Prolonged Elimination Half-life Research Articles

Determining tissue distribution of the oral antileishmanial agent miltefosine: a physiologically-based pharmacokinetic modeling approach.

Miltefosine (MTS) is the only approved oral drug for treating leishmaniasis caused by intracellular Leishmania parasites that localize in macrophages of the liver, spleen, skin, bone marrow, and lymph nodes. MTS is extensively distributed in tissues and has prolonged elimination half-lives due to its high plasma protein binding, slow metabolic clearance, and minimal urinary excretion. Thus, understanding and predicting the tissue distribution of MTS help assess therapeutic and toxicologic outcomes of MTS, especially in special populations, e.g., pediatrics. In this study, a whole-body physiologically-based pharmacokinetic (PBPK) model of MTS was built on mice and extrapolated to rats and humans. MTS plasma and tissue concentration data obtained by intravenous and oral administration to mice were fitted simultaneously to estimate model parameters. The resulting high tissue-to-plasma partition coefficient values corroborate extensive distribution in all major organs except the bone marrow. Sensitivity analysis suggests that plasma exposure is most susceptible to changes in fraction unbound in plasma. The murine oral-PBPK model was further validated by assessing overlay of simulations with plasma and tissue profiles obtained from an independent study. Subsequently, the murine PBPK model was extrapolated to rats and humans based on species-specific physiological and drug-related parameters, as well as allometrically scaled parameters. Fold errors for pharmacokinetic parameters were within acceptable range in both extrapolated models, except for a slight underprediction in the human plasma exposure. These animal and human PBPK models are expected to provide reliable estimates of MTS tissue distribution and assist dose regimen optimization in special populations.

A phase 1/1b, first-in-human, multi-part study of DF6215, an engineered IL-2Rα-active agonist, to investigate the safety, tolerability, pharmacokinetics, and biological and clinical activity in patients with advanced solid tumors.

TPS2704 Background: IL-2 is a pleiotropic cytokine that stimulates strong anti-tumor responses by promoting expansion and activation of cytotoxic tumor-infiltrating immune cells including CD8 + T cells and NK cells (1). Aldesleukin is an approved rhIL-2; however, it has clinical limitations due to short half-life, requirement for 5 days of hospitalization per cycle, and high toxicity [eg, cytokine-related toxicity, capillary leak syndrome (CLS)] that limits its use [aldesleukin USPI]. DF6215 is a modified monovalent human IL-2 that binds to the IL2R. Preclinically, DF6215 administration results in sustained and modulated IL-2 pharmacology, leading to protracted pharmacodynamic (PD) effects and enhanced anti-tumor activity without observation of CLS in murine and primate toxicology studies. In response to the limitations of previous IL-2 therapeutics, DF6215 was designed as an IL-2Rα-active agonist with increased IL-2Rβγ stimulation to improve the benefit-to-risk ratio of historic IL-2 drugs. An additional design element is a prolonged elimination half-life due to Fc fusion, allowing for less frequent dosing. Methods: This is a first-in-human, open-label, multipart, Phase 1/1b clinical trial to characterize the initial safety, tolerability, pharmacokinetics, and preliminary efficacy of DF6215 in patients with advanced solid tumors. The Phase 1 dose escalation (DE) starting dose is 10 ug/kg IV every 2 weeks (up to 42 subjects expected to be enrolled), and the Safety/PK/PD will be explored at doses already characterized as safe in dose escalation and potentially efficacious (max of 40 subjects). Phase 1b includes an efficacy expansion (EE) cohort in subjects with advanced melanoma who have received prior anti-PD-1 agents and, if the tumor harbors a BRAF-activating mutation, a BRAF inhibitor. Key inclusion criteria include ≥ 18 years of age; ECOG PS of 0 or 1; adequate organ function, and locally advanced or metastatic solid tumors for which standard therapy options have been exhausted; and availability of baseline tumor biopsy. Primary objectives include determination of the MTD of DF6215 in DE and demonstration of clinical activity of DF6215 in the EE. Secondary objectives include assessment of safety and tolerability, pharmacokinetics, and immunogenicity of DF6215. This study plans to enroll up to 102 subjects across ~30 global centers in the US, European, and the Asia/Pacific regions, and is currently open to enrollment. 1. Arenas-Ramirez N, et al. 2015. Trends Immunol. Clinical trial information: NCT06108479 .

Novel inhalable powder formulation of pirfenidone with sustained release properties to improve pulmonary deposition

The aim of this study was to develop a new respirable powder (RP) formulation of pirfenidone (PFD) with sustained release properties to ameliorate the pharmacokinetic drawbacks of the previously-developed PFD-RP on rapid elimination from the lung after insufflation. Based on screenings using several polymers, Kollidon® SR was chosen to produce a solid dispersion of PFD with sustained release properties (SRSD/PFD), and an RP formulation of SRSD/PFD (SRSD/PFD-RP) was prepared. Characteristics of SRSD/PFD-RP were examined in terms of biopharmaceutical, pharmacological, and phototoxic properties. In laser diffraction analysis, SRSD/PFD-RP could be dispersed to SRSD/PFD and lactose carrier particles, and SRSD/PFD in SRSD/PFD-RP had suitable particle sizes for inhalation. Insufflated SRSD/PFD-RP (0.03 mg-PFD/rat) showed a prolonged elimination half-life and mean residence time of PFD since these values were approximately 3.7-fold higher than those of insufflated PFD-RP (0.3 mg-PFD/rat: a pharmacologically-effective dose). Insufflated SRSD/PFD-RP (0.03 mg-PFD/rat) showed a similar anti-inflammatory potential in the lung of antigen-evoked lung inflammatory models compared with insufflated PFD-RP (0.3 mg-PFD/rat). Obvious skin phototoxicity was negligible after insufflation of SRSD/PFD-RP (0.03 mg-PFD/rat). In conclusion, SRSD/PFD-RP would be an attractive dosage form for an inhalation system of PFD and contribute to PFD medication for idiopathic pulmonary fibrosis with high efficacy and safety.

Development of a bioengineered Erwinia chrysanthemi asparaginase to enhance its anti-solid tumor potential for treating gastric cancer

Asparaginase has been traditionally applied for only treating acute lymphoblastic leukemia due to its ability to deplete asparagine. However, its ultimate anticancer potential for treating solid tumors has not yet been unleashed. In this study, we bioengineered Erwinia chrysanthemi asparaginase (ErWT), one of the US Food and Drug Administration-approved types of amino acid depleting enzymes, to achieve double amino acid depletions for treating a solid tumor. We constructed a fusion protein by joining an albumin binding domain (ABD) to ErWT via a linker (GGGGS)5 to achieve ABD-ErS5. The ABD could bind to serum albumin to form an albumin-ABD-ErS5 complex, which could avoid renal clearance and escape from anti-drug antibodies, resulting in a remarkably prolonged elimination half-life of ABD-ErS5. Meanwhile, ABD-ErS5 did not only deplete asparagine but also glutamine for ∼2 weeks. A biweekly administration of ABD-ErS5 (1.5 mg/kg) significantly suppressed tumor growth in an MKN-45 gastric cancer xenograft model, demonstrating a novel approach for treating solid tumor depleting asparagine and glutamine. Multiple administrations of ABD-ErS5 did not cause any noticeable histopathological abnormalities of key organs, suggesting the absence of acute toxicity to mice. Our results suggest ABD-ErS5 is a potential therapeutic candidate for treating gastric cancer.

Identification of the perpetrator imperatorin in Xin-yi-san-theophylline interaction: observed and predicted herb-drug interaction in rats.

Theophylline is a bronchodilator with a narrow therapeutic index and primarily metabolised by cytochrome P450 (CYP) 1A2. Xin-yi-san (XYS) is a herbal formula frequently used to ameliorate nasal inflammation. This study aimed to investigate the effects of XYS and its ingredient, imperatorin, on theophylline pharmacokinetics in rats. The kinetics of XYS- and imperatorin-mediated inhibition of theophylline oxidation were determined. Pharmacokinetics of theophylline were analysed. Comparisons were made with the CYP1A2 inhibitor, fluvoxamine. XYS extract and its ingredient, imperatorin, non-competitively inhibited theophylline oxidation. Fluvoxamine (50 and 100 mg/kg) and XYS (0.5 and 0.9 g/kg) significantly prolonged the time to reach the maximum plasma concentration (tmax) of theophylline by 3-10 fold. In a dose-dependent manner, XYS and imperatorin (0.1-10 mg/kg) treatments significantly decreased theophylline clearance by 27-33% and 19-56%, respectively. XYS (0.9 g/kg) and imperatorin (10 mg/kg) significantly prolonged theophylline elimination half-life by 29% and 142%, respectively. Compared with the increase (51-112%) in the area under curve (AUC) of theophylline by fluvoxamine, the increase (27-57%) by XYS was moderate. XYS decreased theophylline clearance primarily through imperatorin-suppressed theophylline oxidation. Further human studies are essential for the dose adjustment in the co-medication regimen.

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.

Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635. Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule. In Part B, these participants were administered a 50-mg capsule either following a high-fat meal or with a PPI in the fasted state. In Study 2 (CYP1A2 mediated drug-drug interaction study), a 25-mg AZD4635 capsule was administered to smokers and nonsmokers (fasted) with or without 100 mg of fluvoxamine. In Study 1 (N =21), AZD4635 exposure was comparable between the capsule and nanosuspension. The high-fat meal produced a 12% decrease in AUCinf , a ≥50% reduction in Cmax and delayed absorption (Tmax : 4.0 h vs 1.5 h) for the capsule. The PPI did not affect the oral bioavailability of the AZD4635 capsule. In Study 2 (N =28), AZD4635 + fluvoxamine (compared with AZD4635 alone) produced ~5-fold increases in AUCinf , 2-fold increases in Cmax and prolonged AZD4635 elimination half-life in smokers (22.7 vs 9.0 h) and nonsmokers (22.4 vs 9.2 h). All treatment regimens were well tolerated. The most common adverse events included dizziness, nausea and headache. The high-fat meal reduced the rate but not the extent of AZD4635 absorption. The effect of gastric pH on AZD4635 was minimal. Smoking had no effect on the exposure (Cmax and AUCinf ) of AZD4635, while fluvoxamine increased AZD4635 Cmax and total exposure. No new safety concerns were identified.

Effect of Dispersion Medium on Pharmacokinetic Profile of Rotigotine Crystalline Suspension following Subcutaneous Injection.

Rotigotine (RTG) is prescribed as a once-daily transdermal patch for managing early Parkinson’s disease (PD), which presents issues such as skin irritation and poor patient adherence. Therefore, the aims of the present study were to formulate aqueous and oily vehicle-based RTG crystalline suspensions for prolonged delivery and to compare their pharmacokinetic profiles and the local behaviors of RTG crystals. RTG-loaded aqueous (AS) and oil suspensions (OS) were fabricated using bead-milling technology (100 mg/mL as RTG), employing carboxymethyl cellulose and sesame oil as suspending agent and oily vehicle, respectively. RTG AS and OS exhibited comparable physical properties in terms of particle size (about 800−900 nm), crystallinity, and dissolution profile, despite higher drug solubility in OS than AS (19.6 and 0.07 mg/mL, respectively). However, AS and OS exhibited markedly distinctive local distribution and inflammatory responses at the injection site, which further promoted different pharmacokinetic patterns following subcutaneous injection in rats. With OS, no drug aggregates were observed with prolonged persistence of the Sudan III-stained oily vehicle at the injection site. In contrast, with AS injection, drug clusters > 7 mm were formed, followed by an enclosure with macrophages and a fibroblastic band. Accordingly, AS exhibited a protracted pharmacokinetic profile over 3 weeks, with prolonged elimination half-life. The local inflammatory response caused by AS injection was almost alleviated after 3 weeks post-dosing. Based on these findings, we conclude that RTG AS system can be a platform to design sophisticated long-acting delivery systems with extended dosing intervals to manage PD.

Management of Drug Related Problems in the Elderly - A Review

Drug Related Problems (DRPs) also known as Medication Related Problems (MRPs) are the problems that occur because of the drugs when a person is undergoing a treatment. Older patients are particularly vulnerable to ADRs because of age-related changes in pharmacokinetics and pharmacodynamics, such as reduced hepatic and renal function, prolonged elimination half-life, and increased sensitivity to drugs, which have been shown to be associated with an increased risk of ADRs. This may (in most cases) interfere with the desired outcome of the therapy. This in turn, reduces the quality of life of a person. DRPs may be life-threatening in some and this poses the importance of identification of DRPs. The DRPs can be identified and can be categorized as whether it is preventable or not. It can also be classified into different classes- Adverse Drug Reaction (ADR) and Drug Interaction being the most common causes for the incidence of DRP. The pharmacist can play a key role in identification, categorization and prevention of DRPs. The aim of this review is for the better understanding of DRPs and to shine light on the causes of DRPs that is often left unseen or under-estimated. This review also aims to show the big role that can be played by pharmacist in identifying, preventing DRPs and thereby improving the quality of life of patients. Keywords: Drug related problems, Quality of life, Pharmacist’s role

Optimization and Validation of Glycerol-induced Acute Renal Failure Model in Rats in Predicting the Pharmacokinetics in Patients with Acute Renal Failure

The study standardized the glycerol induced (intra-peritoneal and intra-muscular) acute renal failure (ARF) models in Sprague-Dawley rats and validated its potential to predict the change in pharmacokinetics of the selected probe drugs in renal impairment. We assessed the induction of ARF by measuring the serum creatinine and blood-urea-nitrogen (BUN) levels at different time points (baseline, 6 h, 12 h, 24 h, 48 h and 72 h). Glycerol administrations via both intra-peritoneal and intra-muscular routes caused a significant increase in serum creatinine and BUN levels in rats at 6 h; however, the levels decreased within 24 h with intra-peritoneal administration. In contrast, with intra-muscular administration, a sustained increase in serum creatinine and BUN levels was observed up to 72 h post glycerol treatment demonstrating a sustained ARF like condition in rats that was suitable to evaluate the pharmacokinetics of drugs. Therefore, intra-muscular glycerol administration model was used to evaluate the pharmacokinetics of selected probe drugs including metformin, digoxin, atorvastatin and linezolid. The pharmacokinetics of metformin and digoxin were significantly altered in ARF versus control rats with increase in plasma exposure, prolonged elimination half-life and decreased systemic clearance. However, the pharmacokinetics of atorvastatin and linezolid did not show significant differences between ARF and control rats. These results demonstrated the utility of the ARF model in rats in predicting pharmacokinetic changes in patients with renal impairment. Such models may prove useful in early discovery work to screen and prioritize compounds requiring dose adjustment in patients with renal impairment.

Pharmacovigilance of Herb-Drug Interactions: A Pharmacokinetic Study on the Combined Administration of Tripterygium Glycosides Tablets and Leflunomide Tablets in Rats by LC-MS/MS.

A popular and widely used combination therapy of leflunomide (LEF) and Tripterygium glycosides tablets (TGTS) has become a valuable clinical tool in China for the treatment of rheumatoid arthritis. This regimen has not been evaluated either in terms of interaction or toxicity, even given the rising concerns about LEF’s prolonged elimination half-life and TGT’s narrow therapeutic index, in addition to the current trend of using high doses of LEF. Thus, this study determines the potential adverse drug reactions between these two medicines. Reliable validated LC-MS/MS methods were used for the determination of teriflunomide (TER, the only active metabolite of LEF), and the main components of TGT: wilforlide A, wilforgine, wilfortrine, wilfordine, and wilforine. The results obtained from this investigation, as paralleled with the control groups, revealed that the Cmax and AUC0-t of TER were significantly decreased with separate co-administration, as the Cmax and AUC0-t were 30.17 ± 1.55 μg/mL and 24.47 ± 2.50 μg/mL, 374.55 ± 15.54 μg h/mL and 336.94 ± 21.19 μg h/mL, respectively (p < 0.05). Meanwhile, the pharmacokinetic profiles of the main components of TGT have also been affected by separate co-administration in rats. Therefore, herb–drug interactions between LEF and TGT have been proven.

New Developments in Pediatric Antifungal Pharmacology.

New Developments in Pediatric Antifungal Pharmacology.

Integrated electrophysiologic analyses of amiodarone in human iPSC-derived cardiomyocytes

Abnormalities in cardiac rhythm, or arrhythmia, affect more than 2% of individuals and can cause sudden cardiac death. Amiodarone, the most frequently prescribed antiarrhythmic drug, is effective yet exhibits significant toxicity. Amiodarone is extensively metabolized and displays a prolonged elimination half-life, lipophilic partitioning, and blockade of multiple ionic currents that form the cardiac action potential, complicating characterization of its therapeutic mechanisms. Further constraining this effort is the limited availability of clinical samples of healthy human cardiac cells and tissues.

Effect of ketoprofen on intravenous pharmacokinetics of ganciclovir in chukar partridges (Alectoris chukar).

The aim of the study was to determine the effect of ketoprofen (2mg/kg) on the intravenous pharmacokinetics of ganciclovir (10mg/kg) in chukar partridges (Alectoris chukar). Eight clinically healthy partridges were used in the study. The study was performed in two periods using a cross-over design following a 15-day drug washout period. Plasma concentrations of ganciclovir were determined using the high-pressure liquid chromatography-ultraviolet detector and analyzed by non-compartmental analysis. The elimination half-life (t1/2ʎz ), area under the concentration-time curve (AUC0-∞ ), total body clearance, and volume of distribution at steady state of ganciclovir were 1.63h, 33.22h*μg/ml, 0.30 L/h/kg, and 0.53 L/kg, respectively. Ketoprofen administration increased the t1/2ʎz and AUC0-∞ of ganciclovir by 78% and 108%, respectively, and while decreased ClT by 53%. The increased plasma concentration and prolonged elimination half-life of ganciclovir caused by ketoprofen may result in the prolonged duration of action and therapeutic effect of ganciclovir. However, the concomitant use requires determination of the pharmacokinetics of ketoprofen and the safety of both drugs.

A radioiodinated FR-β-targeted tracer with improved pharmacokinetics through modification with an albumin binder for imaging of macrophages in AS and NAFL.

The formation of advanced plaques, which is characterized by the uninterrupted aggregation of macrophages with high expression of folate receptor-β (FR-β), is observed in several concomitant metabolic syndromes. The objective of this study was to develop a novel FR-β-targeted single-photon emission computed tomography (SPECT) radiotracer and validate its application to the noninvasive detection of atherosclerosis (AS) plaque and non-alcoholic fatty liver (NAFL). Two radioiodinated probes, [131I]IPBF and [131I]IBF, were developed, and cell uptake studies were used to identify their specific targets for activated macrophages. Biodistribution in normal mice was performed to obtain the pharmacokinetic information of the probes. Apolipoprotein E knockout (ApoE-/-) mice with atherosclerotic aortas were induced by a high-fat and high-cholesterol (HFHC) diet. To investigate the affinity of radiotracers to FR-β, Kd values were determined using in vitro assays. In addition, the assessments of the aorta in the ApoE-/- mice at different stages were performed using in vivo SPECT/CT imaging, and the findings were compared by histology. Both [131I]IPBF and [131I]IBF were synthesized with > 95% radiochemical purity and up to 3MBq/nmol molar activity. In vitro assay of [131I]IPBF showed a moderate binding affinity to plasma proteins and specific uptake in activated macrophages. The prolonged blood elimination half-life (t1/2z) of [131I]IPBF (8.14h) was observed in a pharmacokinetic study of normal mice, which was significantly longer than that of [131I]IBF (t1/2z = 2.95h). As expected, the Kd values of [131I]IPBF and [131I]IBF in the Raw 264.7 cells were 43.94 ± 9.83nM and 61.69 ± 15.19nM, respectively. SPECT imaging with [131I]IPBF showed a high uptake in advanced plaques and NAFL. Radioactivity in excised aortas examined by ex vivo autoradiography further confirmed the specific uptake of [131I]IPBF in high-risk AS plaques. In summary, we reported a proof-of-concept study of an albumin-binding folate derivative for macrophage imaging. The FR-β-targeted probe, [131I]IPBF, significantly prolongs the plasma elimination half-life and has the potential for the monitoring of AS plaques and concomitant fatty liver.

Pharmacokinetics, metabolism and off-target effects in the rat of 8-[(1H- benzotriazol-1-yl)amino]octanoic acid, a selective inhibitor of human cytochrome P450 4Z1: β-oxidation as a potential augmenting pathway for inhibition

8‐[(1H‐1,2,3‐benzotriazol‐1‐yl)amino]octanoic acid (8-BOA) was recently identified as a selective and potent mechanism-based inactivator (MBI) of breast cancer-associated CYP4Z1 and exhibited favourable inhibitory activity in vitro, thus meriting in vivo characterization. The pharmacokinetics and metabolism of 8-BOA in rats was examined after a single IV bolus dose of 10 mg/kg. A biphasic time-concentration profile resulted in relatively low clearance and a prolonged elimination half-life. The major circulating metabolites identified in plasma were products of β-oxidation; congeners losing two and four methylene groups accounted for >50% of metabolites by peak area. The –(CH2)2 product was characterized previously as a CYP4Z1 MBI and so represents an active metabolite that may contribute to the desired pharmacological effect. Ex vivo analysis of total CYP content in rat liver and kidney microsomes showed that off-target CYP inactivation was minimal; liver microsomal probe substrate metabolism also demonstrated low off-target inactivation. Standard clinical chemistries provided no indication of acute toxicity. In silico simulations using the free concentration of 8-BOA in plasma suggested that the in vivo dose used here may effectively inactivate CYP4Z1 in a xenografted tumour.

Facile fabrication of robust, hyaluronic acid-surfaced and disulfide-crosslinked PLGA nanoparticles for tumor-targeted and reduction-triggered release of docetaxel

It is highly tempting to develop high-efficacy targeted nanotherapeutics based on FDA approved polymers like PLGA. Herein, we describe facile fabrication of robust, hyaluronic acid-surfaced and disulfide-crosslinked star-PLGA nanoparticles (HA-sPLGA XNPs) for targeted and reduction-triggered release of docetaxel (DTX), achieving markedly enhanced treatment of A549 lung tumor in vivo. HA-sPLGA XNPs carrying 5.2 wt.% DTX (DTX-HA-sPLGA XNPs) had a size of 105.5 ± 0.5 nm and great stability while almost completely released DTX under 10 mM glutathione. Confocal and flow cytometry experiments revealed fast cellular uptake of HA-sPLGA XNPs by CD44-overexpressing A549 cells. DTX-HA-sPLGA XNPs held much higher potency to A549 cells than DTX-loaded HA-surfaced and non-crosslinked star-PLGA nanoparticles (DTX-HA-sPLGA NPs), DTX-loaded HA-surfaced and non-crosslinked linear-PLGA nanoparticles (DTX-HA-lPLGA NPs), and free DTX (IC50 = 0.18 versus 0.38, 1.21 and 0.83 µg DTX equiv./mL). Intriguingly, DTX-HA-sPLGA XNPs revealed a prolonged elimination half-life of 4.18 h and notable accretion of 9.49%ID/g in A549 tumor after 8 h injection. Accordingly, DTX-HA-sPLGA XNPs demonstrated significantly better suppression of subcutaneous A549 lung tumor than DTX-HA-PLGA NPs, DTX-HA-lPLGA NPs, and free DTX controls. HA-sPLGA XNPs with low toxicity and multi-functionality appear to be a unique targeted vehicle for chemotherapy of CD44-overexpressing tumors. Statement of significancePLGA nanoparticles with superior safety and biodegradability are among the most advanced vehicles for therapeutic delivery. The efficacy of nanomedicines based on PLGA is, however, suboptimal, due to poor tumor cell selectivity and uptake, drug leakage, and slow drug release at the pathological site. It is highly desired to develop functional PLGA nanoparticles to improve their tumor-targeting ability and therapeutic efficacy. The sophisticated fabrication and potential toxicity concerns of reported novel PLGA nanoformulations, nevertheless, preclude their clinical translation. Here, we developed hyaluronic acid-surfaced and disulfide-crosslinked star-PLGA nanoparticles (HA-sPLGA XNPs) that enabled stable encapsulation and targeted delivery of docetaxel (DTX) to CD44+ A549 lung cancer cells in vitro and in vivo, affording markedly improved tumor accumulation and repression and lower side effects compared with free DTX control. Importantly, HA-sPLGA XNPs are based on fully biocompatible materials and comparably simple to fabricate. The evident tumor targetability and safety makes HA-sPLGA XNPs a unique and potentially translatable platform for chemotherapy of CD44+ cancers.

Side Effects of Chloroquine and Hydroxychloroquine on Skeletal Muscle: a Narrative Review

Purpose of ReviewConcerning adverse neuromuscular effects, there are quite a few reports about the incidence and prevalence of chloroquine (CQ) and hydroxychloroquine (HCQ) myopathy. Given the above, I decided to explore the relationships of these drugs with skeletal muscle in an attempt to clarify how they affect the muscle now and in the future, as millions of people are using CQ and HCQ.Recent FindingsThe literature review identified 28 publications about CQ/HCQ myopathy, totaling 56 patients, from 1963 to 2020. A compilation of all patients was carried out by computing demographic features, clinical aspects, laboratory exams, and clinical evolution. All articles but two represented a large series about incidence and prevalence of the myopathy. Fifty-nine percent used QC, mean daily dose was 393 mg per day, and mean duration of treatment was 37 months. The predominant underlying diseases were rheumatoid arthritis (42.8%) and lupus erythematosus (26.8%). Respiratory distress was present in 12.5% in patients with proximal muscle weakness (87.2%). Dysphagia and cervical and axial weakness were observed in a smaller percentage. Creatine kinase was elevated in 60.7%, and EMG showed a myopathic pattern in 54%. Muscle biopsy showed a vacuolar pattern in 53.7%, and curvilinear bodies (CB) were the predominant ultrastructural finding (86.8%). After drug withdrawal, 85.4% of patients improved, and 12.7% died from other causes than myopathy.SummaryCQ and HCQ myopathy has been known for a long time, but the incidence is low, being described only with long-term use. The use of these drugs for a short period has not been reported, although a prolonged elimination half-life of these drugs actually exists.

Cannabis legalisation and testing for cannabis use in safety- and risk-sensitive environments.

The legalisation of cannabis by the High Court of South Africa, which was confirmed by the Constitutional Court, imposes challenges to occupational medical practitioners acting as medical review officers in compliance testing and fit-for-service medical examinations. The lipophilic character of the psychoactive component of cannabis, delta-9-tetrahydrocannabinol (Δ9-THC), and its prolonged elimination half-life, create challenges for the ethically and scientifically correct management of the legal use of cannabis in risk-sensitive environments. Important issues to consider in testing for cannabis use are: the stance of 'zero tolerance'; screening and confirmation cut-off concentrations; and the bio-matrices used for testing. Constitutional rights relate to privacy, freedom, autonomy, freedom of religion and the equal enjoyment of rights and privileges, which must be balanced against the health and safety of others.

Pharmacological Characterization of Apraglutide, a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist, for the Treatment of Short Bowel Syndrome.

Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications in which the integrity or absorptive function of the intestinal mucosa is compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33-amino acid peptide secreted from the small intestine, contributes to nutritional absorption but has a very short half-life because of enzymatic cleavage and renal clearance and thus is of limited therapeutic value. The GLP-2 analog teduglutide (Revestive/Gattex; Shire Inc.) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life, and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP-2, whereas glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide, and apraglutide had clearances of 25, 9.9, 2.8, and 0.27 ml/kg per minute, respectively, and elimination half-lives of 6.4, 19, 16, and 159 minutes, respectively. The unique PK profile of apraglutide administered via intravenous and subcutaneous routes was confirmed in monkey and minipig and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Apraglutide showed greater intestinotrophic activity than the other peptides when administered at less-frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases, such as SBS. SIGNIFICANCE STATEMENT: Apraglutide is a potent and selective GLP-2 agonist with an extremely low clearance and prolonged elimination half-life, which differentiates it from teduglutide (the only approved GLP-2 agonist). The enhanced pharmacokinetics of apraglutide will benefit patients by enabling a reduced dosing frequency and removing the need for daily injections.

A rapid and sensitive UHPLC-MS/MS method for the determination of ziyuglycoside I and its application in a preliminary pharmacokinetic study in healthy and leukopenic rats

Ziyuglycoside I (ZgI), one of the main active ingredients in the popular Diyushengbai tablet made from Sanguisorba officinalis L., has been proven to relieve leukopenia clinically. However, to our knowledge, no studies have investigated the pharmacokinetics of either Diyushengbai tablet or ZgI in leukopenic vs. healthy individuals. In the present study, a rapid and sensitive UHPLC-MS/MS method was developed for detecting ZgI. On using this method on a novel cyclophosphamide-induced leukopenia model, we investigated differences in the pharmacokinetic characteristics of ZgI between leukopenic and normal rats. Chromatographic separation of ZgI and glycyrrhetinic acid (IS) was achieved via gradient elution in 0.5 min, and the total run time lasted for 5 min. Methodological validation results presented a good accuracy (102.6 %–110.8 %) and precision (% RSD ≤ 13.8) with a limit of quantitation of 0.5 ng/mL. Pharmacokinetic results showed a significantly shortened peak time (Tmax) (0.93 vs. 0.33 h) while a remarkably decreased maximum concentration (Cmax) (7.96 vs. 3.40 ng/L) in the 20 mg/kg leukopenia group in comparison with those in the 20 mg/kg normal group. In addition, a prolonged elimination half-life (t1/2β) was observed in the 20 mg/kg leukopenia group (5.02 vs. 18.51 h). We observed similar trends in the 5 mg/kg oral dosing treatment and control groups, except for Cmax, which did not differ between the groups. We did not find pharmacokinetic differences in ZgI between the two leukopenia groups. Thus, the pharmacokinetic parameters of ZgI (e.g., Tmax, Cmax, and T1/2β) changed based on the presence of a leukopenic state. This study may provide guidance for the development of ZgI as an agent for the treatment of leukopenia.