Prolonged Elimination Research Articles

Hydroxy levamisole and its phase II conjugates as potential indicators of levamisole doping in thoroughbred horses.

According to previous research, aminorex is the major metabolite of levamisole; however, in the screening of levamisole-positive racehorse urine and plasma samples, aminorex could only be detected in trace amounts or not at all. In forensic laboratories, hydroxy levamisole and its phase II conjugates make it easier to confirm levamisole misuse and to differentiate between the abuse of levamisole and aminorex. This study aimed to identify the major levamisole metabolites that can be detected along with the parent drug. The study describes levamisole and its metabolites in thoroughbred horses following oral administration and in vitro with equine liver microsomes. The plausible structures of the detected metabolites were postulated using liquid chromatography combined with high-resolution mass spectrometry. Under the experimental conditions 26 metabolites (17 phase I, 2 phase II, and 7 conjugates of phase I metabolites) were detected (M1-M26). The major phase I metabolites identified were formed by hydroxylation. In phase II, the glucuronic acid conjugates of levamisole and hydroxy levamisole were detected as the major metabolites. In plasma, the parent drug and major metabolites are detectable for up to eight days, while in urine, they are detectable for up to twenty days. Levamisole levels rapidly increased at 45 min following administration, then declined gradually until detectable levels were reached approximately 8days after administration, according to a pharmacokinetics study. A prolonged elimination profile and relatively high concentration of hydroxy metabolites suggest that the detection of hydroxy metabolites is imperative for investigating levamisole doping in horses.

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

Metabolic Disposition of Triazolam and Clobazam in Humanized CYP3A Mice with a Double-Knockout Background of Mouse Cyp2c and Cyp3a Genes.

Knockout (KO) of mouse Cyp3a genes increases the expression of hepatic CYP2C enzymes, which can metabolize triazolam, a typical substrate of human CYP3A. There is still marked formation of 1'-hydroxytriazolam in Cyp3a-KO (3aKO) mice after triazolam dosing. Here, we generated a new model of humanized CYP3A (hCYP3A) mice with a double-KO background of Cyp3a and Cyp2c genes (2c3aKO), and we examined the metabolic profiles of triazolam in wild-type (WT), 2c3aKO, and hCYP3A/2c3aKO mice in vitro and in vivo In vitro studies using liver microsomes showed that the formation of 1'-hydroxytriazolam in 2c3aKO mice was less than 8% of that in WT mice. The formation rate of 1'-hydroxytriazolam in hCYP3A/2c3aKO mice was eightfold higher than that in 2c3aKO mice. In vivo studies showed that area under the curve (AUC) of 1'-hydroxytriazolam in 2c3aKO mice was less than 3% of that in WT mice. The AUC of 1'-hydroxytriazolam in hCYP3A/2c3aKO mice was sixfold higher than that in 2c3aKO mice. These results showed that formation of 1'-hydroxytriazolam was significantly decreased in 2c3aKO mice. Metabolic functions of human CYP3A enzymes were distinctly found in hCYP3A mice with the 2c3aKO background. Moreover, hCYP3A/2c3aKO mice treated with clobazam showed human CYP3A-mediated formation of desmethylclobazam and prolonged elimination of desmethylclobazam, which is found in poor metabolizers of CYP2C19. The novel hCYP3A mouse model without mouse Cyp2c and Cyp3a genes (hCYP3A/2c3aKO) is expected to be useful to evaluate human CYP3A-mediated metabolism in vivo SIGNIFICANT STATEMENT: Humanized CYP3A (hCYP3A/2c3aKO) mice with a background of double knockout (KO) for mouse Cyp2c and Cyp3a genes were generated. Although CYP2C enzymes played a compensatory role in the metabolism of triazolam to 1'-hydroxytriazolam in the previous hCYP3A/3aKO mice with Cyp2c genes, the novel hCYP3A/2c3aKO mice clearly showed functions of human CYP3A enzymes introduced by chromosome engineering technology.

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.

Dermatological toxicity of acute lymphoblastic leukemia treatment by protocol ALL IC-BFM 2002

Background. Аcute lymphoblastic leukemia (ALL) in children is not only the most common but also potentially curable disease in 8590% cases. The other side of high effectiveness of modern treatment protocols their toxicity. Inspite of skin and mucosal toxicity is not a life threatening condition, it requires a supportive care to prevent infectious complications, which prolong hospitalization, administration of antibacterial, antifungal and in some cases antiviral drugs.
 Aim. To study skin and mucosal toxicity in patients with ALL, treated by ALL IC-BFM 2002 protocol.
 Materials and methods. One hundred and nineteen pediatric patients with primary diagnosed ALL were enrolled the study. All the patients were treated by ALL IC-BFM 2002 protocol. Toxicity assessment was performed on each step by the scale of National Cancer Institute (NCI) USA, 2d version.
 Results. The most often variants of skin and mucosal toxicity during ALL IC-BFM 2002 protocol were found on protocol mM/M, based on high-dosed methotrexate. In 42.1% stomatitis 2st. was diagnosed on methotrexate dose 5000 mg/m2, 3st. 15.8%, 4st. 5,3%. Methotrexate dosed 2000 mg/m2 coused stomatitis 3 st. in 6.3%, in other patients stomatitis was 12st. Exfoliative dermatitis was in 1 (1%) case with prolonged methotrexate elimination. Block polychemotherapy used in high risk group of patients was complicated with stomatitis 34 st. in 90%. In 20% naso-gastral catheter was performed and in 25% used partial/hole parenteral nutrition support. Alopecia was reversible and observed in 100% patients. Protocols I, II and maintenance treatment were free of clinically significant skin and mucosal toxicity.
 Conclusion. The skin and mucosal toxicity profile of ALL IC-BFM 2002 protocol was tolerable. Hole volume of supportive care, preventing and treatment of dermatological toxicity of chemotherapy can prevent of severe skin and mucosal toxicity (soft tissue infections, sepsis, metabolic disorders).

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.

Safely resuming neglected tropical disease control activities during COVID-19: Perspectives from Nigeria and Guinea.

Since its early spread in early 2020, the disease caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Coronavirus Disease 2019 (COVID-19) has caused mass disruptions to health services. These have included interruptions to programs that aimed to prevent, control, and eliminate neglected tropical diseases (NTDs). In March 2020, the World Health Organization (WHO) released interim guidelines recommending the temporary cessation of mass drug administration (MDA), community-based surveys, and case detection, while encouraging continuation of morbidity management and vector control where possible. Over the course of the following months, national programs and implementing partners contributed to COVID-19 response efforts, while also beginning to plan for resumption of NTD control activities. To understand the challenges, opportunities, and recommendations for maximizing continuity of disease control during public health emergencies, we sought perspectives from Nigeria and Guinea on the process of restarting NTD control efforts during the COVID-19 pandemic. Through semistructured interviews with individuals involved with NTD control at the local and national levels, we identified key themes and common perspectives between the 2 countries, as well as observations that were specific to each. Overall, interviewees stressed the challenges posed by COVID-19 interruptions, particularly with respect to delays to activities and related knock-on impacts, such as drug expiry and prolonged elimination timelines, as well as concerns related to funding. However, respondents in both countries also highlighted the benefits of a formal risk assessment approach, particularly in terms of encouraging information sharing and increasing coordination and advocacy. Recommendations included ensuring greater availability of historical data to allow better monitoring of how future emergencies affect NTD control progress; continuing to use risk assessment approaches in the future; and identifying mechanisms for sharing lessons learned and innovations between countries as a means of advancing postpandemic health systems and disease control capacity strengthening.

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.

PHARMACOKINETICS OF SUBCUTANEOUS ALPHA LIPOIC ACID, A PROPOSED THERAPEUTIC AID FOR DOMOIC ACID INTOXICATION IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

Domoic acid (DA) is a potent neurotoxin produced by certain marine algae that can cause neurologic and cardiac dysfunction by activating glutamate receptors. Glutamate receptor overexcitation results in continuous cellular activation, oxidative damage, and cell death. DA toxicosis causes disorientation and seizures, and antiseizure medications are the primary treatment. Alpha lipoic acid (ALA), a powerful antioxidant and glutathione precursor widely used in humans and dogs, can cross the blood-brain barrier to provide antioxidant availability to brain tissue. Hundreds of stranded California sea lions (CSL; Zalophus californianus) are diagnosed annually with DA toxicosis and thus are an appropriate animal in which to establish ALA dosing recommendations for treatment. The objective of this study was to determine the population pharmacokinetics of a single 10- or 20-mg/kg dose of ALA administered subcutaneously into the interscapular region to healthy rehabilitated CSL. Blood was collected at two time points between 15 min and 24 h after administration. Serum ALA concentrations were measured by liquid chromatography-mass spectrometry, and parameters were evaluated using a nonlinear mixed effects model. ALA was rapidly absorbed for each dose, peaking within 20 to 30 minutes, and t1/2 of 40 and 32 min (10 and 20 mg/kg, respectively), followed by an initial steep distribution phase and prolonged elimination phase. Peak concentration (CMAX) was 1,243 ng/ml (10-mg/ml dose) and 5,010 ng/ml (20-mg/ml dose). Serum from 13 CSLd with DA toxicosis treated with 10 mg/kg ALA for 1 to 9 d had measurable levels, and ALA was also measurable in cerebrospinal fluid from two treated CSLs. Therapeutic effects are noted with a CMAX of 4,000 to 5,000 ng/ml in humans; thus in CSLs, 20 mg/kg administered subcutaneously once daily may be sufficient to achieve a therapeutic level in this species. Determination of efficacy and optimal dosing interval and duration require additional investigation.

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.

Metabolic Retroversion of Piperaquine (PQ) via Hepatic Cytochrome P450-Mediated N-Oxidation and Reduction: Not an Important Contributor to the Prolonged Elimination of PQ.

As a partner antimalarial with an extremely long elimination half-life (∼30 days), piperaquine (PQ) is mainly metabolized into a pharmacologically active N-oxide metabolite [piperaquine N-oxide (PN1)] in humans. In the present work, the metabolic retroversion of PQ and PN1, potentially associated with decreased clearance of PQ, was studied. The results showed that interconversion existed for PQ and its metabolite PN1. The N-oxidation of PQ to PN1 was mainly mediated by CYP3A4, and PN1 can rapidly reduce back to PQ via cytochrome P450 (P450)/flavin-containing monooxygenase enzymes. In accordance with these findings, the P450 nonselective inhibitor (1-ABT) or CYP3A4 inhibitor (ketoconazole) inhibited the N-oxidation pathway in liver microsomes (>90%), and the reduction metabolism was inhibited by 1-ABT (>90%) or methimazole (∼50%). Based on in vitro physiologic and enzyme kinetic studies, quantitative prediction of hepatic clearance (CLH) of PQ was performed, which indicated its negligible decreased elimination in humans in the presence of futile cycling, with the unbound CLH decreasing by 2.5% (0.069 l/h per kilogram); however, a minor decrease in unbound CLH (by 12.8%) was found in mice (0.024 l/h per kilogram). After an oral dose of PQ (or PN1) to mice, the parent form predominated in the blood circulation, and PN1 (or PQ) was detected as a major metabolite. Other factors probably associated with delayed elimination of PQ (intestinal metabolism and enterohepatic circulation) did not play a key role in PQ elimination. These data suggested that the metabolic interconversion of PQ and its N-oxide metabolite contributes to but may not significantly prolong its duration in humans. SIGNIFICANCE STATEMENT: This paper investigated the interconversion metabolism of piperaquine (PQ) and its N-oxide metabolite in vitro as well as in mice. The metabolic profiles of PQ were reestablished by this futile cycling, which contributes to but may not significantly prolong its elimination in humans. Enzyme phenotyping indicated a low possibility of interaction of PQ during artemisinin drug-based combination therapy treatment.

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.

Is the Urine Cannabinoid Level Measured via a Commercial Point-of-Care Semiquantitative Immunoassay a Cannabis Withdrawal Syndrome Severity Predictor?

Background: For cannabis-dependent subjects, the relationship between cannabis withdrawal syndrome (CWS) severity and the urine cannabinoid concentrations are unclear; we investigated this using a commercial point-of-care (POC) enzyme immunoassay detecting 11-nor-9-carboxy-Delta-9-tetrahydrocannabinol (THC-COOH).Methods: Observational study of 78 adult chronic cannabis-dependent subjects assessed over a 24-day inpatient detoxification treatment, with 13 serial measurement days. Repeated Measures Correlation and Multilevel Linear Models were employed.Results: Absolute urinary THC-COOH levels significantly correlated with Marijuana Withdrawal Checklist (MWC) scores across the entire study duration (r = 0.248; p < 0.001). Correlation between serial creatinine-adjusted THC-COOH ratios and serial MWC scores emerged as significant only in the sample with higher MWC scores (>11 points) at admission (n = 21; r = 0.247; p = 0.002). The aforementioned significant relationships have persisted when replacing the absolute THC-COOH-levels with the (relative) day-to-day change in urinary THC-COOH levels. MWC scores were significantly correlated with the Clinical Global Impression-Severity (CGI-S; r = 0.812; p < 0.001). Females showed a significantly slower decline in urine THC-COOH levels and prolonged CWS course characterized by substantial illness severity (per CGI-S), occurring in nearly 30% of cases.Conclusion: Urine cannabinoid levels (THC-COOH) determined by POC assay significantly predicted CWS severity (moderate correlation), guiding detoxification treatment duration. In patients with MWC > 11 points upon admission, creatinine-adjusted THC-COOH ratios also significantly predicted CWS severity—again with moderate effect size. Females showed prolonged urinary THC-COOH elimination and cannabis withdrawal.

Gastrointestinal involvement in children with SARS-COV-2 infection: An overview for the pediatrician.

Gastrointestinal symptoms are common findings in children with SARS‐CoV‐2 infection. Diarrhea and vomiting have been reported in about 8%‐9% of cases, reaching more than 20% in some studies. Children with gastrointestinal involvement appear to be younger than those without, but the severity of the disease seems to be similar between the two groups of subjects. Fecal shedding in children has been reported in 20%‐30% of children and has been observed in both those with and those without overt gastrointestinal involvement. Moreover, prolonged fecal elimination, lasting several days after negativization of real‐time polymerase chain reaction assay on respiratory swabs, has been reported with variable frequency in children with SARS‐CoV‐2 infection. These observations raise the question regarding the possibility of oral‐fecal transmission and the possible role of children in spreading the infection, particularly when they appear asymptomatic or with gastrointestinal symptoms but with no respiratory involvement, as well as during their convalescent phase.

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.