Metabolite Profiling and Distribution of Militarine in Rats Using UPLC-Q-TOF-MS/MS.

Militarine, a natural glucosyloxybenzyl 2-isobutylmalate, isolated from Bletilla striata, was reported with a prominent neuroprotective effect recently. The limited information on the metabolism of militarine impedes comprehension of its biological actions and pharmacology. This study aimed to investigate the metabolite profile and the distribution of militarine in vivo, which help to clarify the action mechanism further. A total of 71 metabolites (57 new metabolites) in rats were identified with a systematic method by ultra-high-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). The proposed metabolic pathways of militarine include hydrolyzation, oxidation, glycosylation, esterification, sulfation, glucuronidation and glycine conjugation. Militarine and its metabolites were distributed extensively in the treated rats. Notably, six metabolites of militarine were identified in cerebrospinal fluid (CSF), which were highly consistent with the metabolites after oral administration of gastrodin in rats. Among the metabolites in CSF, five of them were not reported before. It is the first systematic metabolic study of militarine in vivo, which is very helpful for better comprehension of the functions and the central nervous system (CNS) bioactivities of militarine. The findings will also provide an essential reference for the metabolism of other glucosylated benzyl esters of succinic, malic, tartaric and citric acids.

Effects of D-α-tocopherol polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles on the absorption, pharmacokinetics, and pharmacodynamics of salinomycin sodium.

Although salinomycin sodium (SS) has shown in-vitro potential to inhibit cancer stem cell growth and development, its low water solubility makes it a poor candidate as an oral chemotherapeutic agent. To improve the bioavailability of SS, SS was encapsulated here using D-α-tocopherol polyethylene glycol succinate (TPGS)-emulsified poly(lactic-co-glycolic acid) (PLGA) nanoparticles and compared with its parent SS in terms of absorption, pharmacokinetics, and efficacy in suppressing nasopharyngeal carcinomas stem cells. The pharmacokinetics of SS and salinomycin sodium-loaded D-α-tocopherol polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles (SLN) prepared by nanoprecipitation were analyzed in-vivo by timed-interval blood sampling and oral administration of SS and SLN to rats. Sensitive liquid chromatography-mass spectrometry (LC-MS) was developed to quantify plasma drug concentrations. SS and SLN transport in Caco-2 cells was also investigated. The therapeutic efficacy of SS and SLN against cancer stem cells was determined by orally administering the drugs to mice bearing CNE1 and CNE2 nasopharyngeal carcinoma xenografts and then evaluating CD133 cell proportions and tumorsphere formation. The in-vivo trial with rats showed that the Cmax, AUC(0-t), and Tmax for orally administered SLN were all significantly higher than those for SS (P<0.05). These findings were corroborated by a Caco-2 cell Transwell assay showing that relative SLN absorption was greater than that of SS on the basis of their apparent permeability coefficients (Papp). Significantly, therapeutic SLN efficacy against nasopharyngeal carcinoma stem cells was superior to that of SS. TPGS-emulsified PLGA nanoparticles effectively increase SS solubility and bioavailability. SLN is, therefore, promising as an oral chemotherapeutic agent against cancer stem cells.

Improved in vitro and in vivo performance of carbamazepine enabled by using a succinic acid cocrystal in a stable suspension formulation.

Currently cocrystals are considered as an established approach for making crystalline solids with overall improved physico-chemical properties. However, some otherwise well behaving cocrystals undergo rapid dissociation during dissolution, with ultimate conversion to parent drug and thus apparent loss of improved solubility. The polymeric carriers are long known to manipulate this conversion during dissolution to parent crystalline drug, which may hinder or accelerate the dissolution process if used in a dosage form. The goal of this study was to deliver in vivo a more soluble carbamazepine-succinic acid (CBZ-SUC) cocrystal in suspension formulation utilizing Hydroxypropyl methyl cellulose (HPMC-AS) as a crystallization inhibitor and Polyvinyl carpolactam-polyvinyl acetate-polyethylene glycol graft copolymer ® as solubilizer. The concentration of these polymers were systemically varied during in vitro dissolution studies, while selected formulations from dissolution studies were tested in vivo. Pharmacokinetic studies (PK) in rabbits demonstrated that formulation F7-X (1% cocrystal, 1% HPMC-AS and 2% Polyvinyl carpolactam-polyvinyl acetatepolyethylene glycol graft co-polymer®) caused almost 6fold improvement in AUC0-72 (***P k 0.05) as well as much higher Cmax of 4.73µ.mL-1 to that of 1.07µ.mL-1 of unformulated 'neat' cocrystal given orally. When reference formulation of CBZ (F5-X) with similar composition to F7-X were given to rabbits, cocrystal formulation gave 1.37fold (***P k 0.05) bioavailability than CBZ reference formulation. Cmax of reference formulation observed was 3.9µmL-1.

Simultaneous determination and pharmacokinetic study of four phenol compounds in rat plasma by ultra-high performance liquid chromatography with tandem mass spectrometry after oral administration of Echinacea purpurea extract.

A rapid and sensitive assay based on ultra-high performance liquid chromatography with electrospray ionization tandem mass spectrometry was established and validated for the simultaneous determination of cichoric acid, chlorogenic acid, quinic acid, and caffeic acid in rat plasma after oral administration of Echinacea purpurea extract using butylparaben as the internal standard. Samples were pretreated by liquid-liquid extraction with ethyl acetate. The separations for analytes were performed on an ACQUITY UPLC HSS C18 column (1.8 µm 2.1 × 100 mm) using a gradient elution program with acetonitrile/10 mM ammonium acetate (pH 5.6) at a flow rate of 0.3 mL/min. The analytes were detected in multiple reaction monitoring mode with negative electrospray ionization. The lower limit of quantification of each analyte was not higher than 10.85 ng/mL. The relative standard deviation of the intraday and interday precisions was less than 14.69%. The relative errors of accuracies were in the range of -13.80 to 14.91%. The mean recoveries for extraction recovery and matrix effect were higher than 80.79 and 89.98%, respectively. The method validation results demonstrated that the proposed method was sensitive, specific, and reliable, which was successfully applied to the pharmacokinetic study of four components after oral administration of Echinacea purpurea extract.

Curcumin diethyl disuccinate encapsulated in chitosan/alginate nanoparticles for improvement of its in vitro cytotoxicity against MDA-MB-231 human breast cancer cells.

Curcumin diethyl disuccinate (CDD) is a succinate prodrug of curcuminoids that has better stability in human plasma and improved in vitro cytotoxicity compared to curcumin. Therefore, CDD has the potential for further development as an anticancer agent. In this study, we focused on optimization of the formulation of CDD-loaded chitosan/alginate nanoparticles using Box-Behnken statistical design to enhance the therapeutic efficacy of CDD. Oil-in-water emulsification followed by ionotropic gelification was used to prepare the CDD-loaded chitosan/ alginate nanoparticles. A formulation with a 0.05:1 chitosan/alginate mass ratio, 0.65% (w/v) Pluronic F127 and 1.5 mg/ml CDD was found to be optimal. FTIR, TGA and XRD confirmed the encapsulation of CDD molecules in the nanoparticles. In vitro cytotoxicity and cellular uptake studies showed that CDD-loaded chitosan/alginate nanoparticles had significantly higher cytotoxicity and cellular uptake in human breast adenocarcinoma MDA-MB-231 cells, compared to free CDD. Physical and chemical stability studies indicated that the optimally formulated CDD-loaded chitosan/alginate nanoparticles were stable at 4 °C for 3 months.

Simultaneous determination of sarpogrelate and its active metabolite in human plasma by liquid chromatography with tandem mass spectrometry and its application to a pharmacokinetic study.

We established a rapid and simple liquid chromatography with tandem mass spectrometry method for the simultaneous determination of sarpogrelate and its active metabolite, M-1, in human plasma. Sarpogrelate, M-1, and the internal standard, ketanserin, were extracted from a 50 µL aliquot of human plasma by protein precipitation using acetonitrile. Chromatographic separation was performed on a Shim-pack GIS ODS C18 column (100 × 3.0 mm; 3 µm) with an isocratic mobile phase consisting of 10 mM ammonium acetate and acetonitrile (70:30, v/v) at a flow rate of 0.6 mL/min; the total run time was <2.5 min. Mass spectrometric detection was conducted in selected reaction-monitoring mode with positive electrospray ionization at m/z 430.35 → 135.10 for sarpogrelate, m/z 330.30 → 58.10 for M-1, and m/z 395.70 → 188.85 for ketanserin. The linear ranges of concentration for sarpogrelate and M-1 were 1-1000 and 0.5-500 ng/mL, respectively. The coefficient of variation for the assay's precision was ≤9.95%, and the accuracy was 90.6-107%. All analytes were stable under various storage and handling conditions, and no relevant crosstalk and matrix effect was observed. This method was successfully applied to a pharmacokinetic study after oral administration of a 100 mg sarpogrelate tablet to healthy male Korean volunteers.

Multiple-Dose Study to Evaluate Pharmacokinetics, Pharmacodynamics, and Safety in Healthy Subjects: A Comparison of Controlled-Release Sarpogrelate and Immediate-Release Sarpogrelate.

AIMS: To compare the pharmacokinetics, pharmacodynamics, and safety of sarpogrelate between controlled-release (CR) and immediate-release (IR) formulations after multiple-dose administration. METHODS: This study was a randomized, open-label, 2-period, 2-treatment, crossover study in healthy subjects. All subjects received CR sarpogrelate 300 mg once daily and IR sarpogrelate 100 mg three times daily by random order each for 3 days with a 7-day washout period. Serial blood sampling was performed over 24 h. Pharmacokinetic parameters were determined by noncompartmental methods. Platelet aggregation to collagen, measured by light transmission aggregometry, was reported as maximal platelet aggregation. RESULTS: Thirty-two subjects completed the study. CR sarpogrelate increased rapidly, reaching Cmax in 1.25 h (vs. 1.00 h in IR sarpogrelate) and declined with a t1/2 of 3.59 h (vs. 1.12 h in IR sarpogrelate). The 90% CIs for the geometric mean ratio of AUCτ and Cmax,ss between IR and CR formulations were 1.18 to 1.40 and 0.99 to 1.29, respectively. The degree of inhibition of platelet aggregation was similar between two formulations. CONCLUSIONS: CR sarpogrelate showed slightly higher systemic exposure and similar peak concentration compared with IR sarpogrelate. The profiles of pharmacodynamics and safety were comparable between two formulations.

Evaluation of hepatocyteprotective and anti-hepatitis B virus properties of Cichoric acid from Cichorium intybus leaves in cell culture.

Hepatitis B is the most common serious liver infection in the world. To date, there is still no complete cure for chronic hepatitis B. Natural caffeic acid analogues possess prominent antiviral activity, especially anti-hepatitis B virus (HBV) and anti-human immunodeficiency virus effects. Cichoric acid is a caffeic acid derivative from Cichorium intybus. In the study, the anti-hepatitis B property of cichoric acid was evaluated by the D-galactosamine (D-GalN)-induced normal human HL-7702 hepatocyte injury model, the duck hepatitis B virus (DHBV)-infected duck fetal hepatocytes and the HBV-transfected cell line HepG2.2.15 cells, respectively. The results showed that cichoric acid attenuated significantly D-GalN-induced HL-7702 hepatocyte injury at 10-100 µg/mL and produced a maximum protection rate of 56.26%. Moreover, cichoric acid at 1-100 µg/mL inhibited markedly DHBV DNA replication in infected duck fetal hepatocytes. Also, cichoric acid at 10-100 µg/mL reduced significantly the hepatitis B surface and envelope antigen levels in HepG2.2.15 cells and produced the maximum inhibition rates of 79.94% and 76.41%, respectively. Meanwhile, test compound at 50-100 µg/mL inhibited markedly HBV DNA replication. In conclusion, this study verifies the anti-hepatitis B effect of cichoric acid from Cichorium intybus leaves. In addition, cichoric acid could be used to design the antiviral agents.

Pharmacokinetics of a new once-daily controlled-release sarpogrelate hydrochloride compared with immediate-release formulation and the effect of food.

WHAT IS KNOWN AND OBJECTIVE: Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A antagonist that inhibits platelet aggregation and vasoconstriction. The aim of this study was to compare the pharmacokinetics of a sarpogrelate controlled-release formulation (CR) with those of the immediate-release formulation (IR). The effect of food on the pharmacokinetics of CR sarpogrelate was also evaluated. METHODS: A randomized, open-label, 3-period, 3-treatment crossover study was conducted in 50 healthy male subjects. Subjects were allocated into one of six sequence groups. In one period, a 100-mg IR formulation was administered three times at 6-h intervals, and in the other two periods, a 300-mg CR formulation was administered once to fasting and once to fed subjects. Each period was separated by a 7-day washout period. Serial blood samples were collected up to 24 h after the first drug administration in each period. The plasma concentrations of sarpogrelate were analysed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS AND DISCUSSION: After the administration of the IR formulation, the plasma concentration reached a peak at 0·48 h and the drug was eliminated with a half-life (t1/2 ) of 0·7 h. After administration of the CR formulation, the plasma concentration reached a peak at 0·5 h and the drug was eliminated with a t1/2 of 3·23 h. The geometric mean ratios (CR/IR) for sarpogrelate area under the plasma concentration-time curve (AUC) and the maximum plasma drug concentration (Cmax) were 1·2040 (90% confidence interval (CI): 1·0992-1·3188) and 0·9462 (90% CI: 0·8504-1·0529). When CR was administered to fed subjects, the time to peak concentration was prolonged to 3·97 h and t1/2 was shortened to 1·45 h. The geometric mean ratios (fasting/fed) for sarpogrelate AUC and Cmax were 0·8573 (90% CI: 0·7687-0·9561) and 0·6452 (90% CI: 0·5671-0·7341). WHAT IS NEW AND CONCLUSION: After the administration of CR and IR formulations of the same daily dose of sarpogrelate hydrochloride, the overall systemic exposure was slightly higher for the CR than for the IR formulation, whereas peak concentration was comparable between the two formulations. Food reduced the bioavailability of sarpogrelate CR.

[Experimental study of dicholine succinate pharmacokinetics].

We have conducted for the first time an experimental study of pharmacokinetics of dicholine succinate (DCS) for different ways of its administration in rats The quantitative evaluation of DCS and its metabolites was performed by the radioactive isotope technique. Various parameters of DCS pharmacokinetics were estimated, including the dose dependence of drug content in the blood plasma, total bioavailability, distribution kinetics, and the main ways of DCS excretion.

Pharmacokinetics and antioxidant activity of dihydrocaffeic acid grafted chitosan nanomicelles loaded with chicoric acid in broilers.

Chicoric acid (CA) is a natural nutrient found in plants, showcasing diverse biological activities, including anti-inflammatory and antioxidant properties. Despite its valuable properties, CA faces limitations in bioavailability and susceptibility to oxidative breakdown during utilization. Previous research introduced synthesized dihydrocaffeic acid grafted chitosan self-assembled nanomicelles (DA-g-CS), demonstrating its potential to enhance CA absorption. This study aims to investigate the pharmacokinetics, tissue distribution, and antioxidant activity of both CA and DA-g-CS loaded CA (DA-g-CS/CA) in broilers. An IPEC-J2 cell model was established and evaluated to delve deeper into the transport mechanism and antioxidant potential. The in vivo pharmacokinetic analysis in broilers highlighted a substantial difference: the maximum plasma concentration (Cmax) of DA-g-CS/CA exceeded CA by 2.6-fold, yielding a notable increased relative bioavailability to 214%. This evidence underscores the significant enhancement in CA's oral absorption, facilitated by DA-g-CS. The collective evaluation outcomes affirm the successful development of the cell model, indicating its suitability for drug transporter experiments. The findings from the intestinal transit analysis revealed that both CA and DA-g-CS/CA underwent passive entry into IPEC-J2 cells. Notably, the cellular uptake rate of DA-g-CS loaded with CA was significantly amplified, reaching 2.1 times higher than that of CA alone. Intracellular transport mechanisms involved microtubules, lysosomes, and the endoplasmic reticulum, with an additional pathway involving the endoplasmic reticulum observed specifically for DA-g-CS/CA, distinguishing it from CA. Moreover, the results from both in vivo and in vitro antioxidant assessments highlight the potent antioxidant activity of DA-g-CS/CA, showcasing its efficacy in preventing and treating cellular damage induced by oxidative stress. In summary, these findings underscore the significant enhancement of CA's efficacy facilitated by DA-g-CS, establishing a robust theoretical foundation for the prospective application of CA within livestock and poultry farming.

An improved small-molecule inhibitor of FtsZ with superior in vitro potency, drug-like properties, and in vivo efficacy.

The bacterial cell division protein FtsZ is an attractive target for small-molecule antibacterial drug discovery. Derivatives of 3-methoxybenzamide, including compound PC190723, have been reported to be potent and selective antistaphylococcal agents which exert their effects through the disruption of intracellular FtsZ function. Here, we report the further optimization of 3-methoxybenzamide derivatives towards a drug candidate. The in vitro and in vivo characterization of a more advanced lead compound, designated compound 1, is described. Compound 1 was potently antibacterial, with an average MIC of 0.12 µg/ml against all staphylococcal species, including methicillin- and multidrug-resistant Staphylococcus aureus and Staphylococcus epidermidis. Compound 1 inhibited an S. aureus strain carrying the G196A mutation in FtsZ, which confers resistance to PC190723. Like PC190723, compound 1 acted on whole bacterial cells by blocking cytokinesis. No interactions between compound 1 and a diverse panel of antibiotics were measured in checkerboard experiments. Compound 1 displayed suitable in vitro pharmaceutical properties and a favorable in vivo pharmacokinetic profile following intravenous and oral administration, with a calculated bioavailability of 82.0% in mice. Compound 1 demonstrated efficacy in a murine model of systemic S. aureus infection and caused a significant decrease in the bacterial load in the thigh infection model. A greater reduction in the number of S. aureus cells recovered from infected thighs, equivalent to 3.68 log units, than in those recovered from controls was achieved using a succinate prodrug of compound 1, which was designated compound 2. In summary, optimized derivatives of 3-methoxybenzamide may yield a first-in-class FtsZ inhibitor for the treatment of antibiotic-resistant staphylococcal infections.

Peptide backbone replacement of hepatitis C virus NS3 serine protease C-terminal cleavage product analogs: discovery of potent succinamide inhibitors.

A number of potent peptidic inhibitors of the NS3 protease have been described in the literature based on a substrate-based approach. In an on-going effort to reduce the peptidic character of this class of inhibitors, two novel series of analogs have been prepared in which the usual P3 amino acid residue is replaced by a succinamide fragment. This new backbone modification not only reduces the peptidic nature of traditional inhibitors but also provides new SAR opportunities for the capping group. Optimization of each of these two series resulted in inhibitors with sub-nanomolar potencies.

Effect of food intake on the pharmacokinetics of sarpogrelate and its active metabolite following oral administration to beagle dogs.

1. The objectives of this study were to develop a pharmacokinetic model for sarpogrelate and its metabolite M-1 and to identify the effect of food on sarpogrelate and M-1 pharmacokinetics in beagle dogs. 2. A single 100 mg oral dose of sarpogrelate was administered to fasted and fed beagle dogs and the plasma concentrations of sarpogrelate and M-1 were measured simultaneously by liquid chromatography tandem mass spectrometry. The resultant data were analyzed by modeling approaches using ADAPT5. 3. The plasma concentration time course of sarpogrelate and M-1 were described using a parent-metabolite compartment model with first-order absorption and elimination. The systemic exposure of sarpogrelate and its metabolite after the administration of a single 100 mg oral dose was significantly decreased under the fed condition compared to that under the fasting condition. Modeling approaches have sufficiently explained the food effect of sarpogrelate, i.e. an increased Vc and decreased Ka, in fed dogs. The food effect of sarpogrelate was due to its pH-dependent dissolution. 4. These findings suggest that food intake affects both the rate and extent of absorption of sarpogrelate, and that the pharmacological effect of sarpogrelate can differ significantly according to food intake.

Comparison of pharmacokinetics between sarpogrelate hydrochloride immediate-release formulation and controlled-release formulation.

OBJECTIVE: Sarpogrelate hydrochloride is a selective 5-hydroxytryptamine receptor subtype 2A (5HT(2A)) antagonist that blocks serotonin-induced platelet aggregation. The aim of this study was to compare the pharmacokinetics of sarpogrelate and its metabolite after dosing with a controlledrelease (CR) formulation or an immediaterelease (IR) formulation. METHODS: In this open-label, 2-period, 2-treatment crossover study, 36 healthy male subjects were evenly allocated to two groups in a sequence-randomized manner. In the first period, the first group received 100-mg sarpogrelate IR 3 times at a 6-h interval, and the second group received 300-mg sarpogrelate CR once. After a 7-day washout, the two groups switched their dosing schedule. Serial blood sampling was performed up to 24 hours after the first drug administration during each period. Plasma concentrations of sarpogrelate and its metabolite (M-1) were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods. RESULTS: There were no significant differences between two formulations in the pharmacokinetic properties in the time to reach maximum plasma concentration (C(max)) of sarpogrelate and its metabolite. The CR-to-IR geometric mean ratios, as measured by area under the plasma concentration-time curve (AUC) were 1.31 (90% confidence interval, 1.22 - 1.41) for sarpogrelate and 1.21 (1.14 - 1.29) for M-1. The C(max) was 0.98 (0.85 - 1.12) for sarpogrelate and 1.07 (0.96 - 1.19) for M-1. CONCLUSIONS: After the administration of sarpogrelate hydrochloride CR and IR formulations using the same daily dose, AUCs were slightly higher for the CR formulation than for the IR formulation for both sarpogrelate and its metabolite M-1, but the C(max) values were similar.

[The study of dynamics of clinical and molecular phenotypes in the generalized form of myasthenia with optimized and combined treatment].

The aim of the study was the research of clinical and molecular phenotypes in the generalized form of myasthenia with optimized treantment, which includes the application of basic mode of the treatment and meglumine sodium succinate, and also the combined mode of the treatment, which includes the mode of the treatment and meglumine sodium succinate and ozonotherapy. The most epressed improvement of indicators of the clinical and neurologic status (the eliminaton of motoring breakdown, eye movement disrders, the weaknesses of mimic, respiratory and chewing muscles, bulbar syndrome, the doubling in eye and ptosis, pharyngeal violations and increase in volume of movement of eyes) was observed in the group of patients receiving the combined therapy. The reduction of the epressiveness of the defeat of the neuromotor device and the decrement of the amplitude of the various degree of M-answer in patients with myasthenla is revealed in the application of the combined therapy in the comparison with the application of the basic and optimized therapy. For the first time we have investigaed the dynamics of the intensity of the expression of specfic peptides and proteins in blood serum in patients with the application of basic therapy, reamberin and ozonotherapy, which have allowed to open the new mechanisms of the efficiency ofthe combined therapy of the disease.

Real-time molecular imaging of tricarboxylic acid cycle metabolism in vivo by hyperpolarized 1-(13)C diethyl succinate.

The Krebs tricarboxylic acid cycle (TCA) is central to metabolic energy production and is known to be altered in many disease states. Real-time molecular imaging of the TCA cycle in vivo will be important in understanding the metabolic basis of several diseases. Positron emission tomography (PET) with FDG-glucose (2-[(18)F]fluoro-2-deoxy-d-glucose) is already being used as a metabolic imaging agent in clinics. However, FDG-glucose does not reveal anything past glucose uptake and phosphorylation. We have developed a new metabolic imaging agent, hyperpolarized diethyl succinate-1-(13)C-2,3-d(2) , that allows for real-time in vivo imaging and spectroscopy of the TCA cycle. Diethyl succinate can be hyperpolarized via parahydrogen-induced polarization (PHIP) in an aqueous solution with signal enhancement of 5000 compared to Boltzmann polarization. (13)C magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) were achieved in vivo seconds after injection of 10-20 µmol of hyperpolarized diethyl succinate into normal mice. The downstream metabolites of hyperpolarized diethyl succinate were identified in vivo as malate, succinate, fumarate, and aspartate. The metabolism of diethyl succinate was altered after exposing the animal to 3-nitropropionate, a known irreversible inhibitor of succinate dehydrogenase. On the basis of our results, hyperpolarized diethyl succinate allows for real-time in vivo MRI and MRS with a high signal-to-noise ratio and with visualization of multiple steps of the TCA cycle. Hyperpolarization of diethyl succinate and its in vivo applications may reveal an entirely new regime wherein the local status of TCA cycle metabolism is interrogated on the time scale of seconds to minutes with unprecedented chemical specificity and MR sensitivity.

A single-center, randomized, open-label, dose-escalation study to evaluate the pharmacokinetics of tacrine analogue octahydrogenacridine succinate tablets in healthy Chinese subjects.

The objectives of the present study were to investigate the pharmacokinetics (PK) of tacrine analogue octahydrogenacridine (OHA) succinate tablets in healthy Chinese subjects. A single-center, randomized, open-label, dose-escalation study was conducted in 42 healthy Chinese subjects. Part I of the study (n=30, 16 male and 14 female) evaluated the PK profiles of OHA in healthy Chinese subjects (aged 18-45 years) after single and multiple doses of 2 mg, 4 mg and 8 mg. Part II (n=10) assessed food effect on PK characteristics of OHA. The 10 participants of 4 mg dose group in part I were given another single dose of 4 mg OHA under fed condition. Part III (n=12, 7 male and 5 female) investigate PK behavior of OHA in elderly (aged 65-75 years) Chinese healthy subjects. In Part I, following a single- and multiple-dose, octahydrogenacridine succinate was rapidly absorbed with a median t(max) of 0.67 to 1.00 h, and was eliminated with a mean t1/2 of 2.27 to 2.98 h in all dose groups and did not appear to be dose dependent. In Part II, there were no significant differences in Cmax, AUC0-tn or tmax between 4 mg single dose fasting group and fed group (p=0.257, 0.153, 0.098, respectively). In Part III, both in single-dose and multiple-dose treatment, the main PK parameters of OHA in the elderly healthy Chinese subjects showed no statistical difference with those of non-elderly group. All these results indicated that OHA might be a promising drug under development for Alzheimer's disease (AD) therapy.

[Hepatotropic medicines: current status].

Limits of administration, efficacy and safety of hepatotropic drugs are not finally formulated yet because of lack of clinical trials which satisfy current principles of evidence-based medicine. The review analyses data on clinical use of drugs for which hepatotropic action is leading, prevalent or clinically independent; gives information on composition of some drugs, pharmacodynamics, pharmacokinetics, principles of clinical administration, side effects, clinical trials; outlines a mechanism of action and area of application of a new original hepatotropic drug remaxol. Experimental data are available on remaxol ability to reduce hepatic affection induced by hepatotoxic agents and severity of carbohydrate, protein and fat dystrophy, to activate regeneration of the liver Clinical trials demonstrate remaxol efficacy in management of roxemia, cytolysis, cholestasis. The above effectiveness and its antiasthenic and antidepressive activity makes this drug a universal hepatotropic medicine effective in various hepatic diseases (viral hepatitis C, toxic and pharmacological damage) both in therapeutic and prophylactic schemes.

[Metabolic correction of the lipid-transport system in experimental diffuse purulent peritonitis].

The research was performed in 55 male chinchilla rabbits. For the first time the effect of metabolic preparations "citoflavin" and "neoton" of the protein-lipid spectrum of blood was studied in experimental diffuse purulent peritonitis. The development of diffuse purulent peritonitis caused negative changes in blood lipid-transport system which resulted in a decreased blood protein level and high density lipoproteins (HDL) and growth of triglycerides. In the HDL phospholipid spectrum the pathological changes are characterized by an increased lisophosphotide content and compensatory growth of the level of poliglycerophosphatides. A comparative analysis has shown that both preparations possess unidirectional action which is more pronounced in "citoflavin" than in "neoton".