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PubMed2026

Evaluation of carbapenem inactivation method-based phenotypic assays for the detection of GES-type carbapenemases in Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.

UNLABELLED: Detection of GES-type carbapenemases remains challenging because of their low prevalence and frequently weak hydrolytic activity against carbapenems. Carbapenem inactivation method (CIM)-based assays are widely used as phenotypic screening tools for carbapenemase detection; however, their performance in large collections of GES producers has not been systematically evaluated. We assessed the performance of CIM, modified CIM (mCIM), and CIM-Tris in a diverse collection of GES-producing clinical isolates, including 110 Enterobacterales and 108 Pseudomonas aeruginosa, recovered from Spanish hospitals (2010-2024), and 10 Acinetobacter baumannii isolates, mostly obtained from a hospital in Egypt. Whole-genome sequencing was carried out for species confirmation and resistome analysis. Meropenem MICs were determined by broth microdilution. Overall, 92.1% of isolates were GES-carbapenemase producers (CP), whereas 7.9% expressed GES-type extended-spectrum β-lactamases (ESBLs). In Enterobacterales (predominantly carrying blaGES-6), mCIM improved sensitivity compared with CIM (63.6% vs 40.0%), although many isolates remained undetected due to low meropenem MICs (MIC50, 0.5 µg/mL). In CP-P. aeruginosa (mainly blaGES-5), CIM, mCIM, and CIM-Tris showed sensitivities of 89.1%, 94.6%, and 100%, respectively; however, CIM-Tris yielded false-positive results in 50% of non-CP isolates (mostly blaGES-1 producers). Meropenem MICs in P. aeruginosa were higher (MIC50, >32 µg/mL). In A. baumannii, CIM-Tris improved sensitivity compared with CIM (100% vs 25.0%). These findings indicate that CIM-based methods can detect GES-type carbapenemases, but performance varies according to bacterial species and GES variant, and reduced specificity may occur in isolates producing GES-type ESBLs. Complementary molecular testing may therefore be necessary to ensure accurate detection of GES-type carbapenemases in routine clinical laboratories. IMPORTANCE: GES-type carbapenemases represent an important but underrecognized diagnostic challenge due to their low global prevalence, heterogeneous hydrolytic activity, and the limited performance data available for routine phenotypic detection methods. Although CIM-based assays are widely implemented in clinical microbiology laboratories for carbapenemase screening, their performance against GES-producing organisms has not been comprehensively evaluated across different bacterial genera and GES variants. In this study, we evaluated the performance of CIM, modified CIM (mCIM), and CIM-Tris in a large multicenter collection of well-characterized GES-producing clinical isolates, including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii. Our findings demonstrate substantial variability in assay performance according to bacterial species and GES variant. Notably, mCIM improved sensitivity among Enterobacterales with low meropenem MICs, whereas CIM-Tris achieved excellent sensitivity in P. aeruginosa and A. baumannii but at the expense of reduced specificity in isolates producing GES-type ESBLs. To the best of our knowledge, this is the first study directly comparing multiple CIM-based approaches in such a large and taxonomically diverse collection of GES-producing isolates.

beta-Lactamases↗
PubMed1983

Effect of prenatal and postnatal exposure to therapeutic doses of chlorimipramine on emotionality in the rat.

Prenatal administration of high doses of tricyclic antidepressants have been reported to produce teratogenic and behavioral effects in rat offspring. In the present work, behavioral abnormalities are described in offspring of rats treated with therapeutic doses of chlorimipramine (CIM) during pregnancy (CIM-P), lactation (CIM-L) and during the whole pregnancy-lactation period (CIM-PL). CIM-P treatment did not produce teratogenic effects, did not affect number or body weight of pups at birth and did not induce neonatal mortality. At 2 months of age, the CIM-P males showed a significant increase in digging and grooming (familiar environment test), a decrease in "exploration" (novel environment test) and a decrease in active social interactions (social behavior test). Females were more resistant than males to the prenatal CIM treatment. The results suggest increased emotionality in CIM-P pups. Some behavioral abnormalities were also observed in the tests performed at 4 months of age. CIM-L treatment had minor effects on litter behavior. CIM-PL treatment potentiated the effects of the CIM-P treatment. In the CIM-PL males, impairment of exploration of a novel environment still remained in the tests performed at 4 months of age. It is speculated that when prenatal brain development is altered by CIM, further postnatal treatment may impair compensatory processes occurring in early postnatal life.

Animals↗
PubMed2000

Gastric cardia intestinal metaplasia: biopsy follow-up of 85 patients.

BACKGROUND: Gastric cardia intestinal metaplasia (CIM), denoted by goblet cells is common. The frequency of persistent CIM is unknown. METHODS: 85 patients with CIM and follow-up endoscopies were prospectively identified during the time period of 10/6/94-12/21/97. The presence of goblet cells was the defining feature of CIM, other metaplastic cell types were not evaluated. AU 85 patients initially had biopsies that straddled the squamocolumnar junction (SCJ) showed CIM, an otherwise normal proximal stomach, lower esophagus, and squamocolumnar junction. The SCJ lay within the 2 cm of mucosa immediately proximal to the uppermost gastric fold and overlaid the junction of the tubular esophagus and the saccular dilatation of the stomach in all patients. The patients underwent endoscopy for many reasons. They were randomly identified based on the absence of a hiatal hernia and the presence of CIM. RESULTS: Ten of the 85 patients had CIM on repeat biopsy. Among patients with no CIM in the first repeat endoscopy, the degree of cardia inflammation decreased between the initial and first repeat endoscopy, whereas there was no change in the amount of inflammation among patients who had CIM in the first repeat endoscopy. The changes in mean inflammation score was significantly different between the two groups (P = .024). Twenty-two patients underwent a second repeat endoscopy and five had a third repeat endoscopy. Including all follow-up biopsies, six of the 85 patients (7%) had CIM. Four patients who did not have CIM on initial repeat endoscopy had CIM on their second repeat endoscopy, probably reflecting sampling issues. None of the biopsies had dysplasia. CONCLUSIONS: Cardia inflammation is a stimulus for cardia intestinal metaplasia, and a reduction in inflammation may allow the metaplastic mucosa to revert to normal.

Adult↗
PubMed1984

Tubular transport and metabolism of cimetidine in chicken kidneys.

Renal tubular transport and renal metabolism of [14C]cimetidine (CIM) were investigated by unilateral infusion into the renal portal circulation in chickens (Sperber technique). [14C]CIM was actively transported at a rate 88% that of simultaneously infused p-aminohippuric acid, and its transport was saturable. The following organic cations competitively inhibited the tubular transport of [14C]CIM with decreasing potency: CIM, ranitidine, thiamine, procainamide, guanidine and choline. CIM inhibited the transport of [14C]thiamine, [14C]amiloride and [14C]tetraethylammonium. During CIM infusion, two renal metabolites, CIM sulfoxide and hydroxymethylcimetidine, were found in urine. When CIM sulfoxide was infused, its transport efficiency was 32% and not saturable. CIM sulfoxide did ot inhibit the simultaneous renal tubular transport of p-aminohippuric acid or tetraethylammonium. CIM is transported by the organic cation transport system and the kidney metabolizes CIM. Transport of CIM and other cationic drugs could produce a drug interaction to alter drug excretion.

Animals↗
PubMed1991

Differential effects of clomipramine given locally or systemically on extracellular 5-hydroxytryptamine in raphe nuclei and frontal cortex. An in vivo brain microdialysis study.

The antidepressant drug clomipramine (CIM) blocks 5-hydroxytryptamine (5-HT) uptake in vitro. Electrophysiological studies have shown that CIM also reduces the firing of serotonergic neurons in the dorsal raphe nucleus. In order to assess the effects of CIM on serotonergic transmission in vivo, the technique of intracerebral microdialysis was used. CIM was administered either through the dialysis probe or i.p., and dialysate 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were determined in frontal cortex and/or raphe nuclei. In addition, the action of extracellular 5-HT in raphe nuclei on the release of 5-HT in frontal cortex was studied. The administration of CIM through the dialysis probe increased dialysate 5-HT in frontal cortex in a dose-dependent fashion. An actual ED50 of 3.15 microM CIM for the in vivo inhibition of 5-HT uptake can be calculated in this brain area. When given systemically (10 or 20 mg/kg i.p.), CIM did not increase dialysate 5-HT in the frontal cortex. The occurrence of extracellular 5-HT in the the raphe area was demonstrated. This pool of 5-HT increased markedly after local (10 or 40 microM) or systemic (20 mg/kg i.p.) administration of CIM. We also examined the effect of CIM applied locally in the raphe nuclei on extracellular 5-HT in the frontal cortex. The increased dialysate 5-HT in raphe after 10 or 40 microM CIM paralleled a decrease of dialysate 5-HT in the two areas correlated negatively. The administration of CIM through the dialysis probe slightly decreased dialysate 5-HIAA in the frontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Etiology of intestinal metaplasia at the gastroesophageal junction.

BACKGROUND: Intestinal metaplasia occurs in the esophagus as a consequence of gastroesophageal reflux disease and in the stomach secondary to H. pylori infection. The etiology of intestinal metaplasia limited to the gastroesophageal junction or cardia (CIM) is disputed. We hypothesized that CIM has dual etiologies: gastroesophageal reflux in some, H. pylori infection in others, and that cytokeratin immunostaining can help to differentiate between these two etiologies. METHODS: We defined CIM as the presence of intestinal metaplasia within cardiac mucosa on biopsy from an endoscopically normal-appearing gastroesophageal junction. Thirty patients with CIM who had multiple biopsy specimens taken from the esophagus, gastroesophageal junction, and stomach were identified. Tissue blocks from biopsy specimens taken at the gastroesophageal junction were sectioned and immunostained for cytokeratins 7 and 20. The cytokeratin 7/20 staining of the CIM in each patient was determined to be either a Barrett's or non-Barrett's pattern. H. pylori infection was assessed by Giemsa staining of antral biopsy specimens. RESULTS: H. pylori infection was present in 16 patients. A Barrett's cytokeratin 7/20 staining pattern in the CIM was present in only 46% of the H. pylori-positive patients, as compared to 86% in the 14 patients with CIM and no H. pylori (p = 0.025). Objective evidence of reflux disease was present in 71% of patients with CIM and no H. pylori, as compared to 31% of patients with H. pylori. CONCLUSIONS: The two different patterns of cytokeratin 7/20 staining found in patients with CIM support the concept of dual etiologies for CIM. A Barrett's staining pattern was associated with objective evidence of gastroesophageal reflux and the absence of H. pylori, suggesting that cytokeratin 7/20 immunostaining is useful to determine the likely etiology of CIM.

Biopsy↗
PubMed2004

Distinction between intestinal metaplasia in the cardia and in Barrett's esophagus: the role of histology and immunohistochemistry.

Intestinal metaplasia in Barrett's esophagus (BIM) is a precancerous condition, whereas the carcinogenic potential of intestinal metaplasia of the cardia (CIM) is uncertain. Although clinically important, histological distinction between both conditions by endoscopic biopsies is considered problematic. In the present study, 4-mm samples of BIM (n=31) and CIM (n=9) were selected from esophagectomy specimens that had been resected for esophageal cancer. Slides were coded and stained with hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff (PAS), cytokeratins (CK) 7 and 20, and CD10, which labels the intestinal brush border. The predictive value of these stains for the recognition of BIM and CIM was evaluated independently by two senior pathologists. With the use of H&E-stained slides exclusively, BIM samples were categorized correctly in 93.5% and 83.9% of cases (pathologists 1 and 2, respectively), and CIM samples, in 100% and 88.9% of cases. Alcian blue-PAS-positive goblet cells were identified by both investigators in all BIM and CIM samples. BIM-typical CK 7 and 20 immunostaining pattern was identified in 90.3%/83.9% of BIM but only in 11.1%/11.1% of CIM. CD10-positive brush border was present in 32.3%/25.8% of BIM and in 88.9%/88.9% of CIM. When HE-stained slides and immunohistologically stained slides were used together for tissue recognition, BIM were categorized correctly in 90.3%/80.6% of cases, and CIM, in 88.9%/88.9% of cases. In conclusion, BIM and CIM can be usually distinguished on the basis of HE sections. CK 7 and CK 20 expression pattern analysis discriminates correctly between BIM and CIM in the majority of cases. CD10-positive intestinal brush border is present in the majority of CIM but only in a minority of BIM. However, immunohistochemical investigations could not improve the diagnostic accuracy of HE histology alone.

Adult↗
PubMed2002

On the efficiency of composite interval mapping in an outbred population.

Composite interval mapping (CIM) has been successfully applied to the detection of QTL in experimental animals and plants. However, practical analyses based on CIM have been reported mainly for populations derived from cross between inbred lines. There are few studies on QTL analyses with CIM in outbred populations. To evaluate the applicability of CIM to outbred populations is prerequisite for the fine mapping of QTL in industrial animals such as pig and chicken. Some markers are usually not fully informative in outbred populations. In application of CIM to outbred populations, the influence of inclusion of such uninformative markers used as covariates on the efficiency of CIM should be investigated. In this paper a least-squares method for CIM was formalized in an F(2) population derived by crossing two outbred lines. The efficiencies of CIM were evaluated for outbred populations in comparison with simple interval mapping (SIM) for several cases of marker informativeness using simulations. By incorporating markers linked to a tested position as well as those unlinked, CIM showed a higher efficiency to separate two linked QTL over SIM. The efficiency of dissection was enhanced as the marker informativeness was increased. The power of CIM to detect an isolated QTL was improved by excluding markers linked to a tested position from covariates and higher than SIM regardless of marker informativeness. In conclusion, CIM is a useful procedure for the analysis of QTL in outbred populations even under low marker informativeness.

Animals↗
PubMed1998

Quantitative prediction of the interaction of midazolam and histamine H2 receptor antagonists in rats.

To quantitatively evaluate drug-drug interactions involving metabolic processes in the liver, we attempted to predict the increasing ratio of the plasma concentration of midazolam (MDZ) in the presence of cimetidine (CIM) or nizatidine (NZD) in rats. Under steady-state conditions for the plasma concentration of CIM or NZD, MDZ was administered through the portal vein. The AUC of MDZ in the presence of CIM was 2.5-fold higher than that in the absence of CIM. There was no effect of NZD on the AUC of MDZ. The liver/plasma concentration ratios for CIM and NZD were 4.0 and 2.7, respectively. The estimated liver unbound concentration (CH,f)/plasma unbound concentration (Cp,f) ratios for CIM and NZD were 1.9 and 2.4, respectively, suggesting concentrative hepatic accumulation of both drugs. The oxidative metabolism of MDZ in rat liver microsomes was competitively inhibited by CIM or NZD, and the Ki values of CIM and NZD were 110 and 2600 microM, respectively. Based on these data obtained in vivo and in vitro, the increasing ratios for MDZ in the presence of CIM or NZD were predicted using the equations Rp = 1 + Cp,f/Ki and RH = 1 + CH,f/Ki. The observed increasing ratios in the presence of CIM were very close to RH, compared with Rp. However, Cp, f and CH,f were much less than Ki and there was no difference between Rp and RH in the presence of NZD. Consequently, Cp,f and CH, f were greater than or equal to Ki and Cp,f was not equal to CH,f, as in the presence of CIM, and it was indicated that CH,f was more suitable for quantitatively predicting the drug-drug interactions than was Cp,f.

Animals↗
PubMed1999

Cimetidine inhibits nitric oxide associated nitrate production in a soft-tissue inflammation model in the horse.

Cimetidine (CIM) is an H2-receptor antagonist that has been used in racehorses in an attempt to reduce the occurrence of stress-related gastric ulceration. It has also been shown to produce several useful effects other than its gastric acid suppression properties. Further, it is a well documented antagonist of cytochrome P-450 (CYP) mediated oxygenation reactions. Nitric oxide (NO), a recently discovered mediator or modifier of numerous physiological functions, is generated by several forms of nitric oxide synthase (NOS), one of which is inducible (iNOS). Inducible NOS, expressed in neutrophils and macrophages as part of the inflammatory response to noxious stimuli, contains both a CYP and a CYP reductase domain. Because of the similarity of structure of iNOS and CYP, it was decided to determine whether CIM could reduce NO production, using a carrageenan inflammation model in the horse. Two experiments were conducted. In Trial 1, six female Thoroughbred horses each had three tissue chambers inserted subcutaneously on the sides of the neck. The study was divided into three treatments: 0.9% NaCl (NaCI), CIM (3 mg/kg), and aminoguanidine (AG; 25 mg/kg), an inhibitor of iNOS. Each mare received three i.v. injections 12 h apart prior to instillation of 1 mL of carrageenan into the test chamber. Blood and tissue chamber fluid (TCF) were collected serially. Concentrations of NO3- (the major metabolite of NO), albumin, total protein, CIM and AG were measured and complete cell counts and differentials were conducted. Trial 2 also used six female Thoroughbred horses implanted with at least two tissue chambers inserted subcutaneously on the sides of the neck. The study was divided into two treatments: NaCl (0.9%) and CIM (6 mg/kg). Each mare received seven i.v. injections of either NaCl or CIM 8 h apart prior to instillation of 1 mL of carrageenan into the test chamber. Blood and TCF were collected serially as before, and analysed for NO3- and CIM content. Areas under the curve (AUC) of the different parameters were calculated for the periods of -1-1, -1-3 and -1-7 days (Trial 1) and -2-1 for Trial 2. Absolute values were also compared at 4, 8 and 12 h postcarrageenan. Saline treatment did not reduce the elevated concentrations of NO3- in either plasma or TCF. Plasma, test chamber and control chamber NO3-concentrations rose from 0 to 12 h, and were very similar in all three sampled fluids. Cimetidine significantly (P< or =0.05) decreased NO3- production in plasma over the periods of -1-1, -1-3, and -1-7 days post inflammation when compared to NaCl treatment in Trial 1. Aminoguanidine and CIM decreased NO3-production in TCF for the periods -1-1, 1-3, and -1-7 days post inflammation in Trial 1 and -2-1 for Trial 2. Both CIM and AG also significantly reduced NO3-concentrations in plasma and TCF at 12 h postinitiation (Trials 1 and 2). Thus CIM, at the doses studied, was capable of reducing NO3- concentrations in this model as effectively as AG, a relatively specific inhibitor of iNOS activity.

Animals↗
PubMed2004

Detection of cardia intestinal metaplasia: do the biopsy number and location matter?

BACKGROUND AND AIM: Presence of intestinal metaplasia in the gastric cardia (cardia intestinal metaplasia, CIM) has been reported in 5-34% of patients undergoing upper endoscopy and is a topic of interest given the rising incidence of cancer in this location. The aim of this article is to determine the prevalence of CIM in biopsies obtained from two separate locations within the gastric cardia. METHODS: Patients presenting to the endoscopy unit for upper endoscopy for any symptoms were invited to participate in the study. The biopsy protocol included: eight biopsies from the gastric cardia, four from upper cardia (forceps across the squamocolumnar junction), four from lower cardia (within 1 cm of upper cardia), and four each from the gastric body and antrum. All cardia biopsies were stained with hematoxylin and eosin (H&E) and alcian blue at pH 2.5 for the presence of goblet cells and the body/antrum biopsies were stained with Steiner silver stain for Helicobacter pylori detection. In patients testing negative for H. pylori by histology, a serology test was performed. RESULTS: Sixty-five patients have been evaluated by this protocol; median age 54 yr (range: 34-81 yr), 63 males, 53 Caucasians, and 12 African Americans. The detection of CIM was as follows: upper cardia only, 7, both upper and lower cardia, 5, and lower cardia only, 7. Thus, CIM was detected in 12 patients (18%) in the upper cardia biopsies, in 12 patients (18%) in the lower cardia; overall prevalence of CIM was 29% (19 patients). Fifty-eight percent of CIM patients tested positive for H. pylori by either histology or serology. The addition of serology allowed for the detection of eight additional H. pylori-positive CIM patients. CONCLUSIONS: The prevalence of CIM in this study was similar (18%, four biopsies) at each location; however, if both locations were considered (eight biopsies), the prevalence increased to 29%. Thus, CIM prevalence may vary depending on the number of biopsies obtained as well as on the location of biopsies. Use of additional testing detects more patients who are H. pylori positive and should be performed if association of CIM with H. pylori is contemplated. Future endoscopic studies of the gastric cardia should specify the location of biopsies, the number of biopsies obtained, and the tests used to diagnose H. pylori.

Adult↗
PubMed1991

The effect of cimetidine on adaptive cytoprotection by mild irritant dose of HCl in the rat gastric mucosa.

While cimetidine (CIM) is strikingly effective in inhibiting gastric acid secretion, its effect on the defensive mechanisms of the gastric mucosa has been controversial. The aims of the present study were to test if administration of CIM at an antisecretory dose is protective against acid-induced injury and to assess its effect on adaptive cytoprotection induced by non-necrotizing concentrations of HCl in rats. A dose of 100 mg/kg of CIM was administered once, or twice a day for 5 days intraperitoneally. To study the effect of CIM on HCl-induced damage, 0.6 N HCl was given orally one hour after the last administration of CIM. To study the effect of CIM on adaptive cytoprotection, 0.35 N HCl was given orally one hour after the last administration of CIM. Fifteen minutes later, 0.6 N HCl was given orally. Thirty minutes after the administration of 0.6 N HCl, the stomach was removed and ulcer indices were calculated. Pretreatment with CIM did not prevent 0.6 N HCl induced gastric damage. Prior administration of 0.35 N HCl significantly reduced ulcer indices caused by 0.6 N HCl. Short or long term treatment with CIM did not have significant effects on the reduction of ulcer indices. These results suggest that CIM at an antisecretory dose neither acts as a protective agent nor modulates the protective process of the gastric mucosa.

Adaptation, Physiological↗
PubMed1991

The effect of cimaterol and its withdrawal on carcass composition and meat tenderness of broiler chickens.

To examine the effects of cimaterol (CIM) and its withdrawal on meat tenderness and carcass composition, 21-d-old broiler chickens (n = 288) were randomly assigned to one of nine treatments. For Treatments 1 through 6, birds were fed a control diet or a diet containing 1 ppm CIM until slaughter at 35, 42, or 49 d of age. Treatments 7 and 8 consisted of birds fed the CIM diet for 14 d and then withdrawn from CIM for either 7 or 14 d before slaughter (42 or 49 d of age). In Treatment 9, birds were fed the CIM diet to 42 d of age, then withdrawn from CIM for 7 d. Breast muscle (BM) weight, leg muscle (LM) weight, whole body weight, and BM and LM cathepsin B and L activities were obtained on 12 birds/treatment. Body, LM and BM composition and BM shear values were obtained on 12 additional birds/treatment. Eight birds/treatment were used to balance the number of birds per pen. Leg muscle weight, as a percentage of whole body weight, was elevated in CIM-fed birds at all ages, and BM percentage was greater at 35 d of age (P less than .05). Leg muscle fat percentage was reduced at 35 and 42 d of age (P less than .05), and LM protein was elevated at 42 and 49 d of age (P less than .05) in CIM-fed birds. Percentage of protein in the BM of CIM-fed birds was elevated at 35 and 42 d of age. Protein content of the whole body was also increased at 35 d of age. Shear values were higher in 42- and 49-d-old CIM-fed birds.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1989

Muscle protein turnover and tenderness in broiler chickens fed cimaterol.

To investigate the impact of cimaterol (CIM) on muscle protein turnover, carcass and muscle composition, muscle cathepsin B + L activity and meat tenderness, 21-d-old broiler chickens (n = 88) were assigned to dietary treatments of either 0 or 1 ppm CIM. Fractional synthesis rates (FSR), fractional accretion rates (FAR), proximate composition and collagen content were determined in the breast muscle (BM); pectoralis major) and a group of leg muscles (LM; gastrocnemius and peroneous longus) from groups of six birds per treatment within each of two time periods (age = 38 or 56 d). Whole body composition, serum hydroxyproline content and BM cathepsin B + L activity also were measured. Fractional degradation rates (FDR) were calculated as the difference between FSR and FAR. Feeding CIM increased (P less than .01) whole body protein content. Weights of LM and percentage of body weight as BM and LM were increased (P less than .05) when CIM was included in the diet. Although FSR was not significantly reduced by CIM feeding it decreased (P less than .05) with increasing age. Due to decreases in FAR, FDR thereby was reduced by CIM 31.5% and 11.9% in BM and 38.2% and 37.4% in LM at 38 d and 56 d of age, respectively. Cathepsin B + L activities also were reduced 33.6% (P less than .01) and shear forces were increased by 41% (P less than .05) by CIM feeding. For chickens fed CIM, the correlation between cathepsin B + L activity and shear force was -.63 (P less than .01). Feeding CIM improved carcass leanness and muscling due to reductions in FDR and proteolytic enzyme activity. Feeding CIM also reduced meat tenderness.

Administration, Oral↗
PubMed2000

Follow-up of GFR estimated from plasma creatinine after cimetidine administration in patients with diabetes mellitus type 2.

BACKGROUND: The glomerular filtration rate (GFR) can be estimated from plasma creatinine according to the formula of Cockcroft and Gault (CG). When tubular secretion of creatinine is inhibited by cimetidine the mean difference between the Cockcroft-Gault clearance (CG(Cim) and GFR approximates zero, but there is still some interindividual difference, especially in type-2-diabetic patients. We studied during longitudinal follow-up, whether the discrepancies between CG(Cim) and GFR per patient are consistent in time in type-2-diabetic patients. PATIENTS AND METHODS: In 1996 and 1998 (interval 20-26 months) GFR was measured in 21 patients as the urinary clearance of continuously infused 125I-iothalamate. Plasma creatinine was analyzed with an enzymatic assay before and after oral cimetidine 800 mg t.i.d. during 24 hours. GFR estimations were calculated with the Cockcroft-Gault formula before (CG) and after cimetidine (CG(Cim)) and expressed as means +/- SEM. RESULTS: GFR deteriorated from 89.7 +/- 5.7 to 81.3 + 5.8 ml/min/1.73 m2 and CG(Cim) from 85.3 +/- 5.7 to 81.1 +/- 6.6 ml/min/1.73 m2, whereas CG decreased from 102.4 +/- 6.8 to 98.4 +/- 7.0 ml/min/1.73 m2. Changes in GFR and changes in CG(Cim) were correlated (r = 0.72, p < 0.001) and were not significantly different from each other. The discrepancy between CG(Cim) and GFR per patient in 1996 also correlated with the discrepancy between CG(Cim) and GFR in 1998 (r = 0.85, p < 0.001 ). CONCLUSIONS: In individual patients the discrepancies between the CG(Cim) and GFR are consistent in time and the change in GFR is reflected by the change in CG(Cim). This small variability means that CG(Cim), based on an enzymatic plasma creatinine assay, would be suitable for follow-up of GFR in type-2-diabetic patients, independent of albuminuria.

Adult↗
PubMed1983

Pharmacokinetics of chlorimipramine and its demethylated metabolite in blood and brain regions of rats treated acutely and chronically with chlorimipramine.

The pharmacokinetic profiles for chlorimipramine (CIM) and its demethylated metabolite desmethylchlorimipramine (DCIM) in blood and in specific brain regions were obtained in rats after acute or chronic treatment with 15 mg/kg of the tricyclic antidepressant CIM. In blood, chronic drug treatment resulted in 1) a decrease in the time to maximal concentration of DCIM; 2) increases in maximal concentrations of CIM and of DCIM; and 3) a decrease in T1/2 of elimination of both CIM and DCIM. These changes induced a small reduction in the area under the CIM curve and a 4-fold increase in the area under the DCIM curve. In brain, both CIM and DCIM were unevenly distributed after both treatment schedules. Maximal accumulations of CIM and DCIM elimination were greatly enhanced in all brain areas by the chronic treatment. In brain, the area under the CIM concentration-time curve was only slightly affected by the chronic treatment, chronic drug treatment induced a 4-fold increase in the DCIM area. The subcellular distribution of CIM and DCIM in brain was similar in the acutely and chronically treated animals. The highest specific activity was found in the soluble fraction. These results demonstrate 1) regional brain differences in CIM and DCIM distribution and accumulation; 2) differences in pharmacokinetics between acute and chronic tricyclic antidepressant drug treatment regimens; and 3) differences between blood and brain drug and metabolite pharmacokinetics were observed which suggest that generalizations based on blood parameters should be made with great caution.

Animals↗
PubMed1999

A prospective study of cutaneous intolerance to topical mechlorethamine therapy in patients with cutaneous T-cell lymphomas. French Study Group of Cutaneous Lymphomas.

OBJECTIVE: To study the exact frequency and the histological features of cutaneous intolerance to mechlorethamine (CIM) hydrochloride therapy in patients with cutaneous T-cell lymphomas, including Langerhans cell histiocytosis. DESIGN: A multicenter prospective study was conducted from January 1, 1994, to May 31, 1996, in 12 different hospitals in France. PATIENTS: Of the 52 patients with cutaneous T-cell lymphomas or Langerhans cell histiocytosis, 35 were men and 17 were women, aged 18 to 87 years. Of the 52 patients, 35 had mycosis fungoides, 8 had nonepidermotropic cutaneous lymphoma, 7 had lymphomatoid papulosis, 1 had Sézary syndrome, and 1 had Langerhans cell histiocytosis. METHODS: Patients were treated with topical applications of a 0.02% aqueous solution of mechlorethamine. The diagnosis of CIM was determined by the presence of erythema and pruritus. Patients who developed CIM underwent closed patch testing with three 10-fold dilutions of 0.02% mechlorethamine solution. A positive patch test result was the presence of erythema and pruritus, a weak result was the presence of simple erythema without pruritus, and a negative result was the absence of erythema and pruritus. Skin biopsy specimens from patients with positive patch test results were obtained in patients who developed CIM. The biopsy specimens were reviewed, and the results determined by 2 pathologists (E.T. and J.W.). The histopathological findings were classified in 3 categories: (1) spongiotic dermatitis, (2) irritant dermatitis, and (3) insignificant or normal. In September 1998, the referring physicians were contacted if mechlorethamine therapy had been continued in patients with CIM. RESULTS: Of the 52 patients, 43 were evaluated for tolerance to mechlorethamine therapy. Of the 43 patients, CIM developed in 23, from 4 days to 9 months after the initiation of mechlorethamine therapy. Of those 23 patients, CIM developed within 3 months in 21 and within 1 month in 13. Closed patch tests were performed in 21 of the 23 patients who developed CIM. The results of the patch test were positive in 12, weak in 4, and negative in 5. Of these 21 patients, 14 skin biopsy specimens were obtained in 14 different patients who had positive or weak patch test results. The specimens showed histological features that were consistent with spongiotic dermatitis in 9 patients, irritant dermatitis in 2, and insignificant or normal in 3. All 9 patients with histological features of spongiotic dermatitis discontinued mechlorethamine therapy. All 5 patients without histological features of spongiotic dermatitis were able to resume mechlorethamine therapy. These results do not correlate with those of previous study results. CONCLUSIONS: Mechlorethamine therapy is a cost-effective and easily administered treatment for cutaneous T-cell lymphomas. Our study shows that allergic dermatitis caused by mechlorethamine therapy is an early and frequent adverse reaction in patients with cutaneous T-cell lymphomas. The most common histological feature of patients with CIM is spongiotic dermatitis.

Administration, Cutaneous↗
PubMed2004

Critical illness myopathy serum fractions affect membrane excitability and intracellular calcium release in mammalian skeletal muscle.

The pathogenesis of myopathies occurring in critically ill patients (critical illness myopathy, CIM) is poorly understood. Both local and systemic responses to sepsis and other severe insults to the body are presumed to be involved but the precise mechanisms by which muscle function is impaired are far from clear. To elucidate such mechanisms we investigated the effects of blood serum fractions (5 kDa to 100 kDa molecular weight cut-off, MWCO) from patients with CIM and from control persons on membrane and contractile functions in intact mammalian single skeletal muscle fibres and chemically skinned fibre bundles. In intact fibres, resting membrane potentials were less negative when exposed to CIM serum fractions compared with control serum fractions. Half-width and maximum rise time of action potentials (AP) were smaller in CIM serum low MWCO fractions vs. control serum. Peak amplitudes of fast inward sodium currents (I(Na)) were increased by low MWCO-CIM fractions compared with control sera fractions. Additionally, voltage dependent inactivation of I(Na) was shifted towards more positive potentials by high MWCO fractions of CIM sera. In skinned fibres, pCa-force relations were similar in CIM and control serum fractions but peak force of Ca2+ induced force transients was decreased by low MWCO-CIM vs. control serum fractions. Our results (i) provide the first evidence that serum from CIM patients affects membrane excitability and the excitation-contraction coupling process at the level of the sarcoplasmic reticulum Ca2+ release of mammalian muscle fibres and (ii) also show that even control serum fractions "per se" alter the response to important physiological membrane and contractility parameters compared with physiological saline.

Animals↗