Quantification of Etoricoxib in Low Plasma Volume by UPLC-PDA and Application to Preclinical Pharmacokinetic Study.

An ultra-performance liquid chromatography with photodiode array (UPLC-PDA) UV detection method was developed here for the first time for simple, rapid, selective and sensitive quantification of the commonly prescribed selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib in low plasma volumes (50 µL). The method includes protein precipitation followed by liquid-liquid extraction, evaporation and reconstitution. A gradient mobile phase of 75:25 going to 55:45 (v/v) water:acetonitrile (1 mL/min flow rate) was applied. Total run time was 8 min, representing a significant improvement relative to previous reports. Excellent linearity (r2 = 1) was obtained over a wide (0.1-12 µg/mL) etoricoxib concentration range. Short retention times for etoricoxib (4.9 min) and the internal standard trazodone (6.4 min), as well as high stability, recovery, accuracy, precision and reproducibility, and low etoricoxib LOD (20 ng/mL) and LOQ (100 ng/mL), were achieved. Finally, the method was successfully applied to a pharmacokinetic study (single 20 mg/kg orally administered etoricoxib mini-capsule) in rats. In conclusion, the advantages demonstrated in this work make this analytical method both time- and cost-efficient for drug monitoring in pre-clinical/clinical settings.

[IMPACT OF CLINICAL PHARMACIST CONSULTATIONS ON RATE OF COMPLICATIONS, RE-HOSPITALIZATIONS AND MORTALITY IN PATIENTS UNDERGOING BARIATRIC SURGERY].

BACKGROUND: Patients undergoing bariatric surgery are prone to changes in absorption, improvement in their chronic diseases and other pharmacokinetic/pharmacodynamic alteration which can affect continuation and the required doses of their chronic medications. OBJECTIVES: To examine the effect of a clinical pharmacist's consultation on the rate of complications, re-hospitalizations and mortality among patients who underwent bariatric surgery. METHODS: In this retrospective cohort study, results of bariatric patients who were consulted by a clinical pharmacist between the years 2013-2019 were compared with the results of a wider group of bariatric patients with chronic diseases who were recorded in the Israeli General Bariatric Registry during the same years. The intervention cohort included bariatric patients members of Clalit Health Services, who were treated at the Herzliya Medical Center and who were identified by the treating staff as complex cases requiring drug counseling. The primary outcomes measured in the study included: rates of surgical complications, re-hospitalizations, and death up to one year after surgery. RESULTS: The intervention group included 165 patients; the 12 month rate of re-hospitalization in the intervention group was 10.9% vs. 19.5% in the comparison group (p=0.005). The rate of documented postoperative complications was 2.7% vs. 3.9% (p=0.462) and mortality was null vs. 0.16%. CONCLUSIONS: Although the intervention population was identified in advance as more complex in terms of age and background morbidity, the rate of re-hospitalization and mortality was significantly lower in the intervention group than in the general bariatric surgery population in Israel. These results demonstrate the importance of referring to a specialized clinical pharmacist around bariatric surgery for improving patient safety, especially in complex patients.

Ethanol-based solubility-enabling oral drug formulation development: Accounting for the solubility-permeability interplay.

The aim of the current work was to investigate the key factors that govern the success/failure of an ethanol-based solubility-enabling oral drug formulation, including the effects of the ethanol on the solubility of the drug, the permeability across the intestinal membrane, the drug's dissolution in the aqueous milieu of the gastrointestinal tract (GIT), and the resulting solubility-permeability interplay. The concentration-dependent effects of ethanol-based vehicles on the solubility, the in-vitro Caco-2 permeability, the in-vivo rat permeability, and the biorelevant dissolution of the BCS class II antiepileptic drug carbamazepine were studied, and a predictive model describing the solubility-permeability relationship was developed. Significant concentration-dependent solubility increase of CBZ was obtained with increasing ethanol levels, that was accompanied by permeability decrease, both in Caco-2 and in rat perfusion studies, demonstrating a tradeoff between the increased solubility afforded by the ethanol and a concomitant permeability decrease. When ethanol absorption was accounted for, an excellent agreement was achieved between the predicted permeability and the experimental data. Biorelevant dissolution studies revealed that minimal ethanol levels of 30 % and 50 % were needed to fully dissolve 1 and 5 mg CBZ dose respectively, with no drug precipitation.In conclusion, key factors to be accounted for when developing ethanol-based formulation include the drug's solubility, permeability, the solubility-permeability interplay, and the drug dose intended to be delivered. Only the minimal amount of ethanol sufficient to solubilize the drug dose throughout the GIT should be used, and not more than that, to avoid unnecessarily permeability loss, and to maximize overall drug absorption.

Can Consultation by a Clinical Pharmacist Prevent Morbidity and Mortality in Patients Undergoing Bariatric Surgery?

The purpose of this work was to investigate the effect of clinical pharmacist consultation on the long-term morbidity and mortality outcomes among patients undergoing bariatric surgery. In this retrospective cohort study, 165 bariatric patients at Herzliya Medical Center who were identified as complex cases and were consulted by a clinical pharmacist (2013-2019) were compared with a wider group of bariatric patients with chronic diseases who were recorded in the Israeli General Bariatric Registry during the same years. The primary outcomes were rates of surgical complications, re-hospitalizations, and death up to one year after surgery. The secondary outcome was the rate of re-hospitalizations in different time periods. The twelve (12)-month rate of re-hospitalization in the intervention group was 10.9% vs. 19.5% in the comparison group (p = 0.005); the rate of documented postoperative complications was 2.7% vs. 3.9% (p = 0.462), and mortality was null vs. 0.16%, respectively. As for the secondary outcomes, the rates of re-hospitalizations in the periods of 0-30, 31-90, 91-180, and 181-365 days after surgery were 1.8% vs. 5.3% (p = 0.046), 2.4% vs. 4.1% (p = 0.278), 3.6% vs. 4.8% (p = 0.476), and 7.3% vs. 9.9% (p = 0.256) in the intervention vs. comparison cohorts, respectively. In conclusion, this study demonstrates the importance and benefit of referring to a specialized clinical pharmacist around bariatric surgery for improving patient safety, especially in complex patients. This is the first study to look at the long-term effects of clinical pharmacist consultation on re-hospitalization and mortality among bariatric patients, and our encouraging outcomes should hopefully stimulate more studies to show the invaluable role of specialized clinical pharmacists.

Solubility-enabling formulations for oral delivery of lipophilic drugs: considering the solubility-permeability interplay for accelerated formulation development.

INTRODUCTION: Tackling low water solubility of drug candidates is a major challenge in today's pharmaceutics/biopharmaceutics, especially by means of modern solubility-enabling formulations. However, drug absorption from these formulations oftentimes remains unchanged or even decreases, despite substantial solubility enhancement. AREAS COVERED: In this article, we overview the simultaneous effects of the formulation on the solubility and the apparent permeability of the drug, and analyze the contribution of this solubility-permeability interplay to the success/failure of the formulation to increase the overall absorption and bioavailability. Three different patterns of interplay were identified: (1) solubility-permeability tradeoff in which every solubility gain comes with a price of concomitant permeability loss; (2) an advantageous interplay pattern in which the permeability remains unchanged alongside the solubility gain; and (3) an optimal interplay pattern in which the formulation increases both the solubility and the permeability. Passive vs. active intestinal permeability considerations in the context of the solubility-permeability interplay are also thoroughly discussed. EXPERT OPINION: The solubility-permeability interplay pattern of a given formulation has a critical effect on its overall success/failure, and hence, taking into account both parameters in solubility-enabling formulation development is prudent and highly recommended.

The Complexity of Bariatric Patient's Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass.

Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1-5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.

An Emerging Strategy for Neuroinflammation Treatment: Combined Cannabidiol and Angiotensin Receptor Blockers Treatments Effectively Inhibit Glial Nitric Oxide Release.

Cannabidiol (CBD), the major non-psychoactive phytocannabinoid found in cannabis, has anti-neuroinflammatory properties. Despite the increasing use of CBD, little is known about its effect in combination with other substances. Combination therapy has been gaining attention recently, aiming to produce more efficient effects. Angiotensin II activates the angiotensin 1 receptor and regulates neuroinflammation and cognition. Angiotensin receptor 1 blockers (ARBs) were shown to be neuroprotective and prevent cognitive decline. The present study aimed to elucidate the combined role of CBD and ARBs in the modulation of lipopolysaccharide (LPS)-induced glial inflammation. While LPS significantly enhanced nitric oxide synthesis vs. the control, telmisartan and CBD, when administered alone, attenuated this effect by 60% and 36%, respectively. Exposure of LPS-stimulated cells to both compounds resulted in the 95% inhibition of glial nitric oxide release (additive effect). A synergistic inhibitory effect on nitric oxide release was observed when cells were co-treated with losartan (5 µM) and CBD (5 µM) (by 80%) compared to exposure to each compound alone (by 22% and 26%, respectively). Telmisartan and CBD given alone increased TNFα levels by 60% and 40%, respectively. CBD and telmisartan, when given together, attenuated the LPS-induced increase in TNFα levels without statistical significance. LPS-induced IL-17 release was attenuated by CBD with or without telmisartan (by 75%) or telmisartan alone (by 60%). LPS-induced Interferon-γ release was attenuated by 80% when telmisartan was administered in the absence or presence of CBD. Anti-inflammatory effects were recorded when CBD was combined with the known anti-inflammatory agent dimethyl fumarate (DMF)/monomethyl fumarate (MMF). A synergistic inhibitory effect of CBD and MMF on glial release of nitric oxide (by 77%) was observed compared to cells exposed to MMF (by 35%) or CBD (by 12%) alone. Overall, this study highlights the potential of new combinations of CBD (5 µM) with losartan (5 µM) or MMF (1 µM) to synergistically attenuate glial NO synthesis. Additive effects on NO production were observed when telmisartan (5 µM) and CBD (5 µM) were administered together to glial cells.

Towards Effective Antiviral Oral Therapy: Development of a Novel Self-Double Emulsifying Drug Delivery System for Improved Zanamivir Intestinal Permeability.

Self-double emulsifying drug delivery systems have the potential to enhance the intestinal permeability of drugs classified under the Biopharmaceutics Classification System (BCS) class III. One such example is the antiviral agent zanamivir, exhibiting suboptimal oral absorption (with a bioavailability range of 1-5%). To address this challenge, we have developed an innovative oral formulation for zanamivir: a self-double nanoemulsifying Winsor delivery system (SDNE-WDS) consisting of the microemulsion, which subsequently yields final double nanoemulsion (W1/O/W2) upon interaction with water. Two distinct formulations were prepared: SDNE-WDS1, classified as a W/O microemulsion, and SDNE-WDS2, discovered to be a bicontinuous microemulsion. The inner microemulsions displayed a consistent radius of gyration, with an average size of 35.1 ± 2.1 nm. Following self-emulsification, the resultant zanamivir-loaded nanoemulsion droplets for zSDNE-WDS1 and zSDNE-WDS2 measured 542.1 ± 36.1 and 174.4 ± 3.4 nm, respectively. Both types of emulsions demonstrated the ability to enhance the transport of zanamivir across a parallel artificial membrane. Additionally, in situ rat intestinal perfusion studies involving drug-loaded SDNE-WDSs revealed a significantly increased permeability of zanamivir through the small intestinal wall. Notably, both SDNE-WDS formulations exhibited effective permeability (Peff) values that were 3.5-5.5-fold higher than those of the low/high permeability boundary marker metoprolol. This research emphasizes the success of SDNE-WDSs in overcoming intestinal permeability barriers and enabling the effective oral administration of zanamivir. These findings hold promise for advancing the development of efficacious oral administration of BCS class III drugs.

Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics.

Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs.Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivoin aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles.For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased âˆ¼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower Cmax and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery.This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery.

Therapeutic Potential of Phytocannabinoid Cannabigerol for Multiple Sclerosis: Modulation of Microglial Activation In Vitro and In Vivo.

Multiple sclerosis (MS) is a widespread chronic neuroinflammatory and neurodegenerative disease. Microglia play a crucial role in the pathogenesis of MS via the release of cytokines and reactive oxygen species, e.g., nitric oxide. Research involving the role of phytocannabinoids in neuroinflammation is currently receiving much attention. Cannabigerol is a main phytocannabinoid, which has attracted significant pharmacological interest due to its non-psychotropic nature. In this research, we studied the effects of cannabigerol on microglial inflammation in vitro, followed by an in vivo study. Cannabigerol attenuated the microglial production of nitric oxide in BV2 microglia and primary glial cells; concomitant treatment of the cells with cannabigerol and telmisartan (a neuroprotective angiotensin receptor blocker) decreased nitric oxide production additively. Inducible nitric oxide synthase (iNOS) expression was also reduced by cannabigerol. Moreover, tumor necrosis factor-α (TNF-α), a major cytokine involved in MS, was significantly reduced by cannabigerol in both cell cultures. Next, we studied the effects of cannabigerol in vivo using a mice model of MS, experimental autoimmune encephalomyelitis (EAE). The clinical scores of EAE mice were attenuated upon cannabigerol treatment; additionally, lumbar sections of EAE mice showed enhanced neuronal loss (relative to control mice), which was restored by cannabigerol treatment. Altogether, the set of experiments presented in this work indicates that cannabigerol possesses an appealing therapeutic potential for the treatment of MS.

Enabling oral delivery of antiviral drugs: Double emulsion carriers to improve the intestinal absorption of zanamivir.

Antiviral drugs play a major role in the control of seasonal influenza epidemics and may provide prophylactic and therapeutic benefits during an eventual pandemic. Among the neuraminidase inhibitors, zanamivir has been shown to be a potent inhibitor of influenza viruses, and similarly against emerging resistant strains. Despite its high antiviral efficiency, zanamivir suffers from poor intestinal permeability, therefore administered via inhalation. Enabling oral delivery of zanamivir will augment the available antiviral tools in clinical practice, increase patient compliance and ultimately improve public health. Encapsulation of hydrophilic drugs within double emulsions (DEs), is an efficacious approach to enhance the oral bioavailability of BCS Class III drugs, such as zanamivir. The objective of this research was to increase the intestinal absorption of zanamivir by means of compatible DEs. Two different types of stable DEs were prepared comprising different internal aqueous phases (W1). These micro-sized DEs showed high encapsulation efficacy (96.6-98.9 %) and markedlyretardedtherelease rateof the antiviral drug. Both types of the zanamivir loaded DEs (zDEs) significantly increased the transport ability of zanamivir across a parallel artificial membrane. Furthermore, in-situ perfusion of zDEs revealed outstanding permeability of zanamivir across the intestinal wall of rats. The zDEs containing carbomer gel (rather than carboxymethyl cellulose) as W1 obtained superior in-vivo effective permeability (Peff); yet, both zDEs exhibited higher Peff values (2-6-fold) than the low/high permeability marker (metoprolol). In conclusion, the DEs delivery system allowed overcoming the intestinal permeability barriers, towards successful oral administration of zanamivir.

Carbamazepine Therapy After Bariatric Surgery: Eight Sleeve Gastrectomy Cases and Review of the Literature.

Bariatric surgery modifies the anatomy and physiology of the gastrointestinal tract. Carbamazepine (CBZ) is an anticonvulsant with multiple neuropsychiatric indications. Given CBZ physicochemical properties and narrow therapeutic index, bariatric surgery may potentially introduce clinically significant changes in CBZ oral absorption and bioavailability. In this communication, we describe eight patients undergoing sleeve gastrectomy (SG) and treated with CBZ, including therapeutic drug monitoring (TDM) and dosage adjustments at different timeframes before vs. after the surgery (< 3, 4-6, and 7-12 months post-SG), as well as clinical outcomes. We then provide a review of the available literature on CBZ therapy among bariatric patients, concluding with a mechanistic analysis of the results. Four of the eight patients presented with decreased post-SG CBZ levels, and two of them also experienced significant worsening of their previously well-controlled disease. Overall, altered CBZ levels are likely for at least a year after SG. Clinical recommendations include consultation with a clinical pharmacist, careful clinical monitoring, and periodic TDM after (vs. before) the bariatric surgery.

The Role of Paracellular Transport in the Intestinal Absorption and Biopharmaceutical Characterization of Minoxidil.

The purpose of this study was to evaluate mechanisms behind the intestinal permeability of minoxidil, with special emphasis on paracellular transport, and elucidate the suitability of minoxidil to be a reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil (vs. metoprolol) was evaluated in-silico, in-vitro using both the PAMPA assay and across Caco-2 cell monolayers, as well as in-vivo in rats throughout the entire intestine. The permeability was studied in conditions that represent the different segments of the small intestine: upper jejunum (pH 6.5), mid small intestine (pH 7.0), distal ileum (pH 7.5), and colon (pH 6.5). Since we aimed to investigate the paracellular transport of minoxidil, we have also examined its permeability in the presence of quercetin (250 µM), which closes the tight junctions, and sodium decanoate (10 mM), which opens the tight junctions. While metoprolol demonstrated segmental-dependent rat and PAMPA permeability, with higher permeability in higher pH regions, the permeability of minoxidil was pH-independent. Minoxidil PAMPA permeability was significantly lower than its rat permeability, indicating a potential significant role of the paracellular route. In rat intestinal perfusion studies, and across Caco-2 monolayers, tight junction modifiers significantly affected minoxidil permeability; while the presence of quercetin caused decreased permeability, the presence of sodium decanoate caused an increase in minoxidil permeability. In accordance with these in-vitro and in-vivo results, in-silico simulations indicated that approximatelly 15% of minoxidil dose is absorbed paracellularly, mainly in the proximal parts of the intestine. The results of this study indicate that paracellular transport plays a significant role in the intestinal permeability of minoxidil following oral administration. Since this permeation route may lead to higher variability in comparison to transcellular, these findings diminish the suitability of minoxidil to serve as the low/high BSC permeability class benchmark.

Antiallergic Treatment of Bariatric Patients: Potentially Hampered Solubility/Dissolution and Bioavailability of Loratadine, but Not Desloratadine, Post-Bariatric Surgery.

Gastrointestinal anatomical/physiological changes after bariatric surgery influence variables affecting the fate of drugs after ingestion, and medication management of these patients requires a thorough and complex mechanistic analysis. The aim of this research was to study whether loratadine/desloratadine antiallergic treatment of bariatric patients is at risk of being ineffective due to impaired solubility/dissolution. The pH-dependent solubility of loratadine/desloratadine was studied in vitro, as well as ex vivo, in gastric content aspirated from patients before versus after bariatric surgery. Then, a biorelevant dissolution method was developed to simulate the gastric conditions after sleeve gastrectomy (SG) or one-anastomosis gastric bypass (OAGB), accounting for key variables (intragastric volume, pH, and contractility), and the dissolution of loratadine/desloratadine was studied pre- versus post-surgery. Dissolution was also studied after tablet crushing or syrup ingestion, as these actions are recommended after bariatric surgery. Finally, these experimental data were implemented in a newly developed physiologically based pharmacokinetic (PBPK) model to simulate loratadine/desloratadine PK profiles pre- versus post-surgery. For both drugs, pH-dependent solubility was demonstrated, with decreased solubility at higher pH; over the pH range 1-7, loratadine solubility decreased ∼2000-fold, and desloratadine decreased ∼120-fold. Ex vivo solubility in aspirated human gastric fluid pre- versus post-surgery was in good agreement with these in vitro results and revealed that while desloratadine solubility still allows complete dissolution post-surgery, loratadine solubility post-surgery is much lower than the threshold required for the complete dissolution of the drug dose. Indeed, severely hampered loratadine dissolution was revealed, dropping from 100% pre-surgery to only 3 and 1% post-SG and post-OAGB, respectively. Tablet crushing did not increase loratadine dissolution in any post-bariatric condition, nor did loratadine syrup in post-OAGB (pH 7) media, while in post-laparoscopic SG conditions (pH 5), the syrup provided partial improvement of up to 40% dissolution. Desloratadine exhibited quick and complete dissolution across all pre-/post-surgery conditions. PBPK simulations revealed pronounced impaired absorption of loratadine post-surgery, with 84-88% decreased Cmax, 28-36% decreased Fa, and 24-31% decreased overall bioavailability, depending on the type of bariatric procedure. Desloratadine absorption remained unchanged post-surgery. We propose that desloratadine should be preferred over loratadine in bariatric patients, and as loratadine is an over-the-counter medication, antiallergic therapy after bariatric surgery requires special attention by patients and clinicians alike. This mechanistic approach that reveals potential post-surgery complexity, and at the same time provides adequate substitutions, may contribute to better pharmacotherapy and overall patient care after bariatric surgery.

Transformation of dolutegravir into an ultra-long-acting parenteral prodrug formulation.

Ultra-long-acting integrase strand transfer inhibitors were created by screening a library of monomeric and dimeric dolutegravir (DTG) prodrug nanoformulations. This led to an 18-carbon chain modified ester prodrug nanocrystal (coined NM2DTG) with the potential to sustain yearly dosing. Here, we show that the physiochemical and pharmacokinetic (PK) formulation properties facilitate slow drug release from tissue macrophage depot stores at the muscle injection site and adjacent lymphoid tissues following single parenteral injection. Significant plasma drug levels are recorded up to a year following injection. Tissue sites for prodrug hydrolysis are dependent on nanocrystal dissolution and prodrug release, drug-depot volume, perfusion, and cell-tissue pH. Each affect an extended NM2DTG apparent half-life recorded by PK parameters. The NM2DTG product can impact therapeutic adherence, tolerability, and access of a widely used integrase inhibitor in both resource limited and rich settings to reduce HIV-1 transmission and achieve optimal treatment outcomes.

PLA2-Triggered Activation of Cyclosporine-Phospholipid Prodrug as a Drug Targeting Approach in Inflammatory Bowel Disease Therapy.

Oral medication with activity specifically at the inflamed sites throughout the gastrointestinal tract and limited systemic exposure would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). For this purpose, we have designed a prodrug by linking active drug moiety to phospholipid (PL), the substrate of phospholipase A2 (PLA2). PLA2 expression and activity is significantly elevated in the inflamed intestinal tissues of IBD patients. Since PLA2 enzyme specifically hydrolyses the sn-2 bond within PLs, in our PL-based prodrug approach, the sn-2 positioned FA is replaced with cyclosporine, so that PLA2 may be exploited as the prodrug-activating enzyme, releasing the free drug from the PL-complex. Owing to the enzyme overexpression, this may effectively target free cyclosporine to the sites of inflammation. Four PL-cyclosporine prodrugs were synthesized, differing by their linker length between the PL and the drug moiety. To study the prodrug activation, a novel enzymatically enriched model was developed, the colonic brush border membrane vesicles (cBBMVs); in this model, tissue vesicles were produced from colitis-induced (vs. healthy) rat colons. PLA2 overexpression (3.4-fold) was demonstrated in diseased vs. healthy cBBMVs. Indeed, while healthy cBBMVs induced only marginal activation, substantial prodrug activation was evident by colitis-derived cBBMVs. Together with the PLA2 overexpression, these data validate our drug targeting strategy. In the diseased cBBMVs, quick and complete activation of the entire dose was obtained for the 12-carbon linker prodrug, while slow and marginal activation was obtained for the 6/8-carbon linkers. The potential to target the actual sites of inflammation and treat any localizations throughout the GIT, together with the extended therapeutic index, makes this orally delivered prodrug approach an exciting new therapeutic strategy for IBD treatment.

Prodrug-Based Targeting Approach for Inflammatory Bowel Diseases Therapy: Mechanistic Study of Phospholipid-Linker-Cyclosporine PLA2-Mediated Activation.

Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A2 (PLA2) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA2 in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA2. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA2.

Lamotrigine therapy in patients after bariatric surgery: Potentially hampered solubility and dissolution.

Bariatric surgery is an effective treatment of obesity and related comorbidities. With surgery, the stomach undergoes major anatomical/physiological changes that may affect the oral exposure of drugs, especially marginally soluble weak bases, such as lamotrigine. The aim of this work was to study the solubility/dissolution of lamotrigine in conditions simulating the stomach before vs. after bariatric surgery. Lamotrigine solubility was studied in-vitro, as well as ex-vivo in gastric content aspirated from patients before vs. after bariatric surgery. We then compared the dissolution kinetics of various marketed lamotrigine products in pre- vs. post-operative stomach conditions, different in volume, pH, agitation strength and speed. Decreased lamotrigine solubility with increasing pH (from 1.37 ± 0.09 (pH = 1) to 0.22 ± 0.03 mg/mL (pH = 7)) was obtained. Twelve-fold higher lamotrigine solubility was revealed in gastric content aspirated before vs. after surgery (8.5 ± 0.7 and 0.7 ± 0.01 mg/mL, respectively). Dissolution studies showed that only the lowest dose (25 mg) fully dissolved in the post-surgery stomach conditions, while at higher doses, lamotrigine tablet dissolution was impaired. Neither fast-dissolving tablet, nor tablet crushing, helped resolving this problem. Based on these results, and given that dissolution of the drug dose governs the subsequent absorption, close monitoring of this essential drug is advised after bariatric surgery.

Managing the Unpredictable: Mechanistic Analysis and Clinical Recommendations for Lamotrigine Treatment after Bariatric Surgery.

Bariatric surgery may alter the absorption and overall bioavailability of oral drugs. Lamotrigine is a major antiepileptic and mood stabilizer, that its use after bariatric surgery has not yet been studied. In this article, we provide a thorough mechanistic analysis of the effects of bariatric surgery on multiple mechanisms important for the absorption, bioavailability and overall pharmacokinetics of lamotrigine. Attributable to its pharmacokinetic properties and drug characteristics, the use of lamotrigine after bariatric surgery may be challenging. The complex situation in which some mechanisms may lead to increased drug exposure (e.g., decreased metabolism, weight loss) while others to its decrease (e.g., hampered dissolution/solubility, decreased gastric volume), may result in lowered, unchanged, or enhanced lamotrigine plasma levels after the surgery. We conclude with a set of clinical recommendations for lamotrigine treatment after bariatric surgery, aiming to allow better patient care, and emphasizing the extra caution that needs to be taken with these patients.