Development and Greenness Assessment of HPLC Method for Studying the Pharmacokinetics of Co-Administered Metformin and Papaya Extract

Foods with medical value have been proven to be beneficial, and they are extensively employed since they integrate two essential elements: food and medication. Accordingly, diabetic patients can benefit from papaya because the fruit is low in sugar and high in antioxidants. An RP-HPLC method was designed for studying the pharmacokinetics of metformin (MET) when concurrently administered with papaya extract. A mobile phase of 0.5 mM of KH2PO4 solution and methanol (65:35, v/v), pH = 5 ± 0.2 using aqueous phosphoric acid and NaOH, and guaifenesin (GUF) were used as an internal standard. To perform non-compartmental pharmacokinetic analysis, the Pharmacokinetic program (PK Solver) was used. The method’s greenness was analyzed using two tools: the Analytical GREEnness calculator and the RGB additive color model. Taking papaya with MET improved the rate of absorption substantially (time for reaching maximum concentration (Tmax) significantly decreased by 75% while maximum plasma concentration (Cmax) increased by 7.33%). The extent of absorption reduced by 22.90%. Furthermore, the amount of medication distributed increased (30.83 L for MET concurrently used with papaya extract versus 24.25 L for MET used alone) and the clearance rate rose by roughly 13.50%. The results of the greenness assessment indicated that the method is environmentally friendly. Taking papaya with MET changed the pharmacokinetics of the drug dramatically. Hence, this combination will be particularly effective in maintaining quick blood glucose control.

Pharmacokinetics and Metabolism Study of Deep-Sea-Derived Butyrolactone I in Rats by UHPLC–MS/MS and UHPLC–Q-TOF-MS

Butyrolactone I (BTL-I) is a butanolide isolated from the deep-sea-derived fungus, Aspergillus sp. It provides a potential new target for the prevention and treatment of food allergies. This study aimed to investigate the metabolic and pharmacokinetic profile of BTL-I in rats. The metabolic profiles were obtained by UHPLC–Q-TOF-MS. As a result, eleven metabolites were structurally identified, and the proposed metabolic pathways of BTL-I were characterized. The main metabolites were the oxidative and glucuronidative metabolites. In addition, a sensitive UHPLC–MS/MS method was established for the quantitation of BTL-I in rat plasma (LOQ = 2 ng/mL). The method was fully validated and successfully applied to the pharmacokinetic study of BTL-I in rats after oral administration or intravenous administration. The oral bioavailability was calculated as 6.29%, and the maximum plasma concentrations were 9.85 ± 1.54 ng/mL and 17.97 ± 1.36 ng/mL for intravenous and intragastric dosing groups, respectively.

IBEX Ribbon Separation Using Spherical Harmonic Decomposition of the Globally Distributed Flux

Remote imaging of plasmas in the heliosphere and very local interstellar medium is possible with energetic neutral atoms (ENAs), created through the charge exchange of protons with interstellar neutral atoms. ENA observations collected by the Interstellar Boundary Explorer (IBEX) revealed two distinctive sources. One source is the globally distributed flux (GDF), which extends over the entire sky and varies over large spatial scales. The other source encompasses only a narrow circular band in the sky and is called the IBEX ribbon. Here, we utilize the observed difference in spatial scales of these two ENA sources to separate them. We find that linear combinations of spherical harmonics up to degree ℓ max = 3 can reproduce most of the ENA fluxes observed outside the ribbon region. We use these combinations to model the GDF and the difference between the observed fluxes and the GDF yields estimation of the ribbon emission. The separated ribbon responds with a longer time delay to the solar wind changes than the GDF, suggesting a more distant source of the ribbon ENAs. Moreover, we locate the direction of the maximum plasma pressure based on the GDF. This direction is 17°.2 ± 0°.5 away from the upwind direction within the plane containing the interstellar flow and interstellar magnetic field vectors. This deflection is consistent with the expected position of the maximum external pressure at the heliopause. The maps with separated ribbon and GDF are posted concurrently with this paper and can be used to further study these two sources.

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats

A combination of the tyrosine kinase inhibitor—sorafenib—and the opioid analgesic—morphine—can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug–drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration–time curves (AUC0–t, and AUC0–∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0–t of its active metabolite—sorafenib N-oxide—was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0–t, and AUC0–∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

Pharmacokinetics and Pharmacodynamics of Vancomycin derivative LYSC98 in a Murine Thigh Infection Model against Staphylococcus aureus

LYSC98 is a vancomycin derivative used for gram-positive bacterial infections therapy. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of LYSC98 against Staphylococcus aureus using a murine thigh infection model. Three Staphylococcus aureus strains were utilized. Single-dose plasma pharmacokinetics of LYSC98 were determined in infected mice after the tail vein injection of 2, 4, and 8mg/kg. The results showed maximum plasma concentration (Cmax) 11466.67 -48866.67 ng/mL, area under the concentration-time curve from 0 to 24 h(AUC0-24) 14788.42 -91885.93 ng/mL·h, and elimination half-life(T1/2) 1.70-2.64 h, respectively. The Cmax (R2 0.9994) and AUC0-24 (R2 0.981) were positively correlated with the dose of LYSC98 in the range of 2-8 mg/kg. Dose fractionation studies using total doses of 2 to 8 mg/kg administered with q6h, q8h, q12h, and q24h were performed to evaluate the correlation of different PK/PD indices with efficacy. Sigmoid model analysis showed Cmax/MIC (R2 0.8941) was the best PK/PD index to predict the efficacy of LYSC98. In the dose ranging studies, two Methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used to infect the mice and 2-fold-increasing doses (1 to 16 mg/kg) of LYSC98 were administered. The magnitude of LYSC98 Cmax/MIC associated with net stasis, 1, 2, 3 and 4 - log10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively. The results of this study showed LYSC98 a promising antibiotic with in vivo potency against MRSA, and will help in the dose design of phase one study for LYSC98.

Safety and pharmacokinetic profile of pretomanid (PA-824) in healthy Chinese participants: Results of a phase I single dose escalation study

We investigated the safety, tolerability and pharmacokinetic (PK) profile of pretomanid (formerly PA-824) in healthy Chinese volunteers. This was a single-center, double-blind, placebo-controlled, phase I dose escalation study, in which healthy volunteers were consecutively allocated to increasing pretomanid dose groups (50, 100, 200, 400, 600, 800, or 1000 mg) and randomized to receive pretomanid or matching placebo. The primary objective was to evaluate the safety, tolerability and PK profile of pretomanid. In total, 306 volunteers were screened, and 60 were assigned to treatment (pretomanid: n=46, placebo: n=14) of whom 83.3% were male, age ranged from 19-39 years and BMI ranged from 19.2-25.9 kg/m2. At least one adverse event (AE) was reported by 67.4% of patients assigned to pretomanid and 50.0% of those who received placebo, there were no serious AEs or AEs leading to withdrawal. Drug-related events that occurred in ≥5% of participants assigned to pretomanid were proteinuria (26.1%), hematuria (15.2%), conjugated hyperbilirubinemia (6.5%), hyperbilirubinemia (6.5%) and elevated uric acid (6.5%). No relationship between pretomanid dose and AEs was observed. In the PK analysis (n=46), maximum pretomanid plasma concentration was reached in a mean of 4 hours in all dose groups except 800 mg (12 hours) and the plasma half-life ranged from 20.2-25.2 hours. No dose proportionality was observed for maximum plasma concentration, or area under the plasma concentration curve. In conclusion, single pretomanid doses from 50-1000 mg were well tolerated in healthy Chinese participants and the PK profile was generally consistent with findings in non-Chinese populations.

Investigation of the plasma-wave interaction in helicon plasmas near the lower hybrid frequency

The study of the characteristics of the plasma-wave interaction in helicon plasmas near the lower hybrid frequency has been carried out. The (0D) dispersion relation is derived to analyse the properties of the wave propagation and the 1D cylindrical plasma-wave interaction model is established to investigate the power deposition and implement the parametric analysis. It is concluded that the lower hybrid resonance is the main mechanism of the power deposition in helicon plasmas when the RF frequency is near the lower hybrid frequency and the power deposition mainly concentrates a very thin layer near the boundary. Therefore, it causes that the plasma resistance has a large local peak near the lower hybrid frequency and the variation of the plasma density and the parallel wavenumber lead to the frequency shifting of the local peaks. It is found that the magnetic field is still proportional to the plasma density for the local maximum plasma resistance and the slope changes due to the transition.

Part Two: Pharmacokinetic Evaluation of E-Liquid Flavors of Vuse Solo Electronic Nicotine Delivery System, An Unblinded, Parallel, Randomized Study To Assess Nicotine Uptake In Smokers

This paper reports the findings of a randomized nicotine pharmacokinetic (PK) study of a closed electronic nicotine delivery system (ENDS). The study evaluated four flavor variants of Vuse Solo ENDS where subjects used their randomized investigational product (IP) for 10 minutes ad libitum and blood samples were collected for PK assessments that included maximum plasma nicotine concentration (Cmax) and area under the nicotine concentration-vs-time curve up to 60 minutes (AUCnic0–60). Baseline-adjusted mean Cmax ranged from 6.53 to 8.21 ng/mL, and mean AUCnic0–60 ranged from 206.87 to 263.52 ng*min/mL for all ENDS IPs. Results for Cmax and AUCnic0-60 values were consistent among the ENDS IP flavor variants tested and results indicate that flavors did not affect nicotine uptake in human subjects.

The Effects of Bariatric Surgery and Gastrectomy on the Absorption of Drugs, Vitamins, and Mineral Elements

Bariatric surgery, which is an effective treatment for obesity, and gastrectomy, which is the primary treatment method for gastric cancer, alter the anatomy and physiology of the digestive system. Weight loss and changes in the gastrointestinal tract may affect the pharmacokinetic parameters of oral medications. Both bariatric and cancer patients use drugs chronically or temporarily. It is important to know how surgery affects their pharmacokinetics to ensure an effective and safe therapy. The Cochrane, PubMed, and Scopus databases were searched independently by two authors. The search strategy included controlled vocabulary and keywords. Studies show that bariatric surgery and gastrectomy most often reduce the time to maximum plasma concentration (tmax) and decrease the maximum plasma concentration (Cmax) in comparison with the values of these parameters measured in healthy volunteers. Vitamin and mineral deficiencies are also observed. The effect depends on the type of surgery and the properties of the drug. It is recommended to use the drugs that have been tested on these groups of patients as it is possible to monitor them.

FARMACOCINÉTICA Y BIODISPONIBILIDAD ABSOLUTA DE MARBOFLOXACINA EN BÚFALOS (Bubalus bubalis)

The aim of this study was to evaluate the pharmacokinetic behaviour and the absolute bioavailability of marbofloxacin (MFX) in adult water buffaloes and to estimate the pharmacokinetic parameters for calculating the therapeutic dose in this animal species. Six adult buffaloes (3 males and 3 females) where treated by intravenous (IV) and subcutaneous (SC) route with a 10% experimental MFX injectable formulation at the dose of 2 mg/kg. After administration blood samples were drawn at pre-established times and MFX plasma concentrations where determined by microbiologic method. The pharmacokinetic analysis was made by compartmental analysis. After IV administration MFX presented a clearance of 198.4 ± 21.0 mL.kg.h and a half-life of elimination of 7.64 ± 3.29 h. After SC administration marbofloxacin presented a half-life of elimination of 8.5 ± 2.42 h, reaching it maximum plasma concentration (1.67 ± 0.516 μg/mL) at 1.69 ± 0.231 h, with a bioavailability of 80.8 ± 11.2 %. The estimated values of clearance and bioavailability will be employed in further studies for calculating the therapeutic dose of MFX in water buffaloes.