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PubMed1992

Response time of broiler chickens to cimaterol: meat tenderness, muscle composition fiber size, and carcass characteristics.

The response time to cimaterol (CIM), a beta-adrenergic agonist, by broiler chickens for carcass characteristics, muscle composition, muscle fiber size, catheptic enzyme activity, and tenderness was determined. Two trials were conducted in which chickens were fed a control diet (CON) containing 0 ppm of CIM or a diet containing 1 ppm of CIM. Trial 1 consisted of 55, 31-d-old broiler chickens individually fed for up to 48 h. At 0, 6, 12, 18, 24, and 48 h, five CON and five CIM-fed chickens were killed. Trial 2 consisted of 160, 33-d-old broiler chickens group-fed for up to 14 d. At 2, 4, 6, 8, 10, 12, and 14 d, 10 CON and 10 CIM-fed chickens were killed. The breast muscle (BM) and leg muscle (LM) weight, cathepsin B and L activities, DNA, RNA, and protein concentration, and BM shear force value (SFV) were measured in both trials. Thigh muscle (TM) SFV were measured in Trial 2 only. Fiber size of BM was measured (five birds per treatment) at d 2, 6, 10, and 14. In Trial 1, BM weight and SFV were lower in CIM-fed birds at 6 h (P less than .05). In Trial 2 BM SFV were higher at d 8 (P = .06) and d 10 (P less than .05) in CIM-fed chickens. The SFV of CIM-fed chickens were higher at d 4, 8, 10, 12, and 14 (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1996

Characterization of dose-dependent metabolic responses to close arterial infusion of cimaterol in the hindlimb of steers.

Dose-dependent effects of cimaterol (CIM) on hindlimb metabolism were determined in six steers (247 +/- 22 kg BW) using a close arterial infusion. The external iliac vessels of both hindlimbs were catheterized to accommodate measurement of blood flow, circulating concentrations, and net flux of NEFA, lactate, and alpha-amino nitrogen (AAN) during infusion of CIM at 0, .05, .1, .3, .7, 1 and 3 micrograms/ min. Close arterial infusion of CIM in the hindlimb of steers can be used to achieve a local concentration elevation that is required to differentiate local and systemic effects in vivo. Calculated plasma threshold CIM concentration required to initiate cardiovascular responses was 21 pg/mL, which resulted from an infusion rate of .3 microgram/min. Threshold concentrations of CIM for stimulation of NEFA and lactate net flux in the hindlimb were 38 and 34 pg/mL, respectively, and would be achieved with an infusion rate of .7 microgram/min. All measured responses except AAN net flux exhibited significant linear and quadratic dose effects, and responses in the treated hindlimb were always severalfold greater than in the contralateral control hindlimb. Maximal differences between treated and control hindlimb blood flow occurred with a CIM infusion rate of .7 microgram/min, but the highest infusion rate (3 micrograms/min) was required to maximize differences in NEFA and lactate flux. Therefore, to minimize cardiovascular and other systemic responses and optimize direct hindlimb responses, an infusion rate of .5 microgram of CIM/ min should cause significant stimulation of beta-adrenergic receptors only in the CIM-infused hindlimb of young, growing steers.

Adrenergic beta-Agonists↗
PubMed2001

Whole body positron emission tomography in the treatment of Hodgkin disease.

BACKGROUND: In Hodgkin disease (HD), accurate assessment of the extent of disease is essential because it provides the basis for different treatment strategies. In addition to conventional imaging methods (CIM), positron emission tomography with fluorine-18-fluorodeoxyglucose (FDG-PET) may permit reliable differentiation between lymphoma and nonmalignant tissue and thus improve determination of the stage of the disease. The aim of the current study was to assess the clinical value of FDG-PET for primary staging, treatment monitoring, and assessment in a suspected case of recurrent HD. METHODS: Eighty-one patients with HD underwent 106 FDG-PET studies using a dedicated whole body PET ring scanner. In 25 patients PET was part of the primary staging, 63 PET studies were undertaken for treatment monitoring after the completion of treatment, and in 18 patients PET was performed in cases of suspected recurrence of HD. PET scans were compared with CIM and verified histologically and/or by follow-up evaluation (mean follow-up duration, 20.4 months). RESULTS: With regard to primary staging, in a patient to patient analysis, both PET scans and CIM were positive (i.e., showed pathologic foci indicative of HD) in 24 of 25 cases. In a staging-relevant lesion to lesion analysis, accuracy in the determination of the stage of disease was 96% for PET versus 56% for CIM. PET led to a lower stage classification in 28% and a higher stage classification in 12% of cases, compared with the stage assumed with CIM. With regard to treatment monitoring, PET showed an accuracy of 91% compared with 62% for CIM. The negative predictive value of PET was 96%. With regard to suspected recurrence, PET findings were true-positive in 10 of 12 PET scans and true-negative in 5 of 6 PET scans, resulting in accuracy of 83%, which compares favorably with the accuracy rate of 56% for CIM. CONCLUSIONS: It may be concluded that FDG-PET is capable of determining the stage of HD with great accuracy and is capable of correctly detecting manifestations of HD in treatment monitoring and cases of suspected recurrence, in which CIM occasionally result in equivocal findings. The results of the current study suggest that FDG-PET should become a routine tool in the staging/restaging of HD.

Adult↗
PubMed1989

Sucralfate in the short-term treatment of duodenal ulcer. A double-blind comparison with cimetidine and placebo.

A phase III randomised, double-blind, placebo controlled study was conducted to compare the efficacy and adverse effects of sucralfate and cimetidine in the short-term management of active duodenal ulcer. Standard therapeutic doses were used. Antacids were permitted on an ad lib basis. Eighty patients with endoscopically proven DU were treated for 4 weeks with sucralfate (SUC) (n = 40), cimetidine (CIM) (n = 20) and placebo (PLA) (n = 20), of whom 60 patients--SUC (32), CIM (14) and PLA (14) completed the trial. Baseline clinical and endoscopic data were comparable amongst the 3 groups. The patients were reexamined clinically at 1, 2 and 4 weeks and endoscopically at 2 and 4 weeks. The data comprising pain and non-pain symptom scores, and ulcer size before and after the trial were analysed using the Mann-Whitney test. There were no significant differences in the rate of ulcer healing between SUC and CIM at 4 weeks. 71.8% of the SUC group had complete healing, as compared with 71.4% in the CIM group and 35% in the PLA group. Both SUC and CIM were superior to PLA. (p less than .05) Non-pain symptom scores at the end of 1 week were significantly lower with CIM (p less than 0.001), but levelled at 4 weeks when compared with SUC. Both SUC and CIM were superior to placebo (p less than .001). Day-time pain relief was significantly better with both SUC and CIM as compared to placebo (p less than 0.1). There was no significant difference in night-pain relief between the 3 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Prolactin release in man: influence of cimetidine, thyrotrophin-releasing hormone and acute hypercalcaemia.

The responsiveness of anterior pituitary lactotrophs and thyrotrophs to cimetidine (Cim) was investigated in healthy volunteers. Four-hundred mg Cim, injected iv, raised the serum prolactin level (Prl) from 14 +/- 2 to 58 +/- 9 ng/ml (P less than 0.001), but left the serum thyrotrophin level (TSH) unaffected. Acute hypercalcaemia, induced by iv infusion of calcium, blunted this Cim-elicited Prl response by 35 +/- 4% (P less than 0.01). Iv injection of 25 micrograms thyrotrophin-releasing hormone (TRH) had similar Prl-releasing potency as 400 mg Cim, and raised the Prl level from 14 +/- 1 to 51 +/- 6 ng/ml (P less than 0.001). In contrast to Cim, TRH also increased the TSH level significantly. Although oral pre-treatment with Cim for 3 days (1000 mg/day) failed to affect the Prl response to TRH in this study, iv injection of the drug more than doubled the above mentioned Prl response to TRH. The TSH response to TRH remained unaffected both by oral and by iv administration of Cim. These results imply that acute changes in serum calcium affect the release pattern of Prl, and that iv administration of Cim may add Prl-releasing power to TRH in healthy individuals.

Administration, Oral↗
PubMed1994

Cytokinin regulation of a soybean pollen allergen gene.

Cytokinin treatment of suspension-cultured soybean cells stimulated the accumulation of an mRNA, called cim 1, by a factor of ca. 20 within 4 h. Induction of cim 1 mRNA accumulation occurred at benzyladenine concentrations as low as 10(-8) M. Furthermore, cim 1 mRNA accumulation was stimulated in the absence of cytokinin by staurosporine (an inhibitor of protein kinases) and inhibited in the presence of cytokinin by okadaic acid (an inhibitor of protein phosphatases 1 and 2a), suggesting that cim 1 accumulation in response to cytokinin is dependent on cytokinin-induced dephosphorylation of one or more cellular proteins. The deduced amino acid sequence of the cim 1 protein product, derived from the complete nucleotide sequence of a cim 1 cDNA, was 40% identical to that of a perennial rye grass pollen allergen cDNA (Lol Pl). This sequence also indicated that the cim 1 protein product contains a putative signal peptide followed by predominantly hydrophilic residues, consistent with the hypothesis that it is exported to the apoplast.

Alkaloids↗
PubMed1987

Interaction of cimetidine and histamine with superoxide generated in a cell-free system and in neutrophils.

We investigated the influence of CIM and HIS on the SUP and CH in the SUP generating cell-free xanthine oxidase system and in human neutrophils. As measured by CCR or CH, we found that HIS inhibited SUP output in both systems. The HIS concentration required for a measurable inhibition was somewhat higher in the xanthine oxidase system than in neutrophils. CIM increased CH in neutrophils significantly. A similar effect of CIM was not observed in the xanthine oxidase system. CIM antagonized in neutrophils the effect of HIS. However, a five or ten times higher molar concentration of CIM than of HIS was necessary to produce this effect. The antagonistic effect of CIM was not found in the xanthine oxidase system within the concentrations applied. In addition to an interaction of HIS with neutrophils on the cellular level, we suggest a superoxidase scavenging effect caused by HIS. At the present no suggestions can be made regarding the observed SUP output stimulating activity of CIM.

Cell-Free System↗
PubMed2003

Electrophoretic determination of the myosin/actin ratio in the diagnosis of critical illness myopathy.

OBJECTIVE: To develop a rapid method to quantify myosin in muscle biopsy specimens from patients with critical illness myopathy (CIM). DESIGN: Percutaneous muscle biopsy specimens at different stages of CIM were examined by light microscopy and transmission electron microscopy (TEM) and by horizontal pore gradient SDS electrophoresis (SDS-PAGE). The myosin/actin ratio was calculated densitometrically. Neurophysiological examinations were performed at various times during the course of CIM. SETTING: All patients were treated in intensive care units at Karolinska Hospital. PATIENTS AND PARTICIPANTS: We studied 11 patients with CIM, 5 patients with axonal neuropathies, and 42 control individuals. MEASUREMENTS AND RESULTS: The histopathological changes included in all cases muscle fiber atrophy, degeneration, regeneration, nuclear changes, and reduction in myofibrillar ATPase activity in both type I and II fibers. In severely affected muscles fiber type differentiation was lost. On TEM preferential loss of thick filaments was the dominant finding. In some patients changes were present only in parts of the specimen. The neurophysiological examinations indicated myopathy in five patients and combined myopathy and neuropathy in five and suggested neuropathy in one. The SDS-pore PAGE used showed a technical variation of 4-5%. Quantitative results were obtained within 1 day and night. The mean value of the myosin/actin ratio in controls was 1.37+/-0.21 and in CIM patients 0.37+/-0.17, without overlapping with the control values. CONCLUSIONS: Considering the diagnostic difficulty using morphological and neurophysiological methods, especially in early stages of CIM, we suggest including SDS-pore PAGE to determine the myosin/actin ratio for rapid diagnosis of CIM.

Actins↗
PubMed2002

Elevated interleukin-6 predicts progressive carotid artery atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity.

The cardiovascular mortality rate is unacceptably high in patients with end-stage renal disease (ESRD), which suggests an accelerated atherogenic process. The cause(s) of the accelerated atherogenesis in ESRD patients are not known, though recent studies suggest that persistent infection, such as Chlamydia pneumoniae, and proinflammatory cytokines may contribute. Forty-five ESRD patients (26 men) aged 51 +/- 2 years was studied at a time-point close to start of dialysis treatment and again after about 12 months of dialysis treatment. By using noninvasive B-mode ultrasonography, we evaluated changes in a surrogate marker of atherosclerosis, calculated intima media (cIM) area, in the common carotid artery. C-reactive protein (CRP), S-albumin, and interleukin-6 (IL-6) assessed the presence of an inflammatory reaction. We also measured C pneumoniae antibodies by microimmunofluorescence, nutritional status by subjective global assessment, lipid parameters, smoking habits, and the presence of comorbidity close to the start of dialysis. No significant changes in the prevalence of carotid plaques or the mean cIM area were observed during the first 12 months of dialysis. However, because some patients showed marked increases in the cIM area during only 12 months of dialysis we divided the patients into 2 groups: 23 nonprogressors ((delta)cIM area -2.7 +/- 0.4 mm2) and 22 progressors ((delta)cIM area 3.6 +/- 0.7 mm2). Sex, age, body mass index, comorbidity, blood lipid levels, S-albumin, and CRP levels did not differ significantly between the 2 groups. On the other hand, progressors had a significantly elevated basal median level of IL-6 (5.7 versus 3.1 pg/mL; P < 0.05) and an increased prevalence of positive (> or 1/64) immunoglobulin (Ig) A antichlamydia antibodies (59% versus 17%; P < 0.01) compared with nonprogressors. A significant positive (R = 0.41; P < 0.01) correlation was found between Log IL-6 and changes in the cIM area during 12 months of dialysis. In a stepwise multiple regression model, Log IL-6 did predict, independently (P < 0.01) of traditional risk factors and C pneumoniae antibodies, changes in the cIM area. These data suggest that a persistent chlamydial infection stimulates IL-6 levels, which in turn may be involved in the pathogenesis of accelerated carotid atherosclerosis in dialysis patients.

Arteriosclerosis↗
PubMed1993

Effects of increased beta 2-agonist dose in tumor-bearing animals.

Cachexia and malnutrition are major contributing causes of significant morbidity and mortality in the cancer patient. Although supplemental nutrition alone does not reverse the cachectic process, the use of anabolic beta 2-adrenergic agonists in conjunction with supplemental nutrition does significantly reverse cachectic processes in tumor-bearing (TB) animals. To determine the most efficacious dose of the beta 2-agonist cimaterol (CIM), male Fischer-344 rats with dorsal subcutaneous methylcholanthrene sarcomas were maintained on supplemental enteral nutrition via surgically placed gastrostomy tubes. TB rats were given daily subcutaneous injections of either saline (Sal) or one of three doses of CIM for seven days. TB-Sal animals demonstrated significant cachexia with decreased extensor digitorum longus and gastrocnemius muscle dry weight and protein content. There was a significant increase in both extensor digitorum longus and gastrocnemius muscle dry weight and protein content in all treatment groups compared with TB controls. The greatest increase was in the 0.30 mg/kg CIM treatment group. Increased cardiac mass was associated with increasing dosage, with the greatest effect being observed in the 0.60 mg/kg CIM treatment group. This dosage, however, was associated with a decreased effect on muscle weight and protein content compared with the 0.30 mg/kg CIM dose. Thus the peak anabolic effect in TB animals was reached with the 0.30 mg/kg dose of CIM. Therefore, use of the beta 2-agonist CIM may prove useful in the treatment of cancer-induced cachexia.

Adrenergic beta-Agonists↗
PubMed1992

Analysis and pharmacokinetics of cimaterol in growing Holstein steers.

Pharmacokinetic parameters for the beta 2-adrenergic agonist, cimaterol (CIM), were determined in growing Holstein steers. Compartmental analysis was used after measurement of CIM in body fluids by affinity chromatography and HPLC using UV detection. Recoveries from spiked plasma and urine standards were 70 +/- 1.2% and 68 +/- 1.1%, respectively. The minimum detection level in plasma was 1 ng/mL and the average CV was 5.1% for concentrations that ranged from 1 to 30 ng/mL. Four steers (276 +/- 24 kg) received 15 mg of CIM by bolus intravenous injection. Plasma CIM levels declined in a biphasic manner with half-lives of 2.5 min for the distribution phase and 54 min for the elimination phase. A two-compartment open model was used to describe the disappearance of CIM and the following pharmacokinetic parameters were obtained: central compartment volume (Vc) = .76 L/kg, apparent volume of distribution (Vd) = 4.1 L/kg, and transfer rate constants from the central to peripheral compartment (k12) = .177/min, from the peripheral to central compartment (k21) = .054/min and elimination from the central compartment (kel) = .074/min. After 8 h, total urinary CIM accounted for only 18.3% of the administered dose. Results suggest that circulating concentrations of CIM in growing steers are influenced by its accumulation in an unidentified peripheral pool and its conversion into unknown metabolite(s) before elimination.

Adrenergic beta-Agonists↗
PubMed1987

Effect of the repartitioning agent cimaterol on growth, carcass and skeletal muscle characteristics in lambs.

Ten crossbred (Suffolk X Rambouillet) whether lambs were randomly assigned to receive 0 or 10 ppm cimaterol (CIM) in a completely mixed high-concentrate diet for 8 wk. Total weight gain and feed efficiency were improved 29% (P less than .05) and 14%, respectively, in the CIM-fed group. CIM also improved (P less than .01) dressing percent by 4.9 percentage points and improved yield grade by one grade. CIM increased longissimus muscle (LD) area 38% (P less than .01) and the yield of four lean cuts 28% (P less than .01). No difference was found in the proportion of type I (slow-contracting, oxidative) and type II (fast-contracting, mixed glycolytic/oxidative) fibers in LD and semitendinosus (ST) muscles between control and CIM groups, indicating no change in fiber type. The cross-sectional area of type II fibers in LD and ST muscles of the CIM group was 2,081 and 1,951 micron 2 as compared with 1,391 and 1,296 micron2 of the control group, respectively. The increase was approximately 50% (P less than .01). No difference was found in cross-sectional area of type I fibers, indicating that the increase of muscle mass was due to hypertrophy of type II fibers only. DNA concentration (micrograms/g wet muscle or microgram/g protein) of CIM muscle was much lower (P less than .01) than that of control muscle, suggesting that the protein accretion in muscle was accomplished without additional incorporation of nuclei from satellite cells.

Adrenergic beta-Agonists↗
PubMed2006

Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review).

Cimetidine (CIM), the prototypical histamine H2 receptor antagonist (H2RA), was brought to market based on its ability to accelerate healing of gastrointestinal ulcers through the inhibition of gastric acid secretion. Cimetidine, the most studied H2RA, has been demonstrated to possess anti-tumor activity against colon, gastric and kidney cancers, and melanomas. This activity involves a number of different mechanisms of action: a) CIM antagonizes tumor cell-mediated interleukin-1-induced activation of selectins in liver sinusoids, inhibiting tumor cell binding on liver sinusoids, thereby reducing the development of liver metastasis; b) histamine acts as a growth factor in various tumor cell types via the activation of H2 receptors; CIM therefore may antagonize this effect; c) CIM acts as an immunomodulator by enhancing the host's immune response to tumor cells. With respect to malignant gliomas, CIM added to temozolomide was superior in vivo when compared to temozolomide alone in extending survival of nude mice with human glioblastoma cells orthotopically xenografted into their brain. We review the various mechanisms of action potentially associated with the therapeutic effects of CIM in the case of experimental glioblastomas, observations we hope will encourage clinical investigation of CIM in the management of highly malignant gliomas.

Antineoplastic Agents↗
PubMed1990

[Effects of ranitidine and cimetidine on automaticity in isolated myocardium of guinea pig].

At 0.1-30 mumols/L, neither ranitidine (Ran) nor cimetidine (Cim) inhibited the rate of spontaneous contraction in isolated right atria of guinea pig. When the concentration was higher than 100 mumols/L, both Ran and Cim exhibited weak negative chronotropic effects with IC50 of 109 +/- 3 and 436.5 +/- 1.9 mumols/L, respectively. However, the positive chronotropic effects of histamine (H) were markedly antagonized by Ran and Cim with IC50 of 0.40 +/- 0.29 and 1.8 +/- 0.6 mumols/L respectively. Ran (0.1 mumols/L) and Cim (1 mumols/L) competitively antagonized the concentration-dependent response of positive chronotropic effect mediated by H and had no influence on that induced by isoproterenol in right atria of guinea pig. Ran (10 mumols/L) and Cim (50 mumols/L) prevented the abnormal automaticity elicited by H and H (0.12 +/- 0.09 mumols/L) + Oua (0.04 +/- 0.02 mumols/L) which acted synergically. The abnormal automaticity induced by Oua (1.5 +/- 2.3 mumols/L) was antagonized by Ran (10 mumols/L) and not by Cim (50 mumols/L). Our results suggest that these effects of Ran and Cim are mainly attributed to cardiac H2 receptor blockade.

Animals↗
PubMed1990

Effect of histamine receptor antagonists on mortality in compound 48/80-induced shock.

The roles of histamine and H1 and H2 receptors in shock are uncertain. We have found that treatment of aged rats with compound 48/80 (a mast cell degranulator) produced lethal (LD99) shock which was completely prevented by lodoxamide (LOD), a mast cell degranulation inhibitor. This study evaluated the effect of H1 and H2 receptors and age on mortality of 48/80-induced shock in rats. To assess survival, 65 young male (125 g), 65 mature male (250 g) and 30 aged male (500 g) SD rats were placed in groups and treated intraperitoneally with saline; 48/80; LOD + 48/80; the H1 blocker diphenhydramine (DPH) + 48/80; the H2 blocker cimetidine (CIM) + 48/80; or DPH and CIM + 48/80. Rats were observed for 30 min or until death. All 125 g rats survived. Of the 250 g rats, 50% of 48/80-treated and 100% of CIM + 48/80-treated rats died; all others survived. All 500 g 48/80- and CIM + 48/80-treated rats died; all other 500 g rats survived. For all ages, survival differences between saline-, 48/80-, and CIM + 48/80-treated rats were highly significant (P less than or equal to 0.0001). In addition, both 48/80 and CIM + 48/80 greatly reduced mean survival time in the 250 g and 500 g groups (P less than or equal to 0.0001) compared to all other treatments. Both LOD and DPH were protective against 48/80, and DPH was also protective against CIM + 48/80, for both absolute survival and mean survival time (P less than or equal to 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Cellular phenotypes of differentiated-type adenocarcinomas and precancerous lesions of the stomach are dependent on the genetic pathways.

To elucidate the relationship between genetic alterations and cellular phenotypes in differentiated-type carcinomas and precancerous lesions of the stomach, mutations of p53, APC and K-ras genes were examined, as well as microsatellite instability (MSI), in 52 tumours of the stomach. Tumours were selected with the following phenotypical features, using mucin histochemical and immunohistochemical analyses, in addition to their morphological features: (1) tumours with an extremely well-preserved gastric foveolar phenotype (foveolar-type); (2) tumours with an extremely well-preserved complete-type intestinal metaplastic phenotype (CIM-type); and (3) ordinary tumours without extreme phenotypes (ordinary-type). MSI occurred in 45% of foveolar-type, 24% of ordinary-type, and 0% of CIM-type tumours. p53 gene alterations occurred in 5% of foveolar-type, 18% of ordinary-type, and 31% of CIM-type. APC gene alterations were detected in 9% of foveolar-type, 6% of ordinary-type, and 0% of CIM-type. No K-ras gene mutation was detected in any of the three types. These results indicate that the genetic pathways are quite different among the phenotypes of tumours of the stomach. The 'mutator pathway', characterized by MSI, plays an important role in the tumourigenesis of foveolar-type, but not CIM-type tumours. The 'suppressor pathway', represented by p53 alteration, could participate in the tumourigenesis of the CIM-type, but is rare in foveolar-type tumours.

Adenocarcinoma↗
PubMed1989

Effect of cimetidine on hepatic biochemical changes, liver toxicity and major urinary metabolite excretion of trichloroethylene in rats.

The effects of cimetidine (CIM) (an inhibitor of the hepatic microsomal monooxygenase system) on the metabolism and hepatotoxicity of trichloroethylene (TRI) were studied in male Sprague-Dawley rats. Rats were given three doses of 120 mg/kg i.p. (low-dose regimen) of CIM at 0, 6 and 11 h for 1 day, or ten doses of 200 mg/kg (high-dose regimen) at 8, 11, 14 and 17 h for 2 days and 8 and 11 h on 3rd day. Trichloroethylene (0.5 or 0.65 ml/kg) was administered i.p. 1 h after 2nd dose (low-dose regimen) or 9th dose (high-dose regimen) of CIM. In the low-dose regimen study, the activity of hepatic microsomal aminopyrine N-demethylase was decreased 1 and 5 h after the second dose and 7 h after the third dose of CIM, but became normal 20 h after the last dose. The cytochrome P-450 content and the activities of aniline hydroxylase and epoxide hydratase remained unchanged. Trichloroethylene at both dose levels produced liver toxicity, as verified by increase in activities of SDH and SGPT as well as by liver histology. Cimetidine alone had no such effect. An apparent reduction in TRI toxicity by CIM (at both dose regimens) could be observed histologically. The biochemical tests (SDH and SGPT) corroborated the histological changes only when TRI was given at a dose of 0.5 ml/kg combined with a high-dose regimen of CIM. Cimetidine at both dose regimens had a tendency to decrease the in vivo metabolism of TRI.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed2006

Dysregulation of sodium channel gating in critical illness myopathy.

Critical illness myopathy (CIM) is the most common caused of acquired weakness in critically ill patients. While atrophy of muscle fibers causes weakness, the primary cause of acute weakness is loss of muscle excitability. Studies in an animal model of CIM suggest that both depolarization of the resting potential and a hyperpolarized shift in the voltage dependence of sodium channel gating combine to cause inexcitability. In active adult skeletal muscle the only sodium channel isoform expressed is Nav1.4. In the animal model of CIM the Nav1.5 sodium channel isoform is upregulated, but the majority of sodium current is still carried by Nav1.4 sodium channels. Experiments using toxins to selectively bock the Nav1.4 isoform demonstrated that the cause of the hyperpolarized shift in sodium channel inactivation is a hyperpolarized shift in inactivation of the Nav1.4 isoform. These data suggest that CIM represents a new type of ion channel disease in which altered gating of sodium channels is due to improper regulation of the channels rather than mutation of channels or changes in isoform expression. The hypothesis that dysregulation of sodium channel gating underlies inexcitability of skeletal muscle in CIM raises the possibility that there maybe dysregulation of sodium channel gating in other tissues in critically ill patients. We propose that there is a syndrome of reduced electrical excitability in critically ill patients that affects skeletal muscle, peripheral nerve, the heart and central nervous system. This syndrome manifests as CIM, critical illness polyneuropathy, reduced cardiac contractility and septic encephalopathy.

Action Potentials↗