Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Theophylline and its derivatives, such as aminophylline, have an established role as bronchodilators, although their mode of action in man is not clear. There is circumstantial evidence that therapeutic doses of theophylline may have a phosphodiesterase inhibiting effect, thus potentiating the effects of cyclic AMP. However, it remains to be established whether this is the primary mode of action of theophylline at the biochemical level. The pathways of theophylline metabolism have been clarified, although most of the enzymes involved have not been characterized. Hepatic microsomal enzyme induction by polycyclic hydrocarbons will increase the rate of theophylline elimination. There are a number of factors which influence theophylline clearance in adults, which is known to be highly variable. These factors include obesity, smoking habit, diet and the presence of such diseases as hepatic cirrhosis, acute pulmonary oedema, cor pulmonale and viral respiratory infection. There is a good correlation between plasma theophylline level and bronchodilator effect. This can be demonstrated at plasma levels as low as 5 microgram/ml, although optimal levels are usually greater than 10 microgram/ml. Unacceptable toxicity usually occurs in association with plasma levels greater than 20 microgram/ml. The maintenance of adequate plasma theophylline levels by the use of a sustained-release aminophylline tablet is discussed.
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PMID:Theophylline: biochemical pharmacology and pharmacokinetics. 22 Jan 19

A new in vitro bleeding time (BT) device was applied to various surgical patients. After setting the optimal assay condition, the normal in vitro bleeding time (T2) and volume (V2) were obtained from healthy volunteers, being 114.7 secs +/- 25.8 (SD) and 272.2 microliter +/- 69.1 (SD), respectively. When the T2 was below 210 secs, the platelet count was inversely proportional to the T2 and V2 of the in vitro BT with p less than 0.01. The value of the in vitro BT was not affected by heparin. Agents, which modify platelet functions, such as PGI2, DN9693 (an inhibitor of phosphodiesterase) and aspirin, prolonged the in vitro BT (T2, V2) dose-dependently. Administration of aspirin (660 mg) to volunteers prolonged the T2 from 108 to over 300 secs and the V2 from 253 to over 600 microliter but ticlopidine (500 mg/day for 3 days) had no effect. In 8 patients with liver cirrhosis who underwent hepatectomy, one patient with a prolonged T2 (260 secs) and a normal skin BT bled postoperatively, however, 3 patients with a prolonged skin BT (greater than 15 min) and a normal T2 had no hemorrhagic complications. From these observations it was concluded that in vitro BT is a convenient and useful tool to examine primary hemostasis or platelet function.
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PMID:Clinical application of a new in vitro bleeding time device on surgical patients. 284 75

An ELISA has been developed for detection of auto-antibodies against calmodulin. There was a significantly increased frequency (63.1%) of autoantibodies against calmodulin in 103 patients with chronic liver diseases as compared to that (30%) of patients with systemic lupus erythematosus and to that (6.9%) of normal subjects (p less than 0.01). IgG autoantibodies against calmodulin were detected in the patients with acute hepatitis (37.9%), chronic liver disease (45.6%) and also in the patients with systemic lupus erythematosus (30%). IgM autoantibodies against calmodulin were frequently found in patients with liver cirrhosis (52.2%), primary biliary cirrhosis (50%) and autoimmune chronic active hepatitis (38.7%), but rarely in patients with acute hepatitis (13.8%), chronic persistent hepatitis (9.5%) and systemic lupus erythematosus (0%). IgA autoantibodies against calmodulin were frequently found in liver cirrhosis (33.3%), primary biliary cirrhosis (42.9%) and autoimmune chronic active hepatitis (53.6%), but rarely in chronic persistent hepatitis (15.8%), chronic active hepatitis (14.3%) and systemic lupus erythematosus (0%). The occurrences of autoantibodies against calmodulin correlated neither with those of antismooth muscle antibody, antinuclear antibody and antimitochondrial antibody, nor with serum IgG concentrations. Autoantibodies against calmodulin did not cross-react with troponin, myosin light chain, calf thymus DNA and actin. The titer of autoantibodies against calmodulin was decreased by absorption of serum with calmodulin and the liver plasma membrane fraction. The immunoblotting experiment revealed the binding of autoantibodies against calmodulin to calmodulin. IgG fraction from a patient with autoimmune chronic active hepatitis inhibited the activation of phosphodiesterase by calmodulin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Anticalmodulin autoantibody in liver diseases: a new antibody against a cytoskeleton-related protein. 355 8

Resistance to the natriuretic action of atrial natriuretic peptide (ANP) is a hallmark of states of pathological sodium retention including congestive heart failure, cirrhosis of the liver, and nephrotic syndrome. A variety of mechanisms including reduced delivery of filtrate to ANP-sensitive sites in the inner medullary collecting duct and diminished receptor density in this tubular segment have been offered to account for this resistance. Recent studies in experimental nephrotic syndrome and in liver disease produced by ligation of the common bile duct in rats suggest that increased activity of cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase may be an important mediator of renal resistance to ANP. Such increased enzyme activity rapidly catabolizes the second messenger cGMP, normally formed when ANP interacts with its biologically active natriuretic peptide. A receptors, thereby leading to blunted ANP responsiveness. This increased phosphodiesterase activity offers a novel approach to the management of clinical conditions associated with sodium retention and edema formation.
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PMID:Phosphodiesterases (PDEs) hydrolyze the 3' phosphoester bond of the purine 3',5'-cyclic monophosphates, cAMP and cGMP. 876 Feb 35

Resistance to the natriuretic action of atrial natriuretic peptide (ANP) is a hallmark of states of pathological sodium retention including congestive heart failure, cirrhosis of the liver, and nephrotic syndrome. A variety of mechanisms including reduced delivery of filtrate to ANP-sensitive sites in the inner medullary collecting duct and diminished receptor density in this tubular segment have been offered to account for this resistance. Recent studies in experimental nephrotic syndrome and in liver disease produced by ligation of the common bile duct in rats suggest that increased activity of cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase may be an important mediator of renal resistance to ANP. Such increased enzyme activity rapidly catabolizes the second messenger cGMP, normally formed when ANP interacts with its biologically active natriuretic peptide A receptors, thereby leading to blunted ANP responsiveness. This increased phosphodiesterase activity offers a novel approach to the management of clinical conditions associated with sodium retention and edema formation.
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PMID:Phosphodiesterase activity as a mediator of renal resistance to ANP in pathological salt retention. 876 Feb 36

A possible defect of guanosine 3'-5'-cyclic monophosphate (cGMP) content in the renal tissue caused by an increased activity of cGMP phosphodiesterase (PDE) has, so far, not been evaluated in the pathogenesis of renal resistance to endogenous natriuretic peptides (ENP) in cirrhosis with ascites. To test this hypothesis the activity of cGMP-PDE and the concentration of cGMP were evaluated in vitro in the renal tissue of 10 control rats and 10 cirrhotic rats with ascites before and after the intravenous (IV) administration of Zaprinast (Sigma, St. Louis, MO), a specific cGMP-PDE inhibitor (30 microgram/kg/min). Moreover, the effects of the intravenous administration of Zaprinast (15 microgram/kg/min and 30 microgram/kg/min) on renal plasma flow (RPF), glomerular filtration rate (GFR), and urinary sodium excretion (U(Na)V) were evaluated in 10 conscious control rats and 10 conscious cirrhotic rats with ascites. The effects of Zaprinast on plasma renin activity (PRA) was also evaluated in 10 control rats and in 10 cirrhotic rats with ascites. Finally, the effect of Zaprinast on RPF, GFR, and U(Na)V were evaluated in 10 cirrhotic rats after the IV administration of the ENP-receptor antagonist, HS-142-1. The renal content of cGMP was reduced in cirrhotic rats because of increased activity of cGMP-PDE. Zaprinast inhibited cGMP-PDE activity and increased the renal content of cGMP in these animals. The inhibition of cGMP-PDE was associated with an increase in RPF, GFR, and U(Na)V and a reduction in PRA. HS-142-1 prevented any renal effect of Zaprinast in cirrhotic rats. In conclusion, an increased activity of the cGMP-PDE in renal tissue contributes to the renal resistance to ENP in cirrhosis with ascites.
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PMID:Increased activity of guanosine 3'-5'-cyclic monophosphate phosphodiesterase in the renal tissue of cirrhotic rats with ascites. 1065 50

Chronic hepatitis C progresses to cirrhosis within 20 years in an estimated 20-30% of patients, while running a relatively uneventful course in most others. Certain HCV proteins, such as core and NS5A, can induce derangement of lipid metabolism or alter signal transduction of infected hepatocytes which leads to the production of reactive oxygen radicals and profibrogenic mediators, in particular TGF-beta1. TGF-beta1 is the strongest known inducer of fibrogenesis in the effector cells of hepatic fibrosis, i.e. activated hepatic stellate cells and myofibroblasts. However, fibrogenesis proceeds only when additional profibrogenic stimuli are present, e.g. alcohol exposure, metabolic disorders such as non-alcoholic steatohepatitis, or coinfections with HIV or Schistosoma mansoni that skew the immune response towards a Th2 T cell reaction. Furthermore, profibrogenic polymorphisms in genes that are relevant during fibrogenesis have been disclosed. This knowledge will make it possible to identify those patients who are most likely to progress and who need antiviral or antifibrotic therapies most urgently. However, even the best available treatment, the combination of pegylated interferon and ribavirin, which is costly and fraught with side effects, eradicates HCV in only 50% of patients. While the suggestive antifibrotic effect of interferons (IF-gamma>alpha,beta), irrespective of viral elimination, has to be proven in randomised prospective studies, additional, well tolerated and cost-effective antifibrotic therapies have to be developed. The combination of cytokine strategies, e.g. inhibition of the key profibrogenic mediator TGF-beta, with other potential antifibrotic agents appears promising. Such adjunctive agents could be silymarin, sho-saiko-to, halofuginone, phosphodiesterase inhibitors, and endothelin-A-receptor or angiotensin antagonists. Furthermore, drug targeting to the fibrogenic effector cells appears feasible. Together with the evolving validation of serological markers of hepatic fibrogenesis and fibrolysis an effective and individualised treatment of liver fibrosis is anticipated.
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PMID:Hepatitis C and liver fibrosis. 1265 47

Vasopressin (AVP) stimulates collecting duct water reabsorption through cAMP-mediated membrane targeting and increased expression of the aquaporin-2 (AQP2) water channel. Rats with liver cirrhosis induced by common bile duct ligation (CBL) show decreased protein expression of AQP2 despite increased plasma concentrations of AVP. The present study was conducted to investigate possible mechanisms behind this uncoupling of AVP signaling. The rats were examined 4 wk after CBL or sham operation. The CBL rats had increased plasma AVP concentrations (CBL: 3.2 +/- 0.2 vs. sham: 1.4 +/- 0.4 pg/ml, P < 0.05) and reduced AQP2 (0.62 +/- 0.11) and phosphorylated AQP2 (0.50 +/- 0.06) protein expression compared with sham-operated rats. However, examination of subcellular AQP2 localization by immunohistochemistry showed unchanged plasma membrane targeting in CBL rats, indicating a sustained ability of AQP2 short-term regulation. In a separate series of animals, thirsting was found to normalize AQP2 expression, indicating that AVP uncoupling in CBL rats is a physiological compensatory mechanism aimed at avoiding dilutional hyponatremia. Studies on microdissected collecting ducts from CBL rats showed decreased cAMP accumulation in response to AVP stimulation. The presence of the nonspecific phosphodiesterase inhibitor IBMX normalized the cAMP accumulation, indicating that cAMP-phosphodiesterase activity is increased in CBL rats. However, in contrast to this, Western blotting showed a decreased expression of several phosphodiesterase splice variants. We conclude that CBL rats develop an escape from AVP to prevent the formation of dilutional hyponatremia in response to increased plasma AVP concentrations. The mechanism behind AVP escape seems to involve decreased collecting duct sensitivity to AVP as a result of increased cAMP-phosphodiesterase activity.
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PMID:Uncoupling of vasopressin signaling in collecting ducts from rats with CBL-induced liver cirrhosis. 1517 84

In the present study, we tested the hypothesis that inhibition of renal phosphodiesterase type 5 (PDE5) in patients with liver cirrhosis and ascites increases sodium excretion. The effect of sildenafil citrate was studied in a randomized double-blind. placebo-controlled crossover study. Diuretics were withdrawn, and a fixed sodium diet (100 mmol/day) was given to the patients for 5 days before both study days. After a 60-min basal period, eight patients received either oral sildenafil (50 mg) or placebo. Glomerular filtration rate (GFR) and renal blood flow (RBF) were determined by 99mTc-diethylenetriamine-pentaacetate and (131)I-hippuran clearances. In human nephrectomy specimens, PDE5 mRNA was expressed at similar levels in the cortex (n = 6) and inner medulla (n = 4). Histochemical staining showed PDE5 immunoreactivity in collecting ducts and vascular smooth muscle. At baseline, cirrhotic patients exhibited elevated plasma concentrations of ANP, renin, ANG II, and aldosterone that did not differ on the 2 study days. Basal sodium excretion was similar at the 2 study days (median 17 and 18 mmol, respectively), and patients were in positive sodium balance. Sildenafil increased heart rate, plasma renin activity, plasma ANG II, and aldosterone concentrations significantly after 60 min. Plasma cGMP concentration was increased after 120 and 180 min, and urinary sodium excretion and mean arterial blood pressure were decreased significantly at 120 and 180 min. Plasma ANP concentration, GFR, and RBF did not change after sildenafil. In patients with ascites and cirrhosis, inhibition of PDE5 did not promote natriuresis but led to increased plasma levels of the renin-angiotensin-aldosterone system.
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PMID:Inhibition of cGMP-specific phosphodiesterase type 5 reduces sodium excretion and arterial blood pressure in patients with NaCl retention and ascites. 1561 22

Several drugs that quicken recovery from neuromuscular blockade caused by vecuronium in anesthetized patients are reviewed. Ulinastatin, a protease inhibitor, is thought to promote the release of acetylcholine at the neuromuscular junction and increases hepatic blood flow and urine volume. For this reason, ulinastatin quickens recovery from neuromuscular blockade in anesthetized patients receiving vecuronium. Additionally, pretreatment with ulinastatin avoids prolongation of vecuronium-induced neuromuscular blockade in patients with hepatic cirrhosis. Gabexate mesilate is also a protease inhibitor. During a continuous infusion of gabexate mesilate, recovery from neuromuscular blockade was quickened. Amino acid-enriched solution supplies energy to the skeletal muscles and causes an increase in muscle strength. An infusion of amino acid-enriched solution hastens recovery from neuromuscular blockade in anesthetized patients. When amino acids supply energy to the skeletal muscles, they simultaneously produce heat in the skeletal muscles. This thermal generation may be closely related to fast recovery from neuromuscular blockade. Amino acid-enriched solution makes recovery from neuromuscular blockade quick and avoids hypothermia during general anesthesia. Milrinone, a phosphodiesterase III inhibitor, is supposed to increase the release of acetylcholine at the neuromuscular junction and make the neuromuscular junction sensitive to acetylcholine. Therefore, recovery from neuromuscular blockade is hastened. Nicorandil enhances membrane K+ conductance in skeletal muscle and increases contraction of the skeletal muscle. Thus, nicorandil quickens recovery from neuromuscular blockade.
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PMID:Drugs to facilitate recovery of neuromuscular blockade and muscle strength. 1626 67


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