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Publications | School of Pharmacy

Publications

2020
Boris Zingerman, Ziv, Danny , Feder Krengel, Netta , Korzets, Asher , and Matok, Ilan . 2020. Cessation Of Bezafibrate In Patients With Chronic Kidney Disease Improves Renal Function.. Scientific Reports, 10, 1, Pp. 19768. doi:10.1038/s41598-020-76861-1. Abstract
Bezafibrate (BzF) is eliminated by renal excretion and dosage must be reduced in patients with chronic kidney disease (CKD). There is a concern that BzF causes a further deterioration in renal function in patients with CKD. This study assessed whether BzF discontinuation or dose reduction in CKD patients improves renal function. 117 CKD patients treated with BzF between 2009 and 2014 were studied for demographics, comorbid conditions and laboratory variables. Data compared 2 groups: an intervention group of 64 patients where recommendations regarding BzF administration was implemented and a control group of 37 patients. Follow-up was maintained for 12 months. In the intervention group, estimated glomerular filtration rate (eGFR) increased from 38 to 42 mL/min/1.73 m(2) (p = 0.01); blood urea levels decreased from 81 to 77 mg/dL (p = 0.04). Serum creatinine decreased by more than 0.2 mg/dL in 45% of the intervention group, as compared to 19% of the control group (p < 0.01). Improvement in eGFR was seen exclusively in patients who stopped BzF completely (eGFR increased from 38 to 44 mL/min/1.73 m(2)). In the intervention group, TG level increased from 183 to 220 mg/dL (p < 0.001). BzF cessation in approximately 50% of patients with CKD was associated with an increase in eGFR.
Mark Feldman, Sionov, Ronit , Reem Smoum, , Raphael Mechoulam, , Ginsburg, Isaac , and Steinberg, Doron . 2020. Comparative Evaluation Of Combinatory Interaction Between Endocannabinoid System Compounds And Poly-L-Lysine Against Streptococcus Mutans Growth And Biofilm Formation.. Biomed Research International, 2020, Pp. 7258380. doi:10.1155/2020/7258380. Abstract
Endocannabinoid/endocannabinoid-like (EC/EC-like) are natural endogenous compounds which have been found to affect MRSA pathogenicity. Our previous studies showed that EC/EC-like was able to impair staphylococcal biofilm formation and maintenance as well as to alter biofilm-associated virulence factors. In the present study, we investigated the combinatory effect of the selected EC/EC-like with a natural antimicrobial agent, poly-L-lysine, on cariogenic bacteria Streptococcus mutans growth and biofilm formation. Among four tested EC/EC-like, only two, anandamide (AEA) and oleoylethanolamide (OEA), exhibited synergistic combinatory effect with poly-L-lysine against S. mutans. We attribute this distinct effect to differences in the fatty acid chain structure of the selected EC/EC-like compounds. Moreover, AEA exerted a specific antibiofilm mode of action against S. mutans by effecting total inhibition of biofilm formation while still allowing bacteria viability. Finally, we postulate that the presence of EC/EC-like and poly-L-lysine could enhance the permeability and efficacy of each other via hydrophobic and electrostatic interactions with the S. mutans membrane. In conclusion, we assume that a combination of endogenous natural compounds such as EC/EC-like and poly-L-lysine may benefit oral hygiene by preventing dental plaque.
Martyna Lubinska-Szczygeł, Polkowska, Żaneta , Dymerski, Tomasz , and Gorinstein, Shela . 2020. Comparison Of The Physical And Sensory Properties Of Hybrid Citrus Fruit Jaffa(®) Sweetie In Relation To The Parent Fruits.. Molecules (Basel, Switzerland), 25, 12. doi:10.3390/molecules25122748. Abstract
In the presented study, an overall Jaffa sweetie evaluation was made to find a correlation between Citrus grandis Osbeck × Citrus paradisi Macf. and its parent fruits' (Citrus grandis Osbeck, Citrus paradisi Macf.) properties. Based on the sensory analysis, it was found that the taste and aroma of the new hybrid fruit are close to pummelo. By the use of chromatographic analysis, the selected monoterpenes present in the fruits were quantified. $\alpha$-terpineol was typed as the main monoterpene compound in the headspace of sweetie and grapefruit, with the concentrations: 20.96 and 87.9 $μ$g/g, respectively. In turn, $\gamma$-terpinene was chosen as the most important monoterpene determining the flavor of sweetie fruit. Based on two-dimensional gas chromatography (GC × GC-TOF-MS) and principal component analysis (PCA) of the data, several volatile compounds were associated with analyzed fruits' aroma. Jaffa Sweetie is the hybrid fruit with sensory properties similar to pummelo with a higher content of monoterpenes, which improves its health benefits compared to the parent fruit. The research presents an instrumental method for assessing the aroma properties of the fruit as a reference method for sensory analysis, commonly used in the industry.
Constantin Itin, Komargodski, Rinat , Domb, Abraham J, and Hoffman, Amnon . 2020. Controlled Delivery Of Apomorphine Through Buccal Mucosa, Towards A Noninvasive Administration Method In Parkinson's Disease: A Preclinical Mechanistic Study.. Journal Of Pharmaceutical Sciences, 109, 9, Pp. 2729–2734. doi:10.1016/j.xphs.2020.05.017. Abstract
Apomorphine (APO), a potent treatment for Parkinson's disease, is only administered parenterally either as intermittent injections or as an infusion. This is due to extensive hepatic "first pass" metabolism. Prolonged delivery through buccal mucosa may be potential substitute for parenteral infusions. To investigate this concept of buccal mucosal delivery, permeability ex vivo studies were performed through excised porcine buccal mucosa by utilizing Ussing diffusion chamber. Permeability rates were assessed for APO from simulated saliva medium at pH 7.4 as well as with utilization of different permeability modifying methods. Lowering the pH to 5.9 decreased permeability rate six-fold, while addition of ethanol : propylene glycol solution elevated it four-fold. Addition of nano-scale lipospheres to the donor compartment delayed the accumulation of APO at the receiver side, prolongating the lag-time from one to approx. three hours. These findings were strengthened by results obtained with co-administration of permeability markers (standards) atenolol and metoprolol. Simulation of the obtained permeability rates to in vivo setup in human showed therapeutically relevant plasma levels when using the outcomes of the current study. These findings verify the novel concept of APO prolonged release buccal administration as a noninvasive substitute for parenteral infusions in treating Parkinson's disease.
Emilio Perucca and Bialer, Meir . 2020. Critical Aspects Affecting Cannabidiol Oral Bioavailability And Metabolic Elimination, And Related Clinical Implications.. Cns Drugs, 34, 8, Pp. 795–800. doi:10.1007/s40263-020-00741-5. Abstract
This article provides a critical appraisal of the available evidence concerning clinical exposure to orally administered cannabidiol (CBD), with special reference to factors affecting gastrointestinal absorption, presystemic elimination, and susceptibility to metabolic drug interactions. Although detailed studies have not been published, the available data suggest that the absolute bioavailability of CBD after oral dosing under fasting conditions is approximately 6%, and increases fourfold when the medication is co-administered with a high-fat meal. Based on measurements of CBD plasma exposure after oral dosing and a 6% absolute oral bioavailability estimate, the actual clearance of CBD in adults can be inferred to be in the order of 67 L/h, which is similar to the value of 74 ± 14 L/h (mean ± standard deviation) determined after intravenous injection of a 20-mg dose of deuterium-labeled CBD in five healthy subjects. Assuming that the CBD blood-to-plasma ratio is about 1, as in the case of tetrahydrocannabinol (THC), and that CBD metabolism takes place virtually entirely in the liver, it can be estimated that about 70 to 75% of an orally absorbed dose of CBD can be removed by hepatic metabolism before reaching the systemic circulation, and additionally CBD gastrointestinal absorption is incomplete. A formulation with improved biopharmaceutical properties could increase the extent of CBD absorption about fourfold (i.e., to the level achieved with the currently available formulations co-administered with a high-fat meal) and minimize the influence of food effects on CBD bioavailability. There is also potential for favoring the absorption of CBD through the enteric lymphatic system, thereby reducing the extent of presystemic hepatic elimination. Evidence that CBD can behave as a high hepatic clearance compound also has implications when predicting the magnitude of drug-drug interactions affecting CBD metabolism. These considerations have important clinical relevance, particularly with respect to the objective of minimizing pharmacokinetic variability and consequent intra- and interindividual differences in therapeutic response and susceptibility to adverse effects.
Yossi Bitton and Diav-Citrin, Orna . 2020. Cutaneous Leishmaniasis: Case Series On Pregnancy Outcome.. Open Forum Infectious Diseases, 7, 11, Pp. ofaa479. doi:10.1093/ofid/ofaa479. Abstract
We report the pregnancy outcomes of 6 women with cutaneous leishmaniasis; 5 of these women received topical antileishmenial therapy during gestation with paromomycin plus methylbenzethonium chloride combination ointment and/or sodium stibogluconate intralesional injections. No teratogenic effects were reported. Furthermore, no vertical transmission was observed.
Sapir Ron-Doitch and Kohen, Ron . 2020. The Cutaneous Physiological Redox: Essential To Maintain But Difficult To Define.. Antioxidants (Basel, Switzerland), 9, 10. doi:10.3390/antiox9100942. Abstract
Skin is a unique tissue, possessing extremely efficient protective and regulative mechanisms, similar only to the gut and lungs. These tissues serve as an interface with the environment and are exposed to stressors from both endogenous and exogenous sources. Interestingly, all these stressors lead downstream to a cellular production of reactive oxygen species (ROS) and other electrophiles, which, in turn could have deleterious outcomes for the living organism. Hence, such tissues should always maintain a "high-alert" condition in order to cope with these various insults. Nevertheless, a moderate production of ROS induced by stressors could actually be beneficial, although it is impossible to predict if and which exposure would lead to which outcome. Consequently, a parameter which would indicate the skin's readiness to cope with continuously fluctuating conditions is required. It has been proposed that the redox status may serve as a suitable indicator. In this opinion manuscript, we argue that the redox status is a vague parameter that is difficult to characterized and quantify due to its extremely dynamic nature. The common convention that the redox status is composed solely of the balance between oxidants and reductants (ROS and antioxidants) is also thought-provoking. Since this parameter in vivo behaves in a dynamic and complex manner, it better fits the description of a process, rather than an individual parameter. We suggest that the homeostatic modulation of the physiological redox (PR) should be in focus, rather than the redox status parameter itself. It is further suggested that low molecular weight antioxidants (LMWA) are, in fact, rather insignificant concerning the PR maintenance, and that the major contributors to this delicate modulation are regulative, protein-based systems such as the protective phase II antioxidant enzymes. Moreover, we show that skin microbiome and cutaneous advanced lipid peroxidation end-products (ALEs) take part in sustaining the cutaneous PR homoeostasis via activation of the Nrf2-Keap1 protective pathway.
Alaa Talhami, Swed, Avi , Hess, Shmuel , Ovadia, Oded , Greenberg, Sarit , Schumacher-Klinger, Adi , Rosenthal, David , Shalev, Deborah E. , Hurevich, Mattan , Lazarovici, Philip , Hoffman, Amnon , and Gilon, Chaim . 2020. Cyclizing Painkillers: Development Of Backbone-Cyclic Taps Analogs. Frontiers In Chemistry, 8. doi:10.3389/FCHEM.2020.532577. Abstract
Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6), which is metabolically stable and has the potential to become a peripheral painkiller being a full $μ$ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6), we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6).
Noam Y Steinman, Campos, Luis M, Feng, Yakai , Domb, Abraham J, and Hosseinkhani, Hossein . 2020. Cyclopropenium Nanoparticles And Gene Transfection In Cells.. Pharmaceutics, 12, 8. doi:10.3390/pharmaceutics12080768. Abstract
Non-viral vectors for the transfection of genetic material are at the frontier of medical science. In this article, we introduce for the first time, cyclopropenium-containing nanoparticles as a cationic carrier for gene transfection, as an alternative to the common quaternary ammonium transfection agents. Cyclopropenium-based cationic nanoparticles were prepared by crosslinking poly(ethylene imine) (PEI) with tetrachlorocyclopropene. These nanoparticles were electrostatically complexed with plasmid DNA into nanoparticles ($\sim$50 nm). Their cellular uptake into F929 mouse fibroblast cells, and their eventual expression in vitro have been described. Transfection is enhanced relative to PEI with minimal toxicity. These cyclopropenium nanoparticles possess efficient gene transfection capabilities with minimal cytotoxicity, which makes them novel and promising candidates for gene therapy.
Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects. We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report. Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials. Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication. Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.
Paweł Zagrodzki, Paśko, Paweł , Galanty, Agnieszka , Tyszka-Czochara, Małgorzata , Wietecha-Posłuszny, Renata , Rubió, Pol Salvans , Bartoń, Henryk , Prochownik, Ewelina , Muszyńska, Bożena , Sułkowska-Ziaja, Katarzyna , Bierła, Katarzyna , Łobiński, Ryszard , Szpunar, Joanna , and Gorinstein, Shela . 2020. Does Selenium Fortification Of Kale And Kohlrabi Sprouts Change Significantly Their Biochemical And Cytotoxic Properties?. Journal Of Trace Elements In Medicine And Biology : Organ Of The Society For Minerals And Trace Elements (Gms), 59, Pp. 126466. doi:10.1016/j.jtemb.2020.126466. Abstract
BACKGROUND: The sprouts of Brassica vegetables are known from their nutritional and chemopreventive values. Moreover, sprouts fortification with some trace elements, like selenium, may increase their importance in human diet. Thus, the aim of our study was to examine if selenium enrichment of kale and kohlrabi sprouts may influence their biochemical properties (phenolic acids and L-tryptophan content, antioxidant potential) or cytotoxic activity. Additional aim of the study was to evaluate the profile of selenium compounds and to describe the multidimensional interactions between the mentioned parameters. METHODS: Selenium content in the sprouts was evaluated by double-channel atomic fluorescence spectrometer AFS-230 with the flow hydride-generation system. Separation of selenium species in water soluble fraction was performed by size-exclusion LC-ICP-MS. The identification and quantification of phenolic acids and L-tryptophan was performed by HPLC. For antioxidant activity DPPH and FRAP methods were used. Cytotoxic activity of the sprouts extracts on a panel of human metastatic carcinoma cells was evaluated by MTT test. RESULTS: Selenium content in the fortified sprouts was several orders of magnitude higher than in the unfortified ones. Only small percentage of supplemented selenium (ca. 10 %) was incorporated into the sprouts as seleno-L-methionine, while the other detected selenium species remained unidentified. Selenium fortification differently stimulated the production of phenolic acids (sinapic, chlorogenic, isochlorogenic and caffeic acid) in the tested sprouts, depending on the particular species, selenium dose and the investigated compound. PCA analysis revealed strong correlation between antioxidant parameters and phenolic acids and L-tryptophan, while Se correlated only with caffeic acid. The sprouts extracts (≥1 mg/mL) showed cytotoxic potency to all the studied cancer cell lines (SW480, SW620, HepG2, SiHa), regardless the selenium supplementation. CONCLUSION: Se-fortified kale and kohlrabi sprouts are good candidates for functional food ingredients. Moreover, these results indicate that the sprouts enriched with sodium selenite show higher nutritional value, without significant changes in their cytotoxic activity.
Shiran Udi, Hinden, Liad , Ahmad, Majdoleen , Drori, Adi , Iyer, Malliga R, Cinar, Resat , Herman-Edelstein, Michal , and Tam, Joseph . 2020. Dual Inhibition Of Cannabinoid Cb(1) Receptor And Inducible Nos Attenuates Obesity-Induced Chronic Kidney Disease.. British Journal Of Pharmacology, 177, 1, Pp. 110–127. doi:10.1111/bph.14849. Abstract
BACKGROUND AND PURPOSE: Obesity, an important risk factor for developing chronic kidney disease (CKD), affects the kidneys by two main molecular signalling pathways: the endocannabinoid/CB(1) receptor system, whose activation in obesity promotes renal inflammation, fibrosis, and injury, and the inducible NOS (iNOS), which generates ROS resulting in oxidative stress. Hence, a compound that inhibits both peripheral CB(1) receptors and iNOS may serve as an effective therapeutic agent against obesity-induced CKD. EXPERIMENTAL APPROACH: Here, we describe the effect of a novel peripherally restricted, orally bioavailable dual CB(1) receptor/iNOS antagonist, MRI-1867 (3 mg·kg(-1) ), in ameliorating obesity-induced CKD, and compared its metabolic and renal efficacies to a stand-alone peripheral CB(1) receptor antagonist (JD5037; 3 mg·kg(-1) ), iNOS antagonist (1400W; 10 mg·kg(-1) ), and pair feeding. Mice with high-fat diet-induced obesity were treated orally with these compounds or vehicle (Veh) for 28 days. Standard diet-fed mice treated with Veh served as controls. KEY RESULTS: Enhanced expression of CB(1) receptors and iNOS in renal tubules was found in human kidney patients with obesity and other CKDs. The hybrid inhibitor ameliorated obesity-induced kidney morphological and functional changes via decreasing kidney inflammation, fibrosis, oxidative stress, and renal injury. Some of these features were independent of the improved metabolic profile mediated via inhibition of CB(1) receptors. An additional interesting finding is that these beneficial effects on the kidney were partially associated with modulating renal adiponectin signalling. CONCLUSIONS AND IMPLICATIONS: Collectively, our results highlight the therapeutic relevance of blocking CB(1) receptors and iNOS in ameliorating obesity-induced CKD.
Michal Linial, Stern, Amos , and Weinstock, Marta . 2020. Effect Of Ladostigil Treatment Of Aging Rats On Gene Expression In Four Brain Areas Associated With Regulation Of Memory.. Neuropharmacology, 177, Pp. 108229. doi:10.1016/j.neuropharm.2020.108229. Abstract
Episodic and spatial memory decline in aging and are controlled by the hippocampus, perirhinal, frontal and parietal cortices and the connections between them. Ladostigil, a drug with antioxidant and anti-inflammatory activity, was shown to prevent the loss of episodic and spatial memory in aging rats. To better understand the molecular effects of aging and ladostigil on these brain regions we characterized the changes in gene expression using RNA-sequencing technology in rats aged 6 and 22 months. We found that the changes induced by aging and chronic ladostigil treatment were brain region specific. In the hippocampus, frontal and perirhinal cortex, ladostigil decreased the overexpression of genes regulating calcium homeostasis, ion channels and those adversely affecting synaptic function. In the parietal cortex, ladostigil increased the expression of several genes that provide neurotrophic support, while reducing that of pro-apoptotic genes and those encoding pro-inflammatory cytokines and their receptors. Ladostigil also decreased the expression of axonal growth inhibitors and those impairing mitochondrial function. Together, these actions could explain the protection by ladostigil against age-related memory decline.
Dvora Izgelov, Shmoeli, Eliyahu , Domb, Abraham J, and Hoffman, Amnon . 2020. The Effect Of Medium Chain And Long Chain Triglycerides Incorporated In Self-Nano Emulsifying Drug Delivery Systems On Oral Absorption Of Cannabinoids In Rats.. International Journal Of Pharmaceutics, 580, Pp. 119201. doi:10.1016/j.ijpharm.2020.119201. Abstract
The aim of this research was to investigate the effect of the lipid component in self-emulsifying drug delivery systems on the oral absorption of major cannabinoids $Δ$(9)-tetrahydrocannabinol (THC) and Cannabidiol (CBD). The investigated lipids were either long chain triglycerides (LCT) or medium chain triglycerides (MCT) with different composition, fatty acid chain length, degree of saturation and their absorption pathway to the systemic circulation. Formulations were developed with the purpose of creating thermodynamically stable oil-in-water nano emulsions/suspensions with particle size of 50 nm or less which carry the lipophilic drug and increase water solubility. Following a methodic screening of suitable excipients in-vitro, leading formulations based on sesame oil or MIGLYOL® 812N (Type I LCT/MCT SNEDDS) and cocoa butter or tricaprin (Type II LCT/MCT SNEDDS) were investigated in the freely moving rat model. Results in rat model demonstrated that the effect of each type of lipid on bioavailability of cannabinoids is not straightforwardly anticipated. The differences in the effect of LCT and MCT on absorption was not substantial for Type I formulations, however, more prominent for Type II formulations. This unpredictable behavior in-vivo demonstrates the importance of investigating each vehicle pre-clinically, following the in-vitro development.
Noam Y. Steinman, Bentolila, Noam Y. , and Domb, Abraham J. . 2020. Effect Of Molecular Weight On Gelling And Viscoelastic Properties Of Poly(Caprolactone)–B‐ Poly(Ethylene Glycol)–B‐Poly(Caprolactone) (Pcl– Peg–Pcl) Hydrogels. Polymers, 12, 10, Pp. 1–12. doi:10.3390/POLYM12102372. Abstract
Hydrogels based on poly(caprolactone)–b‐poly(ethylene glycol)–b‐poly(caprolactone) (PCL–PEG–PCL) have been evaluated extensively as potential injectable fillers or depots for controlled release of drugs. Common drawbacks of these copolymer systems include instability of aqueous solutions and low mechanical strength of gels, issues which are commonly overcome by adding pendant groups to the end of the copolymer chains. Here, a systematic study of the effects of increasing polymer molecular weight (MW) is presented, utilizing PEG blocks of MW 2, 4 or 8 kDa. Triblock copolymers were prepared by the ring‐opening polymerization of Ɛ‐caprolactone by PEG. Copolymers prepared with PEG MW 2 kDa did not form hydrogels at any copolymer molecular weight. Copolymers prepared with PEG MW 4 kDa formed gels at MW between 11 and 13.5 kDa, and copolymers prepared with PEG MW 8 kDa formed gels at MW between 16 and 18 kDa. Copolymers with PEG block 8 kDa formed hydrogels with high viscosity (17,000 Pa∙s) and mechanical strength (G' = 14,000 Pa). The increased gel strength afforded by increased molecular weight represents a simple modification of the reactants used in the reaction feed without added synthetic or purification steps. Shear‐thinning of PCL‐PEG‐PCL triblock copolymer hydrogels allowed for injection through a standard 23G syringe, allowing for potential use as dermal fillers or drug delivery depots.
Ayala Hirsch, Wanounou, Maor , Perlman, Amichai , Hirsh-Raccah, Bruria , and Muszkat, Mordechai . 2020. The Effect Of Multidrug Exposure On Neurological Manifestations In Carbamazepine Intoxication: A Nested Case-Control Study.. Bmc Pharmacology & Toxicology, 21, 1, Pp. 47. doi:10.1186/s40360-020-00425-2. Abstract
BACKGROUND: In acute intoxication, carbamazepine concentration above 40 mcg/ml is associated with a risk of severe neurological consequences, including depressed consciousness, respiratory depression, cardiac conduction disorders, seizures, and death. Carbamazepine intoxication is often associated with the use of concomitant medications. However, the effect of exposure to other central-nervous-system (CNS) acting medications on the neurological manifestations of carbamazepine toxicity has not been evaluated. OBJECTIVE: To examine the effect of exposure to CNS-acting medications on the neurological effects of carbamazepine toxicity. METHODS: A retrospective nested case-control study of all patients > 18 years of age, with at least one test of carbamazepine levels > 18 mcg/ml recorded at the Hadassah Hospital Central Laboratory, between the years 2004-2016. Sociodemographic and clinical data were collected from the computerized medical records, and the characteristics of patients with and without severe neurological symptoms of carbamazepine intoxication were compared. RESULTS: Eighty patients were identified. In bivariate analyses, the odds of severe neurological symptoms was higher in patients with antidepressants use (odds ratio 8.7, 95% confidence interval: 1.8-41.2, p = 0.007), benzodiazepines use (8.6, 2.0-37.1, p = 0.004), and carbamazepine concentration above 30 mcg/ml (8.1, 1.9-33.3, p = 0.004). Multivariate models demonstrated that antidepressants and benzodiazepines were associated with severe neurological manifestations during carbamazepine intoxication, independently of carbamazepine concentration over 30 mcg/ml. ICU admission was associated in multivariate analysis with antidepressants (but not benzodiazepines) use, and with carbamazepine levels > 30 mcg/ml. CONCLUSIONS: Among patients with carbamazepine intoxication, severe neurological symptoms are associated with exposure to benzodiazepines or antidepressants and with carbamazepine levels higher than 30 mcg/ml.
Dvora Izgelov, Domb, Abraham J, and Hoffman, Amnon . 2020. The Effect Of Piperine On Oral Absorption Of Cannabidiol Following Acute Vs. Chronic Administration.. European Journal Of Pharmaceutical Sciences : Official Journal Of The European Federation For Pharmaceutical Sciences, 148, Pp. 105313. doi:10.1016/j.ejps.2020.105313. Abstract
Piperine is an alkaloid naturally found in black pepper with a myriad of pharmacological attributes. Piperine's most far reaching indication is drug absorption enhancment, with supportive data regarding its ability to inhibit first pass effect mechanisms. However, alongside these findings, the role of piperine as an absorption enhancer is undermined with publications stating an apparent effect of a metabolic inducer. The aim of this work is to investigate the effect of repeated administration of piperine in a lipid-based formulation ,on oral absorption of cannabidiol (CBD), compared to acute piperine dosing. The effect of piperine on CBD absorption was determined pre-clinically in the freely moving rat model. Results of this work demonstrated that there was no significant difference in piperine's effect, when given chronically or in a single dose regimen. Both groups resulted in approximate 2.5-fold increase in oral bioavailability of CBD compared to control group without piperine.
Rakesh Kumar, Geron, Matan , Hazan, Adina , and Priel, Avi . 2020. Endogenous And Exogenous Vanilloids Evoke Disparate Trpv1 Activation To Produce Distinct Neuronal Responses.. Frontiers In Pharmacology, 11, Pp. 903. doi:10.3389/fphar.2020.00903. Abstract
Neuronal signals are processed along the nociceptive pathway to convey discriminative information, which would manifest in the produced pain sensation. The transient receptor potential vanilloid 1 (TRPV1), an important signaling complex in nociceptors termini, is activated by different noxious stimuli that underlie distinct pain sensations. For example, while endovanilloids are associated with inflammatory pain and hypersensitivity through TRPV1 activation, the exovanilloid toxin, capsaicin, evokes an acute pain by activating this channel. Differences in the TRPV1 activation profile evoked by exogenous and endogenous vanilloids were suggested to underlie this disparity in pain sensations. However, the cellular processes that lead to these differences in pain sensation mediated by the same channel are not fully understood. Here, we sought to describe the neuronal response of TRPV1-expressing nociceptors to exo-and endovanilloids. To this end, we performed current-clamp recordings in rat trigeminal neurons exposed to either capsaicin or intracellular endovanilloids produced downstream of the bradykinin receptor BK2. Our results show that lipoxygenase metabolites generate persistent TRPV1-dependent action potential firing while capsaicin evokes robust depolarization and high-frequency firing that is quickly terminated by depolarization block. Additionally, we found that a weak TRPV1 activation prolongs action potential firing. Overall, our results indicate different firing patterns evoked by inflammatory mediators and capsaicin via TRPV1 that correlate with the respective subsequent pain sensation. These findings also suggest that differences in neuronal activation stem from the variable degree of TRPV1 activation they produce.
Michal Chehover, Reich, Reuven , and Davidson, Ben . 2020. Expression Of Wnt Pathway Molecules Is Associated With Disease Outcome In Metastatic High-Grade Serous Carcinoma.. Virchows Archiv : An International Journal Of Pathology, 477, 2, Pp. 249–258. doi:10.1007/s00428-019-02737-z. Abstract
The objective of this study was to analyze the expression and clinical role of Wnt pathway molecules in metastatic high-grade serous carcinoma (HGSC). mRNA expression by qPCR of 20 molecules related to Wnt signaling (WNT1, WNT2, WNT3, WNT4, WNT5A, WNT6, WNT7, WNT11, FZD1, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, LRP5, LRP6, DKK, CCND, RUNX2) was analyzed in 87 HGSC effusions. Thirty-nine surgical specimens (19 ovarian, 20 from other intra-abdominal sites) were analyzed for comparative purposes. Protein expression of YAP and LRP and their phosphorylated forms by western blotting were analyzed in 52 tumors. Significant differences in mRNA expression as a function of the anatomic site were observed for WNT3 (p = 0.005), WNT5A (p = 0.008), WNT7 (p < 0.001), FRZ5 (p = 0.04), and FRZ6 (p < 0.001). YAP and LRP and their phosphorylated forms were detected in HGSC specimens. FZD10 was overexpressed in effusions from patients who had complete response to chemotherapy compared with those with less favorable response (p = 0.037). WNT4 (p = 0.005), WNT7 (p = 0.047), RUNX2 (p = 0.038), LRP5 (p = 0.022), LRP6 (p = 0.011), FZD6 (p = 0.036), FZD7 (p = 0.004), and FZD10 (p = 0.015) levels were inversely related to primary chemoresistance. High FZD5 levels in pre-chemotherapy effusions tapped at diagnosis and high WNT2 levels in post-chemotherapy disease recurrence effusions were related to shorter overall survival (p = 0.018 and p = 0.011, respectively), whereas high RUNX2 (p = 0.031) and FZD1 (p = 0.029) in post-chemotherapy effusions were associated with longer overall survival. In multivariate analysis of post-chemotherapy cases, WNT2 (p = 0.002), RUNX2 (p = 0.017), FZD1 (p = 0.036), and FZD4 (p = 0.013) were independent prognosticators. In conclusion, expression of Wnt pathway molecules is anatomic site dependent. In HGSC effusions, it is informative of chemoresponse and survival.
Sindhu Doppalapudi, Jain, Anjali , Khan, Wahid , and Domb, Abraham J. 2020. Fenoldopam Mesylate For Treating Psoriasis: A New Indication For An Old Drug.. International Journal Of Pharmaceutics, 573, Pp. 118726. doi:10.1016/j.ijpharm.2019.118726. Abstract
Fenoldopam, a highly selective dopamine receptor agonist, is available in clinics as Corlopam™ i.v. for the management of severe hypertension. Recent reports demonstrate its anti-proliferative activity in vitro in a dose dependent manner. However, stability issues of the drug due to its susceptibility to oxidation, pH sensitivity, poor transdermal flux, and the barrier properties of skin present challenges to develop a topical formulation of fenoldopam. The aim of the present study is to suggest a stable topical formulation of fenoldopam for the treatment of psoriasis. Water washable ointment and glycerin-based carbopol anhydrous gel of fenoldopam intended for topical delivery were prepared and evaluated in vitro and in vivo. Results from pH dependent stability studies suggest the necessity to maintain acidic pH in final formulations. The presence of an acidic adjuster in ointment and unneutralised carbopol dispersion of anhydrous gel maintain the desired acidic environment in the formulations. Stability studies of prepared formulations performed for 90 days indicate that the drug remains stable in formulations. In vivo studies demonstrate the applicability of the formulations for better skin penetration, skin compliance, and photosafety. Efficacy studies using an imiquimod induced psoriasis model confirm the promising application of developed fenoldopam topical formulations for psoriasis.