Assembly of In-Situ Gel Containing Nano-Spanlastics of an Angiotensin II Inhibitor as a Novel Epitome for Hypertension Management: Factorial Design Optimization, In-vitro Gauging, Pharmacokinetics, and Pharmacodynamics Appraisal.

More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.

Combination of losartan and puerarin induced pharmacokinetic interaction in hypertension rats enhances the antihypertensive effect of losartan.

The co-administration of losartan and puerarin in hypertension rat models was investigated aiming to evaluate their interaction and potential mechanism.Hypertension rat models were established with N (omega)-nitro-L-arginine methyl ester and the pharmacokinetics and antihypertensive effect of losartan were analyzed in normal and hypertension rats. In vitro, the metabolic stability of losartan was evaluated in rat liver microsomes, and the effect of puerarin on the activity of CYP2C9 and 3A4 was assessed in human liver microsomes.Puerarin significantly changed the pharmacokinetic profiling of losartan in hypertension rats, with the behaviour of increasing AUC, AUMC, Cmax, and prolonged t1/2. The antihypertensive effect of losartan was enhanced by the co-administration of puerarin, which reduced the systolic blood pressure and diastolic blood pressure below normal levels. In vitro, puerarin significantly improved the metabolic stability of losartan with a reduced intrinsic clearance rate. Puerarin also showed significant inhibitory effects on the activity of CYP2C9 and 3A4 with the IC50 of 17.15 and 7.69 µM, respectively.Losartan co-administered with puerarin increased the system exposure and metabolic stability of losartan and enhanced its antihypertensive effect. The inhibition of CYP2C9 and 3A4 by puerarin was the potential mechanism mediating their interaction.

Formulation and Pharmacokinetic Evaluation of Ethyl Cellulose/HPMC-Based Oral Expandable Sustained Release Dosage of Losartan Potassium.

Prolonged retention of losartan potassium in the upper gastrointestinal tract is anticipated to increase its absorption and exposure to CYP450 enzyme subfamilies, undertaking its conversion to more potent (10-40 times) active metabolite, losartan carboxylic acid (LCA). Consistent with this, hydroxypropyl methylcellulose K4M/ethyl cellulose-based novel expandable films (EFs) containing losartan potassium (LP) suitable for prolonged retention in the stomach were developed. The films were prepared by solvent casting method. USP type II dissolution apparatus (0.1 N HCl, 37°C, 100 rpm) was used to perform the dissolution testing (drug release, unfolding behavior, film integrity, erosion, and water uptake) of the films. In vivo pharmacokinetic studies were carried out in rabbits. An HPLC-UV method was used for the quantification of the drug and its active metabolite in plasma. These folded films placed inside hard gelatin capsule shells unfolded to full dimensions in dissolution medium and provided sustained drug release throughout 12 h. The plasma drug concentration-time curves obtained from the in vivo studies were used to determine pharmacokinetic parameters, such as area under the plasma drug concentration-time curve (AUC), area under first moment curve (AUMC), mean residence time (MRT), Cmax, Tmax, t1/2, ke, and Fr in comparison with that of the market formulation, Cozaar®. The novel EFs significantly changed the pharmacokinetic parameters of the drug and its active metabolite. The apparent elimination rate constant (ke) significantly decreased, while MRT and elimination half-life (t1/2) increased in both cases. The relative bioavailabilities (Fr) of both LP and E3174 using the novel formulation were higher than that of Cozaar®.

Preparation of Losartan Potassium Controlled Release Matrices and In-Vitro Investigation Using Rate Controlling Agents.

Controlled release matrices have predictable drug release kinetics, provide drugs for an extended period of time, and reduce dosing frequency with improved patient compliance as compared with conventional tablet dosage forms. In the current research work, losartan potassium controlled release matrix tablets were fabricated and prepared with rate altering agents; that is, Ethocel grade 100 combined with Carbopol 934PNF. Various drug to polymer ratios were used. HPMC, CMC, and starch were incorporated in some of the matrices by replacing some amount of filler (5%). The direct compression method was adopted for the preparation of matrices. In phosphate buffer (pH 6.8), the dissolution study was conducted by adopting the USP method-I as the specified method. Drug release kinetics was determined and dissolution profiles were also compared with the reference standard. Prolonged release was observed for all matrices, but those with Ethocel 100FP Premium showed more extended release. The co-excipient (HPMC, CMC, and starch) exhibited enhancement in the drug release rates, while all controlled release matrices released the drug by anamolous non-Fickian diffusion mechanism. This combination of polymers (Ethocel grade 100 with Carbopol 934PNF) efficiently extended the drug release rates up to 24 h. It is suggested that these matrix tablets can be given in once a day dosage, which might improve patient compliance, and the polymeric blend of Ethocel grade 100 with Carbopol 934PNF might be used in the development of prolonged release matrices of other water-soluble drugs.

Prediction of CYP-mediated silybin A-losartan pharmacokinetic interactions using physiological based pharmacokinetic modeling.

The concomitant use of herbal products and synthetic drugs necessitates the assessment of their interaction potentials. The herbal hepatoprotective medicine, silybin A inhibits cytochrome P450 (CYP) 2C9 and 3A4 enzymes, thus, may interact with the drugs that are substrates of CYP2C9 and 3A4, such as losartan. The three most prominent genotypes, expressed by CYP2C9 are the CYP2C9*1/*1, CYP2C9*1/*2 and CYP2C9*1/*3. This study aimed to assess silybin A-losartan interaction in different CYP2C9 genotypes using physiological-based pharmacokinetic (PBPK) model approach. The individual PBPK models for silybin A and losartan were developed using PK-Sim®. Losartan pharmacokinetics was predicted with or without co-administration of silybin A in individuals of different CYP2C9 genotypes to find herbal-drug interaction. The predicted drug plasma curves and pharmacokinetic parameters were optimized using parameter identification tool and were compared with reported pharmacokinetic parameters from the published clinical studies for model validation. The silybin-losartan interactions were predicted by change in area under the curve (AUC) and peak systemic concentration (Cmax). The co-treatment of silybin A, 420 mg/24 h (140 mg/8 h) with losartan 50 mg/24 h, exhibited a genotype-dependent change in the losartan's AUC and Cmax. In CYP 2C9*1/*1 genotype, AUC and Cmax of losartan were increased 1.16 and 1.37 folds, respectively falling in a range stipulated for negligible interaction. Increase in AUC and Cmax by 0.873 and 0.294 folds, respectively in CYP2C9*1/*3 after co-administration of silybin A exhibited a minor interaction with losartan. However, in individuals with CYP2C9*1/*2 genotype, the losartan's AUC and Cmax were decreased by 0.01 folds, manifesting a moderate interaction. Hence, in CYP2C9*1/*1 and CYP2C9*1/*3 genotypes, silybin A is a weak CYP inhibitor for losartan while in CYP2C9*1/*2 genotype, the co-administration of silybin consequents into a moderate pharmacokinetic interaction with losartan.

Prediction of the Area under the Curve Using Limited-Point Blood Sampling in a Cocktail Study to Assess Multiple CYP Activities.

A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were <39.5% in Model 1 and <26.2% in Model 2 which were created using 1- and 4-point sampling data. MAE shows larger values in the administration of inducer in compared with the administration of inhibitors. The accuracy of the prediction in Model 2 could be acceptable for screening of inhibitions. MAE for caffeine, dextromethorphan, and midazolam were acceptable in the model that used 4 sampling points from all data. The use of this method could reduce the burden on the subject and make it possible to evaluate each AUC in a minimally invasive manner.

Investigating the Impact of Gastric Emptying on Pharmacokinetic Parameters Using Delay Differential Equations and Principal Component Analysis.

BACKGROUND AND OBJECTIVES: Losartan presents multiple peaks after single oral administration, which can be attributed to gastric emptying. The aim of this study was to describe the multiple peak phenomenon of losartan using a delay differential model and a model with sine function. The impact of gastric emptying on pharmacokinetic parameters was investigated by applying principal component analysis to the individual parameter estimates. METHODS: Using MonolixTM, two population pharmacokinetic models were developed to describe the multiple peak phenomenon; the first using delay differential equations and the second using a sine function. Matlab® delay differential equation solver was used to arithmetically solve both functions. Principal component analysis and all statistical analyses were performed in the R language. RESULTS: The description of losartan multiple peaks can be achieved by the use of either delay differential equations or typical sine wave functions. Principal component analysis unveiled the impact of gastric emptying on the pharmacokinetic parameters. In the case of the delay differential equation model, a negative relationship was found between the constant delay tau1 and the parameters reflecting rate and extent of absorption (i.e., area under the curve [AUC], peak plasma concentration [Cmax], and the absorption rate constant). Similar results were obtained from the sine model, where a higher amplitude and lower period (i.e., higher frequency) of gastric emptying were associated with higher AUC and Cmax values. CONCLUSIONS: The observed multiple peaks for certain drugs like losartan can be attributed to gastric emptying. Parameters describing gastric emptying can be associated with pharmacokinetic metrics like AUC and Cmax.

Losartan prevents mesenteric vascular bed alterations in high-fat diet fed rats / Losartán previene las alteraciones del lecho vascular mesentérico en ratas alimentadas con dieta alta en grasas

Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model

La disfunción del tejido adiposo perivascular del lecho mesentérico posee una participación en la fisiopatología de la hipertensión arterial relacionada con el síndrome metabólico. Por lo tanto, podría considerarse como un nuevo blanco terapéutico en las enfermedades cardiovasculares y metabólicas. Además de su efecto antihipertensivo, existe un interés creciente en las acciones pleiotrópicas de losartán, antagonista del receptor de angiotensina II. El objetivo del estudio fue analizar las acciones de losartán sobre el índice de adiposidad y la liberación de prostanoides del lecho vascular mesentérico y su relación con la presión arterial, así como en el índice HOMA-IR (modelo de evaluación homeostático de la resistencia a la insulina) en ratas con dieta alta en grasas. Observamos que la dieta alta en grasas incrementó la adiposidad del lecho vascular mesentérico y la liberación de prostanoides vasoconstrictores como tromboxano (TX) B2 y prostaglandina (PG) F2α, así como la PGE2, un prostanoide inflamatorio en el contexto de resistencia a la insulina e hipertensión. También encontramos una correlación positiva entre el índice de adiposidad y la presión arterial sistólica y ambos parámetros se correlacionan positivamente con el índice HOMA IR. Adicionalmente observamos que la liberación de estos prostanoides se correlaciona con la presión arterial sistólica, así como con el índice de adiposidad del lecho vascular mesentérico. El tratamiento con losartán previno todas estas alteraciones y normalizó la relación PGI2/TXA2 en ratas alimentadas con una dieta alta en grasa. Concluimos entonces que losartán puede ejercer acciones beneficiosas sobre las alteraciones del tejido adiposo perivascular y la disfunción endotelial a través de la restauración del equilibrio normal de sustancias vasoactivas en este modelo experimental

Pharmacodynamic and pharmacokinetic interaction of losartan with glimepiride-metformin combination in rats and rabbits.

OBJECTIVES: The presence of comorbidities such as cardiovascular disease, peripheral vascular disease, and chronic renal disease, or and the prevention of these ailments in diabetics, frequently demands multiple drug treatments, increasing the risk of drug-drug interactions (DDIs). The current study was focused on identifying possible DDIs on concomitant administration of losartan, a drug used to regulate hypertension along with a combination of glimepiride + metformin, widely used to treat diabetes mellitus. Possible pharmacodynamic and pharmacokinetic interactions were observed for, following single-dose as well as multiple-dose treatment protocols in normal and alloxan-induced diabetes in albino Wistar rats and rabbits. MATERIALS AND METHODS: Blood samples from surviving rats/rabbits obtained through orbital venous sinus bleeding/marginal ear vein bleeding, respectively, at predetermined intervals and put through to biochemical estimations of sugar level in the blood by Glucose oxidase/peroxidase method; insulin levels in serum using the enzyme-linked immunosorbent assay and serum glimepiride levels using the high-performance liquid chromatography. RESULTS AND DISCUSSION: Losartan, when treated as a single drug, resulted in a slight lowering of blood glucose levels in normal rats, diabetic rats and normal rabbits. Hypoglycemic activity of a combination of glimepiride + metformin was enhanced when losartan was co-administered as a single dosage schedule as well as a multiple dose schedule as indicated by a reduced blood glucose level and enhanced levels of insulin in rats as well as in rabbits. Serum glimepiride levels were also higher and pharmacokinetic parameters of glimepiride including mean residence time, Cmax, T1/2, AUMC0-∞, AUMC0-t, and AUC0-∞, were significantly higher, whereas its clearance was decreased in the two regimens of losartan that was followed. CONCLUSION: It can therefore be concluded, that in diabetics with hypertension as a comorbidity condition, co-administration of losartan with glimepiride + metformin should be avoided or the dosage of a combination of glimepiride + metformin needs to be tittered to avoid recurrence of hypoglycemic episodes.

Formulation and Characterization of Losartan Loaded Chitosan Microspheres: Effect of Crosslinking Agents.

OBJECTIVE: The present investigation entailed determination of effect of diverse cross-linking agents on Losartan Potassium loaded chitosan microspheres. The emulsion cross-linking method was employed to formulate the microspheres with an endeavour to achieve maximum sustained effect. METHODS: The FTIR studies revealed absence of any interaction between Losartan and chitosan. The emulsion cross linking method was accomplished in three steps encompassing formation of an aqueous and oily phase, emulsification and cross-linking. A total of eighteen Losartan formulations were developed using six different cross-linkers at three varying level were screened for optimum parameters. The in vitro drug release parameters of optimum formulations (LC3, LE3, LF3, LG3, LS3 and LV3) containing citric acid, epichlorohydrin, formaldehyde, glutaraldehyde, suphuric acid and vanillin as cross-linkers were assessed to determine the sustained effect. RESULTS: The values of evaluated parameters including percent yield (94.67%), average particle size (51.19 µm), drug content (44.38 mg) and entrapment efficiency (88.77%) connoted LG3 as the best formulation. Additionally, the values of relative measure of skewness (ß1=0.01 and γ1=0.10) and platykurtic (ß2=1.26) size distribution were least for LG3 with spherical shape and smooth surface as revealed by SEM studies. CONCLUSION: The outcome of in vitro release and other characterizations of microspheres explicitly revealed glutaraldehyde as the best cross-linker amongst the cross-linkers used herewith. The maximum sustained effect (lasting over a period of 24 h) accompanied with higher MDT and t50% with lower%DE and Q14h values thus corroborated the objective of attaining sustained release of Losartan.

ABCB1 c.2677G>T/c.3435C>T diplotype increases the early-phase oral absorption of losartan.

Losartan has been shown to be a substrate of the drug-efflux transporter MDR1, encoded by the ABCB1 gene. ABCB1 c.2677G>T and c.3435C>T variants are known to be associated with reduced expression and function of P-glycoprotein (P-gp). We investigated the effects of ABCB1 diplotype on the pharmacokinetics of losartan. Thirty-eight healthy Korean volunteers with different ABCB1 diplotypes [c.2677G> T and c.3435C>T; carriers of GG/CC (n = 13), GT/CT (n = 12) and TT/TT (n = 13) diplotype] were recruited and administered a single 50 mg oral dose of losartan potassium. Losartan and its active metabolite E-3174 samples in plasma and urine were collected up to 10 and 8 h after drug administration, respectively, and the concentrations of both samples were determined by HPLC method. Significant differences were observed in Cmax of losartan and losartan plus E-3174 (Lo + E) among the three diplotype groups (both P < 0.01). However, the power of the performed test is less than the desired power (0.800). The tmax of losartan and E-3174 in three diplotype groups were also significantly different (both P < 0.01). The AUC values of Lo + E were significantly different among the three diplotype groups until 6 h after losartan administration (P < 0.01). On the contrary, AUC at the periods of 8-10 h and 10 h-infinity of Lo + E were significantly lower in the TT/TT group than in the GG/CC group. Urinary excretion of losartan until 4 h after losartan administration in the TT/TT group was higher than that of the GG/CC group. These results suggest that c.2677G>T/c.3435C>T diplotypes of ABCB1 may significantly increase the early-phase absorption of losartan, but not the total absorption.

Losartan potassium sustained release pellets with improved in vitro and in vivo performance.

The aim of this study was to formulate and evaluate SR matrix pellets containing losartan potassium (LP) solid dispersion using extrusion-spheronization technique to minimize the fluctuation of its plasma concentration. LP solid dispersions were prepared by using different hydrophobic polymers at different weight ratios (0.5, 1, 2, and 5%). LP-Eudragit RS solid dispersion at 1:5 ratio resulted in slower drug release (only 20% of LP was released in about 8 h). Different concentrations of hydrophilic polymer, PEG 6000, were mixed with Avicel® PH 101 to prepare the LP SR matrix pellets containing solid dispersion using 32 full factorial design to evaluate the effects of formulation parameters on the pellets attributes. The magnitude of torque for the pellet wet masses and binder ratio were decreased significantly with increasing PEG 6000 concentration. LP sustained release pellet formula composed of 9.24% PEG 6000 and 8 × 10-9% PVP K30 solution was chosen as optimized formula. Pharmacokinetic studies revealed that calculated t max was 9.72 ± 2.22 h from the optimized sustained release pellets compared to 2.11 ± 0.49 h in case of Cozaar® immediate release tablet, indicating a slower release of the LP from pellets.

Controversias sobre el tratamiento con IECA/ARA-II y Covid-19 / Controversy regarding ACE inhibitors / ARBs in Covid-19

No disponible

A review of clinically significant drug-drug interactions involving angiotensin II receptor antagonists and antiepileptic drugs.

INTRODUCTION: Angiotensin II receptor blockers are widely used for the treatment of arterial hypertension and heart failure. However, recent studies on animal models of seizures showed that in the brain, the renin-angiotensin-aldosterone system might be involved in neuroinflammation; therefore, the administration of angiotensin II receptor blockers that cross the blood/brain barrier, reduces not only blood pressure but reduces neuroinflammation-induced neuronal injury. Apart from this neuroprotective effect, these drugs exhibit anticonvulsant activity in animal models of seizures, and losartan is associated with a probable anti-epileptogenic activity. AREAS COVERED: In this review, we intended to highlight the role of drug-drug interactions involving angiotensin II receptor antagonists with antiepileptic drugs accompanied by a brief characteristic of the role of RAS in neuroinflammation. EXPERT OPINION: Some combinations of antiepileptic drugs (lamotrigine or valproate) with sartans are particularly effective in terms of enhanced seizure control. Considering a possible anti-epileptogenic activity of losartan, its combinations with antiepileptic drugs may prove especially beneficial in epileptogenesis inhibition.

Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility.

A decrease in the drug release rate over time typically affects the performance of hydrophilic matrices for oral prolonged release. To address such an issue, a Non-Uniform Drug Distribution Matrix (NUDDMat) based on hypromellose was proposed and demonstrated to yield zero-order release. The system consisted of 5 overlaid layers, applied by powder layering, having drug concentration decreasing from the inside towards the outside of the matrix according to a descending staircase function. In the present study, manufacturing and performance of the described delivery platform were evaluated using drug tracers having different water solubility. Lansoprazole, acetaminophen and losartan potassium were selected as slightly (SST), moderately (MST) and highly (HST) soluble tracers. By halving the thickness of the external layer, which contained no drug, linear release of HST and MST was obtained. The release behavior of the NUDDMat system loaded with a drug having pH-independent solubility was shown to be consistent in pH 1.2, 4.5 and 6.8 media. Based on these results, feasibility of the NUDDMat platform by powder layering was demonstrated using drugs having different physico-technological characteristics. Moreover, its ability to generate zero-order release was proved in the case of drugs with water solubility in a relatively wide range.

Comparison of Pharmacokinetics of a Fixed-Dose Combination of Amlodipine/Losartan/Rosuvastatin with Concomitant Administration of Amlodipine/Losartan and Rosuvastatin in Healthy Volunteers.

BACKGROUND: A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet. SUBJECTS AND METHODS: A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUClast) and the maximum plasma concentration (Cmax) were calculated. Safety was monitored throughout the study. RESULTS: The GMR (90% CI) values of AUClast and Cmax were 0.9946 (0.9663-1.0238) and 0.9690 (0.9379-1.0011) for amlodipine, 0.9855 (0.9422-1.0308) and 0.9178 (0.8349-1.0089) for losartan, 0.9814 (0.9501-1.0136) and 0.9756 (0.9313-1.0219) for EXP3174, and 0.9448 (0.8995-0.9923) and 0.9609 (0.8799-1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment. CONCLUSION: We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.

Effect of Hibiscus sabdariffa and Zingiber officinale on the antihypertensive activity and pharmacokinetic of losartan in hypertensive rats.

The present study aimed to determine the effect of Hibiscus sabdariffa and Zingiber officinale on antihypertensive activity and pharmacokinetic of losartan in hypertensive rats.Hypertension was induced in rats by oral administration of L-NAME (40 mg/kg per day). Pharmacodynamics and pharmacokinetics of losartan were evaluated without and with herbal treatment in hypertensive rats.Treatment of hypertensive rats with investigated herbs substantially reduced systolic blood pressure (SBP), and diastolic blood pressure (DBP) of rats. Treatment of rats (n = 5) with L-NAME plus H. sabdariffa plus losartan and L-NAME plus Z. officinale plus losartan reduced SBP by 16.20% and 14.88% and DBP by 14.82% and 17.52% respectively after 12 h, as compared to L-NAME alone treated rats. In a pharmacokinetic study, the Cmax and AUC0-t of losartan in L-NAME plus H. sabdariffa plus losartan and L-NAME plus Z. officinale plus losartan treated rats was increased by 0.7, 1.99 and 1.51, 3.00 fold respectively in comparison to the Cmax and AUC0-t obtained for L-NAME plus losartan treated group. In conclusion, both the investigated herbs significantly increased the antihypertensive effect and plasma concentration of losartan in L-NAME induced hypertensive rats. The current study predicted that the herb-drug interaction between H. sabdariffa-losartan and Z. officinale-losartan could occur; hence these results in rats may warrant further studies in humans, either in humans or in in vitro human liver microsomes.

Modelling gastric emptying: A pharmacokinetic model simultaneously describing distribution of losartan and its active metabolite EXP-3174.

Losartan presents multiple peaks in the concentration-time profile. This characteristic can be attributed to gastric emptying, which is known to significantly affect the disposition of highly soluble and permeable compounds. The aim of this study was to develop a population pharmacokinetic model for losartan and its active metabolite (EXP-3174) in order to describe the effect of gastric emptying on their disposition. Population pharmacokinetic analysis was performed using concentration-time data derived from a crossover bioequivalence study in 31 volunteers after a single oral dose of 100 mg losartan potassium in the fasted state. Delay differential equations (DDEs) were explored for the description of losartan absorption and EXP-3174 formation, since when solved they result in oscillatory behaviour. A two-compartment model preceded by a pre-absorption compartment (referring to small intestine) adequately described the observed concentration-time profiles of losartan. In the final model, a sinusoidal equation was used for the description of gastric emptying in view of its simplicity, leading to enhanced stability of the model and its capacity to describe periodicity. In case of EXP-3174, a one-compartment model, with a delayed first-order formation rate from losartan's central compartment, best described its disposition. Using the model developed, it was shown through simulations that changes in gastric emptying parameters lead to changes in the C-t profiles of both compounds. In particular, plasma oscillations can be enhanced or completely suppressed, simply by changing parameters affecting gastric emptying.

Evaluation of potential herbal-drug interactions of a standardized propolis extract (EPP-AF®) using an in vivo cocktail approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs. AIM OF THE STUDY: The main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach. MATERIALS AND METHODS: Subtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves. RESULTS: After exposure to EPP-AF®, it was observed decrease in the AUC0-∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80-1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80-1.25. CONCLUSIONS: In conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis.

Interaction of pseudoephedrine and azithromycin with losartan: Spectroscopic, dissolution and permeation studies.

This study aims at investigating the potential effect of selected cationic drugs (azithromycin (AZN) and pseudoephedrine sulfate (PSD) on the dissolution profile and intestinal permeation of losartan potassium (LOS) that might occur due to ion pair salt formation. DSC, FT-IR and 1H NMR indicated the formation of ion pair salts between LOS and each of AZN and PSD. Based on NMR chemical shifts calculations, utilizing specialized software, the most likely structures of the salt were proposed and revealed interesting structural features. The obtained ion pair products were shown to have lower aqueous solubilities (water and phosphate buffer pH 6.8) and higher apparent partition coefficient values compared to the parent compound. Neither of the cations affected the dissolution of LOS tablet (Cozaar® 100 mg) in the studied media (HCl pH 1.2 and phosphate buffer pH 6.8). Interestingly, AZN significantly increased the dissolution of LOS in phosphate buffer pH 4.5 (f2 = 33), and an explanation based on distinguished association pattern between AZN and LOS (CH/π) was offered. Employing permeation test across Caco-2 cells monolayer, the apparent permeability coefficient (Papp) of LOS increased significantly (from 0.9 × 10-5 cm/s to 1.8 × 10-5 cm/s) in the presence of the selected cations. Therefore, while the employed cationic drugs were not shown to form ion pair salts under the in-vitro dissolution conditions, they may still participate in significant in-vivo interaction with LOS.