Level,Causes and Risk Factors of Neonatal Mortality,in Jordan: Results of a National Prospective Study

Objective The present study aimed at assessment of the magnitude of neonatal mortality in Jordan, and its causes and associated factors. Methods Through a multistage sampling technique, a total of 21,928 deliveries with a gestational period ≥20 weeks from 18 hospitals were included in the study. The status of their babies 28 days after birth, whether dead or alive, was ascertained. Extensive data were collected about mothers and their newborns at admission and after 28 days of birth. Causes of death were classified according to the neonatal and intrauterine death classification according to etiology. Preventability of death was classified according to Herman’s classification into preventable, partially preventable, and not preventable. Results Neonatal mortality rate, overall and for subgroups of the study was obtained. Risk factors for neonatal mortality were first examined in bivariate analyses and finally by multivariate logistic regression models to account for potential confounders. A total of 327 babies ≥20 weeks of gestation died in the neonatal period (14.9/1000 LB). Excluding babies <1000 g and <28 weeks of gestation to be consistent with the WHO and UNICEF’s annual neonatal mortality reports, the NNMR decreased to 10.5/1000 LB. About 79 % of all neonatal deaths occurred in the first week after birth with over 42 % occurring in the first day after birth. According to NICE hierarchical classification, most neonatal deaths were due to congenital anomalies (27.2 %), multiple births (26.0 %), or unexplained immaturity (21.7 %). Other important causes included maternal disease (6.7 %), specific infant conditions (6.4 %), and unexplained asphyxia (4.9 %). According to Herman’s classification, 37 % of neonatal deaths were preventable and 59 % possibly preventable. An experts’ panel determined that 37.3 % of neonatal deaths received optimal medical care while the medical care provided to the rest was less than optimal. After adjusting for socio-demographic characteristics, type of the hospital, and clinical and medical history of women, the following variables were significantly associated with neonatal mortality: male gender, congenital defects, inadequate antenatal visits, multiple pregnancy, presentation at delivery, and gestational age. Conclusion The present study showed the level, causes, and risk factors of NNM in Jordan. It showed also that a large proportion of NNDs are preventable or possibly preventable. Providing optimal intrapartum, and immediate postpartum care is likely to result in avoidance of a large proportion of NNDs.     

Antinociceptive activity of a synthetic curcuminoid analogue, 2,6-bis-(4-hydroxy-3-methoxybenzylidene)cyclohexanone, on nociception-induced models in mice

Abstract: This study investigated the potential antinociceptive efficacy of a novel synthetic curcuminoid analogue, 2,6‐bis‐(4‐hydroxy‐3‐methoxybenzylidene)cyclohexanone (BHMC), using chemical‐ and thermal‐induced nociception test models in mice. BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) administered via intraperitoneal route (i.p.) produced significant dose‐related inhibition in the acetic acid‐induced abdominal constriction test in mice with an ID₅₀ of 0.15 (0.13–0.18) mg/kg. It was also demonstrated that BHMC produced significant inhibition in both neurogenic (first phase) and inflammatory phases (second phase) of the formalin‐induced paw licking test with an ID₅₀ of 0.35 (0.27–0.46) mg/kg and 0.07 (0.06–0.08) mg/kg, respectively. Similarly, BHMC also exerted significant increase in the response latency period in the hot‐plate test. Moreover, the antinociceptive effect of the BHMC in the formalin‐induced paw licking test and the hot‐plate test was antagonized by pre‐treatment with the non‐selective opioid receptor antagonist, naloxone. Together, these results indicate that the compound acts both centrally and peripherally. In addition, administration of BHMC exhibited significant inhibition of the neurogenic nociception induced by intraplantar injections of glutamate and capsaicin with ID₅₀ of 0.66 (0.41–1.07) mg/kg and 0.42 (0.38–0.51) mg/kg, respectively. Finally, it was also shown that BHMC‐induced antinociception was devoid of toxic effects and its antinociceptive effect was associated with neither muscle relaxant nor sedative action. In conclusion, BHMC at all doses investigated did not cause any toxic and sedative effects and produced pronounced central and peripheral antinociceptive activities. The central antinociceptive activity of BHMC was possibly mediated through activation of the opioid system as well as inhibition of the glutamatergic system and TRPV1 receptors, while the peripheral antinociceptive activity was perhaps mediated through inhibition of various inflammatory mediators.     

Phospholipase A(2)-susceptible liposomes of anticancer double lipid-prodrugs

A novel approach to anticancer drug delivery is presented based on lipid-like liposome-forming anticancer prodrugs that are susceptible to secretory phospholipase A(2) (sPLA(2)) that is overexpressed in several cancer types. The approach provides a selective unloading of anticancer drugs at the target tissues, as well as circumvents the necessity for "conventional" drug loading. In our attempts to improve the performance of the liposomes in vivo, several PEGylated and non-PEGylated liposomal formulations composed of a retinoid prodrug premixed with the sPLA(2)-hydrolyzable DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) were prepared. Besides favorably modifying the physicochemical properties of the liposomes, the incorporation of DPPC and PEG-lipids in the liposomes should substantially enhance the enzymatic activity, as concluded from literature. In addition, one can reap benefits from the presumed permeability enhancing effect of the liberated fatty acids and lysolipids. The size distribution of the prepared liposomes as well as their phase behavior, enzymatic hydrolysis, and cytotoxicity, in the presence and absence of sPLA(2), were determined. The liposomes were around 100nm in diameter and in the gel/fluid coexistence region at 37°C. The enzymatic hydrolysis of the prodrug was pronouncedly accelerated upon the premixing with DPPC, and the hydrolysis was further enhanced by PEGylation. Interestingly, the faster hydrolysis of the prodrug and the released fatty acids and lysolipids from DPPC did not improve the cytotoxicity of the mixture; the effect of combining the prodrug with DPPC was additive and not synergistic. The data presented here question the significance of the permeability enhancing effects claimed for fatty acids and lysolipids at the target cell membrane, and whether these effects can be achieved using physiologically achievable concentrations of fatty acids and lysolipids.     

Prior Antiplatelet Use and Cardiovascular Outcomes in Patients Presenting with Acute Coronary Syndromes

Background

Although antiplatelet therapy effectively reduces ischemic events, the cardiovascular (CV) outcome in some cases is still unpredictable.

Objective

The objective of this study was to evaluate the impact of prior single or dual antiplatelet (PAP) use in patients presenting with acute coronary syndromes (ACS).

Methods

Data were collected from the 2nd Gulf Registry of Acute Coronary Events between October 2008 and June 2009. Patients were grouped according to whether they were PAP users or not (NAP). Patients’ characteristics and outcomes were analyzed and compared. Mortality was assessed at 1 and 12 months.

Results

Among 7827 consecutive ACS patients, 41% were PAP users (70% aspirin, 1% clopidogrel, and 29% dual antiplatelet agents). In comparison with NAP use, PAP use was associated with a higher rate of comorbidities, atypical presentation, severe left ventricular dysfunction, three-vessel disease, and a high GRACE risk score. After adjustment for relevant covariates, PAP use was an independent predictor for recurrent ischemia in unstable angina (odds ratio [OR] 1.7; 95% CI 1.17, 2.57) and non-ST-elevation myocardial infarction (NSTEMI) [OR 1.9; 95% CI 1.38, 2.65] and for heart failure in NSTEMI (OR 1.5; 95% CI 1.11, 2.15) and STEMI (OR 1.4; 95% CI 1.08, 1.93). Although PAP use was associated with high mortality in STEMI and NSTEMI, it was not an independent predictor for mortality. Among PAP patients, percutaneous coronary intervention independently reduced the risk of hospital (adjusted OR 0.25; 95% CI 0.20, 0.32), 1-month (OR 0.31; 95% CI 0.26, 0.37), and 12-month mortality (OR 0.28; 95% CI 0.24, 0.33).

Conclusion

PAP use identified a high-risk population across the ACS spectrum. Early coronary revascularization may improve CV outcomes in these patients.     

Zerumbone inhibits interleukin-6 and induces apoptosis and cell cycle arrest in ovarian and cervical cancer cells

Interleukin-6 is one of the factors affecting sensitivity to cytotoxic agents. Therefore, the current study was designed to investigate the role of IL-6 and IL6 receptors in the cytotoxic effects of zerumbone in ovarian and cervical cancer cell lines (Caov-3 and HeLa, respectively). Exposure of both cancer cells to zerumbone or cisplatin demonstrated growth inhibition at a dose-dependent manner as determined by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,Sdiphenyltetrazolium bromide) reduction assay. Both laser scanning confocal microscopy and TUNEL assay showed typical apoptotic features in treated cells. The studies conducted seems to suggest that zerumbone induces cell death by stimulating apoptosis better than cisplatin, based on the significantly higher percentage of apoptotic cells in zerumbone's treated cancer cells as compared to cisplatin. In addition, zerumbone and cisplatin arrest cancer cells at G2/M phase as analyzed by flow cytometry. Our results indicated that zerumbone significantly decreased the levels of IL-6 secreted by both cancer cells. In contrast, HeLa and Caov-3 cells were still sensitive to cisplatin and zerumbone, even in the presence of exogenous IL-6. However, membrane-bound IL-6 receptor is still intact after zerumbone treatment as demonstrated using an immune-fluorescence technique. This study concludes that the compound, zerumbone inhibits both cancer cell growth through the induction of apoptosis, arrests cell cycle at G2/M phase and inhibits the secretion levels of IL-6 in both cancer cells. Therefore, zerumbone is a potential candidate as a useful chemotherapeutic agent in treating both cervical and ovarian cancers in future.     

Protective effects of acute lithium preconditioning against renal ischemia/reperfusion injury in rat: role of nitric oxide and cyclooxygenase systems

Delayed graft function secondary to ischemia/reperfusion injury has been shown to be associated with increased rate of allograft failure following kidney transplantation. Previously, we have shown that chronic lithium pretreatment protects kidney against ischemia/reperfusion injury. In the present study we aimed to examine the effects of acute lithium administration on the renal ischemia/reperfusion injury in rat. Ischemia/reperfusion injury was induced by clamping left renal pedicle for 60 min, two weeks after right nephrectomy. The mechanism of lithium-mediated renoprotection was explored by combined use of lithium and nitro-l-arginine methyl ester (L-NAME) (non-selective nitric oxide synthase inhibitor) and/or indomethacin (non-selective cyclooxygenase pathway inhibitor). Lithium-treated animals were given 40 mg/kg lithium chloride intraperitoneally, 30 min before ischemia. To investigate the role of nitric oxide and cyclooxygenase pathways in renoprotective effect of lithium, L-NAME and/or indomethacin were administered before lithium injection. Serum creatinine, blood urea nitrogen, and renal histology were assessed after 24h of reperfusion. Lithium preconditioning significantly reduced creatinine and blood urea nitrogen (P<0.001) and improved renal histology. Administration of L-NAME completely reversed renoprotective effect of lithium. In contrast indomethacin significantly potentiated the lithium renoprotection. Moreover, co-administration of L-NAME and indomethacin completely abolished the protective effects of lithium. The results show that a single dose of lithium significantly improves renal function following ischemia/reperfusion injury. In conclusion, the ability of lithium to enhance renal tissue tolerance against ischemia/reperfusion injury suggests a potential clinical application in the setting of kidney transplantation. However, more detailed investigations are required before any definite conclusion.     

PNIPAM nanoparticles for targeted and enhanced nose-to-brain delivery of curcuminoids: UPLC/ESI-Q-ToF-MS/MS-based pharmacokinetics and pharmacodynamic evaluation in cerebral ischemia model

Stroke is a one of the leading causes of disease and deaths worldwide, which causes irreversible deterioration of the central nervous system. Curcuminoids are reported to have a potential role in the amelioration of cerebral ischemia but they exhibit low serum and tissue levels due to low solubility and poor absorption. Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)-loaded PNIPAM nanoparticles (NPs) were prepared by free radical polymerization and characterized for particles size, entrapment efficiency, zeta potential, in vitro release and ex vivo permeation study. Optimized CUR, DMC and BDMC-loaded NPs had the mean size of 92.46?±?2.8, 91.23?±?4.2 and 94.28?±?1.91?nm; zeta potential of ?16.2?±?1.42, ?15.6?±?1.33 and ?16.6?±?1.21 mV; loading capacity of 39.31?±?3.7, 38.91?±?3.6 and 40.61?±?3.6% and entrapment efficiency of 84.63?±?4.2, 84.71?±?3.99 and 85.73?±?4.31%, respectively. Ultra-performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectroscopy based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency and brain drug-targeting potential studies post-intranasal (i.n.) administration which showed enhanced bioavailability of curcuminoids in brain as compared to intravenous administration. Improved neurobehavioural activity (locomotor and grip strength) and reduced cytokines levels (TNF-α and IL-1β) was observed in middle cerebral artery occlusion induced cerebral ischemic rats after i.n. administration of curcuminoids NPs. Finally, the toxicity study was performed which revealed safe nature of developed NPs.     

Synthesis,in vitro potential and computational studies on 2-amino-1, 4-dihydropyrimidines as multitarget antibacterial ligands

In this study, we have investigated small multitargeted molecules containing 2-aminopyrimidine scaffold that may further act as precursor for developing more potent antibacterials. An efficient route to 2-amino-1,4-dihydropyrimidines by using ultrasound irradiation as the energy source was developed. In silico density functional theory calculations illustrated that tin chloride-mediated Biginelli reaction to produce 2-amino-1,4-dihydropyrimidines has energetics quite accessible under the reaction conditions. Calculated minimum inhibitory concentrations against the various bacterial strains showed that compounds 3 and 11 displayed comparable in vitro activity to ciprofloxacin in Staphylococcus aureus strains and reduced potency in Escherichia coli strains. Further, we investigated in silico ADMET profiling of synthesized compounds in order to understand the mechanism of action that help in explaining in vitro results. Lead compounds 3, 6, and 11 are predicted to have acceptable pharmacokinetic/drug-like properties. Data mining and computational analysis were employed to derive compound promiscuity phenomenon. All the compounds were found nonsubstrate towards various aminergic G-protein coupled receptors, ion-channels, kinase inhibitor, nuclear receptor ligand, protease inhibitor, and enzyme inhibitor. Compound 3 was further investigated by in silico binding to different antibacterial targets. Binding energy data revealed that that these compounds have the ability to bind with other bacterial targets. Hence, combined in silico and in vitro studies shed insights into the mechanism of synthesis and antibacterial activity of 2-amino-1,4-dihydropyrimidines. Results of this study are promising and can be used for further investigation by medicinal chemists to explore their chemical functionalization and in vivo studies.     

Synthesis and anti-bacterial activities of some novel pyrazolobenzothiazine-based chalcones and their pyrimidine derivatives

A novel series of fifteen pyrimidine derivatives was prepared from pyrazolobenzothiazine-based chalcones by refluxing with guanidine hydrochloride. The starting materials 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c][1,2]thiazin-2(4-H)yl)phenyl)ethanone (2) or 4-(3,4-dimethyl-5,5-dioxidobenzo[4,3-c][1,2]thiazin-2(4-H)yl)benzaldehyde (3) were obtained by N-arylation of 3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine 5,5-dioxide (1) with 4-fluoroacetophenone or 4-fluorobenzaldehyde, respectively, using phase transfer catalyst, hexadecyl-tri-n-butylphsophonium bromide. The N-arylated product (2) or (3) was reacted in MeONa/MeOH with diversified aromatic aldehydes or ketones to furnish two series of new chalcones 4 and 5. Refluxing of 4 or 5 with guanidine hydrochloride in KOH_(aq) and H₂O₂/EtOH yielded the 2-(4-(2-amino-6-arylpyrimidin-4-yl)phenyl)3,4-dimethyl-2,4-dihydrobenzo[e]pyrazolo[4,3-c][1,2]thiazine-5,5-dioxide (6). The structures of chalcones (4 or 5) and corresponding pyrimidines (6) were confirmed with spectral data and elemental analysis. Several chalcones as well as pyrimidines showed marked activity against E. coli and S. aureus.     

Supercritical Fluid Technology-Based Trans-Resveratrol SLN for Long Circulation and Improved Radioprotection

Purpose

To alleviate the harmful effects of radiations during occupational radiology, radiotherapy and diagnosis, radioprotective system with lower toxicity and extended activity is imperative. Trans-resveratrol (RVL) acts through free radical scavenging/antioxidant mechanism to mitigate the radiation-induced damage. But, its poor solubility and fast metabolism impede its efficacy. Thus, encapsulation of RVL into long circulating solid lipid nanoparticle (SLN) is aimed.

Method

Supercritical CO₂ solution of RVL, Gelucire®50/02 and Gelucire®50/13 SLN, was rapidly expanded into aqueous phase containing Tween 80, sonicated and lyophilized to get SLN. Particle size, polydispersity index (PDI), entrapment efficiency (%EE), scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), drug release, in vivo pharmacokinetics, antioxidant assays, radiation-induced lipid peroxidation and plasmid DNA relaxation assays were studied. Stability studies were performed to analyze drug degradation and shelf life.

Results

Optimized formulation (F9) had %yield, particle size, PDI, %EE and %drug release (after 72 h) of 68.48?±?5.73 %, 276.7?±?5.33 nm, 0.18?±?0.032, 62.66?±?4.52 % and 70.05?±?3.003 %, respectively. Electron microscopy revealed nearly spherical particles, while DSC and XRD showed reduced crystalline peaks. F9 showed higher AUC and sustained release of RVL in rats (i.v. bolus) and increased antioxidant activities and radioprotection as compared to RVL solution. Shelf life of >2 years was predicted for F9 (at 8 °C).

Conclusion

Results are encouraging to use F9 for radiation exposure prophylaxis.