepatic neoplasms, and management strategies to deal with this problem are urgently required.

Acute sporadic hepatitis in the Republic of Yemen.

The causes of acute icteric viral hepatitis were determined in 78 adult Yemeni patients. Acute hepatitis B (IgM anti-HBc positive) was the most common type (26.9%). Acute hepatitis E (IgM anti-HEV positive) occurred in 14% and was not associated with travel outside Yemen. Sixty percent of all 78 patients were positive for IgG anti-HEV as were 40% of a series of 48 healthy male blood donors and pregnant females, indicating that HEV is prevalent in Yemen. Acute hepatitis A (IgM anti-HAV positive) and hepatitis C and D were responsible for 5.1%, 6.4%, and 2.6% cases, respectively. This totals to 106%, as an infection with two viruses occurred in 6.4% cases. In 51.3% of all cases, no virological markers of acute hepatitis were detected, suggesting an as yet undiscovered agent.

Khat chewing and bladder neck dysfunction. A randomized controlled trial of alpha 1-adrenergic blockade.

OBJECTIVE: To assess whether the effect of chewing khat leaves (Catha edulis) on the urodynamics of healthy males is altered by the selective alpha 1-adrenergic blocking agent indoramin in a prospective randomized double-blind controlled trial. SUBJECTS AND METHODS: The urodynamics of 11 healthy males were studied before and during a khat chewing session preceded by indoramin or placebo. RESULTS: Khat chewing produced a fall in average and maximum urine flow rate. This effect was inhibited by indoramin. CONCLUSIONS: The urinary side-effects of khat chewing are probably mediated through stimulation of alpha 1-adrenergic receptors.