The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade.

Systolic time intervals (STI) were measured in ten healthy male volunteers before and after intravenous (i.v.) administration of 25 mug/kg delta-9-tetrahydrocannabinol (delta-9-THC). Mean +/- SEM heart rate increased 32 +/- 7 beats/min, while systolic and diastolic blood pressures were unchanged after delta-9-THC. Total electromechanical systole lengthened 17 +/- 4.2 msec, left ventricular ejection time (LVETc) prolonged 24 +/- 4.0 msec and pre-ejection period (PEP) shortened 17 +/- 5.1 msec after delta-9-THC. All of these changes were significant (P less than 0.01). In nine other subjects who underwent prior beta adrenergic blockade, similar but less marked changes were noted in heart rate, blood pressure, and STI after delta-9-THC. The shortening of PEP after delta-9-THC was only 9 msec (NS) in beta blocked subjects. Thus, delta-9-THC significantly increased heart rate, shortened PEP and prolonged LVETc without any change in afterload. Beta adrenergic blockade prevented significant shortening of PEP and blunted other responses. These findings suggest that delta-9-THC enhanced cardiac performance. Partial inhibition of this effect was achieved with prior beta adrenergic blockade.     

Lack of cardiovascular effects of delta-9-tetrahydrocannabinol in chemically denervated men.

We have previously reported that 25 micrograms/kg of intravenous (i.v.) delta-9-tetrahydrocannabinol (delta-9-THC) produces marked increases in heart rate, prolongation of left ventricular ejection time corrected for heart rate (LVETc), and a shortening of the pre-ejection period in normal volunteers. Beta-adrenergic blockade partially attenuates these responses. To elucidate further the mechanism of action of delta-9-THC, we gave 10 normal volunteers 0.1 mg/kg of i.v. propranolol and 2 mg of i.v. atropine before they received 25 micrograms/kg of i.v. delta-9-THC. Systolic time intervals were compared in the denervated subjects before and after delta-9-THC. Post delta-9-THC responses were measured at a time approximating peak psychologic high. Mean +/- SEM heart rate before and after delta-9-THC was 89 +/- 4 and 87 +/- 3 beats/min (NS); mean +/- SEM pre-ejection period before and after delta-9-TCH was 107 +/- 5 and 109 +/- 4 ms (NS); and mean +/- SEM LVETc before and after delta-9-THC was 433 +/- 6 and 429 +/- 6 ms (NS). Since previous denervation of our subjects with atropine and propranolol totally abolished changes in heart rate and systolic time intervals, the cardiac effects of delta-9-THC appear to be mediated totally via the autonomic nervous system, probably reflecting direct central nervous system stimulation.     

Nasobiliary drainage in acute cholestatic hepatitis with pruritus

Background/aimCholestatic acute viral hepatitis may have prolonged course. Pruritus is often a prominent feature and difficult to control. Sometimes it may be accompanied by severe cough. There are no reports of endoscopic nasobiliary drainage in these patients.MethodsWe prospectively evaluated the role of nasobiliary drainage in six patients with cholestatic acute viral hepatitis with intractable pruritus and accompanying severe cough in one patient in an uncontrolled study.ResultsThere were five male and one female patient with cholestatic acute viral hepatitis with intractable pruritus. One patient also had severe cough. Nasobiliary drainage relieved pruritus in all patients and patient with cough also showed marked improvement within 24 h. Nasobiliary drainage also hastened the recovery in these patients.ConclusionsShort-term nasobiliary drainage should be considered in patients with cholestatic acute viral hepatitis with intractable pruritus and cough for symptomatic relief. It may help in faster recovery in these patients. However, a larger randomized controlled study is warranted.     

Changes in rat adrenal medulla following delta9-tetrahydrocannabinol treatment. A histochemical study.

The effects of acute (10 mg/kg) and chronic 10 mg/kg for 30 days) administration of delta-9-tetrahydrocannabinol (delta9-THC) have been studied histochemically in the rat adrenal medulla, which include total catecholamines, noradrenaline, histometric measurements of adrenal medullary areas, calcium content of the medullary cells along with adenosine triphosphatase (ATPase), acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE) activities. Acute delta9-THC treatment reduced the total catecholamine content (including noradrenaline) of the gland, was accompanied by increased ATP-ase, AChE, BChE activities and increased calcium distribution in the gland. Chronic delta9-THC treatment caused significant hypertrophy of the chromaffin tissue, with decreased total catecholamine content, although noradrenaline containing areas exhibited no notable change. The calcium content and ATPase activity were increased along with a concomitant increase in AChE and BChE activities. Although the changes in adrenal medullary enzyme activities following both acute and chronic delta9-THC treatment are qualitatively similar, marked quantitative increase is noted in the chronically treated groups. The results indicate an increased total catecholamine releasing activity of the adrenal medulla following acute delta9-THC treatment, while chronic delta9-THC administration produces a preferential release of adrenaline.     

Propofol and Cholestatic Pruritus

Hepatic cholestatis is frequently associated with pruritus. This pruritus is often intractable and resistant to conventional treatment. We treated three patients with intractable cholestatic pruritus with subhypnotic doses of propofol, a new intravenous anesthetic induction agent. All patients rapidly became itch- and scratch-free for a period of 60-90 min. No sedation occurred; no other side effects were observed.     

Management of Pruritus in Primary Biliary Cholangitis: A Narrative Review

Primary biliary cholangitis is an autoimmune condition characterized by destruction of intrahepatic bile ducts. It causes debilitating symptoms that dramatically affect the patient's quality of life. Pruritus affects 60% to 70% of individuals with primary biliary cholangitis and leads to sleep disturbances, fatigue, depression, and suicidal ideation. A complete search was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, Countway Library, and CINAHL with specific search terms. This narrative review was prepared after a comprehensive literature review. Treating patients with cholestatic pruritus is challenging and may have a profound impact on quality of life. The standard of therapy for primary biliary cholangitis, ursodeoxycholic acid, does not have a beneficial effect in cholestatic pruritus. Patients often do not respond to conventional therapies such as cholestyramine, rifampicin, opioid antagonists, and sertraline. These therapies lack long-term efficacy and have side effects. Patients who have not responded to these initial treatments can be considered for experimental therapies or clinical trials. This review outlines the current and emerging treatment modalities for patients with primary biliary cholangitis who have pruritus.     

Metabolic studies of delta-9-tetrahydrocannabinol in cancer patients

The metabolism of oral delta-9-tetrahydrocannabinol (THC) was studied in nine patients with gastrointestinal neoplasms receiving chemotherapy regimens containing 5-FU and semustine. Plasma levels of THC and its metabolites 11-OH-delta-9-THC (11-OH-THC) and 11-nor-9-carboxy-delta-9-THC (C-THC) were measured. Plasma levels of THC and its metabolites were quite variable among the patients studied. Plasma levels of THC and 11-OH-THC tended to peak at the same time; the C-THC levels peaked later and lasted much longer than the others. Mean half-lives of THC, 11-OH-THC, and C-THC were estimated to be 1.5, 2.1, and 4.4 hours, respectively. Multiple doses of THC did not produce a significant additive effect on the plasma concentrations of the biologically active metabolites THC and 11-OH-THC. No correlation between antiemetic effect or cannabinoid toxicity and plasma levels of the three metabolites could be made in this small number of patients.     

Role of plasmapheresis in the treatment of severe pruritus in pregnant patients with primary biliary cirrhosis: case reports.

BACKGROUND: Primary biliary cirrhosis (PBC) may be associated with pruritus and, when present, may be accentuated during pregnancy. Several therapeutic modalities have been used to control itching caused by cholestasis, with variable responses. Drug therapies are ill-advised, particularly in early pregnancy. Plasmapheresis has been successful in controlling pruritus in patients with cholestasis. The use of plasmapheresis to alleviate severe life-threatening pruritus during pregnancy is reported in two patients with PBC. CASE PRESENTATIONS: Two patients with PBC presented during their second trimester of pregnancy with severe pruritus that did not respond to the anion exchange resin cholestyramine. Their symptoms were disabling to the point that one patient had suicidal ideation. Given the severity of their symptoms, multiple sessions of plasmapheresis were instituted with good control of pruritus. Both patients tolerated the procedure well and delivered healthy babies. CONCLUSION: Plasmapheresis is a relatively safe and rapidly effective treatment for severe pruritus during pregnancy in patients with PBC.     

Treatment of severe refractory pruritus with fractionated plasma separation and adsorption (Prometheus)

OBJECTIVE: Severe pruritus is a serious complication of cholestatic liver disease. Prometheus is a recently introduced extracorporeal liver support system with direct toxin adsorption of the patient's albumin fraction (FPSA; fractionated plasma separation and adsorption). Here we report on the effect of Prometheus therapy in patients with intractable cholestatic pruritus. MATERIAL AND METHODS: Seven patients with different liver diseases and severe pruritus refractory to all medical treatment efforts for more than 4 weeks were treated with Prometheus (3-5 times, 18+/-3 h total). Pruritus intensity was assessed using the visual analogue scale (VAS; from 0 = no pruritus to 10 = unbearable pruritus), and VAS, serum bile acids and total bilirubin were evaluated directly before and after Prometheus treatment, as well as 4 weeks later. RESULTS: After Prometheus therapy, VAS values had dropped significantly from 9+/-1 to 3+/-3 (p<0.001). Likewise, serum bile acids decreased (from 248+/-192 to 101+/-85 micromol/l; p<0.03). All patients, with the exception of one with no initial bile acid elevation, reported a pronounced improvement in pruritus with Prometheus therapy, although in two anicteric patients the amelioration lasted only a few days. In the other four patients a distinct benefit was still observed 4 weeks after the treatment. CONCLUSIONS: Prometheus therapy significantly improved refractory pruritus in all patients with elevated bile acid levels, but in some patients the clinical benefit was of short duration. The clinical findings suggest that we have to better characterize those patients who might derive a long-lasting benefit from this invasive and expensive treatment.     

Role of plasmapheresis in primary biliary cirrhosis.

Five patients with primary biliary cirrhosis and prolonged cholestasis underwent intensive plasmapheresis. The indications for plasmapheresis included intractable pruritus or hypercholesterolemia and xanthomatous neuropathy. Patients noted a rapid improvement of pruritus and fatigue which was sustained as long as plasmapheresis was continued. Cholesterol levels were lowered an average of 10.3 mmol/l and xanthomata were reduced in three of four patients. Two patients with painful neuropathy caused by xanthomata experienced relief of this symptom. The liver and spleen size were not affected by plasmapheresis, and activities of aminotransferases, alkaline phosphatase and titres of mitochondrial antibody remained unchanged. We conclude that plasmapheresis has a role in the therapeutic management of patients with advanced primary biliary cirrhosis who are disabled by the complications of pruritus, xanthomatous neuropathy, or hypercholesterolemia with xanthoma formation.     

Albumin liver dialysis as pregnancy-saving procedure in cholestatic liver disease and intractable pruritus

Progressive familial intrahepatic cholestasis type 3 （PFIC3） is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System （MARS） has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.     

Role of intravenous naloxone in severe pruritus of acute cholestasis

Pruritus is a well-known manifestation of various cholestatic disorders. Increased opioidergic tone is one of the mechanisms for this. This prospective, uncontrolled study was done to determine the efficacy of intravenous naloxone in pruritus of acute cholestasis. Twenty-two patients with severe pruritus (based on visual analogue scale [VAS] score of 0–100 and associated symptoms) were treated with intravenous naloxone (0.4 mg every 8 hours) for at least 48 hours. Viral hepatitis E was found to be the most common etiology for cholestatic pruritus (n=12). Eighteen patients (81.8%) patients had significant reduction in VAS after 48 hours of starting naloxone; these patients also showed reduction in alkaline phosphatase and gamma glutamyl transpeptidase. There was no side-effect or ‘breakthrough’ phenomenon noted in any patient over next 6 weeks. Naloxone is safe and efficacious in symptomatic improvement in cholestatic pruritus.     

A case report: nasobiliary drainage inducing remission in benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis is a rare hereditary disorder characterized by recurrent episodes of cholestasis and pruritus without anatomical obstruction. Generally, medical therapy is not effective in benign recurrent intrahepatic cholestasis. Here, we report the case of a young male patient with benign recurrent intrahepatic cholestasis who presented with cholestatic jaundice and pruritus, refractory to standard therapies. He improved on treatment with temporary endoscopic nasobiliary drainage. We propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. A 36-year-old male patient admitted to our outpatient clinic with the complaint of pruritus. His anamnesis revealed that he experienced the same symptoms and signs in 2006. He was hospitalized in a hepatology clinic and was thoroughly examined. Liver biopsy was performed, and he was finally diagnosed as having benign recurrent intrahepatic cholestasis. Medical therapy options all proved to be ineffective and we were able to achieve remission in this patient only with the help of nasobiliary drainage. For this patient, we tried nasobiliary drainage in addition to the standard medical therapies. He improved on nasobiliary drainage. In conclusion, we propose that temporary endoscopic biliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. We hope that this case report contributes to the topic, since only a few nasobiliary drainage case experiences have been reported to date.     

The molecular adsorbent recirculating system as a liver support system. Summary of Mexican experience

Aim. The aim of this study was to assess the effects of the molecular absorbent recirculating system (MARS) on patients with acute liver failure (ALF) and liver failure with cirrhosis (AoCLF) as well as in cholestatic patients with intractable pruritus in a Mexican population.Material and methods. From August 2003 to December 2011, MARS was used in 38 patients with ALF, 15 patients with AoCLF, and 17 cholestatic patients with intractable pruritus. The patients were examined using a standard liver function test and for vital signs, presence of ascites and encephalopathy before and after each treatment. The therapeutic response, patient status, follow-up status, and need for liver transplantation were determined.Results. Seventy-nine MARS procedures were performed. MARS was used for ALF in 54.3% of patients, AoCLF in 24.2%, and cholestatic disease in 21.5%. There were significant improvements in serum bilirubin (p = 0.000), aspartate aminotransferase (p = 0.000), alanine aminotransferase (p = 0.030), gamma-glytamyl transpeptidase (p = 0.044), alkaline phosphatase (p = 0.006), and encephalopathy grade (p = 0.000). Thirty-eight ALF patients were listed for emergency liver transplantation and treated with MARS; 20 of these patients died on a waiting list, 18 survived. only four underwent liver transplantation and 14 (37%) recovered without transplantation after the MARS procedure.Conclusion. MARS is a safe and effective procedure, especially for ALF patients. Our results suggest that MARS therapy can contribute to native liver recovery in ALF patients.     

A case of severe benign intrahepatic cholestasis treated with liver transplantation

A male patient with benign recurrent cholestasis since age 2.5 yr developed unremitting cholestasis with incapacitating pruritus and hepatic fibrosis by age 21. He was tried on numerous medical therapies for pruritus with transient or no relief. He responded only temporarily to biweekly plasmapheresis, which was carried out for 4 yr. He underwent orthotopic liver transplantation at age 25 with immediate resolution of his pruritus. At age 30 he is a happy, asymptomatic, fully employed professional.     

Delta-9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo

The antiemetic activity and side-effects of delta-9-tetrahydrocannabinol (THC) were evaluated in 116 patients (median age 61 years) receiving combined 5-fluorouracil and semustine (methyl CCNU) therapy for gastrointestinal carcinoma. In a double-blind study, patients were randomized to receive THC, 15 mg orally three times a day, prochlorperazine, 10 mg orally three times a day, or placebo. The THC had superior antiemetic activity in comparison to placebo, but it showed no advantage over prochlorperazine. Central nervous system side-effects, however, were significantly more frequent and more severe with THC. With the dosage and schedule we used, and in our patient population of largely elderly adults, THC therapy resulted in an overall more unpleasant treatment experience than that noted with prochlorperazine or placebo. Although THC may have a role in preventing nausea and vomiting associated with cancer chemotherapy, this role must be more clearly defined before THC can be recommended for general use.     

Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome

Alagille syndrome (AGS) causes intractable pruritus and disfiguring xanthomas because of retained bile acids and cholesterol. This study was performed to determine whether partial external biliary diversion (PEBD) is effective for relief of pruritus and xanthomas in AGS patients who fail conventional medical therapy. Between the years 1985 and 2001, 9 AGS patients underwent PEBD. Complete follow-up data were available for all patients. The average age at PEBD was 4.8 (range 1.4-10) years. The average duration of follow-up was 7.5 (range 0.5-16.0) years. All 9 patients had severe, mutilating pruritus (grade 4) prior to diversion. At 1 year post-PEBD, the average pruritus score was 1.1; 8 patients had only mild scratching when undistracted. Three patients with extensive xanthomas prior to PEBD had complete resolution within 1 year. Mean serum bile salt levels (n = 5) decreased from 136.5 to 37.1 micromol/L and mean cholesterol (n = 7) from 724 to 367 mg/dL 1 year after PEBD. A single 21-year-old patient with PEBD for 14 years experienced an increase in pruritus from grade 1 to grade 4 within 2 months of elective reversal of PEBD. In conclusion, PEBD is effective for treating severe pruritus and hypercholesterolemia in AGS patients without cirrhosis who did not respond to medical therapy. PEBD should be considered as a therapeutic option for these patients before referral for liver transplantation because of morbid complications.     

Partial Internal Biliary Diversion: A Solution for Intractable Pruritus in Progressive Familial Intrahepatic Cholestasis Type 1

Biliary diversion offers a potential option for intractable pruritus in children with chronic cholestatic disorders. Progressive familial intrahepatic cholestasis (PFIC) is an inherited disorder of impaired bile acid transport and excretion, which presents with jaundice and pruritus in the first few months of life and progresses to cirrhosis by infancy or adolescence. We report a child with PFIC type 1 who underwent internal biliary diversion for intractable pruritus and was relieved of his symptoms.     

Extrahepatic manifestations of cholestasis

Pruritus, fatigue and metabolic bone disease represent three major extrahepatic manifestations of chronic cholestatic liver disease that considerably affect the patient's quality of life. The present article reviews pathogenetic aspects of and current therapeutic approaches to extrahepatic manifestations of cholestatic liver disease. Pathogenesis of pruritus of cholestasis remains poorly understood. The involvement of putative peripherally acting pruritogens, such as bile acids or endogenous opioids, is being discussed. More recently, central mechanisms, including an increased central opioidergic tone and pertubations in the serotonergic system have been proposed. Treatment of the underlying disease is beneficial also for the control of cholestasis-associated pruritus. Current therapeutic recommendations include ursodeoxycholic acid, cholestyramine, rifampicin and opioid antagonists. Liver transplantation may be indicated when severe pruritus is refractory to medical treatment. Fatigue is being recognized as the most frequent and one of the most disabling complaints in chronic cholestasis. Fatigue is presumably of central origin and its association with other neuropsychiatric disorders (e.g. depression, obsessive-compulsive disorders) is consistent with defective central neurotransmission. No specific therapies are currently available and a healthy lifestyle, regular sleep and avoidance of unnecessary stress and other precipiting factors are recommended. Antidepressant therapy may be warranted in selected patients. Osteopenia and osteoporosis are common in chronic cholestatic liver disease, whereas osteomalacia is rare. The pathophysiology of cholestasis-associated metabolic bone disease is regarded as multifactorial. Therapeutic recommendations include regular exercise, calcium and vitamin D supplementation in late stage disease, hormone replacement therapy in postmenopausal women and bisphosphonates.     

Rifampin relieves pruritus in children with cholestatic liver disease

Chronic cholestatic liver disease in children frequently results in severe intractable pruritus. Current forms of therapy, including cholestyramine, are usually ineffective. Therefore, a 6-wk, double-blind, crossover study was designed to test the ability of rifampin to relieve pruritus in children with chronic cholestasis. Rifampin proved effective in alleviating pruritus in all five children tested compared with a placebo-treated group. After the 6-wk study period, rifampin was continued for 6 mo, and its effectiveness was maintained. No complications resulted from rifampin use. This study and a similar study in older patients with primary biliary cirrhosis suggest that a highly effective form of therapy is available for treatment of severe pruritus in patients with chronic cholestasis. These patients must be carefully selected and frequently monitored.