Cimetidine does not impair pulmonary clearance ofPseudomonas aeruginosa in normal rats

Histamine (H₂) -receptor blockers are commonly used in critically ill patients to prevent gastric bleeding and have been implicated in the pathogenesis of gram-negative bacterial (GNB) nosocomial pneumonia. These experiments were undertaken to determine if cimetidine affects pulmonary GNB clearance. Groups of normal Sprague-Dawley rats were given cimetidine (75 mg/kg) or an equal volume of sterile buffer intraperitoneally every 6 hr for 24 hr prior to intratracheal challenge with 1.0 × 10⁸ Pseudomonas aeruginosa. At 6 and 24 hr after challenge, animals were sacrificed and gastric pH, quantitative lung cultures, and total and differential [alveolar macrophages (AM) and polymorphonuclear leukocytes (PMN)] cell counts in bronchoalveolar lavage fluid were performed. Results showed that cimetidine therapy resulting in gastric pH greater than 4.0 has no effect on the pulmonary clearance ofP. aeruginosa.Supported in part by SmithKline Beecham Laboratories, Philadelphia, Pennsylvania.     

Sorbinil does not prevent hyperfiltration,elevated ultrafiltration pressure and albuminuria in streptozotocin-diabetic rats

Summary The effects of aldose reductase inhibition on kidney function were studied in rats with streptozotocin-induced diabetes mellitus. Diabetic rats were fed sorbinil (20 and 50 mg/kg) by daily gastric gavage and were compared with untreated diabetic rats and normal rats. The rats were under daily supervision with regard to blood glucose control, insulin administration and body weight. The aim was to promote continuous body growth and to maintain the blood glucose concentration at around 22 mmol/l without large day-to-day fluctuations. The renal functional changes observed in this well-established diabetic model closely resembled those reported in human Type 1 (insulin-dependent) diabetes mellitus. Sorbinil treatment completely prevented renal cortical sorbitol accumulation, but did not abolish kidney enlargement or the increase in ultrafiltration pressure and glomerular filtration rate. Albumin excretion was increased to the same extent in the sorbinil-treated and in the untreated diabetic rats. We conclude that increased metabolism of glucose to sorbitol does not cause the hyperfiltration in rats with streptozotocin-induced diabetes.     

Acetaminophen does not impair clearance of zidovudine

OBJECTIVE: To determine whether concurrent treatment with acetaminophen and zidovudine impairs clearance of zidovudine, thereby increasing the risk for zidovudine-induced hematologic toxicity. DESIGN: Dose escalation, drug interaction study. SETTING: University clinical research center. PATIENTS: Patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. INTERVENTIONS: Acetaminophen and 200 mg of zidovudine simultaneously every 4 hours. For 13 patients, the unit dosage of acetaminophen was 325 mg for 3 days; for 8 patients, the dosage was 650 mg for 3 days; and, for 6 patients, the dosage was 650 mg for 7 days. MEASUREMENTS: Zidovudine clearance and production of the glucuronide conjugate of zidovudine were assessed after acetaminophen treatment. MAIN RESULTS: Neither zidovudine clearance nor production of the glucuronide conjugate of zidovudine was impaired after treatment with acetaminophen. Clearance of zidovudine was actually accelerated by 5%, 11%, and 33% with the three acetaminophen regimens, respectively (P = 0.002 by analysis of variance; P = 0.04 for linear trend when changes in the area-under-the-curve for zidovudine were compared). CONCLUSION: Because serum concentrations of zidovudine decrease after the coadministration of acetaminophen, a pharmacokinetic interaction between zidovudine and acetaminophen is unlikely to increase the risk for hematologic toxicity associated with zidovudine.     

Impaired glucose tolerance and mild hyperglycemia in sucrose-fed rats does not impair insulin secretion

We fed normal rats a high sucrose diet in order to test the hypothesis that mild hyperglycemia can induce defects in pancreatic beta-cell function and impair glucosestimulated insulin release. Rats provided with free access to a sucrose solution (35%) voluntarily consumed 50% more carbohydrate than control per day. After 7 days of sucrose feeding, glucose tolerance was significantly impaired; the area under the glucose tolerance test curve (GTT) was 683±61 mmol/120 min compared with 472±56 mmol/120 min in controls (P<0.05). Impaired glucose tolerance was still present after a further 12 days (area under the GTT: 749±99 mmol/120 min). Sucrosefed rats were significantly (P<0.05) hyperglycemic by 1.5 mmol/l over controls. When insulin secretion was assessed in vivo and in vitro in control and sucrose-fed rats, no significant differences were apparent in plasma samples collected over a 1-h period or in statically incubated or perifused isolated pancreatic islets. In addition, the rates of glucose utilisation and oxidation were normal in islets from sucrose-fed rats. These data do not support the hypothesis that minimal hyperglycemia is sufficient to impair glucose-stimulated insulin release.     

Cardiac transplantation does not effect ischaemia-induced arrhythmias in rats

OBJECTIVE: In many species arrhythmias induced by myocardial ischaemia appear to be in part dependent upon cardiac sympathetic nerves. However, previous experiments in rats did not suggest that myocardial or other catecholamines are involved in ischaemic arrhythmogenesis in this species. The aim of this study was to investigate this further using transplanted hearts. METHODS: We transplanted 'donated' hearts onto the abdominal aorta of recipient rats and, at varying periods after transplantation, subjected donated and recipient hearts to occlusion of the left anterior descending (LAD) coronary artery. Donated and recipient hearts were tested at various times after transplantation for responsiveness to drugs acting upon aspects of the autonomic nervous system. The intention of this latter study was to assess the status of innervation and receptors simultaneously in both donated and recipient hearts. RESULTS: Donated (transplanted) hearts showed responses consistent with denervation and receptor supersensitivity. Changes varied with the duration of the transplant. Over the same period recipient hearts did not change in responsiveness to drugs. When subjected to coronary artery occlusion, transplanted hearts responded to occlusion with the same frequency and severity of arrhythmias as recipient and other control hearts, regardless of the duration of transplant, or sensitivity to drugs. CONCLUSIONS: The results of these experiments suggest that cardiac innervation is not an important factor in the genesis of ischaemia-induced arrhythmias in rats.     

Cyclosporin treatment does not impair the release of nitric oxide in human coronary arteries.

OBJECTIVE--It has been hypothesised that compromised endothelial function can contribute to the toxic manifestations associated with cyclosporin therapy. In vitro animal studies have implicated inhibition of release of the endothelium derived relaxing factor, nitric oxide; however, this has not been investigated in human tissue. The present study investigated the effect of cyclosporin A on nitric oxide release in human coronary arteries. DESIGN--Study of in vitro organ bath preparations and in vivo angiographic measurements in the coronary circulation. PATIENTS--For the in vitro experiments coronary arteries were harvested from the excised hearts of 10 patients requiring transplantation for reasons other than ischaemic heart disease. Three of these patients were being re-transplanted for obliterative bronchiolitis and had been receiving cyclosporin for a mean of 22 months. The in vivo study was performed on a group of 12 cardiac transplant recipients who were clinically well 1-5 years postoperatively and were not undergoing allograft rejection at the time of assessment. RESULTS--Isolated vessel segments in vitro relaxed in a dose dependent manner in response to substance P (10(-11)-10(-7) mol/l). The maximum response was 76.6 (7.4)% of the response to 1 microgram/ml glyceryl trinitrate. Incubation with 1000 and 2000 ng/ml cyclosporin reduced the response to 63.0 (11.5)% and 62.2 (11.1)% respectively; this was not statistically significant. In segments taken from the explanted hearts of three patients requiring re-transplantation, the mean maximum response was 78.0 (11.0)% and there was no correlation between maximum response in segments from each patient and the duration of cyclosporin therapy. The effect of intracoronary substance P in 12 cardiac transplant recipients was also examined (mean cyclosporin blood concentration 228.9 (42.8) ng/ml). The mean maximum dilatations measured as the percentage diameter change induced by substance P and isosorbide dinitrate were 22.1 (3.2)% and 26.0 (2.5)% respectively. There was no correlation between the degree of endothelium mediated vasodilatation in response to substance P and cyclosporin concentration. CONCLUSIONS--The nitric oxide response was preserved in the coronary arteries of patients exposed to cyclosporin. The mechanisms that initiate cyclosporin associated toxicity remain to be elucidated.     

Cyclosporin treatment does not impair the release of nitric oxide in human coronary arteries.

OBJECTIVE--It has been hypothesised that compromised endothelial function can contribute to the toxic manifestations associated with cyclosporin therapy. In vitro animal studies have implicated inhibition of release of the endothelium derived relaxing factor, nitric oxide; however, this has not been investigated in human tissue. The present study investigated the effect of cyclosporin A on nitric oxide release in human coronary arteries. DESIGN--Study of in vitro organ bath preparations and in vivo angiographic measurements in the coronary circulation. PATIENTS--For the in vitro experiments coronary arteries were harvested from the excised hearts of 10 patients requiring transplantation for reasons other than ischaemic heart disease. Three of these patients were being re-transplanted for obliterative bronchiolitis and had been receiving cyclosporin for a mean of 22 months. The in vivo study was performed on a group of 12 cardiac transplant recipients who were clinically well 1-5 years postoperatively and were not undergoing allograft rejection at the time of assessment. RESULTS--Isolated vessel segments in vitro relaxed in a dose dependent manner in response to substance P (10(-11)-10(-7) mol/l). The maximum response was 76.6 (7.4)% of the response to 1 microgram/ml glyceryl trinitrate. Incubation with 1000 and 2000 ng/ml cyclosporin reduced the response to 63.0 (11.5)% and 62.2 (11.1)% respectively; this was not statistically significant. In segments taken from the explanted hearts of three patients requiring re-transplantation, the mean maximum response was 78.0 (11.0)% and there was no correlation between maximum response in segments from each patient and the duration of cyclosporin therapy. The effect of intracoronary substance P in 12 cardiac transplant recipients was also examined (mean cyclosporin blood concentration 228.9 (42.8) ng/ml). The mean maximum dilatations measured as the percentage diameter change induced by substance P and isosorbide dinitrate were 22.1 (3.2)% and 26.0 (2.5)% respectively. There was no correlation between the degree of endothelium mediated vasodilatation in response to substance P and cyclosporin concentration. CONCLUSIONS--The nitric oxide response was preserved in the coronary arteries of patients exposed to cyclosporin. The mechanisms that initiate cyclosporin associated toxicity remain to be elucidated.     

Acute diabetes mellitus does not impair survival rate in rats submitted to left coronary artery ligation

This study was designed to assess whether the acute metabolic disturbances associated with diabetes mellitus of three-days duration could influence the survival of rats submitted to experimental myocardial infarction. Diabetes was induced with streptozotocin (50 mg/kg) in male Wistar rats and three days later left coronary artery ligation was performed in both control (n = 34) and diabetic (n = 31) animals. Diabetic rats had significant alterations in plasma levels of glucose (424 +/- 6 vs 143 +/- 3 mg/dL; p less than 0.001), insulin (10 +/- 1 vs 32 +/- 2 microU/mL; p less than 0.001) and free carnitine (37 +/- 2 vs 52 +/- 2 microM; p less than 0.001). There was no significant difference in the survival rate of diabetic animals, either early after coronary artery ligation (32 vs 42% at 20 min; p greater than 0.1) or later (21 vs 25% at 1 week; p greater than 0.1). This suggests that the increased mortality rate found in diabetic subjects suffering from myocardial infarction is due to some long-term changes associated with chronic diabetes mellitus rather than to the acute metabolic disturbances present at the time of this event.     

Cimetidine does not impair lung host defense in experimental pneumococcal pneumonia

Normal CD-1 mice were administered cimetidine (400 mg/kg/24 h) or control solution by subcutaneous injection and inoculated intratracheally with type S Streptococcus pneumoniae in order to evaluate the effect of the histamine H2-receptor antagonist on pulmonary antibacterial mechanisms. Therapy with cimetidine did not influence overall survival rates. After challenge with 1 X 10(6) colony-forming units (cfu), the eradication of viable pneumococci from the lungs (pulmonary clearance), the generation of a local inflammatory response, and the prevalence of bacteremia were similar in both study groups. Cimetidine also failed to influence pulmonary antimicrobial systems after challenge with lower bacterial inocula (5 X 10(4) and 5 X 10(3) cfu). Further, treatment with cimetidine had no effect on the in vivo phagocytic or bactericidal activity of resident murine alveolar macrophages. Thus, in this animal model, cimetidine does not disrupt host defenses of the lower respiratory tract.     

Beta-blockers do not impair the cardiovascular benefits of endurance training in hypertensives

Aerobic physical exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension. Beta-blockade interacts with heart rate, sympathetic tone, maximal workload and local lactate production. In the present randomized-controlled study, we compared the cardiovascular effects of an endurance training programme in elderly hypertensives with or without beta-blockers and developed a first approach to determine a lactate-based training heart rate in presence of beta-blockade. Fifty-two patients (23 with beta-blocker, 29 without beta-blocker) > or =60 years with systolic 24-h ambulatory blood pressure (ABP) > or =140 mm Hg and/or antihypertensive treatment were randomly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme (lactate 2.0 mmol/l). In the exercise group, the training significantly decreased systolic and diastolic 24-h ABP, blood pressure on exertion (100 W) and increased endothelium-dependent vasodilation (flow-mediated vasodilation, FMD) and physical performance both in the presence and absence of beta-blockade (P<0.05 each). The extent of ABP reduction did not significantly differ in the presence or absence of beta-blockade (Delta systolic ABP 10.6+/-10.5 vs 10.6+/-8.8 mm Hg, Delta diastolic ABP 5.7+/-8.6 vs 5.8+/-4.0 mm Hg). Mean training heart rate was significantly lower in the patients on beta-blockers (97.2+/-7.7 vs 118.3+/-7.5/min, P<0.001). Lactate-based aerobic endurance training evokes comparable cardiovascular benefits in the presence and absence of beta-blockade including a marked improvement of endothelial function. In the present study, target training heart rate with beta-blockers is about 18% lower than without.     

Beta-adrenergic agonism does not impair the GH response to acylated ghrelin in humans

Background  Acylated ghrelin (AG) is a physiological GH secretion amplifier, in part stimulating GHRH neurones and antagonizing somatostatin activity. In humans, AG is one of the most potent pharmacological stimuli of GH secretion and, unlike GHRH, is refractory to the inhibitory effect of glucose, free fatty acids (FFA) and somatostatin. Somatotroph secretion is also profoundly modulated by the adrenergic system. Indeed, beta-adrenergic agonists abolish spontaneous and GHRH-stimulated GH secretion. Based on these data, the aim of the present study was to investigate the effects of beta adrenergic agonism on the GH response to AG.
Subjects and measurements  Six young healthy male volunteers underwent: (a) acute AG intravenous (iv) administration (1·0 µg/kg); (b) salbutamol infusion (SLB; 0·06 µg/kg/min iv); (c) AG + SLB; and (d) saline infusion. In all sessions GH levels were assayed every 15 min from time –30 to +210 min.
Results  SLB induced a significant ( P <  0·05) inhibition of spontaneous GH secretion that persisted up to 75 min after SLB withdrawal. AG induced a marked increase ( P <  0·01) in GH that was not modified by SLB.
Conclusions  The GH-releasing effect of AG is refractory to the inhibitory effect of SLB-induced beta-adrenergic receptor activation. Although further studies are needed to confirm these results during the lifespan and particularly during prolonged exposure to beta agonists, the present data clearly suggest that, among GH stimulatory tests, AG administration might be the most suitable in clinical conditions of chronic treatment with beta-2 agonists, such as in asthmatic disease.     

Regular use of pedometer does not enhance beneficial outcomes in a physical activity intervention study in type 2 diabetes mellitus

The aim of the present study was to investigate whether the use of pedometer increases walking and/or enhances beneficial outcomes in a physical intervention study in type 2 diabetes mellitus. Seventy persons with type 2 diabetes mellitus were randomized to a pedometer and a nonpedometer group (P and non-P groups). All participants were seen by a nurse at a baseline visit (V1), after 1 month, after 3 months, and after 6 months and were then encouraged to increase walking. Subjects in the P group additionally registered pedometer steps 3 days twice per month for 6 months. After V1 and the visit at 6 months, aerobic capacity (VO2peak) was measured; and subjects reported perceived physical fitness and activity. Twenty-two subjects did not complete the study (dropouts). The VO2peak at V1 was lower in dropouts than in subjects who completed the study (completers) (P=.003). In the P group, the number of steps per day did not increase from month 1 to month 6 (P=.65). In completers, taken together, there was a decrease in body weight (P=.005), hemoglobin A1c (P=.034), fasting blood glucose (P=.033), triglycerides (P=.002), and diastolic blood pressure (P=.048) and an increase in high-density lipoprotein cholesterol (P<.001), with no difference between the P group and non-P group for these variables (all P values>.38). Perceived improvement in physical and mental state correlated with improvement in VO2peak (r=0.45, P=.008 and r=0.38, P=.03, respectively; n=34). We conclude that the use of pedometer did not increase walking or enhance beneficial metabolic outcomes. The low aerobic capacity in dropouts indicates that persons most needy of physical exercise are the least compliant in exercise programs.     

Ileoanal-pouch reconstruction does not impair sphincter function or quality of life

BACKGROUND/AIMS: A retrospective trial with regard to continence function and quality of life was conducted in patients who had undergone proctocolectomy and ileo-anal-pouch (IAP) reconstruction for ulcerative colitis (UC) or familial polyposis (FAP), and continence function was compared to patients under conservative treatment for UC. The aim of the study was to evaluate, if proctocolectomy and IAP differed in quality of life and sphincter function from those patients with chronic UC who were not operated on. METHODOLOGY: 50 patients were included in this study: 25 patients had undergone proctocolectomy and ileo-pouch-anal-anastomosis (IPAA) for UC (n=13) or FAP (n=12). The control group included 25 patients under medical treatment for UC (n=25). Anal manometry was performed and quality of life questionnaires were evaluated. RESULTS: No significant differences in maximum basal and squeeze pressure were found. There was a significantly later pouch perception in the patient group (55mL in patients vs. 39mL in controls; p = 0.0054) as well as a significantly greater stool frequency (6 vs. 4 per day; p = 0.0018) and a shorter high pressure zone in the patients' group (25 mm vs. 35 mm; p < 0.0001). Patients demonstrated superior but not significantly better values for Gastrointestinal Quality of Life Score (GLQI) and Activity Index (AI). Furthermore, there was a significant negative correlation between perception values and GLQI (p = 0.014) and AI (p = 0.04) in this group, indicating that the later the perception the worse the Quality of Life and Activity Index. CONCLUSIONS: Proctocolectomy combined with IPAA neither deteriorates anorectal function nor quality of life compared to conservatively treated controls. These data support that prophylactic proctocolectomy in patients who are at high risk for the development of colorectal cancer can be performed at an early stage of the disease.     

Reduced myocardial flow reserve does not impair exercise capacity in asymptomatic men

We examined whether impaired coronary flow reserve in healthy men is associated with changes in cardiac performance and exercise-induced ischemia. A comparison between 7 asymptomatic men with low flow reserve (<3.5) and 8 men with normal flow reserve (>3.5) showed no differences in these parameters, suggesting that the mechanisms that control myocardial blood flow during exercise remain normal despite the alterations in the mechanisms that control the vasodilatory reaction to dipyridamole.     

Age does not impair the efficacy of immunochemotherapy in patients with metastatic renal carcinoma

PURPOSE: Based on the increasing proportion of elderly cancer patients, we compared the efficacy of subcutaneous cytokine based home therapy in older (age > or = 60 years) and younger (age < 60 years) patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: As a rule, patients at an age of 60 years or older received a 20% dose reduction of s.c. IL-2. Treatment consisted of (A) s.c. interferon-alpha2a (s.c. INF-alpha2a), s.c. interleukin-2 (s.c. IL-2), (B) s.c. IFN-alpha2a, s.c. IL-2 and i.v. 5-fluorouracil (5-FU) or (C) s.c. IFN-alpha2a, s.c. IL-2 and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (p.o. 13cRA). RESULTS: Patient age groups > or = 60 years (n=174) and < 60 years (n=251) showed no significant difference in objective response (27% versus 31%), in median overall survival (22 months versus 19 months), and in progression-free survival (6 months versus 5 months). Within the elderly patients group, median overall survival was 20 months (pts. 60-64 years) versus 23 months (pts. > or = 65 years) and median progression-free survival was 4 months (pts. 60-64 years) versus 8 months (pts. > or = 65 years). CONCLUSION: Our results demonstrated that patient age and related IL-2 dose reduction do not impair the efficacy of s.c.-IL-2 plus s.c.-INF-2a based outpatient immunochemotherapy in metastatic renal carcinoma.