Gamma-hydroxybutyric Acid Tolerance and Withdrawal in a Rat Model

Long-term daily use of gamma-hydroxybutyrate (GHB) and related compounds has recently been associated with a withdrawal syndrome. To the best of the authors' knowledge, there are currently no animal models of GHB withdrawal. OBJECTIVES: The authors studied and described the effect of chronic dosing of GHB (3-6 days) on tolerance and withdrawal in a rat model. METHODS: Rats were administered GHB every three hours via intraperitoneal catheter. Groups of rats (2 per group) were dosed with GHB for either 3 (24 doses), 4 (32 doses), 5 (40 doses), or 6 (48 doses) days. The GHB dose was 0.25 g/kg for doses 1-8, 0.75 g/kg for doses 9-12, 1 g/kg for doses 13-16, 1.25 g/kg for doses 17-24, 1.5 g/kg for doses 25-32, 1.75 g/kg for doses 33-40, and 2 g/kg for doses 41-48. Following the last dose of GHB, the rats were scored using a 16-point ethanol intoxication-withdrawal scale rating spontaneous behaviors, response to handling, grooming, and neurological signs. Lower scores indicate intoxication, while higher scores indicate withdrawal. Scores were recorded at hours 0, 1, 2, 3, 4, 5, 6, 9, 12, and 24. RESULTS: Tolerance: Rats dosed with GHB for more days were less intoxicated one hour after their last GHB dose despite receiving higher doses. WITHDRAWAL: The scores for all rats dosed with GHB increased at hours 4 (p = 0.028), 5 (p = 0.037), 6 (p = 0.007), and 9 (p = 0.024) after the last dose, indicating withdrawal. The scores demonstrated a linear increase dependent upon the number of days of GHB dosing at hours 3 (p < 0.000), 4 (p = 0.004), 5 (p = 0.002), and 12 (p = 0.039) as well as prior to the last dose at hour 0 (p = 0.000). No rats developed seizures. CONCLUSIONS: Tolerance and mild withdrawal in rats can be induced by administering intraperitoneal GHB every three hours for 3-6 days. More prolonged dosing and higher doses of GHB may be necessary to induce severe withdrawal.     

可逆性胆硷酯酶抑制剂二甲氨基甲酸-5-二氢吲哚酯的合成

为了深入研究催醒宁类化合物的结构与抑酶活性的关系,设计合成了-系列1-,3-或5-位不同取代的二氢吲哚类衍生物(中间体和终产物共24个新化合物)。中间体1,3-二甲基-5-烷氧基-2-二氢吲哚酮(A)的C₃烷化。采用相转移催化方法进行;反应中还分离到三个副产物(Ⅶ～Ⅸ)。初筛结果表明:这些化合物大多有较强的抑酶活性;1,3-或5-位取代基的改变均明显影响其活性。     

A somatostatin analogue decreases embryonic loss following superovulation in rats by normalizing insulin-like growth factor-I action in the uterus

This study was designed to determine whether the somatostatin analogue, octreotide, could prevent embryonic loss by normalizing increased uterine insulin-like growth factor-I (IGF-I) action related to hyperoestrogenaemia following superovulation. Superovulated immature and oestradiol-17beta-treated adult rats were infused with 100 or 300 microg/ml of octreotide respectively, or injected daily with 1 or 10 microg of octreotide from day 1 to day 3 of pregnancy. On day 3, embryos were collected from the oviducts and uteri. Uterine luminal fluid was subjected to embryo culture. The amounts of uterine IGF-I and IGF binding proteins (IGFBP) were determined by radioimmunoassay and ligand binding assay respectively. Octreotide infusion normalized uterine IGF-I action following superovulatory and oestradiol-17beta treatment, by reducing IGF-I concentrations and increasing IGFBP concentrations. Octreotide infusion increased the number of normal embryos by 2.7-fold and 1.7-fold in superovulated and oestradiol-17beta- treated rats respectively, and reversed the detrimental effects of uterine luminal fluid on embryonic development caused by superovulatory and oestradiol-17beta treatment. Daily injections with octreotide had similar but reduced effects in all parameters examined in both treatment groups. In conclusion, octreotide may reduce embryonic loss, at least in part, by normalizing IGF-I action following superovulation.      

Administration of a CXC Chemokine Receptor 2 (CXCR2) Antagonist,SCH527123, Together with Oseltamivir Suppresses NETosis and Protects Mice from Lethal Influenza and Piglets from Swine-Influenza Infection

Excessive neutrophil influx, their released neutrophil extracellular traps (NETs), and extracellular histones are associated with disease severity in influenza-infected patients. Neutrophil chemokine receptor CXC chemokine receptor 2 (CXCR2) is a critical target for suppressing neutrophilic inflammation. Herein, temporal dynamics of neutrophil activity and NETosis were investigated to determine the optimal timing of treatment with the CXCR2 antagonist, SCH527123 (2-hydroxy-N,N-dimethyl-3-[2-([(R)-1-(5-methyl-furan-2-yl)-propyl]amino)-3,4-dioxo-cyclobut-1-enylamino]-benzamide), and its efficacy together with antiviral agent, oseltamivir, was tested in murine and piglet influenza-pneumonia models. SCH527123 plus oseltamivir markedly improved survival of mice infected with lethal influenza, and diminished lung pathology in swine-influenza–infected piglets. Mechanistically, addition of SCH527123 in the combination treatment attenuated neutrophil influx, NETosis, in both mice and piglets. Furthermore, neutrophils isolated from influenza-infected mice showed greater susceptibility to NETotic death when stimulated with a CXCR2 ligand, IL-8. In addition, CXCR2 stimulation induced nuclear translocation of neutrophil elastase, and enhanced citrullination of histones that triggers chromatin decondensation during NET formation. Studies on temporal dynamics of neutrophils and NETs during influenza thus provide important insights into the optimal timing of CXCR2 antagonist treatment for attenuating neutrophil-mediated lung pathology. These findings reveal that pharmacologic treatment with CXCR2 antagonist together with an antiviral agent could significantly ameliorate morbidity and mortality in virulent and sublethal influenza infections.

Influenza virus infections during pandemic outbreaks and yearly seasonal epidemics cause significant morbidity and mortality rates globally.¹ Seasonal influenza-associated deaths have increased in recent years, with an estimated of >600,000 fatalities annually.² A significant proportion of hospitalized patients with influenza develop complications of acute respiratory distress syndrome, characterized by widespread alveolar-capillary injury, inflammation, edema, and parenchymal hemorrhage.3, 4, 5, 6, 7, 8 These pathologic manifestations are driven by virus-inflicted cytopathic effects as well as exaggerated host immune responses.9, 10, 11 Vaccination is the logical choice for controlling the virus. However, because of unrelenting emergence of new strains and their mutative ability, vaccination presents a major challenge during influenza outbreaks.^12,13 In such cases, treatment primarily depends on antiviral therapy. Administration of antiviral drugs may not always be effective, as considerable lung pathology is mediated by exaggerated host-immune responses in addition to virus-inflicted cytotoxicity.14, 15, 16, 17Previously, we established that massive neutrophil influx, their induced neutrophil extracellular traps (NETs), and extracellular histones (ECHs) aggravate pulmonary pathology in severe influenza.18, 19, 20, 21, 22, 23 Aberrant neutrophil activity and accumulation of NETs are also documented in patients with severe influenza.^24,25 Neutrophils are recruited to the site of injury/infection via chemokine signaling, mediated through chemokine receptors. Among various chemokine receptors, CXC chemokine receptor 2 (CXCR2) plays a critical role in modulating neutrophil functionality during influenza.²⁶ Numerous clinical studies have also tested CXCR2 antagonists for their efficacy in reducing inflammation and organ injuries in acute and chronic diseases.27, 28, 29, 30, 31 Recently, human phase 2 trials evaluated the safety and efficacy of a CXCR2 antagonist, danirixin, alone or in combination with oseltamivir in influenza-infected patients.^27,28 Although administration of danirixin was found to be safe and well-tolerated, no differences in the clinical scores were observed between patients given oseltamivir alone and those given danirixin plus oseltamivir.²⁷ Furthermore, there was inconsistency in neutrophil numbers among different treatment groups. This inconsistency may be attributed to the absence of rational determination of the optimal timing and dosing of danirixin, to achieve the fine balance of suppressing excessive neutrophil influx, without compromising the beneficial host immunity by neutrophils. Moreover, the underlying mechanistic roles of targeting CXCR2 and its pathogenic association with influenza pneumonia have not been established.NETs are large extracellular web-like chromatin strands that were initially proposed to have a defense mechanism against invading pathogens.³² However, excessive release of NETs aggravates tissue injury and death, as reported in several disease conditions.33, 34, 35, 36 NETosis is regulated by various granule and nuclear proteins.³⁷ Myeloperoxidase (MPO) and neutrophil elastase (NEs) are released from azurophilic granules, anchor chromatin scaffolds in NETs, and mediate histone degradation during NETosis.³⁸ We reported earlier that blocking MPO decreases NETs, but signaling mechanisms in influenza-induced NETosis remain unclear.^17,18 Herein, we evaluated the therapeutic efficacy of a CXCR2 antagonist, SCH527123 (2-hydroxy-N,N-dimethyl-3-[2-([(R)-1-(5-methyl-furan-2-yl)-propyl]amino)-3,4-dioxo-cyclobut-1-enylamino]-benzamide) alone or in combination with antiviral agent, oseltamivir (which inhibits viral neuraminidase and prevents progeny virus release from infected cells), in models of lethal influenza-infected mice and sublethal swine influenza-infected piglets. SCH527123 plus oseltamivir significantly improved survival in lethal influenza-challenged mice, and attenuated lung pathology in swine influenza-infected piglets. Thus, SCH5277123 plus oseltamivir represents a promising combination treatment against influenza pneumonia.     

A prospective trial of short‐fractionation radiotherapy for the palliation of liver metastases

The purpose of this study was to prospectively examine the effectiveness and tolerability of a simple radiotherapy technique for the palliation of symptomatic liver metastases. Twenty‐eight patients with symptomatic liver metastases were enrolled from seven centres, and received targeted (partial or whole) liver irradiation consisting of 10 Gy in two fractions over 2 days. Symptoms at baseline were hepatic pain (27 patients), abdominal distension (19), night sweats (12), nausea (18) and vomiting (eight). Twenty‐two patients (76%) had failed previous treatment with chemotherapy, hormonal therapy and/or high‐dose steroids. Symptoms and potential toxicities were prospectively assessed at the time of treatment, then 2, 6 and 10 weeks later. Individual symptom response rates were 53?66% at 2 weeks. Partial or complete global symptomatic responses were noted in 15 patients (54%) overall. The treatment was well tolerated with two patients (7%) experiencing grade 3 toxicity (one vomiting and one diarrhoea); however, four patients reported temporary worsening of pain shortly after treatment. This simple and well‐tolerated treatment achieves useful palliation.     

Association of dry eye disease with smoking: A systematic review and meta-analysis

There is conflicting evidence for the association between smoking and dry eye disease (DED). We conducted a meta-analysis to determine the true relationship between smoking and DED. A systematic literature search was performed using electronic databases, including PubMed, Embase and Cochrane Library, till August 2021 to identify observational studies with data on smoking as risk factor of DED. Quality assessment of the included studies was conducted using Joanna Briggs Institute (JBI) critical appraisal checklists. The random-effects model was used to calculate the pooled odds ratio (OR). Heterogeneity was evaluated by Cochrane Q and I² index; in addition, subgroup, sensitivity, and meta-regression analyses were performed. Publication bias was assessed using funnel plot and Egger’s regression test. A total of 22 studies (4 cohort and 18 cross-sectional studies) with 160,217 subjects met the inclusion criteria and were included in this meta-analysis. There is no statistically significant relationship between current smokers (OR_adjusted = 1.14; 95% CI: 0.95–1.36; P = 0.15; I² = 84%) and former smokers (OR_adjusted = 1.06; 95% CI: 0.93–1.20; P = 0.38; I² = 26.7%) for the risk of DED. The results remained consistent across various subgroups. No risk of publication bias was detected by funnel plot and Eggers’s test (P > 0.05). No source of heterogeneity was observed in the meta-regression analysis. Our meta-analysis suggest current or former smoking may not be involved in the risk of dry eye disease. Further studies to understand the mechanism of interaction between current smokers and formers smokers with DED are recommended.     

Long term outcome of elective day case percutaneous coronary intervention in patients with stable angina

Patients undergoing elective PCI are traditionally admitted overnight, however day case PCI cuts costs and has been proposed as a safe method for selected patients. We evaluated the success and long term clinical outcomes of day case percutaneous coronary intervention (PCI) for outpatients with stable angina.In total, 484 consecutive patients treated over a five year period with planned day case PCI were studied and followed up for 12 months. Successful PCI with same day discharge was performed in 463 patients (95.7%). There were 21 patients (4.3%) who required hospital admission. Reasons for failed discharge were hematoma formation (n = 7, 1.4%), coronary dissection (n = 4, 0.8%), post-procedural chest pain (n = 3, 0.6%), prolonged procedure (n = 2, 0.4%), and 1 each of acute stent thrombosis, coronary perforation, anaphylaxis, minor drug reaction and a functional study for untreated disease. One year follow up was complete for 439/484 (90.7%). At 12 months there were 6 hospitalizations for angina (1.2%, 95% CI 0.6–3.0%), 20 repeat revascularisations (4.1%, 95% CI 2.7–6.3%), 3 myocardial infarctions (0.6%, 95% CI 0.2–2.1%) and 2 deaths (0.4%, 95% CI 0.1–1.6%). Event free survival at 1 year follow up was 93.6% (95% CI 90.7–95.6%).Selecting patients for day case PCI is safe, and can achieve a high rate of success with excellent long term outcomes.     

The distribution of erythrocyte phospholipids in hereditary spherocytosis demonstrates a minimal role for erythrocyte spectrin on phospholipid diffusion and asymmetry

In the human erythrocyte membrane phosphatidylcholine and sphingomyelin reside mainly in the outer leaflet, whereas the aminophospholipids, phosphatidylethanolamine and phosphatidylserine, are mainly found in the inner leaflet. Maintenance of phospholipid asymmetry has been assumed to involve interactions between the aminophospholipids and the membrane skeleton, in particular spectrin. To investigate whether spectrin contributes to maintaining the phospholipid transbilayer distribution and kinetics of redistribution, we studied erythrocytes from hereditary spherocytosis patients whose spectrin levels ranged from 34% to 82% of normal. The phospholipid composition and the accessibility of membrane phospholipids to hydrolysis by phospholipases were in the normal range. Spin-labeled phosphatidylserine and phosphatidylethanolamine analogues that had been introduced into the outer leaflet were rapidly transported at 37 degrees C to the inner leaflet, whereas the redistribution of spin-labeled phosphatidylcholine was slower. The kinetics of transbilayer movement of these spin-labeled phospholipid in all samples was in the normal range and was not affected by the level of spectrin. Although these erythrocyte membranes contained as little as 34% of the normal level of spectrin and were characterized by several physical abnormalities, the composition, distribution, and transbilayer kinetics of the phospholipids were found to be normal. We therefore conclude that spectrin plays, at best, only a minor role in maintaining the distribution of erythrocyte membrane phospholipid.     

Safety of magnetic resonance imaging one to three days after bare metal and drug-eluting stent implantation

Despite emerging evidence that magnetic resonance imaging (MRI) is safe within 8 weeks after bare metal coronary stenting, there are limited data on the safety of MRI imaging very early (1 to 3 days) after stent implantation and no published studies to date on the safety of MRI after insertion of drug-eluting stents (DESs). Forty-nine patients underwent cardiovascular MRI (1.5 T) at a median of 1 day after complex percutaneous coronary intervention. The average number of stents per patient was 2.2 +/- 1.1, and the average stent length per patient was 37.8 +/- 19.7 mm. In 15 of these patients > or =1 DES was used: paclitaxel DESs in 14 and sirolimus DESs in 1. In the DES group, the average number of stents was 1.75 +/- 1.0 per patient (3 patients received 3 DESs), and average DES length was 36.5 +/- 14.8 mm per patient. No acute thrombosis was recorded, and at 9-month clinical follow-up only 2 patients (4%) developed adverse events (1 target vessel restenosis and 1 nontarget vessel revascularization); these patients were in the non-DES group.