Effect of Centhaquine on the Coagulation Cascade in Normal State and Uncontrolled Hemorrhage: A Multiphase Study Combining Ex Vivo and In Vivo Experiments in Different Species.

Centhaquine is a novel vasopressor acting on α2A- and α2B-adrenoreceptors, increasing venous return and improving tissue perfusion. We investigated the effects of centhaquine on blood coagulation in normal state and uncontrolled hemorrhage using ex vivo and in vivo experiments in different species. Thromboelastography (TEG) parameters included clotting time (R), clot kinetics [K and angle (α)], clot strength (MA), and percent lysis 30 min post-MA (LY30). In normal rat blood, centhaquine did not alter R, K, α, MA, or LY30 values of the normal vehicle group or the antithrombotic effects of aspirin and heparin. Subsequently, New Zealand white rabbits with uncontrolled hemorrhage were assigned to three resuscitation groups: Sal-MAP 45 group (normal saline to maintain a mean arterial pressure, MAP, of 45 mmHg), Centh-MAP 45 group (0.05 mg kg-1 centhaquine plus normal saline to maintain a MAP of 45 mmHg), and Sal-MAP 60 group (normal saline to maintain a MAP of 60 mmHg). The Sal-MAP 45 group was characterized by no change in R, reduced K and MA, and increased α. In the Centh-MAP 45 group, TEG showed no change in R, K, and α compared to saline; however, MA increased significantly (p = 0.018). In the Sal-MAP 60 group, TEG showed no change in R, an increase in α (p < 0.001), a decrease in K (p < 0.01), and a decrease in MA (p = 0.029) compared to the Centh-MAP 45 group. In conclusion, centhaquine does not impair coagulation and facilitates hemostatic resuscitation.

Vancomycin Pharmacokinetics in a Pregnancy Rat Model.

Vancomycin usage is often unavoidable in pregnant patients; however, literature suggests vancomycin can cross the placental barrier and reach the fetus. Understanding the mass transit of vancomycin to the fetus is important in pregnancy. We aimed to (i) identify a relevant population pharmacokinetic (PK) model for vancomycin in pregnancy and (ii) estimate PK parameters and describe the mass transit of vancomycin from mother to pup kidneys. Pregnant Sprague-Dawley rats (i.e., trimester 1 and trimester 3) received 250 mg/kg vancomycin once daily for three days through intravenous injection via an internal jugular vein catheter. Vancomycin concentrations in maternal plasma and pup kidneys were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple compartment models were fitted and assessed using a nonparametric approach with Pmetrics. A total of 10 vancomycin-treated rats and 48 pups contributed PK data. A 3-compartment model adjusted for trimester fit the data well (maternal plasma Bayesian, observed versus predicted R2 = 0.978; pup kidney Bayesian, observed versus predicted R2 = 0.999). The mean rate constant for vancomycin mass transit to the pup kidney was 0.72 h-1 for trimester 1 dams and 0.75 h-1 for trimester 3 dams. Median vancomycin concentrations in pup kidneys from trimester 3 were significantly higher than those in trimester 1 (8.62 versus 0.36 µg/mL, P < 0.001). Vancomycin transited to the fetus from the mother and was; kidney accumulation differed by trimester. This model may be useful for a translational understanding of vancomycin distribution in pregnancy to ensure efficacious and safe doses to both mother and fetus.

Sovateltide Mediated Endothelin B Receptors Agonism and Curbing Neurological Disorders.

Neurological/neurovascular disorders constitute the leading cause of disability and the second leading cause of death globally. Major neurological/neurovascular disorders or diseases include cerebral stroke, Alzheimer's disease, spinal cord injury, neonatal hypoxic-ischemic encephalopathy, and others. Their pathophysiology is considered highly complex and is the main obstacle in developing any drugs for these diseases. In this review, we have described the endothelin system, its involvement in neurovascular disorders, the importance of endothelin B receptors (ETBRs) as a novel potential drug target, and its agonism by IRL-1620 (INN-sovateltide), which we are developing as a drug candidate for treating the above-mentioned neurological disorders/diseases. In addition, we have highlighted the results of our preclinical and clinical studies related to these diseases. The phase I safety and tolerability study of sovateltide has shown it as a safe and tolerable compound at therapeutic dosages. Furthermore, preclinical and clinical phase II studies have demonstrated the efficacy of sovateltide in treating acute ischemic stroke. It is under development as a first-in-class drug. In addition, efficacy studies in Alzheimer's disease (AD), acute spinal cord injury, and neonatal hypoxic-ischemic encephalopathy (HIE) are ongoing. Successful completion of these studies will validate that ETBRs signaling can be an important target in developing drugs to treat neurological/neurovascular diseases.

An Evaluation of Bone Health Parameters in Regularly Transfused Beta-Thalassemia Major Patients.

As beta-thalassemia major patients need regular blood transfusions due to the severe hemoglobin deficiency, the occurrence of related bone defects with simultaneous fluctuations in the biochemical and hematologic parameters is seen. The hospital-based cross-sectional observational study was done to determine and correlate the bone mineral density (BMD) with biochemical parameters and hematologic parameters in 50 regularly transfused beta-thalassemia major patients of older than 6 years of age. Descriptive statistics were analyzed with SPSS version 20.0 software. A P<0.05 was considered as statistically significant. The prevalence of suboptimal BMD at lumbar spine was 86% and at femur neck was 74%. A statistically significant correlation of BMD was found with mean pretransfusion hemoglobin values, serum calcium levels, and serum vitamin D levels (P<0.05). It was concluded that continuous monitoring of the BMD, biochemical, and hematologic parameters in regularly transfused beta-thalassemia major patients may help assess the ongoing deficiencies; helping to maintain timely and regular blood transfusions with supplementation of calcium, vitamin D to ensure good bone health.

Sovateltide (IRL-1620) affects neuronal progenitors and prevents cerebral tissue damage after ischemic stroke.

Stimulation of endothelin B receptors by its agonist IRL-1620 (INN, sovateltide) provides neuroprotection and neurological and motor function improvement following cerebral ischemia. We investigated the effect of sovateltide on stem and progenitor cells mediated neural regeneration and its effect on the cerebral tissue repair and restoration of neurological and motor function. Sovateltide (5 µg/kg) was injected intravenously in permanent middle cerebral artery occluded (MCAO) rats at 4, 6, and 8 h at days 0, 3, and 6. Neurological and motor function tests were carried out pre-MCAO and at day 7 post-MCAO. At day 7, significantly reduced expression of neuronal differentiation markers HuC/HuD and NeuroD1 was seen in MCAO + vehicle than sham rats. Sovateltide treatment upregulated HuC/HuD and NeuroD1 compared to MCAO + vehicle and their expression was similar to sham. Expression of stem cell markers Oct 4 and Sox 2 was similar in rats of all of the groups. Significantly reduced infarct volume and DNA damage with recovery of neurological and motor function was observed in sovateltide-treated MCAO rats. These results indicate that sovateltide initiates a regenerative response by promoting differentiation of neuronal progenitors and maintaining stem cells in an equilibrium following cerebral ischemic stroke.

Evaluation of Fetal and Maternal Vancomycin-Induced Kidney Injury during Pregnancy in a Rat Model.

Previous literature suggests that maternal vancomycin crosses the placental barrier to the fetus. Further, early animal studies indicated that kidney injury was not observed in the progeny. These studies were conducted prior to the availability of sensitive biomarkers for kidney injury. Therefore, a previous finding of no renal damage to the infant may be misleading. Vancomycin was administered intravenously to pregnant rats at a dose of 250 mg/kg of body weight/day (N = 6 per trimester) on three consecutive gestational days (GD) during trimesters 1, 2, and 3 (T1, T2, and T3, respectively) in three independent cohorts. The dams carried to term and delivered vaginally on GD 21. Kidneys were harvested from dams and pups and homogenized. Samples were prepared by protein precipitation and injected in a liquid chromatography tandem mass spectrometer, and vancomycin was quantified. The kidney tissue homogenate from dams and pups were analyzed for kidney injury molecule-1 (KIM-1). As trimesters progressed, the quantity of vancomycin increased linearly in the kidneys of both rat dams and pups (P < 0.0001 for T1 and T3, P < 0.0001 for T2 and T3, and P < 0.0001 for T3 and T3 control for both rat dams and pups). KIM-1 concentrations in pup kidneys were significantly higher when dams were administered vancomycin in trimesters 1 (P = 0.0001) and 2 (P = 0.0024) than in controls in trimester 3. Data demonstrate persistence of vancomycin in maternal and rat pup kidneys in all three trimesters of pregnancy with associated damage to the kidney, as indicated by expression of KIM-1.

Comparative Performance of Urinary Biomarkers for Vancomycin-Induced Kidney Injury According to Timeline of Injury.

Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney injury (VIKI) as defined by histopathologic damage. Male Sprague-Dawley rats (n = 125) were randomized to receive 150 to 400 mg/kg of body weight/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 h prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic (ROC) curves were employed to assess the urinary biomarker performances of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologically defined VIKI (using a national standard pathological assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL with regard to sensitivity and specificity. For the earliest injury, urinary KIM-1 (area under the receiver operating characteristic curve [AUC], 0.662; P < 0.001) and clusterin (AUC, 0.706; P < 0.001) were the most sensitive for predicting even low-level histopathologic damage at 24 h compared to NGAL. KIM-1 and clusterin are the earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin, and OPN best define the extent of damage.

Twenty-four hour pharmacokinetic relationships for intravenous vancomycin and novel urinary biomarkers of acute kidney injury in a rat model.

OBJECTIVES: To identify the pharmacokinetic (PK) and toxicodynamic (TD) relationship for vancomycin-induced kidney injury. METHODS: Male Sprague-Dawley rats received intravenous (iv) vancomycin. Doses ranging from 150 mg/kg/day to 400 mg/kg/day were administered as a single or twice-daily injection over 24 h (total protocol duration). Controls received iv saline. Plasma was sampled with up to eight samples in 24 h per rat. Twenty-four hour urine was collected and assayed for kidney injury molecule 1 (KIM-1), osteopontin and clusterin. Vancomycin in plasma was quantified via LC-MS/MS. PK analyses were conducted using Pmetrics for R. PK exposures during the first 24 h (i.e. AUC0-24h, Cmax 0-24h and Cmin 0-24h) were calculated. PK/TD relationships were assessed with Spearman's rank coefficient (rs) and the best-fit mathematical model. RESULTS: PK/TD data were generated from 45 vancomycin-treated and 5 control rats. A two-compartment model fit the data well (Bayesian: observed versus predicted R2 = 0.97). Exposure-response relationships were found between AUC0-24h versus KIM-1 and osteopontin (R2 = 0.61 and 0.66) and Cmax 0-24h versus KIM-1 and osteopontin (R2 = 0.50 and 0.56) using a four-parameter Hill fit. Conversely, Cmin 0-24h was less predictive of KIM-1 and osteopontin (R2 = 0.46 and 0.53). A vancomycin AUC0-24h of 482.2 corresponded to a 90% of maximal rise in KIM-1. CONCLUSIONS: Vancomycin-induced kidney injury as defined by urinary biomarkers is driven by vancomycin AUC or Cmax rather than Cmin. Further, an identified PK/TD target AUC0-24h of 482.2 mg·h/L may have direct relevance to human outcomes.

24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury.

Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (Cmax), and the minimum concentration. Spearman's rank correlation coefficient (rs ) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage (rs = 0.348, P = 0.017) and proximal tubule damage (rs = 0.342, P = 0.019). The vancomycin AUC and Cmax were most predictive of increases in KIM-1 levels (rs = 0.438 and P = 0.002 for AUC and rs = 0.451 and P = 0.002 for Cmax). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or Cmax.

Maternal Cannabinoid Use Alters Cannabinoid (CB1) and Endothelin (ETB) Receptor Expression in the Brains of Dams but Not Their Offspring.

According to the 2015 National Survey on Drug Use and Health, cannabis (marijuana) is the most commonly used recreational drug in the US. Among pregnant women aged 14-55 years, 3.4% were cannabis users. Presently, little is known about the neurodevelopmental effect of cannabis use during pregnancy and/or nursing on neonates. Endothelin (ET) is essential for normal development of the central nervous system (CNS). Decreases in ETB receptor expression correlate with a decline in nerve growth factor (NGF) and an increase in vascular endothelial growth factor (VEGF) in postnatal brain. Activation of ETB and cannabinoid 1 (CB1) receptors each promote neurogenesis and enhance angiogenesis, indicating that both ET and CB systems play a critical role during early CNS development. Hence the purpose of this study was to determine whether maternal CB abuse during pregnancy and lactation alters the expression of ETB receptors, CB1 receptors, VEGF, and NGF in the postnatal rat brain. Sixteen pregnant Sprague-Dawley rats were administered either saline or anandamide (AEA) at a dose of 3 mg/kg/day i.p. from gestational day 7 and continued through weaning on postnatal day (PND) 21. Rat pups were subdivided into 4 subgroups and sacrificed on PND 2, 7, 14, and 28. Brain tissue of the pups and dams (sacrificed on PND 21) was analyzed via Western blot for the expression of ETB receptors, CB1 receptors, VEGF, and NGF. AEA-exposed dams had significantly fewer live births (p = 0.027), and their pups presented with significantly lower body weights on PND 7 (p = 0.013) and PND 28 (p = 0.018). There was no significant difference noted in ETB receptor, CB1 receptor, NGF, or VEGF expression in the pup brains. In all pups, brain ETB receptor expression decreased and CB1 receptor expression increased with age. In the AEA-exposed dam brain, however, there was a decrease in ETB receptor (p = 0.043) and an increase in CB1 receptor expression (p = 0.033). AEA exposure during pregnancy appears to affect fetal viability and postnatal weight gain in offspring while not altering the expression patterns of ETB receptors, CB1 receptors, NGF, or VEGF in the pup brain. The observed trend to an increase in CB1 receptor expression concurrent with a decrease in ETB receptor expression in both dams and pups may point to a homeostatic regulation between these 2 systems in CNS development and neuroprotection.

Body mass index and outcome of out-of-hospital cardiac arrest patients not treated by targeted temperature management.

BACKGROUND: Obesity has been demonstrated to increase the risk of out-of-hospital cardiac arrest (OHCA) and may influence the quality and effectiveness of cardiopulmonary resuscitation. Our aim was to investigate the association between body mass index (BMI) and the outcome of OHCA victims not treated by targeted temperature management. METHODS: This was a prospective observational study of OHCA patients. The patients were categorized according to BMI into two groups: the normal BMI group (nBMI) and the elevated BMI group (eBMI). The primary endpoint was return of spontaneous circulation (ROSC), while secondary outcomes were survival to intensive care unit (ICU) admission and survival to ICU discharge. RESULTS: Of the initial 99 patients who were transported to the Emergency Department, 84 (85%) were included in the study. Mean BMI was 29.8kg/m2. Thirteen (15.5%) patients achieved ROSC and were admitted to the ICU, with the mean duration of ICU length of stay being 6.7±4.9days. Survival to ICU admission and ICU discharge were higher in the eBMI group (17.6% vs. 6.25%, p=0.010 and 10.3% vs. 6.25%, p=0.021, respectively). Survival to ICU discharge was higher in ventricular fibrillation patients compared to patients with non-shockable rhythms, irrespectively of their BMI (p=0.002). All patients that survived to ICU discharge did so with a cerebral performance category score of 2. CONCLUSIONS: Survival to ICU admission and ICU discharge were higher in the eBMI group.

Centhaquin Effects in a Swine Model of Ventricular Fibrillation: Centhaquin and Cardiac Arrest.

BACKGROUND: Centhaquin citrate is a novel agent being developed for use in the treatment of haemorrhagic shock. The aim of our study was to assess whether the administration of centhaquin would improve initial resuscitation success, 24-hour survival, and neurologic outcome compared with adrenaline alone in a porcine model of ventricular fibrillation. METHODS: Ventricular fibrillation was induced in 20 healthy Landrace/Large White piglets. The animals were randomised to receive placebo plus adrenaline 0.02mg/kg (n=10, Group C) and adrenaline 0.02mg/kg plus centhaquin 0.015mg/kg (n=10, Group S). All animals were resuscitated according to the 2010 European Resuscitation Council guidelines. Haemodynamic variables were measured before arrest, during arrest and resuscitation, and during the first two hours after return of spontaneous circulation (ROSC). Survival and a neurologic alertness score were measured at 24hours after ROSC. RESULTS: A significant difference was observed in ROSC rate between the two groups, as 10 animals (100%) from Group S and 4 animals (40%) from Group C achieved ROSC (p=0.011). Systolic, diastolic, and mean aortic pressure and coronary perfusion pressure were significantly higher in Group S at the end of the second cycle of CPR. In our study, all subjects with ROSC survived for 24hours, while we observed no statistically significant differences in neurologic examination (Group C 100±0, Group S 96±12.64; p=0.527). CONCLUSION: The addition of centhaquin to adrenaline improved ROSC rates in a swine model of VF cardiac arrest.

Evaluation of Vancomycin Exposures Associated with Elevations in Novel Urinary Biomarkers of Acute Kidney Injury in Vancomycin-Treated Rats.

Vancomycin has been associated with acute kidney injury (AKI). However, the pharmacokinetic/toxicodynamic relationship for AKI is not well defined. Allometrically scaled vancomycin exposures were used to assess the relationship between vancomycin exposure and AKI. Male Sprague-Dawley rats received clinical-grade vancomycin in normal saline (NS) as intraperitoneal (i.p.) injections for 24- to 72-h durations with doses ranging 0 to 200 mg/kg of body weight divided once or twice daily. Urine was collected over the protocol's final 24 h. Renal histopathology was qualitatively scored. Urinary biomarkers (e.g., cystatin C, clusterin, kidney injury molecule 1 [KIM-1], osteopontin, lipocalin 2/neutrophil gelatinase-associated lipocalin 2) were assayed using a Luminex xMAP system. Plasma vancomycin concentrations were assayed by high-performance liquid chromatography with UV detection. A three-compartment vancomycin pharmacokinetic model was fit to the data with the Pmetrics package for R. The exposure-response in the first 24 h was evaluated using Spearman's nonparametric correlation coefficient (rs) values for the area under the concentration-time curve during the first 24 h (AUC0-24), the maximum concentration in plasma during the first 24 h (Cmax0-24 ), and the lowest (minimum) concentration in plasma after the dose closest to 24 h (Cmin0-24 ). A total of 52 rats received vancomycin (n = 42) or NS (n = 10). The strongest exposure-response correlations were observed between AUC0-24 and Cmax0-24 and urinary AKI biomarkers. Exposure-response correlations (rs values) for AUC0-24, Cmax0-24 , and Cmin0-24 were 0.37, 0.39, and 0.22, respectively, for clusterin; 0.42, 0.45, and 0.26, respectively, for KIM-1; and 0.52, 0.55, and 0.42, respectively, for osteopontin. However, no differences in histopathological scores were observed. Optimal sampling times after administration of the i.p. dose were 0.25, 0.75, 2.75, and 8 h for the once-daily dosing schemes and 0.25, 1.25, 14.5, and 17.25 h for the twice-daily dosing schemes. Our observations suggest that AUC0-24 or Cmax0-24 correlates with increases in urinary AKI biomarkers.

Centhaquin improves survival in a swine model of hemorrhagic shock.

BACKGROUND: Hemorrhage is a frequent event in hospital and prehospital settings. The aim of the present study was to investigate whether centhaquin improves 24-h survival and reduces the total volume of required fluids in an established model of swine hemorrhagic shock. MATERIAL AND METHODS: Twenty-five pigs were instrumented and subjected to hemorrhagic shock. The animals were randomly allocated in two experimental groups, the control (vehicle) (n = 10) and the centhaquin groups (0.015 mg/kg, n = 10); all animals received lactated Ringer solution in the resuscitation phase until their mean arterial pressure reached 90% of the baseline. A sham group (n = 5) was added a posteriori to mimic the hemodynamic profile of the centhaquin group. RESULTS: A statistically significant difference was observed in the time required for the three groups to reach their target mean aortic pressure, 36.88 ± 3.26 min for the control group versus 9.40 ± 1.01 min for the sham group and 7.10 ± 0.97 min for the centhaquin group (P < 0.001). The total amount of fluids in the control and the sham groups was significantly higher when compared with that of the centhaquin-treated animals (P < 0.001). All 10 animals in the centhaquin group survived for 24 h, whereas only three animals survived in the control group and one animal in the sham group (P = 0.002). CONCLUSIONS: Centhaquin 0.015 mg/kg administered in the fluid resuscitation phase resulted in lower volume of fluids and better survival compared with control and sham-operated animals.

Endothelin ETA receptor antagonist reverses naloxone-precipitated opioid withdrawal in mice.

Long-term use of opioids for pain management results in rapid development of tolerance and dependence leading to severe withdrawal symptoms. We have previously demonstrated that endothelin-A (ETA) receptor antagonists potentiate opioid analgesia and eliminate analgesic tolerance. This study was designed to investigate the involvement of central ET mechanisms in opioid withdrawal. The effect of intracerebroventricular administration of ETA receptor antagonist BQ123 on morphine and oxycodone withdrawal was determined in male Swiss Webster mice. Opioid tolerance was induced and withdrawal was precipitated by the opioid antagonist naloxone. Expression of ETA and ETB receptors, nerve growth factor (NGF), and vascular endothelial growth factor was determined in the brain using Western blotting. BQ123 pretreatment reversed hypothermia and weight loss during withdrawal. BQ123 also reduced wet shakes, rearing behavior, and jumping behavior. No changes in expression of vascular endothelial growth factor, ETA receptors, and ETB receptors were observed during withdrawal. NGF expression was unaffected in morphine withdrawal but significantly decreased during oxycodone withdrawal. A decrease in NGF expression in oxycodone- but not in morphine-treated mice could be due to mechanistic differences in oxycodone and morphine. It is concluded that ETA receptor antagonists attenuate opioid-induced withdrawal symptoms.

The pathophysiologies of asphyxial vs dysrhythmic cardiac arrest: implications for resuscitation and post-event management.

BACKGROUND: Cardiac arrest is not a uniform condition and significant heterogeneity exists within all victims with regard to the cause of cardiac arrest. Primary cardiac (dysrhythmic) and asphyxial causes together are responsible for most cases of cardiac arrest at all age groups. The purpose of this article is to review the pathophysiologic differences between dysrhythmic and asphyxial cardiac arrest in the prearrest period, during the no-flow state, and after successful cardiopulmonary resuscitation. METHODS: The electronic databases of PubMed/Medline, Scopus, and Cochrane were searched for relevant literature and studies. RESULTS/DISCUSSION: Significant differences exist between dysrhythmic and asphyxial cardiac arrest regarding their pathophysiologic pathways and affect consequently the postresuscitation period. Laboratory data indicate that asphyxial cardiac arrest leads to more widespread postresuscitation brain damage compared with dysrhythmic cardiac arrest. Regarding postresuscitation myocardial dysfunction, few studies have addressed a comparison of the 2 conditions with controversial results. CONCLUSIONS: Asphyxial cardiac arrest differs significantly from dysrhythmic cardiac arrest with regard to pathophysiologic mechanisms, neuropathologic damage, postresuscitation organ dysfunction, and response to therapy. Both conditions should be considered and treated in a different manner.

Synthesis and antinociceptive properties of N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide in the mouse tail-flick and hot-plate tests.

The goals of this study, were to synthesize N-phenyl-N-(1-(2-(thiophen-2-yl)ethyl)azepane-4-yl)propionamide (1c) and determine its antinociceptive properties. The effect of clonidine on 1c antinociception and the involvement of opioid, α2-adrenergic, and I2 imidazoline receptors in 1c antinociception were studied. Also examined was the effect of an endothelin ETA receptor antagonist on 1c antinociception. Synthesis of 1c was accomplished in two steps using modifications of previously reported methods. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with 1c; antagonists+1c; clonidine+1c; or antagonists+clonidine+1c. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α2-adrenoceptor antagonist), idazoxan (α2-adrenoceptor/I2-imidazoline antagonist), BU224 (I2-imidazoline antagonist) or BQ123 (endothelin ETA receptor antagonist) to study the involvement of these receptors. Compound 1c produced a dose-dependent increase in antinociceptive latencies; ED50 values were 0.15 mg/kg and 0.16 mg/kg, respectively, in the tail flick and hot plate tests. Naloxone, but not yohimbine, idazoxan or BU224, blocked 1c antinociception. Neither clonidine nor BQ123 potentiated 1c antinociception. Results demonstrate that 1c is 15-times more potent than morphine. The antinociceptive effect of 1c is mediated through opioid receptors. The α2-adrenergic, I2-imidazoline and endothelin ETA receptors are not involved in 1c antinociception.

Nanocarrier-based approaches for treatment and detection of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurological disorder in people over the age of 65. It has been estimated that in 2010 there were 4.7 million individuals aged 65 years or older with AD dementia, and it is projected that the total number of individuals with AD dementia in 2050 will be 13.8 million. The most commonly believed cause and most frequently studied aspect of AD is the aggregation of beta amyloid (Abeta), both as soluble Abeta and in the form of extracellular plaque. Treatment options are limited mainly due to the inability of drugs to cross the blood-brain barrier. Nanoparticulate drug carriers that have been targeted to the brain are able to pass through by virtue of their size, surface potential, surface coatings (e.g., polyethylene glycol, polysorbate), surface decoration with ligands or antibodies attached toward the receptors on the blood-brain barrier. Herein, we discuss the current front-runner nanocarriers under investigation for effective delivery of pharmaceuticals active in the treatment and detection of AD and their mechanisms and discuss a few of the outstanding studies.

Resuscitative effect of centhaquin after hemorrhagic shock in rats.

BACKGROUND: Centhaquin is a cardiovascular active agent that significantly reduced blood lactate levels and enhanced resuscitative effect of hypertonic saline. The present study was carried out to determine the resuscitative effect of centhaquin and compare that with large-volume lactated Ringer (LR) solution in hemorrhaged rats. MATERIALS AND METHODS: Male, adult Sprague-Dawley rats were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery; another pressure-volume catheter SPR-869 was placed into the left ventricle through carotid artery. Hemorrhage was induced by withdrawing blood from the right femoral artery, and the mean arterial pressure (MAP) was maintained at 35 mm Hg for 30 minutes after which resuscitation was performed using LR solution (LR-100) (100% shed blood volume), centhaquin (0.017, 0.05, and 0.15 mg/kg) dissolved in LR (100% shed blood volume), or LR-300 (300% shed blood volume). Arterial blood gases and cardiovascular parameters were determined before the induction of hemorrhage and at various times after hemorrhage. RESULTS: It was found that survival time after resuscitation with LR-100 was 78 ± 10 min. Centhaquin in doses of 0.017 and 0.05 mg/kg significantly improved survival time to 291 ± 57 and 387 ± 39 min, respectively. Blood lactate levels (millimoles per liter) increased from 7.22 ± 0.67 at hemorrhage to 10.20 ± 0.61 at 60 min after resuscitation with LR-100. On the other hand, blood lactate levels significantly decreased to 3.55 ± 0.07 and 4.08 ± 0.28 at 60 min after resuscitation with 0.017 and 0.05 mg/kg doses of centhaquin, respectively. Centhaquin in these doses produced a 55% and 59% increase in MAP, respectively, compared with a 29% decrease by LR-100. A decrease in systemic vascular resistance of 57% and 41% was observed with 0.017 and 0.05 mg/kg doses of centhaquin, respectively, compared with a 6% decrease by LR-100. LR-100 decreased cardiac output (CO) by 28%, whereas 0.017 and 0.05 mg/kg doses of centhaquin increased it by 260% and 180%, respectively. LR-300 commonly used for resuscitation was found to increase MAP and CO. Compared with LR-300, centhaquin (0.05 mg/kg) significantly improved survival time, increased CO, and was effective in resuscitation of hemorrhaged rats. CONCLUSIONS: Centhaquin was found to be more effective than LR-300 as an effective resuscitative agent for the treatment of hemorrhagic shock in rat.

Efficacy of centhaquin as a small volume resuscitative agent in severely hemorrhaged rats.

Centhaquin has been reported to be an effective resuscitative agent. The present study was carried out to determine resuscitative effect of centhaquin when administered using a small volume of 3% hypertonic saline (HS) to hemorrhaged rats. Sprague-Dawley rats were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery; another pressure-volume catheter SPR-869 was placed into the left ventricle. Hemorrhage was induced by withdrawing blood and mean arterial pressure (MAP) was maintained at 35 mm Hg for 30 minutes after which resuscitation was performed. Animals were divided in 2 groups: group A received HS and group B received centhaquin (0.05 mg/kg) dissolved in HS. The time by which MAP fell back to 35 mm Hg was observed at that time all animals were administered fresh blood. It was found that centhaquin significantly reduced blood lactate and improved cardiac output and MAP of hemorrhaged rats compared with HS. The time by which MAP fell back to 35 mm Hg in rats treated with HS was 55 ± 6 minutes, whereas it was 161 ± 14 minutes in centhaquin treated rats. Survival time following administration of fresh blood was 79 ± 7 minutes in vehicle-treated group, whereas it was 105 ± 9 minutes in centhaquin-treated rats. The total time of survival of rats treated with HS or centhaquin was 134 ± 12 minutes and 266 ± 16 minutes, respectively. Centhaquin, in small volume, maintained MAP of hemorrhaged rats for a considerable long time and improved the survival time.