Development and clinical implementation of an LC-HRMS method for ivacaftor, lumacaftor, tezacaftor and elexacaftor in human plasma and breast milk.

The four cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have revolutionised the treatment of CF by direct action on the protein target behind the disease's development. The aim was to develop and validate a quantification method for these CFTR modulators in plasma and breast milk to better understand inter-patient variability in pharmacokinetics and treatment outcome, including the risk of adverse drug reactions. The ability to monitor CFTR modulators in breast milk enables the estimation of the exposure of breastfed infant, with a potential concern for CFTR modulator-induced liver injury.

Pharmacokinetics and pharmacodynamics of a pasireotide subcutaneous depot (CAM4071) and comparison with immediate and long-acting release pasireotide.

Purpose: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of subcutaneous depot CAM4071, a novel, ready-to-use pasireotide formulation.

Methods: This was a phase 1, randomised, open-label study in healthy volunteers. After a single 600 µg dose of pasireotide immediate release (IR), participants were randomised to one of eight groups to receive either a CAM4071 upper thigh (5, 10, 20, 40 or 80 mg) or buttock (20 mg) injection or multiple pasireotide IR 900 µg upper thigh injections twice daily or a single pasireotide long-acting release (LAR) 60 mg intramuscular buttock injection.

Characteristics, complications, and a comparison between early and late tracheostomy: A retrospective observational study on tracheostomy in patients with COVID-19-related acute respiratory distress syndrome.

Background And Aims: As the coronavirus disease 2019 (COVID-19) pandemic spread worldwide in 2020, the number of patients requiring intensive care and invasive mechanical ventilation (IMV) has increased rapidly. During the pandemic, early recommendations suggested that tracheostomy should be postponed, as the potential benefits were not certain to exceed the risk of viral transmission to healthcare workers. The aim of this study was to assess the utility of tracheostomy in patients with COVID-19-related acute respiratory distress syndrome, in terms of patient and clinical characteristics, outcomes, and complications, by comparing between early and late tracheostomy.

Effect of Dihydroartemisinin-Piperaquine on the Pharmacokinetics of Praziquantel for Treatment of Infection.

Praziquantel (PZQ) and dihydroartemisinin-piperaquine (DHP) combination recently showed superior effectiveness than PZQ alone to treat intestinal schistosomiasis. In this follow-up study, we investigated the effect of DHP co-administration on the pharmacokinetics of PZQ and its enantiomers among 64 infected children treated with PZQ alone ( = 32) or PZQ + DHP combination ( = 32). Plasma samples collected at 0, 1, 2, 4, 6, and 8 h post-dose were quantified using UPLCMS/MS.

Nicotine Population Pharmacokinetics in Healthy Smokers After Intravenous, Oral, Buccal and Transdermal Administration.

Background: In 4 decades, numerous nicotine replacement therapy products have been developed. Population pharmacokinetic models can support exposure-response modeling and inform nicotine replacement therapy product development, but only limited model-based cross-study population pharmacokinetic analyses for nicotine replacement therapy products have been published.

Objectives: The aim of this retrospective analysis was to assess the population pharmacokinetics of nicotine across intravenous, oral, transdermal and oromucosal (mouth spray, chewing gum, lozenge and inhaler) routes and formulations in healthy smoking subjects.

A Time-to-Event Model Relating Integrated Craving to Risk of Smoking Relapse Across Different Nicotine Replacement Therapy Formulations.

Smoking increases the risk of cancer and other diseases, causing an estimated 7 million deaths per year. Nicotine replacement therapy (NRT) reduces craving for smoking, therefore, increasing an individual's probability to remain abstinent. In this work, we for the first time quantitatively described the relationship between craving and smoking abstinence, using retrospectively collected data from 19 studies, including 3 NRT formulations (inhaler, mouth spray, and patch) and a combination of inhaler and patch.

Effect of nicotine 6 mg gum on urges to smoke, a randomized clinical trial.

Background: Ability to manage urges to smoke is fundamental to maximizing the chances of success in smoking cessation. Previous studies have linked a higher dose of nicotine in nicotine replacement therapy to a higher success rate for smoking cessation. Thus, this study was performed to compare relief of urges to smoke, up until 5 h following treatment with a new 6 mg nicotine gum versus currently marketed 4 mg nicotine gum.

Relating Nicotine Plasma Concentration to Momentary Craving Across Four Nicotine Replacement Therapy Formulations.

Tobacco use is a major health concern. To assist smoking cessation, nicotine replacement therapy (NRT) is used to reduce nicotine craving. We quantitatively described the relationship between nicotine pharmacokinetics (PKs) from NRTs and momentary craving, linking two different pharmacodynamic (PD) scales for measuring craving.

Carbamazepine, lamotrigine, levetiracetam and valproic acid in dried blood spots with liquid chromatography tandem mass spectrometry; method development and validation.

Monitoring of antiepileptic drugs in children with epilepsy require multiple visits at a clinic for blood collection. Dried blood spot sampling is an alternative way of collection, performed at home by self-collection and can save time and costs for patients and family members. The aim was to develop and validate an LC-MS/MS dried blood spot method for carbamazepine, lamotrigine, levetiracetam and valproic acid with the requirements of using standard equipment and material in a routine laboratory setting.

Single-Dose and Multiple-Dose Pharmacokinetics of Nicotine 6 mg Gum.

Introduction: Under-dosing is a recognized problem with current nicotine replacement therapy (NRT). Therefore, a new 6mg nicotine gum has been developed. To compare the nicotine uptake from the 6mg gum versus currently available NRT products, two pharmacokinetic studies were performed.

District nurses' perspectives on detecting mental health problems and promoting mental health among community-dwelling seniors with multimorbidity.

Aims And Objectives: To describe district nurses' perspectives on detecting mental health problems and promoting mental health among homebound older people with multimorbidity.

Background: Mental health problems among older people with multiple chronic conditions, that is, multimorbidity, are challenging issues. These patients' homes often serve as arenas in which district nurses can promote health.

Home care assistants' perspectives on detecting mental health problems and promoting mental health among community-dwelling seniors with multimorbidity.

Introduction: Elderly people with multiple chronic conditions, or multimorbidity, are at risk of developing poor mental health. These seniors often remain in their homes with support from home care assistants (HCAs). Mental health promotion by HCAs needs to be studied further because they may be among the first to observe changes in clients' mental health status.

Zeolites relieves inhibitory stress from high concentrations of long chain fatty acids.

Protein and fat rich slaughterhouse waste is a very attractive waste stream for the production of biogas because of the high biochemical methane potential of the substrate. The material has however some drawbacks as the sole material for biogas production due to the production of several process disturbing metabolites such as ammonia, sulfides and long chain fatty acids. We can in this work present results that show that zeolites have the potential to relieve inhibitory stress from the presence of long chain fatty acids.

Landowners' incentives for constructing wetlands in an agricultural area in south Sweden.

Eutrophication of the Baltic Sea has in Sweden led to the initiation of government schemes aiming to increase wetland areas in agricultural regions and thereby reduce nutrient transport to the sea. Landowners play a significant role as providers of this ecosystem service and are currently offered subsidies to cover their costs for constructing and maintaining wetlands. We undertook a grounded theory study, in which landowners were interviewed, aiming at identifying landowners' incentives for constructing wetlands on their land.

Effects of nicotine mouth spray on urges to smoke, a randomised clinical trial.

Objective: A new nicotine mouth spray was shown to be an effective stop-smoking treatment. This study was set up to examine the speed with which it relieves urges to smoke, and how it compares with nicotine lozenge in this respect.

Design: Randomised, cross-over trial that compared nicotine mouth spray 2 mg versus nicotine lozenge 2 or 4 mg.

Single-dose pharmacokinetics of nicotine when given with a novel mouth spray for nicotine replacement therapy.

Introduction: As the efficacy of nicotine replacement therapy might be improved by faster systemic nicotine uptake, a new nicotine mouth spray has been developed. The current study was performed to evaluate the single-dose pharmacokinetics of nicotine at 3 doses of the mouth spray and to compare the speed of nicotine uptake from the spray versus nicotine lozenge and gum.

Methods: In a randomized crossover study, 45 healthy adult smokers received single doses of nicotine mouth spray 1, 2, and 4 mg, nicotine lozenge 4 mg, and nicotine gum 4 mg on separate occasions.

Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology.

Many muscular and neurological disorders are associated with mitochondrial dysfunction and are often accompanied by changes in mitochondrial morphology. Mutations in the gene encoding OPA1, a protein required for fusion of mitochondria, are associated with hereditary autosomal dominant optic atrophy type I. Here we show that mitochondrial fragmentation correlates with processing of large isoforms of OPA1 in cybrid cells from a patient with myoclonus epilepsy and ragged-red fibers syndrome and in mouse embryonic fibroblasts harboring an error-prone mitochondrial mtDNA polymerase gamma.

Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production.

The mitochondrial theory of aging proposes that reactive oxygen species (ROS) generated inside the cell will lead, with time, to increasing amounts of oxidative damage to various cell components. The main site for ROS production is the respiratory chain inside the mitochondria and accumulation of mtDNA mutations, and impaired respiratory chain function have been associated with degenerative diseases and aging. The theory predicts that impaired respiratory chain function will augment ROS production and thereby increase the rate of mtDNA mutation accumulation, which, in turn, will further compromise respiratory chain function.

A desymmetrization route to fused Troger's base analogues: synthesis, isolation, and characterization of the first anti-anti diastereomer of a fused tris-Troger's base analogue.

A desymmetrization route to fused Troger's base analogues was developed. In this way, the synthesis of the first example of an anti-anti diastereomer of a fused tris-Troger's base analogue was accomplished. The resulting compound 5b is a nonlinear symmetric regioisomer obtained from p-bromoaniline in 7% yield.

Abnormal Ca(2+) release and catecholamine-induced arrhythmias in mitochondrial cardiomyopathy.

Mitochondrial dysfunction is implicated in numerous cardiac disorders. It has been assumed that the functional defects are directly related to a decreased rate of mitochondrial ATP production, but recent studies have challenged this idea. Here, we used mice with tissue-specific knockout of mitochondrial transcription factor A (Tfam) that leads to progressive cardiomyopathy.

A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts.

We performed global gene expression analyses in mouse hearts with progressive respiratory chain deficiency and found a metabolic switch at an early disease stage. The tissue-specific mitochondrial transcription factor A (Tfam) knockout mice of this study displayed a progressive heart phenotype with depletion of mtDNA and an accompanying severe decline of respiratory chain enzyme activities along with a decreased mitochondrial ATP production rate. These characteristics were observed after 2 weeks of age and became gradually more severe until the terminal stage occurred at 10-12 weeks of age.

Cardiovascular effects of nasal and transdermal nicotine and cigarette smoking.

The purpose of this study was to compare circadian blood pressure and heart rate patterns and other cardiovascular effects of nicotine delivered rapidly (via nasal spray, NNS), slowly (transdermal nicotine, TDN), by cigarette smoking (rapid delivery of nicotine plus other smoke toxins), and placebo NNS. Twelve healthy cigarette smokers were studied on a research ward when they smoked cigarettes (16 per day) or used TDN (15 mg/16 h), NNS (24 1-mg doses per day), or placebo NNS, each for 5 days. There were no significant differences in systolic blood pressure, but diastolic blood pressure was slightly increased during cigarette smoking.

Zeolite beta Induced Rearrangement of Allyl Benzyl Ethers. 6. Variation of the Aromatic Part and Synthesis of Dihydronaphthalene Derivatives.

The zeolite beta induced rearrangement of substituted allyl benzyl ethers to give 4-arylbutanals was investigated with respect to the substituents in the aromatic ring. In some cases the resulting aldehydes cyclized spontaneously to give dihydronaphthalene derivatives. The rearrangement and also the ring closure to dihydronaphthalenes failed or gave poor yields in cases where too weak electron-donating substituents were present in the aromatic ring.