Miniaturized one-step extraction for the analysis of tetrahydrocannabinol ∆- and ∆- isomers, phytocannabinoids, and hexahydrocannabinol in whole blood using liquid chromatography tandem mass spectrometry.

∆-tetrahydrocannabinol (∆-THC) plays a major role in diving under the influence of drugs investigations and workplace drug testing. Additionally, cannabidiol (CBD), as well as semi-synthetic cannabinoids, like hexahydrocannabinol (HHC) and ∆-tetrahydrocannabinol (∆-THC), are increasingly found on regulated and unregulated drug markets. A straightforward bioanalytical method was developed, covering 14 analytes, including ∆-THC, CBD, ∆-THC, and their respective metabolites, as well as HHC and a subset of minor phytocannabinoids.

Relationship between simvastatin pharmacokinetics and muscle toxicity in male mice.

Statins are highly effective in reducing plasma LDL-cholesterol but may be myotoxic. Since the relationship between statin exposure and myotoxicity is not clearly established, the current study aimed to compare blood and skeletal muscle concentrations with myotoxicity in male mice treated orally with 5, 10 and 25 mg/kg/day simvastatin for 3 weeks. After the first dose, simvastatin blood pharmacokinetics was dose-dependent, with exposures corresponding to humans treated with 80, 160 and 400 mg/day simvastatin.

Pharmacokinetics and Pharmacodynamics of Intranasal Diacetylmorphine in Heroin-Assisted Treatment for Severe Opioid Use Disorder.

Background: Intranasal diacetylmorphine (IN DAM) represents a promising new route of administration, which is currently under investigation as a novel treatment approach for opioid use disorder in Switzerland. This study characterized the pharmacokinetics and pharmacodynamics of therapeutically relevant intranasal doses of DAM and its metabolites in patients with severe opioid use disorder.

Methods: In this prospective observational study, patients on intranasal heroin-assisted treatment (HAT) in Basel, Switzerland, self-administered their usual dose of IN DAM before receiving their daily maintenance dose.

A validated single-step saliva and serum sample extraction LC-MS/MS method for the analysis of nicotine, cotinine and 3'-hydroxycotinine for clinical vaping studies.

Introduction: Quantifying low nicotine and metabolite concentrations in biofluids is challenging due environmental nicotine contamination. However, accurate quantification of low concentrations is crucial for studies on electronic nicotine delivery systems (ENDS) using e-liquids with varying nicotine content.

Methods: We developed an LC-MS/MS method to quantify nicotine, cotinine, and 3'-hydroxycotinine (3-OH-cotinine) in serum and saliva for pharmacokinetic (PK) analyses and large studies.

Effect of protein binding on the pharmacokinetics of the six substrates in the Basel phenotyping cocktail in healthy subjects and patients with liver cirrhosis.

Phenotyping serves to estimate enzyme activities in healthy persons and patients in vivo. Low doses of enzyme-specific substrates are administered, and activities estimated using metabolic ratios (MR, calculated as AUC/AUC). We administered the Basel phenotyping cocktail containing caffeine (CYP1A2 substrate), efavirenz (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6) and midazolam (CYP3A) to 36 patients with liver cirrhosis and 12 control subjects and determined free and total plasma concentrations over 24 h.

Novel Patient-Friendly Orodispersible Formulation of Ivermectin is Associated With Enhanced Palatability, Controlled Absorption, and Less Variability: High Potential for Pediatric Use.

Ivermectin has been used since the 1980s as an anthelmintic and antiectoparasite agent worldwide. Currently, the only available oral formulation is tablets designed for adult patients. A patient-friendly orodispersible tablet formulation designed for pediatric use (CHILD-IVITAB) has been developed and is entering early phase clinical trials.

In vivo antimalarial efficacy of Artemisia afra powder suspensions.

Background: A global death toll of 608,000 in 2022 and emerging parasite resistance to artemisinin, the mainstay of antimalarial chemotherapy derived from the Chinese herb Artemisia annua, urge the development of novel antimalarials. A clinical trial has found high antimalarial potency for aqueous extracts of A. annua as well as its African counterpart Artemisia afra, which contains only trace amounts of artemisinin.

Inhibition of the transmembrane transporter ABCB1 overcomes resistance to doxorubicin in patient-derived organoid models of HCC.

Background: Transarterial chemoembolization is the first-line treatment for intermediate-stage HCC. However, the response rate to transarterial chemoembolization varies, and the molecular mechanisms underlying variable responses are poorly understood. Patient-derived hepatocellular carcinoma organoids (HCCOs) offer a novel platform to investigate the molecular mechanisms underlying doxorubicin resistance.

Derivatization-free determination of chiral plasma pharmacokinetics of MDMA and its enantiomers.

3,4-Methylenedioxymethamphetamine (MDMA) is an entactogen with therapeutic potential. The two enantiomers of MDMA differ regarding their pharmacokinetics and pharmacodynamics but the chiral pharmacology of MDMA needs further study in clinical trials. Here, an achiral and an enantioselective high performance liquid chromatography-tandem mass spectrometry method for the quantification of MDMA and its psychoactive phase I metabolite 3,4-methylenedioxyamphetamine (MDA) in human plasma were developed and validated.

Development and validation of an LC-MS/MS method for quantifying diamorphine and its major metabolites 6-monoacetylmorphine, morphine, morphine-3-glucuronide, and morphine-6-glucuronide in human plasma.

Diamorphine, commonly known as heroin, is a semi-synthetic opioid analgesic. In the context of heroin-assisted treatment for opioid-dependent patients, diamorphine is mostly administered intravenously. However, recent attention has shifted towards intranasal administration as a better-tolerated alternative to the intravenous route.

Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study.

Understanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants.

Mechanisms of hepatocellular toxicity associated with the components of St. John's Wort extract hypericin and hyperforin in HepG2 and HepaRG cells.

St. John's Wort preparations are used for the treatment of mild to moderate depression. They are usually well tolerated but can cause adverse reactions including liver toxicity in rare cases.

Pharmacokinetics, pharmacodynamics and urinary recovery of oral lysergic acid diethylamide administration in healthy participants.

Aims: Lysergic acid diethylamide (LSD) is currently investigated for several neurological and psychiatric illnesses. Various studies have investigated the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationship of LSD in healthy participants, but data on urinary recovery and confirmatory studies are missing.

Methods: The present study characterized the pharmacokinetics, pharmacokinetic-pharmacodynamic relationship and urinary recovery of LSD at doses of 85 and 170 μg administered orally in 28 healthy participants.

Pharmacokinetics of ivermectin metabolites and their activity against Anopheles stephensi mosquitoes.

Background: Ivermectin (22,23-dihydroavermectin B: HB) is an endectocide used to treat worm infections and ectoparasites including lice and scabies mites. Furthermore, survival of malaria transmitting Anopheles mosquitoes is strongly decreased after feeding on humans recently treated with ivermectin. Currently, mass drug administration of ivermectin is under investigation as a potential novel malaria vector control tool to reduce Plasmodium transmission by mosquitoes.

The Activity of Members of the UDP-Glucuronosyltransferase Subfamilies UGT1A and UGT2B is Impaired in Patients with Liver Cirrhosis.

Background And Objective: The impact of liver cirrhosis on the activity of UDP-glucuronosyltransferases (UGTs) is currently not well characterized. We investigated the glucuronidation capacity and glucuronide accumulation in patients with liver cirrhosis.

Methods: We administered the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, midazolam) to patients with liver cirrhosis (n = 16 Child A, n = 15 Child B, n = 5 Child C) and n = 12 control subjects and obtained pharmacokinetic profiles of substrates and primary metabolites and their glucuronides.

Acute effects of MDMA and LSD co-administration in a double-blind placebo-controlled study in healthy participants.

There is renewed interest in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. Although acute subjective effects of LSD are mostly positive, negative subjective effects, including anxiety, may occur. The induction of overall positive acute subjective effects is desired in psychedelic-assisted therapy because positive acute experiences are associated with greater therapeutic long-term benefits.

Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants.

Mescaline, lysergic acid diethylamide (LSD), and psilocybin are classic serotonergic psychedelics. A valid, direct comparison of the effects of these substances is lacking. The main goal of the present study was to investigate potential pharmacological, physiological and phenomenological differences at psychoactive-equivalent doses of mescaline, LSD, and psilocybin.

Acute effects of intravenous DMT in a randomized placebo-controlled study in healthy participants.

N,N-dimethyltryptamine (DMT) is distinct among classic serotonergic psychedelics because of its short-lasting effects when administered intravenously. Despite growing interest in the experimental and therapeutic use of intravenous DMT, data are lacking on its clinical pharmacology. We conducted a double-blind, randomized, placebo-controlled crossover trial in 27 healthy participants to test different intravenous DMT administration regimens: placebo, low infusion (0.

Dose Adjustment in Patients with Liver Cirrhosis - Comparison of Two Different Modeling Approaches.

Failure to perform adequate dose adjustment in patients with liver cirrhosis may be associated with increased toxicity. We compared the prediction of area under the curve (AUC) and clearance for the six compounds of the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, and midazolam) using a well-known physiology-based pharmacokinetic approach (physiologically-based pharmacokinetic [PBPK] approach, Simcyp) and a novel top-down method based on the systemic clearance in healthy volunteers adjusted for markers of liver and renal dysfunction ("top-down approach"). With few exceptions, plasma concentration-time curves were accurately predicted by the PBPK approach.

Allosteric targeting resolves limitations of earlier LFA-1 directed modalities.

Integrins are a family of cell surface receptors well-recognized for their therapeutic potential in a wide range of diseases. However, the development of integrin targeting medications has been impacted by unexpected downstream effects, reflecting originally unforeseen interference with the bidirectional signalling and cross-communication of integrins. We here selected one of the most severely affected target integrins, the integrin lymphocyte function-associated antigen-1 (LFA-1, αβ, CD11a/CD18), as a prototypic integrin to systematically assess and overcome these known shortcomings.