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Oral delivery of peptides and proteins is hindered by their rapid proteolysis in the gastrointestinal tract and their inability to permeate biological membranes. Various drug delivery approaches are being investigated and implemented to overcome these obstacles. In the discussed study conducted in pigs, an investigation was undertaken to assess the effect of combination of a permeation enhancer – salcaprozate sodium, and a proteolysis inhibitor – soybean trypsin inhibitor, on the systemic exposure of the peptide teriparatide, following intraduodenal administration. Results demonstrate that this combination achieves significantly higher Cmax and AUC (~10- and ~20-fold respectively) compared to each of these methodologies on their own. It was thus concluded that an appropriate combination of different technological approaches may considerably contribute to an efficient oral delivery of biological macromolecules., Graphical abstract Unlabelled Image, Highlights • Soybean trypsin inhibitor (SBTI) protects hPTH(1–34) from proteolysis in the intestine. • SNAC/SBTI combination significantly raises plasma exposure of oral hPTH(1–34). • Oral formulation hPTH(1–34)/SNAC/SBTI befits the PK profile for osteoporosis treatment. • Endoscopic intraduodenal delivery in pigs enables investigation of absorption mechanisms.

Camptothecin (CPT) exhibits a number of challenges for its oral administration, including a low aqueous solubility, a lactone ring susceptible to hydrolysis, and an affinity to the intestinal P-gp. The aim of this work was to evaluate nanoparticles from Gantrez-based conjugates as carriers for the oral delivery of CPT. For this purpose two different conjugates (G-mPEG and G-HPCD), obtained by the covalent binding of either HP-β-CD or methoxy-PEG (m-PEG) to the polymer backbone of Gantrez™ AN, were synthetized and characterized. Both excipients (m-PEG and HPCD) were selected due to their reported abilities to stabilize the lactone ring of CPT and disturb the effect of intestinal P-gp. The resulting nanoparticles (G-mPEG-NP and G-HPCD-NP) presented a similar size (about 200 nm) and zeta potential (close to −35 mV); although, G-mPEG-NP presented a higher CPT payload than G-HPCD-NP. On the contrary, in rats, nanoparticles based on Gantrez conjugates appeared to be capable of crossing the protective mucus layer and reach the intestinal epithelium, whereas conventional Gantrez nanoparticles displayed a mucoadhesive profile. Finally, the pharmacokinetic study revealed that both formulations were able to enhance the relative oral bioavailability of CPT; although this value was found to be 2.6-times higher for G-mPEG-NP than for G-HPCD-NP., Graphical abstract Unlabelled Image

Remdesivir dry powder for inhalation was previously developed using thin film freezing (TFF). A single-dose 24-h pharmacokinetic study in hamsters demonstrated that pulmonary delivery of TFF remdesivir can achieve plasma remdesivir and GS-441524 levels higher than the reported EC50s of both remdesivir and GS-441524 (in human epithelial cells) over 20 h. The half-life of GS-4412524 following dry powder insufflation was about 7 h, suggesting the dosing regimen would be twice-daily administration. Although the remdesivir-Captisol® (80/20 w/w) formulation showed faster and greater absorption of remdesivir and GS-4412524 in the lung, remdesivir-leucine (80/20 w/w) exhibited a greater Cmax with shorter Tmax and lower AUC of GS-441524, indicating lower total drug exposure is required to achieve a high effective concentration against SAR-CoV-2. In conclusion, remdesivir dry powder for inhalation would be a promising alternative dosage form for the treatment of COVID-19 disease., Graphical abstract Unlabelled Image

Background PB-201, a partial, pancreas/liver-dual glucokinase activator, showed good tolerance and glycaemic effects in multinational studies. This study determined its optimal dose, safety, pharmacokinetics, and pharmacodynamics in Chinese patients with type 2 diabetes. Methods In this double-blind, randomised, four-period, crossover, phase 1 trial in China, conducted at the Peking University Third Hospital, adult patients with drug-naive type 2 diabetes were randomised (1:1:1:1) to four sequence groups using a computer-generated randomisation table. In each period, they received oral placebo or PB-201 (50+50, 100+50, or 100+100 mg split doses) for 7 days. Investigators and patients were masked to treatment assignment. The primary endpoints were safety and pharmacokinetics. Continuous glucose monitoring was used to delineate the glucose excursion profile. Trial registration number: NCT03973515. Findings Between August 27, 2019 and December 19, 2019, 16 patients were randomised. PB-201 showed a dose-proportional pharmacokinetic profile without apparent accumulation in the body and induced dose-dependent lowering of blood glucose. PB-201 at 50+50, 100+50, and 100+100 mg increased mean time in range (49·210% [standard deviation 27], 56·130% [25], and 63·330% [20] with three doses, respectively) versus placebo (49·380% [27]) and reduced estimated glycated haemoglobin from baseline (-0·5445% [1·654], -1·063% [1·236], and -1·888% [1·381] vs -0·581% [1·200]). Fifteen patients (93·8%) had treatment-emergent adverse events, which were mild. No patients had hypoglycaemia with venous/capillary glucose

Peramivir was a novel and highly potent neuraminidase (NA) inhibitor for the treatment of influenza A and B. However, it exhibited a very low oral bioavailability (only 3%) due to the high polarity (log P of −1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated prodrug strategy to improve the oral absorption and develop the oral alternative, seven amino acid ester prodrugs and seven amino acid amide prodrugs have been synthesized. The permeability of these prodrugs across Caco-2 cells were screened. Peramivr-(CH2)2-l-Val and Peramivir-l-Ile were of the highest permeability in ester prodrugs and amide prodrugs, respectively, and then they were selected for further studies. Glycylsarcosine (gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH2)2-l-Val and Peramivir-l-Ile in a concentration-dependent manner, and the IC50 was 1.34 ± 0.31 mM and 1.78 ± 0.48 mM, respectively. The direct uptake of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by gly-sar. The uptake of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile (0.01 to 50 mM) in MDCK-hPEPT1 cells conformed to Michaelis–Menten Equation. The oral bioavailability of peramivir was 65.3% and 37.3% after the oral administration of Peramivir-(CH2)2-l-Val and Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH2)2-l-Val was rapid and extensive, and no Peramivir-(CH2)2-l-Val was found in plasma. Because the amide bond was relatively stable, Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH2)2-l-Val with good oral profiles and rapid bioactivation might be a promising prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug., Graphical abstract Peramivir-(CH2)2-l-Val can increase the oral bioavailability of peramivir from 4.1% to 65.3%.Image, graphical abstract

The phase 2b AMP trials are testing whether the broadly neutralising antibody VRC01 prevents HIV-1 infection in two cohorts: women in sub-Saharan Africa, and men and transgender persons who have sex with men (MSM/TG) in the Americas and Switzerland. We used nonlinear mixed effects modelling of longitudinal serum VRC01 concentrations to characterise pharmacokinetics and predict HIV-1 neutralisation coverage. We found that body weight significantly influenced clearance, and that the mean peripheral volume of distribution, steady state volume of distribution, elimination half-life, and accumulation ratio were significantly higher in MSM/TG than in women. Neutralisation coverage was predicted to be higher in the first (versus second) half of a given 8-week infusion interval, and appeared to be higher in MSM/TG than in women overall. Study cohort differences in pharmacokinetics and neutralisation coverage provide insights for interpreting the AMP results and for investigating how VRC01 concentration and neutralisation correlate with HIV incidence.

Aim: High-dose valproic acid (VPA) improves the survival and neurologic outcomes after asphyxial cardiac arrest (CA) in rats. We characterized the pharmacokinetics, pharmacodynamics, and safety of high-dose VPA in a swine CA model to advance clinical translation. Methods: After 8 ​min of untreated ventricular fibrillation CA, 20 male Yorkshire swine were resuscitated until return of spontaneous circulation (ROSC). They were block randomized to receive placebo, 75 ​mg/kg, 150 ​mg/kg, or 300 ​mg/kg VPA as 90-min intravenous infusion (n ​= ​5/group) beginning at ROSC. Animals were monitored for 2 additional hours then euthanized. Experimental operators were blinded to treatments. Results: The mean(SD) total CA duration was 14.8(1.2) minutes. 300 ​mg/kg VPA animals required more adrenaline to maintain mean arterial pressure ≥80 ​mmHg and had worse lactic acidosis. There was a strong linear correlation between plasma free VPA Cmax and brain total VPA (r2 ​= ​0.9494; p ​

Mucopolysaccharidosis III A (MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. The disorder results in accumulation of heparan sulfate, lysosomal enlargement and cellular and organ dysfunction. Patients exhibit progressive neurodegeneration and behavioral problems and no treatment is currently available. Enzyme replacement therapy is explored as potential treatment strategy for MPS IIIA patients and to modify the disease, sulfamidase must reach the brain. The glycans of recombinant human sulfamidase (rhSulfamidase) can be chemically modified to generate CM-rhSulfamidase. The chemical modification reduced the affinity to the cation-independent mannose-6-phosphate receptor with the aim a prolonged higher concentration in circulation and thus at the blood brain barrier. The pharmacokinetic properties in serum and the distribution to brain and to cerebrospinal fluid (CSF) of chemically modified recombinant human sulfamidase (CM-rhSulfamidase) were studied and compared to those of rhSulfamidase, after a single intravenous (i.v.) 30 mg/kg dose in awake, freely-moving male Sprague Dawley rats. Distribution to brain was studied by microdialysis of the interstitial fluid in prefrontal cortex and by repeated intra-individual CSF sampling from the cisterna magna. Push-pull microdialysis facilitated sampling of brain interstitial fluid to determine large molecule concentrations in awake, freely-moving male Sprague Dawley rats. Together with repeated serum and CSF sampling, push-pull microdialysis facilitated determination of CM-rhSulfamidase and rhSulfamidase kinetics after i.v. administration by non-compartments analysis and by a population modelling approach. Chemical modification increased the area under the concentration versus time in serum, CSF and brain interstitial fluid at least 7-fold. The results and the outcome of a population modelling approach of the concentration versus time data indicated that both compounds pass the BBB with an equilibrium established fairly rapid after administration. We suggest that prolonged high serum concentrations facilitated high brain interstitial fluid concentrations, which could be favorable to reach various target cells in the brain. Keywords: Mucopolysaccharidosis IIIA, Sulfamidase, Enzyme replacement therapy, Microdialysis, Pharmacokinetics, CNS distribution

Background: \ud TKM-130803 is a specific anti-EBOV therapeutic comprised of two small interfering RNAs (siRNA) siLpol-2 and siVP35-2. The pharmacokinetics (PK) of these siRNAs was defined in Ebola virus disease (EVD) patients, with reference to efficacy (ET) and toxicology thresholds (TT). The relationship between PK and patient survival was explored.\ud \ud Methods: \ud Pharmacokinetic (PK) and pharmacodynamic (PD) data were available for seven participants with EVD in Sierra Leone who received 0·3 mg/kg of TKM-130803 by intravenous infusion over 2 h daily for up to 7 days. Plasma concentration of siRNA was compared to survival at 14 days. PK data were fitted to two-compartment models then Monte Carlo simulated PK profiles were compared to ET (Cmax 0·04–0·57 ng/mL and mean concentration 1·43 ng/mL), and TT (3000 ng/mL).\ud \ud Findings: \ud Viral loads (VL) were not significantly different at treatment onset or during treatment (p = 0·1) in subjects who survived or died. siRNA was in quantitative excess of virus genomes throughout treatment, but the 95% percentile exceeded TT. The maximum AUC for which the 95% percentile remained under TT was a continuous infusion of 0·15 mg/kg/day. Plasma concentration of both siRNAs were higher in subjects who died compared to subjects who survived (p

This work was done to investigate succinylated commercial whey protein isolate (S-WPI) as an oral sustained-release delivery carrier for puerarin 5 (PR-5). The succinylation conditions were established for S-WPIs by optimization of single factor study and Box–Beehnken design. The effect of succinylation degree on S-WPIs solubility was evaluated. Physicochemical properties of S-WPIs dried by different three methods on their flow ability, particle size, morphology and in vitro release behavior were studied. After preparing PR-5 sustained release protein tablets with S-WPIs as the carrier by direct powder compression method, the drug release were studied in vitro and the oral pharmacokinetics and bioavailability was evaluated using in vivo dog model. It was observed that concentration of substrate has a significant effect on succinylation. Release behavior in vitro showed spry dried S-WPIs with 100% succinylation rate and 30% drug loading would be applied to the preparation of PR-5 sustained-release protein tablets based on the swelling mechanism (protein loss). Compared with PR-5 conventional tablet with oral administration, Tmax value of PR-5 sustained-release protein tablets was approximately 1.58 fold greater than those of the conventional tablets as further evidenced by the significantly prolonged MRT and T1/2. The findings demonstrated that spray-dried S-WPIs has potential as a promising functional excipient for the design of PR-5 oral sustained-release tablets which can fully improve sustained-release effect and oral bioavailability. Keywords: Whey protein isolate, Succinylation, Puerarin 5, Sustained drug delivery, Pharmacokinetics

Background Clozapine is the most effective drug for treatment-resistant schizophrenia, but its use is limited by toxicity. Because ethnicity has been reported to affect clozapine metabolism, we compared its steady state pharmacokinetics in New Zealand Maori and European patients. Methods Clozapine and norclozapine steady state bioavailability was assessed over 24 h under fasting and fed conditions in 12 Maori and 16 European patients treated for chronic psychotic illnesses with stable once-daily clozapine doses. Plasma clozapine and norclozapine concentrations were assessed using liquid chromatography with tandem mass spectrometry; pharmacokinetic parameters were calculated using standard non-compartmental methods, and compared using unpaired t-tests. Findings Mean pharmacokinetic parameters (AUC, Cmax and Cmin) for clozapine and norclozapine were virtually identical in Maori and European subjects, under both fed and fasted conditions. Discussion Clozapine bioavailability does not vary between Maori and European patients, and thus does not need to be considered in prescribing decisions. Additional studies are needed to identify if there are differences between Maori and European populations for drugs metabolized by other enzyme pathways., Highlights • Metabolism of clozapine, our most effective antipsychotic drug, was compared in New Zealand's two main ethnic groups. • Clozapine pharmacokinetic parameters were similar in Maori and European patients. • Accordingly, clozapine dosing does not need to take Maori or European ethnicity into account. Clozapine is an essential medicine for treatment-resistant schizophrenia, but its use is limited by significant side-effects. We were interested to see if Maori and European patients in New Zealand differed in terms of clozapine pharmacokinetics, as this could influence both clinical response and side-effects. We found essentially no difference in clozapine pharmacokinetics between these groups, meaning that dosing decisions can be made based on clinical factors without regard to ethnicity.

In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2) unadjusted odds ratio (UOR) scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS); (3) adjusted odds ratio (AOR) re-scoring by removing the effect of cofounding factors (age, gender, reporting year); (4) logistic regression (LR) coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: −2.68; p-value, Highlights • An in silico MSBIS approach was developed to identify concomitant drugs that mitigate the side effects of a primary drug. • Fentanyl and loperamide were identified to protect patients against drug-induced tardive dyskinesia (TD). • MSBIS can be generalized to provide rational starting points for drug repurposing and combination therapy design. Many dopamine antagonists cause TD and other severe, irreversible movement disorders. 120 drugs were screened using the MSBIS approach, leading to the discovery of fentanyl and loperamide. When co-administered with dopamine antagonists such as metoclopramide, they may protect patients against drug-induced movement disorders including TD. Their mechanisms of toxicity-mitigating action are remarkably different. The statistical significance of the findings was established using the FDA Adverse Event Reporting System and supported by published clinical reports and pharmacologic data. This study demonstrated the feasibility of the MSBIS approach and its applicability in identifying unknown drug-drug interactions that either mitigate undesirable toxicities or synergize therapeutic effects.

Background The utility of intramuscular (IM) oxytocin for the prevention of postpartum hemorrhage in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. We evaluated the safety, tolerability and pharmacokinetics (PK) of a heat-stable, inhaled (IH) oxytocin formulation. Methods This phase 1, randomized, single-center, single-blind, dose-escalation, fixed-sequence study (NCT02542813) was conducted in healthy, premenopausal, non-pregnant, non-lactating women aged 18–45 years. Subjects initially received IM oxytocin 10 international units (IU) on day 1, IH placebo on day 2, and IH oxytocin 50 μg on day 3. Subjects were then randomized 4:1 using validated GSK internal software to IH placebo or ascending doses of IH oxytocin (200, 400, 600 μg). PK was assessed by comparing systemic exposure (maximum observed plasma concentration, area under the concentration-time curve, and plasma concentrations at 10 and 30 min post dose) for IH versus IM oxytocin. Adverse events (AEs), spirometry, laboratory tests, vital signs, electrocardiograms, physical examinations, and cardiac telemetry were assessed. Findings Subjects were recruited between September 14, 2015 and October 12, 2015. Of the 16 subjects randomized following initial dosing, 15 (IH placebo n = 3; IH oxytocin n = 12) completed the study. IH (all doses) and IM oxytocin PK profiles were comparable in shape. However, systemic exposure with IH oxytocin 400 μg most closely matched IM oxytocin 10 IU. Systemic exposure was approximately dose proportional for IH oxytocin. No serious AEs were reported. No clinically significant findings were observed for any safety parameters. Interpretation These data suggest that similar oxytocin systemic exposure can be achieved with IM and IH administration routes, and no safety concerns were identified with either route. The inhalation route may offer the opportunity to increase access to oxytocin for women giving birth in resource-poor settings., Highlights • First-in-human study of a heat-stable, dry powder oxytocin formulation for oral inhalation using a simple inhaler device • Data suggest that similar oxytocin systemic exposure can be achieved with intramuscular and inhaled administration routes. • This could provide an effective delivery system for prevention of postpartum hemorrhage in women in resource-poor settings. Intramuscular or intravenous oxytocin is the gold standard preventative therapy for postpartum hemorrhage (PPH). However, the utility of intramuscular oxytocin in resource-poor settings is limited by the requirement for temperature-controlled storage and skilled staff to administer the injection. The Innovation Countdown 2030 Initiative has estimated that the introduction of alternative, heat-stable formulations of oxytocin could prevent 146,000 maternal deaths over a period of 8 years. This study provides encouraging preliminary evidence that inhaled oxytocin can be delivered using a heat-stable dried powder for inhalation with no safety concerns. Establishing the clinical utility of this potential medicine will require further studies.

Glyoxalases prevent the formation of advanced glycation end products by converting glycolysis-derived methylglyoxal to d-lactate with the help of glutathione. Vander Jagt and colleagues previously showed that erythrocytes release about thirty times more d-lactate after infection with the human malaria parasite Plasmodium falciparum. Functional glyoxalases in the host-parasite unit might therefore be crucial for parasite survival. Here, we determined the antimalarial and hemolytic activity of two tight-binding glyoxalase inhibitors using infected and uninfected erythrocytes. In addition, we synthesized and analyzed a set of diester derivates of both tight-binding inhibitors resulting in up to threefold lower IC50 values and an altered methemoglobin formation and hemolytic activity depending on the type of ester. Inhibitor treatments of uninfected erythrocytes revealed an extremely slow inactivation of the host cell glyoxalase, irrespective of inhibitor modifications, and a potential dispensability of the host cell enzyme for parasite survival. Our study highlights the benefits and drawbacks of different esterifications of glutathione-derived inhibitors and demonstrates the suitability of glyoxalase inhibitors as a tool for deciphering the relevance and mode of action of different glyoxalase systems in a host-parasite unit., Graphical abstract fx1

Treatment of disseminated tuberculosis in children ≤ 6 years has not been optimized. The pyrazinamide-containing combination regimen used to treat disseminated tuberculosis in babies and toddlers was extrapolated from adult pulmonary tuberculosis. Due to hepatotoxicity worries, there are no dose–response studies in children. We designed a hollow fiber system model of disseminated intracellular tuberculosis with co-perfused three-dimensional organotypic liver modules to simultaneously test for efficacy and toxicity. We utilized pediatric pharmacokinetics of pyrazinamide and acetaminophen to determine dose-dependent pyrazinamide efficacy and hepatotoxicity. Acetaminophen concentrations that cause hepatotoxicity in children led to elevated liver function tests, while 100 mg/kg pyrazinamide did not. Surprisingly, pyrazinamide did not kill intracellular Mycobacterium tuberculosis up to fourfold the standard dose as monotherapy or as combination therapy, despite achieving high intracellular concentrations. Host-pathogen RNA-sequencing revealed lack of a pyrazinamide exposure transcript signature in intracellular bacteria or of phagolysosome acidification on pH imaging. Artificial intelligence algorithms confirmed that pyrazinamide was not predictive of good clinical outcomes in children ≤ 6 years who had extrapulmonary tuberculosis. Thus, adding a drug that works inside macrophages could benefit children with disseminated tuberculosis. Our in vitro model can be used to identify such new regimens that could accelerate cure while minimizing toxicity., Highlights • We designed a pre-clinical of disseminated for simultaneous identification of toxicity and efficacy in children. • The system is a co-culture of infected monocytes and 3 dimensional organotypic liver recapitulating children pharmacokinetics. • Pyrazinamide, central drug in treatment regimen, had no effect as monotherapy or contribute to the combination therapy. Due to fear of toxicity children are often not involved in clinical trials, and as a result the optimal treatment regimens are often lacking. As an example, toddlers and babies develop disseminated tuberculosis but are treated with regimens designed for adults with lung cavity disease. We designed a “glass-mouse” model of disseminated tuberculosis that simultaneously tests for the efficacy and toxicity of the anti-tuberculosis drugs for children with disseminated disease. We found that while not causing dose-dependent liver toxicity, one of the central drugs used to treat this children is likely not efficacious.

Herbal medicine, the backbone of traditional medicine, has played an important role in human health and welfare for a long period. Traditional therapeutic approaches of regional significance are found in Africa, South and Central America, China, India, Tibet, Indonesia, and the Pacific Islands. The considerable scientific significance and commercial potential of traditional medicines have resulted in increased international attention and global market demands for herbal medicines, especially Chinese herbal medicines. Herbal medicines currently are the primary form of health care for the poor in the developing countries, and also are widely used as a supplement or substitute for conventional drugs in developed countries. These traditional medicines have a pivotal role in the treatment of various ailments and more than 50% of drugs used in Western pharmacopoeia are isolated from herbs or derived from modifications of chemicals found in plants. Herbal medicines usually contain a complex mixture of various bioactive molecules, which make its standardization complicated, and there is little information about all compounds responsible for pharmacological activity. Several research papers have been published that claim pharmacological activity of herbal medicines but few are discussing the role of the exact phytoconstituent. Understanding the pharmacokinetic profile of such phytoconstituents is essential. Although there are research papers that deal with pharmacokinetic properties of phytoconstituents, there are a number of phytoconstituents yet to be explored for their kinetic properties. This article reviews the pharmacokinetic profile of 50 different therapeutically effective traditional medicinal plants from the year 2003 onward., Graphical abstract

Gallic acid (GA), also known as 3,4,5-trihydroxybenzoic acid, is a natural secondary metabolite and widely isolated from various fruits, plants and nuts. In recent years, GA has received increasing attention for its powerful anti-inflammatory properties. The purpose of this review is to clearly illuminate the pharmacological activities and related molecular mechanisms of GA in inflammatory diseases. After consulting a large number of literatures, we made a comprehensive exposition on the chemical characteristics, plant origins, pharmacokinetics and toxicity of GA, especially its pharmacological activities and mechanisms of action. Although the plant source of GA is very rich, its lower extraction rate limits the application of GA in development. It is worth mentioning that GA can not only be separated from many plants, but also be produced in large quantities through biological and chemical synthesis. According to pharmacokinetic studies, the absorption and elimination of GA after oral administration are fast, while the structural optimization or dosage form adjustment of GA is beneficial to increase its bioavailability. Promisingly, toxicity studies have shown that GA scarcely has obvious toxicity or side effects in a variety of animal experiments and clinical trials. The results show that the anti-inflammatory mechanisms of GA mainly involved MAPK and NF-κB signaling pathways. It thus weakens the inflammatory response by reducing the release of inflammatory cytokines, chemokines, adhesion molecule and cell infiltration. Due to its excellent pharmacological activities, GA is expected to be a potential candidate for the treatment of various inflammation-related diseases. This paper will provide theoretical basis for the clinical application of GA and guide the future research and medicinal development of GA.

Even if major improvements in therapeutic regimens and treatment outcomes have been progressively achieved, tuberculosis (TB) remains the leading cause of death from a single infectious microorganism. To improve TB treatment success as well as patients' quality of life, drug-drug-interactions (DDIs) need to be wisely managed. Comprehensive knowledge of anti-TB drugs, pharmacokinetics and pharmacodynamic (PK/PD) parameters, potential patients’ changes in absorption and distribution, possible side effects and interactions, is mandatory to built effective anti-TB regimens. Optimization of treatments and adherence to international guidelines can help bend the curve of TB-related mortality and, ultimately, decrease the likelihood of treatment failure and drop-out during anti-TB treatment. Aim of this paper is to describe the most relevant DDIs between anti-TB and other drugs used in daily clinical practice, providing an updated and “easy-to-use” guide to minimize adverse effects, drop-outs and, in the long run, increase treatment success., Highlights • Tuberculosis (TB) remains the leading cause of death from a single infectious microorganism. • Comprehensive knowledge of anti-TB drugs and PK/PD parameters is mandatory to built effective anti-TB regimens. • Drug-drug-interactions (DDIs) need to be avoided and/or wisely managed to ensure treatment success. • Optimization of anti-TB treatment to avoid DDIs can help to bend the curve of TB related mortality.

An association between vedolizumab (VDZ) trough concentrations and therapeutic outcome has been observed in patients with inflammatory bowel diseases. VDZ samples are typically collected via venous sampling for therapeutic drug monitoring (TDM), but can alternatively be collected via dried blood spot (DBS) samples, which can be used for intensive sampling to investigate pharmacokinetic profiles. Therefore, we have developed a DBS method for determining VDZ concentrations and validated this method by comparing VDZ measurements in paired DBS and venous patient samples. First, VDZ was spiked in citrated whole blood and spotted on filter paper. After drying, DBS were extracted and VDZ concentrations were determined in the extracts using ELISA. For clinical validation, 41 paired DBS and serum samples were collected from 19 VDZ-treated patients. VDZ concentrations measured in DBS extracts strongly correlated with serum concentrations (Pearson r = 0.978, p

The paper presents and discusses a basic pharmacokinetic model for vancomycin, an antibiotic that is principally excreted by kidneys. The model accounts for the degree of renal function by employing the CKD-EPI equation. Only one parameter of the model is identified by a nonlinear regression of experimental data, while the other parameters are evaluated a priori via correlations from the scientific literature. We simulate the pharmacokinetic time-curves of vancomycin by accounting for different values of the glomerular filtration rate and show the strong influence of the degree of renal function on the drug pharmacokinetics. In addition, the model can be used to determine the optimal dose for patients featuring varying degrees of renal function. Results underline the importance of individualized treatment.

Triptolide (TP), a major active component of Tripterygium wilfordii Hook.F. (TWHF), is used to treat rheumatoid arthritis (RA). However, it has a narrow therapeutic window due to its serious toxicities. To increase the therapeutic index, a new triptolide-loaded transdermal delivery system, named triptolide-loaded liposome hydrogel patch (TP-LHP), has been developed. In this paper, we used a micro-needle array to deliver TP-LHP to promote transdermal absorption and evaluated this treatment on the pharmacokinetics and pharmacodynamics of TP-LHP in a rat model of collagen-induced arthritis (CIA). The pharmacokinetic results showed that transdermal delivery of microneedle TP-LHP yielded plasma drug levels which fit a one-compartment open model. The relationship equation between plasma concentration and time was C=303.59×(e−0.064t−e−0.287t). The results of pharmacodynamic study demonstrated that TP-LHP treatment mitigated the degree of joint swelling and suppressed the expressions of fetal liver kinase-1, fetal liver tyrosine kinase-4 and hypoxia-inducible factor-1α in synovium. Other indicators were also reduced by TP-LHP, including hyperfunction of immune, interleukin-1β and interleukin-6 levels in serum. The therapeutic mechanism of TP-LHP might be regulation of the balance between Th1 and Th2, as well as inhibition of the expression and biological effects of vascular endothelial growth factor., Graphical abstract A new triptolide-loaded transdermal delivery system, named triptolide-loaded liposome hydrogel patch (TP-LHP), had been developed to treat the rats with collagen-induced arthritis (CIA). Microneedle array was used to promote transdermal absorption. TP-LHP provided stable long-term release of triptolide, and had significant efficacy in CIA model. fx1

Ginsenoside Rg1 (GR), a major bioactive compound of traditional Chinese medicine, such as Panax ginseng or Radix Notoginseng, has been shown to exert neuroprotective effects against ischemic stroke. However, pharmacokinetic studies have suggested that GR could not be efficiently transported through the blood–brain barrier. The mechanism by which GR attenuates cerebral ischemic injury in vivo remains largely unknown. Therefore, this study explored potential neuro-protective effects of GR through its systemic metabolic regulating mechanism by using mass spectrometry–based metabolomic profiling. Rats with middle cerebral artery occlusion (MCAO) were treated with GR intravenously. Their metabolic profiles in serum were measured by gas chromatography coupled with mass spectrometry on 1 and 3 days after MCAO. GR exhibited a potent neuro-protective effect by significantly decreasing the neurological scores and infarct volume in the MCAO rats. Moreover, 18 differential metabolites were tentatively identified, all of which appeared to correlate well with these disease indices. Our findings suggested that GR carries a therapeutic potential in stroke possibly through a feed-back mechanism by regulating systematic metabolic mediation., Graphical abstract The paper demonstrates that the systemic metabolites was significantly differentiated by cerebral ischemic injury, and Rg1 exhibited its neuro-protective effects by a potential systemic feed-back regulating mechanisms.

In this paper the effect of plaque composition, on the accumulation of drug released by a drug eluting stent, is analyzed. The mathematical model is represented by two coupled systems of partial differential equations that describe the pharmacokinetics of drug in the stent coating and in the arterial wall. The influence of the stiffness and porosity of soft and hard plaques is studied. A case study based on optical coherence tomography images is also included.

Citrus aurantium extract has been largely used in weight loss and sports performance dietary supplements. However, the safety of C. aurantium-containing products has been questioned mainly due to the association of its use with adverse events in the cardiovascular system. Therefore, this work aimed to assess the potential for herb-drug interactions among a standardized C. aurantium extract (GMP certificate) and amiodarone (narrow therapeutic index drug) in rats. In a first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of C. aurantium (164 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in a second study, rats were pre-treated during 14 days with C. aurantium (164 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. Overall, after analysis of the pharmacokinetic data, it deserves to be highlighted the significant increase of the peak plasma concentration of amiodarone in rats pre-treated with C. aurantium extract, while the extent of systemic exposure was comparable between both groups. This paper reports, for the first time, data on the potential of herb-drug interaction between C. aurantium extract and amiodarone. However, specific clinical trials should be performed to confirm these results in humans.

Since amyloid beta-protein (A beta) is the primary component of both vascular and parenchymal amyloid deposits in Alzheimer's disease, information regarding its permeability at the blood-brain barrier (BBB) will help elucidate the contribution of circulating A beta to vascular and parenchymal A beta deposition in this disease and in brain aging. The permeability of the D- and L-enantiomers of A beta 1-40 and L-A beta 1-42 at the BBB was determined in the normal adult rat by quantifying the permeability coefficient-surface area product (PS) for each protein after correction for the residual plasma volume (Vp) occupied by the protein [labeled with a different isotope of iodine (125I vs 131I)] in blood vessels of different brain regions. After a single i.v. bolus injection, the plasma pharmacokinetics determined by TCA precipitation, paper chromatography, and SDS-PAGE were similar for both 125I-L-A beta 1-40 and 125I-L-A beta 1-42. The PS at the BBB for L-A beta 1-42 was significantly (1.4- to 1.8-fold) higher than for L-A beta 1-40 and ranged from 17.7 to 26.4 x 10(-6) ml/g/s for different brain regions. A comparison of the PS values at the BBB for L-A beta 1-40 showed no significant difference when determined at 15 or 30 min after i.v. bolus injection, times that reflect different levels of degradation in plasma (37.9% at 15 min and 65.5% at 30 min). The PS values obtained, therefore, were representative of the intact protein rather than degradation products. The PS values obtained for the all-D-enantiomer of A beta 1-40 were very low and comparable to that of albumin and IgG, whose mechanism of transport is by passive diffusion. Taken together, these data imply a stereoisomer-specific, ligand-receptor interaction at the BBB for the L-A beta proteins. The high PS values observed for L-A beta 1-40 and 1-42 compare to insulin, whose uptake is decidedly by a receptor-mediated transport process, and suggest a similar mechanism for L-A beta entry into the brain.

Resumen: En los últimos años, el trastorno por déficit de atención e hiperactividad (TDAH) se ha convertido en el trastorno psiquiátrico más frecuentemente diagnosticado y tratado en población pediátrica. En los años 80 fue aprobado en España el metilfenidato (MFD), un fármaco psicoestimulante, para el tratamiento sintomático del TDAH. Desde entonces, se ha convertido en uno de los medicamentos más ampliamente estudiado y prescrito tanto en niños como en adultos.En este artículo se revisan los principios farmacológicos del MFD especialmente su farmacocinética en matrices biológicas convencionales (sangre, orina) y no convencionales (cabello, saliva y sudor), preparados farmacéuticos, concentraciones terapéuticas y efectos indeseables. Abstract: Attention-deficit hyperactivity disorder (ADHD) has emerged in the last few years as the most commonly diagnosed and treated psychiatric disorder in the paediatric population. In 1980's, methylphenidate (MFD) a psychomotor stimulant drug, was approved in Spain for the symptomatic therapy of ADHD. Since then, MFD has become one of the most extensively prescribed and studied treatment for ADHD both in children and adults.In this paper, the main pharmacological issues of MFD are reviewed, focusing on its pharmacokinetics in conventional (blood and urine) and non-conventional (hair, oral fluid and sweat) biological matrices, its pharmaceutical preparations, therapeutic levels and side effects.

Publisher Summary This chapter discusses the clinical pharmacokinetics of acetylcholinesterase inhibitors. Clinical pharmacokinetics is the study of absorption, distribution, and elimination of drugs in patients. Clinical pharmacokinetics also includes studies on the relationship between any clinical effect and the measured plasma concentrations of the drug. The development of selective and sensitive analytical methods for the assay of biological samples of acetylcholineesterase inhibitors is an important step forward toward understanding their pharmacokinetic properties, and hence their mode of action and the interindividual variation of clinical response provide a guide for dosage strategies aimed at optimal effect without side effects. The chapter surveys the clinical pharmacokinetic information available on the reversible acetylcholinesterase inhibitors and particularly results emanating from the studies. Analysis of acetylcholinesterase inhibitors in biological samples presents a particular challenge to the analytical chemist, because the plasma concentrations of these drugs are usually in the low ng/ml range. Early methods of analysis based on paper chromatography, spectrometry, and radioisotope studies suffer from poor sensitivity and selectivity regarding the accurate measurement of plasma concentrations following therapeutic doses.

The present paper is a review of the pharmacokinetics and pharmacodynamics of haloperidol in man. The background of interindividual differences in clinical response to the drug is discussed. Possible ways of monitoring antipsychotic drug dosage from assessment of drug and prolactin concentration in serum are presented.

1 In the class of substituted benzamides, several products are known for their psychotropic properties, in particular sulpiride. (Dogmatil), which exhibits neuroleptic and thymoleptic properties. Sulpiride is used as a behavior regulator in psycho-pathology of senescence in depression and schizophrenia, in addition to having application to gastroenterology. Numerous publications and symposia have been devoted to the psychotropic properties of this drug. 2 This paper reviews the actual status concerning the metabolism of sulpiride in animals, e.g. the blood level after single and repeated administrations as a function of time, the dose, the pharmacological form, and the route of administration. Further data will be given on the distribution, localization, elimination and metabolic pathway. 3 In addition, because of the neuroendocrinological impact of sulpiride, as for other psychotropic drugs, we will give our results showing the specific localization of the hypophysis, those of an histological approach and an ultrastructural study, which indicate stimulation of prolactin and gonadotrope cells in sulpiride-treated rats. The proposition for the direct action of sulpiride in the hypophysis level as well as our original hypothesis that psychotropic activity of these drugs is due to the action of specific peptides, which are synthesized in the hypophysis under the effect of psychotropic drugs is discussed.