misoprostol and Liver-Diseases

Dysregulated cytokine metabolism plays a critical role in the pathogenesis of many forms of liver disease, including alcoholic and non-alcoholic liver disease. In this study we examined the efficacy of Misoprostol in modulating LPS-inducible TNFα and IL-10 expression in healthy human subjects and evaluated molecular mechanisms for Misoprostol modulation of cytokines in vitro. Healthy subjects were given 14day courses of Misoprostol at doses of 100, 200, and 300μg four times a day, in random order. Baseline and LPS-inducible cytokine levels were examined ex vivo in whole blood at the beginning and the end of the study. Additionally, in vitro studies were performed using primary human PBMCs and the murine macrophage cell line, RAW 264.7, to investigate underlying mechanisms of misoprostol on cytokine production. Administration of Misoprostol reduced LPS inducible TNF production by 29%, while increasing IL-10 production by 79% in human subjects with no significant dose effect on ex vivo cytokine activity; In vitro, the effect of Misoprostol was largely mediated by increased cAMP levels and consequent changes in CRE and NFκB activity, which are critical for regulating IL-10 and TNF expression. Additionally, chromatin immunoprecipitation (ChIP) studies demonstrated that Misoprostol treatment led to changes in transcription factor and RNA Polymerase II binding, resulting in changes in mRNA levels. In summary, Misoprostol was effective at beneficially modulating TNF and IL-10 levels both in vivo and in vitro; these studies suggest a potential rationale for Misoprostol use in ALD, NASH and other liver diseases where inflammation plays an etiologic role.

Topics: Abdominal Pain; Animals; Anti-Ulcer Agents; Cell Line; Cells, Cultured; Cyclic AMP; Cytokines; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Gene Expression; Humans; Interleukin-10; Leukocytes, Mononuclear; Lipopolysaccharides; Liver Diseases; Macrophages; Male; Mice; Misoprostol; Nausea; Signal Transduction; Tumor Necrosis Factor-alpha

Misoprostol has become a popular over the counter self-administered abortifacient in Ghana. This study aimed to compare the socio-demographic characteristics and clinical complications associated with misoprostol and non-misoprostol induced abortions among patients admitted to a tertiary public health facility in Ghana.. This was a cross sectional study conducted at the gynaecological ward of Komfo Anokye Teaching Hospital (KATH), over a four-month period using a structured pre-tested questionnaire. Data were analysed using Chi-square, Fisher's exact and student t-tests. Factors associated with severe morbidity were examined using Poisson regression with robust error variance to estimate crude and adjusted relative risks (RRs) with 95% confidence intervals (CIs). P < 0.05 was considered statistically significant.. Overall, 126 misoprostol users and 126 misoprostol non-users were recruited into the study. About 71% of the clients had self-induced abortions. Misoprostol users were more likely to be younger (p < 0.001), single (p < 0.001), nulliparous (p = 0.001), of higher educational background (p = 0.001), and unemployed (p < 0.001), than misoprostol non-users. Misoprostol users were more likely than non-users to undergo termination of pregnancy because they wanted to continue schooling (p < 0.001) or were not earning regular income to support a family (p = 0.001). Overall, 182 (72.2%) of the women (79.4% misoprostol users vs. 65.1% misoprostol non-users; p = 0.01) suffered severe morbidity. Nulliparous women (adjusted RR, 1.28; 95% CI, 1.08-1.52) and those who had induced abortion after 12 weeks' gestation (adjusted RR, 1.36; 95% CI, 1.18-1.57) were at increased risks of experiencing severe morbidity. The association between mode of abortion induction and severe morbidity was not statistically significant (p = 0.06).. Self-induced abortions using misoprostol is a common practice among women in this study; nearly three quarters of them suffered severe morbidity. Nonetheless, severe morbidity among misoprostol users and non-users did not differ significantly but was directly related to the gestational age at which the induced abortions occurred. Health education on the dangers of self-induced abortions and appropriate use of medication abortion could help reduce complications associated with induced abortions in Ghana.

Topics: Abortifacient Agents, Nonsteroidal; Abortion, Induced; Adolescent; Adult; Age Factors; Case-Control Studies; Cross-Sectional Studies; Educational Status; Employment; Female; Gestational Age; Ghana; Hospitals, Public; Humans; Kidney Diseases; Length of Stay; Liver Diseases; Misoprostol; Multivariate Analysis; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Self Care; Sepsis; Tertiary Care Centers; Uterine Hemorrhage; Young Adult

The aim of this study was to investigate the effect of misoprostol, silymarin or the co-administration of misoprostol + silymarin on the carbon tetrachloride (CCl(4))-induced hepatic injury in rats. Misoprostol (10, 100, 1000 microg/kg), silymarin (25 mg/kg) or misoprostol (100 microg/kg) + silymarin (25 mg/kg) was given once daily orally simultaneously with CCl(4) and for 15 days thereafter. The results showed that misoprostol (10, 100 or 1000 microg/kg) conferred significant protection against the hepatotoxic actions of CCl(4) in rats, reducing serum alanine aminotransferase (ALT) levels by 24.7%, 42.6% and 49.4%, respectively compared with controls. Misoprostol, given at 100 or 1000 microg/kg, decreased aspartate aminotransferase (AST) by 28 and 43.6% and alkaline phosphatase (ALP) by 19.3% and 53.4% respectively. Meanwhile, silymarin reduced ALT, AST and ALP levels by 62.7%, 66.1% and 65.1% respectively. The co-administration of misoprostol (100 microg/kg) and silymarin (25 mg/kg) resulted in 61.4%, 66.1% and 57.5% reduction in ALT, AST and ALP levels respectively. Histopathological alterations and depletion of hepatocyte glycogen and DNA content by CCl(4) were markedly reduced after treatment with misoprostol, silymarin or misoprostol + silymarin. Image analysis of liver specimens revealed a marked reduction in liver necrosis; area of damage: 32.4%, 24% and 10.2% after misoprostol (10, 100 or 1000 microg/kg), 7.2% after silymarin and 10.9% after treatment with misoprostol 100 microg/kg + silymarin, compared with CCl(4) control group (46.7%). These results indicate that treatment with misoprostol protects against hepatocellular necrosis induced by CCl(4). This study suggests a potential therapeutic use for misoprostol in liver injury.

Topics: Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; DNA; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glycogen; Liver Diseases; Liver Function Tests; Male; Misoprostol; Necrosis; Protective Agents; Rats; Rats, Sprague-Dawley; Silymarin

Studies of the molecular and cellular mechanisms of concanavalin A (ConA)-induced liver injury have provided important knowledge on the pathogenesis of many liver diseases involving hepatic inflammation. However, studies identifying hepato-protective factors based on the mechanistic understanding of this model are lacking. Evidence suggests that certain prostaglandin (PG) products of cyclooxygenase (COX)-1 and COX-2 provide important anti-inflammatory and cytoprotective functions in some pathophysiological states. In the present study, we demonstrate a protective role of COX-2 derived PGs in ConA-induced liver injury. COX-2(-/-) mice developed much more severe liver damage upon ConA treatment compared with wild-type and COX-1(-/-) mice. Treatment of COX-2(-/-) mice with misoprostol (a PGE(1/2) analog) or beraprost (a PGI(2) analog) significantly decreased ConA-induced liver injury. Data from both in vivo and in vitro experiments demonstrated that misoprostol and beraprost acted directly on hepatic leukocytes, including natural killer (NK)T and T cells, and down-regulated their production of interferon (IFN)-gamma, which are critical in mediating ConA-induced tissue damage. Collectively, the results provide strong evidence that the protective effects of COX-2 within the liver are mediated through the production of PGE(2) and PGI(2), which exert anti-inflammatory functions. These findings suggest that COX-2-derived PGs may have great therapeutic potentials in treating patients with inflammatory liver diseases.

Topics: Animals; Chemical and Drug Induced Liver Injury; Concanavalin A; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Down-Regulation; Epoprostenol; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Inflammation; Interferon-gamma; Liver Diseases; Male; Mice; Mice, Knockout; Misoprostol; Mitogens

Studies into the mechanism of acetaminophen (APAP)-induced hepatotoxicity have focused mainly at the hepatocellular level. This study aimed to investigate the effect of acetaminophen on the hepatic microvasculature using a vascular casting technique. Acetaminophen was administered at a dose of 650 mg/kg body weight (intraperitoneally) to fasted male Long Evans rats. Microvascular casting was performed at various points after drug administration. Liver casts from control rats showed good patency with normal hepatic microvasculature. Thirty-six hours after overdose with acetaminophen, liver casts showed rounded centrilobular cavities of various sizes, representing regions in which cast-filled sinusoids were absent with relatively normal microvasculature within periportal regions. Evidence of microvascular injury occurred as early as 5 hours after acetaminophen overdose. This injury consisted of changes to centrilobular sinusoids including areas of incomplete filling and dilated centrilobular sinusoids. Misoprostol (a prostaglandin E1 analog) treatment (6 x 25 micrograms/kg) given before and after acetaminophen administration markedly reduced the extent of microvascular injury with only small focal unfilled areas in the casts and a generally intact microvasculature. In conclusion, this study shows that overdosage with APAP resulted in an extensive, characteristic pattern of hepatic microvascular injury in the centrilobular region. The results also suggest that microvascular injury is an early event in the pathogenesis of acetaminophen hepatotoxicity. Misoprostol was found to protect against injury occurring at the microvascular level.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Kinetics; Liver; Liver Diseases; Male; Microcirculation; Microscopy, Electron, Scanning; Misoprostol; Rats

The aim of the study was to determine if pretreatment with misoprostol (a prostaglandin analogue) or nifedipine (a calcium antagonist), know protectants of the whole liver, would ameliorate the ischemia-reperfusion injury (IRI) of resected liver associated with vascular occlusion. Male Wistar rats were allocated to 5 groups (n = 20 each group): sham-operated, liver resection only, liver resection plus pretreatment with 0.1 mg/kg misoprostol, 10 mg/kg, or 2 mg/kg nifedipine during the 3 days before IRI with liver resection. Fifteen percent of the liver was made ischemic by 30-minute continuous vascular occlusion, and the remaining 85% nonischemic liver was resected. The model was designed to have survival of the rats so that liver function could be studied over 3 weeks. Seventeen of 20 control resection rats survived indicating a suitable model for study. The bilirubin level was reduced by 25% on postoperative days 3 through 23 with misoprostol. The serum alanine aminotransferase (ALT) peak was significantly lower on day 1 with misoprostol and high-dose nifedipine (both reduced to half the control resection value). There was a modest but significant reduction of serum alkaline phosphatase (SAP) for low-dose nifedipine on days 1, 2, and 23. Prothrombin had a lower peak and lower values on days 1 through 4 with misoprostol. Liver histological changes were minor, being cytoplasmic vacuolization only, and was slightly more marked in the nifedipine groups. Preoperative misoprostol 0.1 mg/kg and nifedipine 10 mg/kg each ameliorate the IRI associated with liver resection, as measured by liver function tests. Different aspects of liver function were altered by the different agents. These results justify initiating a trial for human liver resections.

Topics: Animals; Calcium Channel Blockers; Disease Models, Animal; Hepatectomy; Liver; Liver Diseases; Liver Function Tests; Male; Misoprostol; Nifedipine; Organ Size; Oxytocics; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury

Effects of misoprostol on histologic and biochemical alterations caused by CCl4 were investigated in the rat. Misoprostol protected against CCl4-induced liver injury. A close correlation occurred between biochemical data and morphological changes. This hepatoprotective effect was observed only when misoprostol was given 30 min before CCl4.

Topics: Alprostadil; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Liver; Liver Diseases; Male; Misoprostol; Rats; Rats, Inbred Strains