C. Itin, D. Barasch, A.J. Domb, and A. Hoffman. 2020. “Prolonged oral transmucosal delivery of highly lipophilic drug cannabidiol.” International Journal of Pharmaceutics, 581. Publisher's Version Abstract
Delivery of drugs through oral mucosa enables bypass of the gastrointestinal tract and “first pass“ metabolism in the liver and the gut. Thus, a higher and less variable bioavailability can be obtained. Mechanisms of this administration route for cannabidiol were investigated in the current research in pigs. Results show that cannabidiol has substantially low permeability rate over 8 h through oral mucosa and accumulates significantly within it. Furthermore, following the removal of the delivery device, residual prolongation of release from the oral mucosa into systemic blood circulation continues for several hours. This method of delivery enabled acquisition of clinically relevant plasma levels of cannabidiol. The absorption profile indicates that cannabidiol, as well as other lipophilic molecules, should be delivered through oral mucosa for systemic absorption from a device that conceals the drug and prevents its washout by the saliva flow and subsequent ingestion into gastrointestinal tract. © 2020 Elsevier B.V.
C. Itin, R. Komargodski, A.J. Domb, and A. Hoffman. 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. Publisher's Version 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. © 2020
D. Izgelov, A.J. Domb, and A. Hoffman. 2020. “The effect of piperine on oral absorption of cannabidiol following acute vs. chronic administration.” European Journal of Pharmaceutical Sciences, 148. Publisher's Version 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. © 2020 Elsevier B.V.
A. Talhami, A. Swed, S. Hess, O. Ovadia, S. Greenberg, A. Schumacher-Klinger, D. Rosenthal, D.E. Shalev, M. Hurevich, P. Lazarovici, A. Hoffman, and C. Gilon. 2020. “Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs.” Frontiers in Chemistry, 8. Publisher's Version 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). © Copyright © 2020 Talhami, Swed, Hess, Ovadia, Greenberg, Schumacher-Klinger, Rosenthal, Shalev, Hurevich, Lazarovici, Hoffman and Gilon.
D. Izgelov, E. Davidson, D. Barasch, A. Regev, A.J. Domb, and A. Hoffman. 2020. “Pharmacokinetic investigation of synthetic cannabidiol oral formulations in healthy volunteers.” European Journal of Pharmaceutics and Biopharmaceutics, 154, Pp. 108-115. Publisher's Version Abstract
Recent advances in the research of medicinal cannabis has placed the non-intoxicating cannabinoid cannabidiol (CBD) at the front of scientific research. The reasons behind this popularity is the compound's therapeutic properties, alongside a safe profile of administration lacking addictive properties such as euphoric state of mind and a wide dosing range. Oral administration of CBD is challenging due to poor solubility in the gastro-intestinal system and susceptibility to extensive first pass metabolism. As a result, the practice in clinic and investigational trials is to administer cannabinoids in edible oils or oil-based solutions. Nonetheless, reported pharmacokinetics of cannabinoids and CBD in particular are not uniform among research groups and are affected by the vehicle of administration. The purpose of the work presented here is to investigate oral absorption processes of synthetic CBD when given in different oral formulations in healthy volunteers. The study design was a three way, blind, cross-over single administration study of 12 healthy male volunteers. CBD was administered in powder form, dissolved in sesame oil and in self-nano-emulsifying drug delivery system (SNEDDS). Administration of CBD in lipid-based vehicles resulted in a significant increase in Cmax and AUC of CBD, as compared to powder form. Overall plasma exposure of CBD did not differ between sesame oil vehicle and the SNEDDS formulation. However, administration of CBD in pure oil resulted in two absorption behaviors of early and delayed absorption among subjects, as opposed to SNEDDS platform that resulted in a uniform early absorption profile. Results of this trial demonstrate the importance of solubilization process of lipophilic drugs such as CBD and demonstrated the ability of the nano formulation to achieve a reliable, predictable PK profile of the drug. These findings offer a standardized oral formulation for the delivery of cannabinoids and contribute data for the growing field of cannabinoid pharmacokinetics. © 2020 Elsevier B.V.
S. El-Atawneh, S. Hirsch, R. Hadar, J. Tam, and A. Goldblum. 2020. “Erratum: Prediction and experimental confirmation of novel peripheral cannabinoid-1 receptor antagonists (J. Chem. Inf. Model. (2019) 59:9 (3996-4006) DOI: 10.1021/acs.jcim.9b00577).” Journal of Chemical Information and Modeling, 60, 10, Pp. 5282. Publisher's Version Abstract
In Section 3.1. “Characteristics of the Models”, page 4000, eq 1 of the “Enrichment Factor” should be (Equation presented). © 2020 American Chemical Society.
B. Da'Adoosh, K. Kaito, K. Miyashita, M. Sakaguchi, and A. Goldblum. 2020. “Computational design of substrate selective inhibition.” PLoS Computational Biology, 16, 3. Publisher's Version Abstract
Most enzymes act on more than a single substrate. There is frequently a need to block the production of a single pathogenic outcome of enzymatic activity on a substrate but to avoid blocking others of its catalytic actions. Full blocking might cause severe side effects because some products of that catalysis may be vital. Substrate selectivity is required but not possible to achieve by blocking the catalytic residues of an enzyme. That is the basis of the need for "Substrate Selective Inhibitors" (SSI), and there are several molecules characterized as SSI. However, none have yet been designed or discovered by computational methods. We demonstrate a computational approach to the discovery of Substrate Selective Inhibitors for one enzyme, Prolyl Oligopeptidase (POP) (E.C, a serine protease which cleaves small peptides between Pro and other amino acids. Among those are Thyrotropin Releasing Hormone (TRH) and Angiotensin-III (Ang-III), differing in both their binding (Km) and in turnover (kcat). We used our in-house "Iterative Stochastic Elimination" (ISE) algorithm and the structure-based "Pharmacophore" approach to construct two models for identifying SSI of POP. A dataset of  1.8 million commercially available molecules was initially reduced to less than 12,000 which were screened by these models to a final set of 20 molecules which were sent for experimental validation (five random molecules were tested for comparison). Two molecules out of these 20, one with a high score in the ISE model, the other successful in the pharmacophore model, were confirmed by in vitro measurements. One is a competitive inhibitor of Ang-III (increases its Km), but non-competitive towards TRH (decreases its Vmax). © 2020 Da'adoosh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
N. Kumar, N. Eghbarieh, T. Stein, A.I. Shames, and A. Masarwa. 2020. “Photoredox-Mediated Reaction of gem-Diborylalkenes: Reactivity Toward Diverse 1,1-Bisborylalkanes.” Chemistry - A European Journal, 26, 24, Pp. 5360-5364. Publisher's Version Abstract
The use of gem-diborylalkenes as radical-reactive groups is explored for the first time. These reactions provide an efficient and general method for the photochemical conversion of gem-diborylalkenes to rapidly access 1,1-bisborylalkanes. This method exploits a novel photoredox decarboxylative radical addition to gem-diborylalkenes to afford α-gem-diboryl carbon-centered radicals, which benefit from additional stability by virtue of an interaction with the empty p-orbitals on borons. The reaction offers a highly modular and regioselective approach to γ-amino gem-diborylalkanes. Furthermore, EPR spectroscopy and DFT calculations have provided insight into the radical mechanism underlying the photochemistry reaction and the stability of the bis-metalated radicals, respectively. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
K.N. Babu, F. Massarwe, R.R. Reddy, N. Eghbarieh, M. Jakob, and A. Masarwa. 2020. “Unsymmetrical 1,1-bisboryl species: Valuable building blocks in synthesis.” Molecules, 25, 4. Publisher's Version Abstract
Unsymmetrical 1,1-bis(boryl)alkanes and alkenes are organo-bismetallic equivalents, which are synthetically important because they allow for sequential selective transformations of C-B bonds. We reviewed the synthesis and chemical reactivity of 1,1-bis(boryl)alkanes and alkenes to provide information for the synthetic community. In the first part of this review, we disclose the synthesis and chemical reactivity of unsymmetrical 1,1-bisborylalkanes. In the second part, we describe the synthesis and chemical reactivity of unsymmetrical 1,1-bis(boryl)alkenes. © 2020 by the authors.
A. Di Pizio, Y. Ben Shoshan-Galeczki, J.E. Hayes, and M.Y. Niv. 2019. “Bitter and sweet tasting molecules: It's complicated.” Neuroscience Letters, 700, Pp. 56-63. Publisher's Version Abstract
“Bitter” and “sweet” are frequently framed in opposition, both functionally and metaphorically, in regard to affective responses, emotion, and nutrition. This oppositional relationship is complicated by the fact that some molecules are simultaneously bitter and sweet. In some cases, a small chemical modification, or a chirality switch, flips the taste from sweet to bitter. Molecules humans describe as bitter are recognized by a 25-member subfamily of class A G-protein coupled receptors (GPCRs) known as TAS2Rs. Molecules humans describe as sweet are recognized by a TAS1R2/TAS1R3 heterodimer of class C GPCRs. Here we characterize the chemical space of bitter and sweet molecules: the majority of bitter compounds show higher hydrophobicity compared to sweet compounds, while sweet molecules have a wider range of sizes. Importantly, recent evidence indicates that TAS1Rs and TAS2Rs are not limited to the oral cavity; moreover, some bitterants are pharmacologically promiscuous, with the hERG potassium channel, cytochrome P450 enzymes, and carbonic anhydrases as common off-targets. Further focus on polypharmacology may unravel new physiological roles for tastant molecules. © 2018 Elsevier B.V.
T. Nassar, A. Rohald, N. Naraykin, D. Barasch, O. Amsalem, P. Prabhu, M. Kotler, and S. Benita. 2019. “Nanocapsules embedded in microparticles for enhanced oral bioavailability and efficacy of Lopinavir as an anti-AIDS drug.” Journal of Drug Targeting, 27, 5-6, Pp. 590-600. Publisher's Version Abstract
Lopinavir (LPV), an efficient drug for HIV infection treatment, was incorporated into biodegradable PLGA nanocapsules (NCs) embedded in microparticles (MCPs) using the spray-drying technique in an attempt to bypass the P-gp efflux and protect the drug from CYP3A pre-systemic metabolism without ritonavir (RTV). SEM observations confirmed the formation of NCs and their entrapment in the MCPs. LPV-loaded NCs and free LPV were released from the MCPs at pH of 7.4 as evidenced by in vitro release studies. Results obtained from rat studies showed a two-fold higher bioavailability of LPV following oral administration of the optimal formulation than Kaletra®, the marketed drug, showing that when properly entrapped, LPV can be effectively protected from CYP degradation in the gut as well as from the liver following systemic absorption. It was also shown that serum derived from rats following LPV oral administration in two formulations and Kaletra® significantly decreased the multiplication of HIV-1 in cultured SupT1 cells. Furthermore, the LPV formulations markedly restricted the titre of infectious HIV-1 production compared with Kaletra® confirming the improved antiviral activity of LPV delivered in the rat blood circulation by the nanocapsules embedded in microparticle formulations. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
Multiple sclerosis (MS) is an autoimmune disease leading to the destruction of myelin with consequent axonal degeneration and severe physical debilitation. The disease can be treated with immunosuppressive drugs that alleviate the symptoms and retard disease aggravation. One such drug in clinical use is glatiramer acetate (Copaxone). The non-psychotropic immunosuppressive cannabinoid compound cannabidiol (CBD) has recently been shown to have beneficial effects on experimental autoimmune encephalomyelitis (EAE). The aim of our study was to compare the efficacy of CBD and standardized extracts from a CBD-rich, ∆ 9 -THC low Cannabis indica subspecies (Avidekel) with that of Copaxone. Our data show that CBD and purified Avidekel extracts are as efficient as Copaxone to alleviate the symptoms of proteolipid protein (PLP)-induced EAE in SJL/J mice. No synergistic effect was observed by combining CBD or Avidekel extracts with Copaxone. Our data support the use of Avidekel extracts in the treatment of MS symptoms. © 2018, Springer Nature Switzerland AG.
M. Brandwein, I. Katz, A. Katz, and R. Kohen. 2019. “Beyond the gut: Skin microbiome compositional changes are associated with BMI.” Human Microbiome Journal, 13. Publisher's Version Abstract
Microbiome compositional changes are associated with obesity in the gut. Emerging evidence points to a connection between gut and skin microbial communities. We hypothesized that skin microbiome compositional changes are associated with different BMI levels and that overweight or obese individuals would have reduced skin microbial diversity. We statistically analyzed gut, oral and skin microbiome samples to recapture previously observed partitioning between the microbiomes of these sites. We further analyzed 822 skin microbiome samples from the American Gut Project database and correlated BMI levels with community structure and composition using QIIME. Gut, oral and skin samples showed distinct community composition, and gut and skin microbial diversity was affected by BMI. Oral microbial diversity was not affected by BMI. Skin beta-diversity and community composition was correlated with BMI category, and Corynebacterium relative abundance was significantly correlated with BMI. In conclusion, non-cutaneous conditions affect the composition of the skin microbiome and the skin microbiome may therefore be used as a biomarker for disease manifestations beyond those with a cutaneous etiology. © 2019 Elsevier Ltd
I. Khuja, Z. Yekhtin, R. Or, and O. Almogi-Hazan. 2019. “Cannabinoids reduce inflammation but inhibit lymphocyte recovery in murine models of bone marrow transplantation.” International Journal of Molecular Sciences, 20, 3. Publisher's Version Abstract
Cannabinoids, the biologically active constituents of Cannabis, have potent neuronal and immunological effects. However, the basic and medical research dedicated to medical cannabis and cannabinoids is limited. The influence of these treatments on hematologic reconstitution and on the development of graft versus host disease (GVHD) after bone marrow transplantation (BMT) is largely unknown. In this research, we compared the influence of D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on lymphocyte activation in vitro and in murine BMT models. Our in vitro results demonstrate that these treatments decrease activated lymphocyte proliferation and affect cytokine secretion. We also discovered that CBD and THC utilize different receptors to mediate these effects. In vivo, in a syngeneic transplantation model, we demonstrate that all treatments inhibit lymphocyte reconstitution and show the inhibitory role of the cannabinoid receptor type 2 (CB2) on lymphocyte recovery. Although pure cannabinoids exhibited a superior effect in vitro, in an allogeneic (C57BL/6 to BALB/c) BMT mouse model, THC-high and CBD-high cannabis extracts treatment reduced the severity of GVHD and improved survival significantly better than the pure cannabinoids. Our results highlights the complexity of using cannabinoids-based treatments and the need for additional comparative scientific results. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
E. Murillo-Rodríguez, D. Millán-Aldaco, M. Palomero-Rivero, D. Morales-Lara, R. Mechoulam, and R. Drucker-Colín. 2019. “Cannabidiol partially blocks the excessive sleepiness in hypocretin-deficient rats: Preliminary data.” CNS and Neurological Disorders - Drug Targets, 18, 9, Pp. 705-712. Publisher's Version Abstract
Background: Excessive daytime sleepiness and cataplexy are among the symptoms of narcolepsy, a sleep disorder caused by the loss of hypocretin/orexin (HCRT/OX) neurons placed into the Hypothalamus (LH). Several treatments for managing narcolepsy include diverse drugs to induce alertness, such as antidepressants, amphetamine, or modafinil, etc. Recent evidence has shown that cannabidiol (CBD), a non-psychotropic derived from Cannabis sativa, shows positive therapeutic effects in neurodegenerative disorders, including Parkinson´s disease. Furthermore, CBD provokes alertness and enhances wake-related neurochemicals in laboratory animals. Thus, it is plausible to hypothesize that excessive somnolence observed in narcolepsy might be blocked by CBD. Objective: Here, we determined whether the systemic injection of CBD (5mg/kg, i.p.) would block the excessive sleepiness in a narcoleptic model. Methods: To test this idea, the neurotoxin hypocretin-2-saporin (HCRT2/SAP) was bilaterally injected into the LH of rats to eliminate HCRT leading to the establishment of narcoleptic-like behavior. Since excessive somnolence in HCRT2/SAP lesioned rats has been observed during the lights-off period, CBD was administered at the beginning of the dark phase. Results: Hourly analysis of sleep data showed that CBD blocked the sleepiness during the lights-off period across 7h post-injection in lesioned rats. Conclusion: Taking together, these preliminary findings suggest that CBD might prevent sleepiness in narcolepsy. © 2019 Bentham Science Publishers.