Selective endothelin B receptor blockade does not influence BNP-induced natriuresis in man

Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) both exhibit natriuretic activity within the human kidney. Furthermore, they both act partly through activation of the endothelial nitric oxide pathway. Since ET-1 may cause vasodilation and natriuresis via stimulation of the ET-B receptor, the aim of the present study was to investigate whether renal ET-B receptors participate in the renal actions of BNP. In this placebo-controlled, crossover study, we infused BNP (4 pmol/kg/min) or placebo (i.v.) for 1 h, with or without co-infusion of the ET-B receptor antagonist BQ-788 (50 nmol/min) for 15 min on 4 separate days, in 10 healthy subjects (mean age 54+/-6 years.). During infusion, we measured effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) using PAH/inulin clearance. Cardiac output was measured before and after infusion, using echocardiography. Blood pressure and heart rate (HR) were monitored as well. Urine and plasma samples were taken every hour to measure diuresis, natriuresis, cyclic 3',5' guanosine monophosphate, and ET-1 levels. BNP with or without ET-B receptor blockade increased natriuresis and diuresis. In addition, BNP alone increased GFR and filtered load, without changing ERPF. BQ-788 infusion did not affect renal hemodynamics or natriuresis. Neither BNP nor BQ-788 altered cardiac output, blood pressure, and heart rate. In conclusion, the present study shows that selective ET-B receptor blockade has no effect on the BNP-induced natriuresis and glomerular filtration rate.     

Electron beam sterilization does not have a detrimental effect on the ability of extracellular matrix scaffolds to support in vivo ligament healing

Extracellular matrix (ECM) scaffolds have been used to enhance anterior cruciate ligament (ACL) repair in large animal models. To translate this technology to clinical care, identifying a method which effectively sterilizes the material without significantly impairing in vivo function is desirable. Sixteen Yorkshire pigs underwent ACL transection and were randomly assigned to bridge‐enhanced ACL repair—primary suture repair of the ACL with addition of autologous blood soaked ECM scaffold—with either (i) an aseptically processed ECM scaffold, or (ii) an electron beam irradiated ECM scaffold. Primary outcome measures included sterility of the scaffold and biomechanical properties of the scaffold itself and the repaired ligament at 8 weeks after surgery. Scaffolds treated with 15 kGy electron beam irradiation had no bacterial or fungal growth noted, while aseptically processed scaffolds had bacterial growth in all tested samples. The mean biomechanical properties of the scaffold and healing ligament were lower in the electron beam group; however, differences were not statistically significant. Electron beam irradiation was able to effectively sterilize the scaffolds. In addition, this technique had only a minimal impact on the in vivo function of the scaffolds when used for ligament healing in the porcine model. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1015–1023, 2015.     

Preoperative epidural ketamine in combination with morphine does not have a clinically relevant intra- and postoperative opioid-sparing effect

In this prospective, randomized, and double-blinded clinical trial, we evaluated the efficacy of preincisional administration of epidural ketamine with morphine compared with epidural morphine alone for postoperative pain relief after major upper-abdominal surgery. We studied 50 ASA I and II patients undergoing major upper-abdominal procedures. These patients were randomly allocated to one of the two treatment groups: patients in Group 1 received epidural morphine 50 microg/kg, whereas those in Group 2 received epidural ketamine 1 mg/kg combined with 50 microg/kg of morphine 30 min before incision. Intraoperative analgesia was provided in addition, with IV morphine, and the requirement was noted. A blinded observer using a visual analog scale for pain assessment observed patients for 48 h after surgery. Additional doses of epidural morphine were provided when the visual analog scale score was more than 4. Analgesic requirements and side effects were compared between the two groups. There were no differences between the two groups with respect to age, sex, weight, or duration or type of the surgical procedures. The intraoperative morphine requirement was significantly (P = 0.018) less in Group 2 patients (median, 6.8 mg; range, 3-15 mg) compared with patients in Group 1 (median, 8.3 mg; range, 4.5-15 mg). The time for the first requirement of analgesia was significantly (P = 0.021) longer (median, 17 h; range, 10-48 h) in Group 2 patients than in Group 1 (median, 12 h; range, 4-36 h). The total number of supplemental doses of epidural morphine required in the first 48 h after surgery was comparable (P = 0.1977) in both groups. Sedation scores were similar in both groups. One patient in Group 2 developed hallucinations after study drug administration. None of the patients in either group developed respiratory depression. Other side effects, such as pruritus, nausea, and vomiting, were also similar in both groups. Although the addition of ketamine had synergistic analgesic effects with morphine (reduced intraoperative morphine consumption and prolonged time for first requirement of analgesia), there was no long- lasting preemptive benefit seen with this combination (in terms of reduction in supplemental analgesia) for patients undergoing major upper-abdominal procedures. IMPLICATIONS: Ketamine added to epidural morphine given before surgery can decrease postoperative pain by its preemptive effect, opioid potentiation, and prevention of acute opioid tolerance. A single epidural bolus of 1 mg/kg of ketamine with morphine given before major upper-abdominal surgery did not result in a clinically relevant reduction in postoperative pain relief.     

Indomethacin does not inhibit the anabolic effect of parathyroid hormone on the long bones of rats

Summary Chronic administration of parathyroid hormone, hPTH 1-34, increased bone mass in normocalcemic, young rats [6]. Since PTH can stimulate prostaglandin E₂ (PGE₂) production in bonein vitro, and since PGE₂ can stimulate bone formation, the anabolic effect of PTH could be mediated by PGE₂. To test this hypothesis, experiments were done to determine if indomethacin, which blocks endogeneous PG production, would inhibit the anabolic response of bone to PTH. In the first experiment, male Sprague-Dawley rats, 70–100 g, in groups of five, were treated for 12 days with either hPTH 1-34, 8 μg/100g/day; PTH vehicle; indomethacin, 2 mg/kg/day; or a combination of PTH and indomethacin. In the second experiment, groups of 6 rats each were given vehicle or hPTH 1-34, 8 μg/100g/day, in combination with indomethacin, 0, 1, 2, or 4 mg/kg/day. Subcutaneous injections of PTH were given once daily and indomethacin was given orally in divided doses, twice a day. Rats were killed on day 12 in both experiments; their sera were analyzed and the trabecular and cortical bone of distal femurs processed to determine calcium (Ca) and hydroxyproline content and dry weight. PTH and indomethacin had no significant effect on serum Ca, phosphate, alkaline phosphatase, urea nitrogen and creatinine, or systemic and long-bone linear growth. In rats treated with PTH alone or in combination with indomethacin, bone Ca of distal femurs increased by 28–44%; dry weight by 29–41%, and hydroxyproline by 17–45%. Indomethacin alone had no effect on bone growth. Since indomethacin did not block the anabolic effect of hPTH 1-34, we concluded that the anabolic effect of PGHin vivo was unlikely to be mediated by prostaglandins.     

Blood transfusion does not have an adverse effect on survival after operation for colorectal cancer.

The effect of perioperative blood transfusion on cancer progression remains controversial because retrospective clinical studies have produced conflicting results. We have collected data prospectively on 379 patients undergoing curative surgery for colorectal adenocarcinoma and assessed the effect of variables, including blood transfusion, on survival. Univariate and multivariate survival analysis has been carried out. When the end-point for analysis used was death due to recurrent colorectal carcinoma and non-cancer deaths were censored, there was no difference in cancer-specific survival between transfused and non-transfused patients. Survival analysis was also carried out without censoring the non-cancer deaths and clearly demonstrated how the statistical analysis and data interpretation could be distorted by age-related non-cancer deaths. The incidence of recurrence of colorectal carcinoma was not greater in the transfused group than in the non-transfused group. We conclude that blood transfusion should not be withheld in colorectal surgery for fear of worsening the prognosis.     

Memory enhancing effect of low-dose sevoflurane does not occur in basolateral amygdala-lesioned rats

BACKGROUND: Certain anesthetics might enhance aversive memory at doses around 0.1 minimum alveolar concentration. This issue was investigated in a rat model of learning and memory. In addition, evidence for basolateral amygdala (BLA) involvement in mediating memory enhancement was sought. METHODS: First, the memory-enhancing potential of various anesthetics was determined. Rats underwent single-trial inhibitory avoidance training (0.3 mA shock/1 s) during exposure to air, 0.11% sevoflurane, 0.10% halothane, 0.77% desflurane, or 0.12% isoflurane. Memory was assessed at 24 h. Second, the BLA contribution to sevoflurane memory enhancement was determined. Rats received bilateral excitotoxic N-methyl-D-aspartate (12.5 mg in 0.2 microl per BLA) lesions of the BLA 1 week before training. Memory of lesioned and control rats was compared 24 h after training in air or sevoflurane. RESULTS: Sevoflurane exposure during training significantly enhanced 24-h retention performance for both nonoperated and sham-operated rats (P < 0.005 for both vs. their respective controls). Halothane, but not desflurane or isoflurane, also enhanced retention performance (P < 0.05). However, halothane-induced hyperalgesia during learning clouds interpreting enhanced retention performance solely as a memory consolidation effect. BLA lesions significantly reduced and equalized retention performance for both sevoflurane- and air-exposed animals. Lesions blocked memory enhancement without also causing a generalized inability to learn, because additional training revealed essentially normal task acquisition and 24-h memory. CONCLUSIONS: Sevoflurane enhances aversive memory formation in the rat. The BLA likely contributes to this effect. The risk of aversive memory formation may be enhanced during exposure to low-dose sevoflurane.     

Dapoxetine, a novel treatment for premature ejaculation, does not have pharmacokinetic interactions with phosphodiesterase-5 inhibitors

Potential pharmacokinetic interactions between dapoxetine, a serotonin transporter inhibitor developed for the treatment of premature ejaculation (PE), and the phosphodiesterase-5 inhibitors tadalafil and sildenafil, agents used in the treatment of erectile dysfunction (ED), were investigated in an open-label, randomized, crossover study (n=24 men) comparing dapoxetine 60 mg, dapoxetine 60 mg+tadalafil 20 mg, and dapoxetine 60 mg+sildenafil 100 mg. Plasma concentrations of dapoxetine, tadalafil, and sildenafil were determined by liquid chromatography-tandem mass spectrometry. Tadalafil did not affect the pharmacokinetics of dapoxetine, whereas sildenafil increased the dapoxetine AUCinf by 22%; these effects were deemed not clinically important. Dapoxetine did not appear to affect the pharmacokinetics of tadalafil or sildenafil. Most adverse events were mild in nature. Thus, dapoxetine has no clinically important pharmacokinetic interactions with tadalafil or sildenafil, and the combinations are well tolerated.     

Glutamate does not play a major role in controlling bone growth.

Bone cells express glutamate-gated Ca2+-permeable N-methyl-D-aspartate (NMDA) receptors and GLAST glutamate transporters. Blocking NMDA receptors has been reported to reduce the number of bone resorption pits produced by osteoclasts, and mechanical loading alters GLAST transporter expression, which should change the extracellular glutamate concentration and NMDA receptor activation. Thus, by analogy with the brain, glutamate is postulated to be an important intercellular messenger in bone, controlling bone formation and resorption. We found that activating or blocking NMDA receptors had no effect on bone formation by rat osteoblasts in culture. The number of resorption pits produced by osteoclasts was reduced by the NMDA receptor blocker MK-801 but not by another blocker AP-5, implying that this effect of MK-801 is unrelated to its glutamate-blocking action. By contrast, MK-801, AP-5, and NMDA had no consistent effect on the volume of pits. In mice with GLAST glutamate transporters knocked out, no differences were detected in mandible and long bone size, morphology, trabeculation, regions of muscle attachment, resorption lacunae, or areas of formation versus resorption of bone, compared with wild-type siblings. These data suggest that glutamate does not play a major role in controlling bone growth.     

Circumcision does not have effect on premature ejaculation: A systematic review and meta‐analysis

We attempted to evaluate whether circumcision has an effect on premature ejaculation. We searched three databases: PubMed, EMBASE and Google scholar on 1 May 2016 for eligible studies that referred to male sexual function after circumcision. No language restrictions were imposed. The Cochrane Collaboration's RevMan 5.2 software was employed for data analysis, and the fixed or the random‐effect model was selected depending on the heterogeneity. Twelve studies were included in the meta‐analysis, containing a total of 10019 circumcised and 11570 uncircumcised men. All studies were divided into five subgroups by types of study design to evaluate the effect of circumcision on premature ejaculation (PE). Intravaginal ejaculation latency time (IELT), difficulty of orgasm, erectile dysfunction (ED) and pain during intercourse were also assessed because PE was usually discussed along with these subjects. There were no significant differences in PE (odds ratio [OR], 0.90; 95% confidence interval (CI), 0.72‐1.13; p = .37) and orgasm (OR, 1.04; 95% CI, 0.89‐1.21; p = .65) between circumcised and uncircumcised group. However, IELT (OR, 0.72; 95% CI, 0.60‐0.83; p < .00001), ED (OR, 0.42;95% CI, 0.22‐0.78; p = .40) and pain during intercourse (OR, 0.36; 95% CI, 0.17‐0.76; p = .007) favoured circumcised group. Based on these findings, circumcision does not have effect on PE.     

Simultaneous removal of liver and pancreas does not have an effect on results of transplantation of these organs

In a retrospective clinical study we compared the outcome after pancreas and liver transplantation when both organs were retrieved from the same donor to the outcome when only one or the other organ was retrieved. The results in this article demonstrate that simultaneous procurement of liver and pancreas grafts has no detrimental effect on the rate of technical failures, or allograft or patient survival after either pancreas or liver transplantation.     

The endothelin receptor antagonist, L-754,142 does not prevent cyclosporine a-induced osteopenia in rats

Cyclosporine A (CsA) is a potent immunosuppressive agent widely used to prevent allograft rejection.In vivo administration of CsA is associated with the development of high-turnover osteopenia. Endothelin-1 (ET), a vasoconstrictive peptide, has been implicated in CsA-induced nephrotoxicty and hypertension. Recent evidence suggests that endothelin plays a pivotal role in bone metabolism. The present study was designed to investigate whether L-754,142 (ETRA), the combined endothelin A and B receptor antagonist, when given to rats, would favorably modify the bone loss caused by CsA. Fifty, 5-month-old male Sprague-Dawley rats were randomly divided into five groups of 10 rats each. The first group served as a basal control. The remaining four groups received, by daily gavage for 28 days, (1) a combined CsA and ETRA vehicle, (2) CsA, 10 mg/kg, (3) ETRA, 30 mg/kg, and (4) CsA, 10 mg/kg and ETRA, 30 mg/kg, respectively. Rats were weighed and venous blood was collected on days 0, 14, 28 for determination of BUN, creatinine, calcium, PTH, osteocalcin, and 1,25(OH)₂D. Tibiae, after double labeling, were removed following sacrifice for histomorphometry. Both CsA-treated rats and CsA/ETRA-treated rats demonstrated trabecular osteopenia with raised serum osteocalcin, and 1,25(OH)₂D levels when compared to control animals (P<0.05). Rats given CsA alone developed renal impairment, as shown by an increased BUN. The combination group did not develop renal impairment. The results suggest that endothelin may contribute to the development of CsA-induced nephrotoxicity, which was prevented by ETRA, but does not seem to play a role in CsA-induced osteopenia.     

Bradykinin B2, but not B1, receptor antagonism has a neuroprotective effect after brain injury.

The aim of the present study was to measure the therapeutic effects of bradykinin antagonists on lesion volume and brain swelling induced by cold injury in the parietal cortex of rat and mouse, respectively. Cold lesion was induced by application of a precooled (-78 degrees C) copper cylinder (3 mm diameter) to the intact dura of rat and mouse for 6 and 30 sec, respectively. At 24 h after the injury, the brains were removed and lesion volume was determined by the triphenyltetrazolium chloride method in rats. In the mouse, brain swelling was expressed as percentage increase in weight of the injured hemisphere which is compared to the contralateral side. After a subcutaneous priming dose of 18 microg/kg, a 1-h pretreatment and 24-h posttreatment using osmotic minipumps (300 ng/kg x min) was applied. Hoe140, a bradykinin receptor 2 antagonist, revealed a 19% reduction of lesion volume (p < 0.05) in the rat and a 14% diminution of brain swelling (p < 0.05) in the mouse. In contrast, the bradykinin receptor 1 antagonist, B 9858, had no effect on lesion volume compared to sham treated rats. When B 9858 was given in combination with Hoe140, a significant reduction in lesion volume was seen which was equivalent to and not different from that seen with Hoe140 alone in the rat. We conclude that brain injury after cold lesion is partially mediated by bradykinin and can be successfully treated with B2 antagonists.     

Midazolam does not potentiate the effect of vecuronium in patients

Reports of midazolam interaction with vecuronium in animals prompted us to compare midazolam (0.25 mg kg-1) with thiopentone (5 mg kg-1) for possible interactions with vecuronium in patients, when used for induction of anaesthesia. After the administration of either of the two induction agents, the patients received vecuronium 0.1 mg kg-1. The onset time, duration of action and 25-75% recovery index of the neuromuscular blockade were recorded by measuring the force of thumb adduction evoked by ulnar nerve stimulation. We found no differences between patients receiving either midazolam or thiopentone in their response to vecuronium. In three of the ten patients receiving midazolam, the injection of this drug produced a 8-29% reduction of the initial twitch height.     

Patent foramen ovale does not have a negative impact on early outcomes in patients undergoing liver transplantation

Alba AC, Verocai Flaman F, Granton J, Delgado DH. Patent foramen ovale does not have a negative impact on early outcomes in patients undergoing liver transplantation.
Clin Transplant 2011: 25: 151–155. © 2010 John Wiley & Sons A/S. Abstract: Objective: To identify the impact of the presence of patent foramen ovale (PFO) in patients undergoing liver transplantation. Methods: Twenty‐seven pre‐liver transplant patients who had a PFO (PFO group) were identified and compared with 61 patients without PFO (NoPFO group). Patients were matched according to age, gender and cause of liver disease. The diagnosis of PFO was made by transthoracic echocardiography prior to liver transplantation. Patient baseline characteristics and complications during the early post‐transplant period were analyzed. Results: The mean age in the PFO group was 47 ± 14 (range 18–68) yr and 50 ± 11 (range 12–65) yr in the NoPFO group. The PFO group had a mean model for end‐stage liver disease (MELD) score of 15 ± 10 whereas in the NoPFO group the MELD score was 19 ± 10 (p = 0.08). There were non‐significant differences in echocardiographic parameters between groups. Duration of mechanical ventilation and the incidence of neurological complications were similar. Thirty‐day mortality rate was similar in both groups; only one patient in the NoPFO group died within the first 30 days post‐transplantation. Conclusions: The presence of PFO in patients with end‐stage liver disease undergoing liver transplantation does not appear to affect patient outcomes during the peri‐operative period.     

Hypothalamic neuropeptide Y (NPY) controls hepatic VLDL-triglyceride secretion in rats via the sympathetic nervous system

Excessive secretion of triglyceride-rich very low-density lipoproteins (VLDL-TG) contributes to diabetic dyslipidemia. Earlier studies have indicated a possible role for the hypothalamus and autonomic nervous system in the regulation of VLDL-TG. In the current study, we investigated whether the autonomic nervous system and hypothalamic neuropeptide Y (NPY) release during fasting regulates hepatic VLDL-TG secretion. We report that, in fasted rats, an intact hypothalamic arcuate nucleus and hepatic sympathetic innervation are necessary to maintain VLDL-TG secretion. Furthermore, the hepatic sympathetic innervation is necessary to mediate the stimulatory effect of intracerebroventricular administration of NPY on VLDL-TG secretion. Since the intracerebroventricular administration of NPY increases VLDL-TG secretion by the liver without affecting lipolysis, its effect on lipid metabolism appears to be selective to the liver. Together, our findings indicate that the increased release of NPY during fasting stimulates the sympathetic nervous system to maintain VLDL-TG secretion at a postprandial level.     

Ondansetron does not inhibit the analgesic effect of alfentanil

5-Hydroxytryptamine (5-HT) causes antinociception via presynaptic5-HT₃ (5-HT subtype 3) receptors on primary afferent nociceptiveneurones in the spinal cord dorsal horn. Therefore, ondansetron(a 5-HT₃ receptor antagonist) may increase the perception ofa noxious stimulus or decrease the effects of concurrently administeredantinociceptive drugs. Using a randomized, doubleblind, crossoverstudy design, we have tested this hypothesis in eight healthyvolunteers who, on three different days, received either ondansetronand placebo, ondansetron and alfentanil or placebo and alfentanil.Experimental pain was induced with heat, cold, mechanical pressureand electrical stimulation. Ondansetron alone did not changethe response to any of the experimental tests, but alfentaniland the combination ondansetron- alfentanil significantly changedthe response compared with ondansetron alone. There was no differencebetween alfentanil alone and the combination ondansetron-alfentanil.We conclude that ondansetron does not change the response topressure, heat, cold or electrical nociceptive stimuli or antagonizethe analgesic effect of alfentanil.