Coadministration of liposomal methylglyoxal increases the activity of amphotericin B against Candida albicans in leukopoenic mice

Abstract

In this study, we investigated the therapeutic efficacy of a combination of liposomal amphotericin B (Lip-Amp B) and Methylglyoxal (Lip-MG) against Candida albicans in the leukopoenic mice. The antifungal efficacy of Lip-Amp B or Lip-MG or a combination of Lip-Amp B and Lip-MG was evaluated by the analysis of the survival rate and the fungal load in the treated mice. The immune-stimulatory effect of Lip-MG on macrophages was evaluated by analysing the secretion of proinflammatory cytokines. C. albicans infected mice treated at the doses of 1 and 2?mg/kg of Lip-Amp B showed 20% and 50% survival rates, respectively. Whereas the mice treated with free Amp B at the same doses died within 40?days of treatment. Interestingly, C. albicans infected mice treated with a combination of Lip-Amp B and Lip-MG had 70% survival rate on day 40 postinfection. Moreover, treatment of macrophages with Lip-MG increased their fungicidal activity and the secretion of proinflammatory cytokines, including TNF-α and IL-1β. These findings suggested that co-treatment with Lip-Amp B and Lip-MG had a synergistic effect and could be effective against C. albicans in immunocompromised subjects.     

Blood-Brain Barrier Permeability of Asiaticoside,Madecassoside and Asiatic Acid in Porcine Brain Endothelial Cell Model

Neurotherapeutic potentials of Centella asiatica and its reputation to boost memory, prevent cognitive deficits and improve brain functions are widely acknowledged. The plant's bioactive compounds, i.e. asiaticoside, madecassoside and asiatic acid were reported to have central nervous system (CNS) actions, particularly in protecting the brain against neurodegenerative disorders. Hence, it is important for these compounds to cross the blood-brain barrier (BBB) to be clinically effective therapeutics. This study aimed to explore the capability of asiaticoside, madecassoside and asiatic acid to cross the BBB using in vitro BBB model from primary porcine brain endothelial cells (PBECs). Our findings showed that asiaticoside, madecassoside and asiatic acid are highly BBB permeable with apparent permeability (P_app) of 70.61 ± 6.60, 53.31 ± 12.55 and 50.94 ± 10.91 × 10^?6 cm/s respectively. No evidence of cytotoxicity and tight junction disruption of the PBECs were observed in the presence of these compounds. Asiatic acid showed cytoprotective effect towards the PBECs against oxidative stress. This study reported for the first time that Centella asiatica compounds demonstrated high capability to cross the BBB, comparable to central nervous system drugs, and therefore warrant further development as therapeutics for the treatment of neurodegenerative diseases.     

Commonly used agent for acute pain management of sickle cell anemia in Saudi Emergency Department: A narrative review

IntroductionSickle-cell disease (SCD) is one of the most common hematologic inherited disorders in Saudi Arabia. Vaso-occlusive pain crisis in SCD is a major cause for emergency visits and patients’ pain may be undertreated. This study presents a narrative literature review of current agents used to manage acute pain crisis in SCD patients presenting to the emergency department in hospitals of Saudi Arabia.MethodWe conducted a narrative review on relevant published articles about sickle cell disease pain crisis management in Saudi Arabia and included seven relevant studies based on our inclusion criteria.ResultsUsing our search strategy, we included 7 studies Out of 4052. Studies included were conducted in different locations in the country. Four studies were in the Eastern region while only one in Western and One in Central regions. Those studies included around 2441 patients, in total. Morphine was used in 5 studies out of the 7 included. Pethidine was used in 4. One study used Isoxsuprine and another study used tinzaparin.ConclusionWe found that continuous administration of IV morphine accompanied by oral analgesics including NSAIDs and acetaminophen is the most commonly used practice for treating SCD patients presenting with a vaso-occlusive pain crisis. Possible effectiveness of tinzaparin, isoxsuprine, and pethidine as therapeutic options may be considered. However, there was no recommendation for a certain agent to be prescribed. We recommend conducting further clinical randomized-controlled trials.     

Pharmacist-led collaborative medication management programs for oral antineoplastic therapies: A systematic literature review

ObjectivesThe aim of this systematic review is to summarize the structure, process, and outcomes of pharmacist-led collaborative medication management programs for oral antineoplastic therapies (OATs).MethodsIncluded studies were peer-reviewed journal articles published in English, between January 2000 to May 2020, and reporting on pharmacist-led collaborative medication management programs for patients on OATs. To be included, studies had to report on the pharmacy practice model, pharmacist interventions, and outcomes of the medication management program. The Donabedian model informed the data extraction and summary. Two independent researchers assessed the risk of bias (confounding) for all included studies (n = 12) using the NIH tool and Cochrane ROBINS-I for observational research.ResultsThere were 12 studies that met inclusion criteria. The structure of the programs included hiring oncology pharmacists to deliver interventions, standardized templates for electronic medical record documentation, and administrative workflow changes (e.g., automatic referrals). The most common pharmacist interventions (processes) were patient education and counseling, adverse event monitoring, and dose modifications. All studies reported one or more positive outcomes, including improved patient adherence, safety, cost savings, cost avoidance, and patient satisfaction. All included studies used an observational study designs, and the majority of studies had moderate to high risk of bias.ConclusionThe evidence suggests that pharmacist-led collaborative medication management programs may have beneficial clinical and economic outcomes. The implementation of these programs could be strengthened by using a conceptual framework to guide program development, implementation, and evaluation and effectiveness-hybrid study designs to assess clinical and implementation outcomes. The risk of bias should be addressed by using more robust study designs and rigorous data collection and analysis methods.     

Role of Nitric Oxide in Neurodegeneration: Function,Regulation, and Inhibition

Reactive nitrogen species (RNS) and reactive oxygen species (ROS), collectively known as reactive oxygen and nitrogen species (RONS), are the products of normal cellular metabolism and interact with several vital biomolecules including nucleic acid, proteins, and membrane lipids and alter their function in an irreversible manner which can lead to cell death. There is an imperative role for oxidative stress in the pathogenesis of cognitive impairments and the development and progression of neural injury. Elevated production of higher amounts of nitric oxide (NO) takes place in numerous pathological conditions, such as neurodegenerative diseases, inflammation, and ischemia, which occur concurrently with elevated nitrosative/oxidative stress. The enzyme nitric oxide synthase (NOS) is responsible for the generation of NO in different cells by conversion of L-arginine (Arg) to L-citrulline. Therefore, the NO signaling pathway represents a viable therapeutic target. Naturally occurring polyphenols targeting the NO signaling pathway can be of major importance in the field of neurodegeneration and related complications. Here, we comprehensively review the importance of NO and its production in the human body and afterwards highlight the importance of various natural products along with their mechanisms against various neurodegenerative diseases involving their effect on NO production.     

2,4,6-Trihydroxy-3-geranyl acetophenone suppresses vascular leakage and leukocyte infiltration in lipopolysaccharide-induced endotoxemic mice

ContextLipopolysaccharide (LPS) exacerbates systemic inflammatory responses and causes excessive fluid leakage. 2,4,6-Trihydroxy-3-geranyl acetophenone (tHGA) has been revealed to protect against LPS-induced vascular inflammation and endothelial hyperpermeability in vitro.ObjectiveThis study assesses the in vivo protective effects of tHGA against LPS-induced systemic inflammation and vascular permeability in endotoxemic mice.Materials and methodsBALB/c mice were intraperitoneally pre-treated with tHGA for 1 h, followed by 6 h of LPS induction. Evans blue permeability assay and leukocyte transmigration assay were performed in mice (n = 6) pre-treated with 2, 20 and 100 mg/kg tHGA. The effects of tHGA (20, 40 and 80 mg/kg) on LPS-induced serum TNF-α secretion, lung dysfunction and lethality were assessed using ELISA (n = 6), histopathological analysis (n = 6) and survivability assay (n = 10), respectively. Saline and dexamethasone were used as the negative control and drug control, respectively.ResultstHGA significantly inhibited vascular permeability at 2, 20 and 100 mg/kg with percentage of inhibition of 48%, 85% and 86%, respectively, in comparison to the LPS control group (IC₅₀=3.964 mg/kg). Leukocyte infiltration was suppressed at 20 and 100 mg/kg doses with percentage of inhibition of 73% and 81%, respectively (IC₅₀=17.56 mg/kg). However, all tHGA doses (20, 40 and 80 mg/kg) failed to prevent endotoxemic mice from lethality because tHGA could not suppress TNF-α overproduction and organ dysfunction.Discussion and conclusionstHGA may be developed as a potential therapeutic agent for diseases related to uncontrolled vascular leakage by combining with other anti-inflammatory agents.     

Clinacanthus nutans attenuates atherosclerosis progression in rats with type 2 diabetes by reducing vascular oxidative stress and inflammation

ContextAtherosclerosis predisposes individuals to adverse cardiovascular events. Clinacanthus nutans L. (Acanthaceae) is a traditional remedy used for diabetes and inflammatory conditions.ObjectivesTo investigate the anti-atherosclerotic activity of a C. nutans leaf methanol extract (CNME) in a type 2 diabetic (T2D) rat model induced by a high-fat diet (HFD) and low-dose streptozotocin.Materials and methodsSixty male Sprague-Dawley rats were divided into five groups: non-diabetic fed a standard diet (C), C + CNME (500 mg/kg, orally), diabetic fed an HFD (DM), DM + CNME (500 mg/kg), and DM + Metformin (DM + Met; 300 mg/kg). Treatment with oral CNME and metformin was administered for 4 weeks. Fasting blood glucose (FBG), serum lipid profile, atherogenic index (AI), aortic tissue superoxide dismutase levels (SOD), malondialdehyde (MDA), and tumour necrosis factor-alpha (TNF-α) were measured. The rats’ aortas were stained for histological analysis and intima-media thickness (IMT), a marker of subclinical atherosclerosis.ResultsThe CNME-treated diabetic rats had reduced serum total cholesterol (43.74%; p = 0.0031), triglycerides (80.91%; p = 0.0003), low-density lipoprotein cholesterol (56.64%; p = 0.0008), AI (51.32%; p < 0.0001), MDA (60.74%; p = 0.0026), TNF-α (61.78%; p = 0.0002), and IMT (39.35%; p < 0.0001) compared to untreated diabetic rats. SOD level, however, increased (53.36%; p = 0.0326). These CNME effects were comparable to those in the metformin-treated diabetic rats.ConclusionsC. nutans possesses anti-atherosclerotic properties, which may be due to reductions in vascular tissue oxidative stress, inflammation, and serum AI. Continued studies on atherosclerotic animal models are suggested.     

Antibacterial Activity of Mother Tinctures of Cholistan Desert Plants in Pakistan

The mother tinctures of desert were screened for antibacterial activity against bacterial strains of Gram-positive and Gram-negative bacteria. Mother tinctures were prepared by maceration process and antibacterial activity of different plants was evaluated and compared by measuring their zones of inhibition. The results indicated that Boerrhavia diffusa mother tincture had excellent activity only against Escherichia coli. Mother tincture of Chorozophora plicata showed highly effective results against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa whereas Echinops echinatus mother tincture showed highly effectiveness only against Salmonella typhi. Heliotropium europaeum mother tincture exhibited highly effective results against Bacillus subtilis in all concentrations. Tamrix aphylla presented maximum activity only against Bacillus subtilis in all three concentrations. Among the selected species Heliotropium europaeum, Chorozophora plicata and Tamrix aphylla were more effective plants against many microorganisms. However, Boerrhavia diffusa and Echinops echinatus were less effective plants against tested pathogenic bacteria.     

Electrochemical determination of Cephalothin antibiotic by adsorptive stripping voltammetric technique

A sensitive and reliable stripping voltammetric method was developed to determine Cephalothin antibiotic drug. This method is based on the adsorptive accumulation of the drug at a hanging mercury drop electrode and then a negative sweep was initiated, which yield a well defined cathodic peak at −625 mV versus Ag/AgCl reference electrode. To achieve high sensitivity, various experimental and instrumental variables were investigated such as supporting electrolyte, pH, accumulation time and potential, drug concentration, scan rate, convection rate and working electrode area. The monitored adsorptive current was directly proportional to the concentration of Cephalothin and it shows a linear response in the range from 4×10⁻⁷ to 1.2×10⁻⁶ mol l⁻¹ (correlation coefficient=0.9995) and the detection limit (S/N=3) is 3.3×10⁻⁹ mol l⁻¹ at an accumulation time of 3 min. The developed AdSV procedure shows a good reproducibility, the relative standard deviation R.S.D.% (n=10) at a concentration level of 5×10⁻⁷ mol l⁻¹ was 0.94%. Possible interferences by other pharmaceutical drugs and surfactants have been also evaluated. The applicability of this approach was illustrated by the determination of Cephalothin in pharmaceutical preparation and biological fluids such as serum and urine.