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  • Haage, Pernilla, 1982- (författare)
  • Forensic Toxicological Aspects of Tramadol : Focus on Enantioselective Drug Disposition and Pharmacogenetics
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • One of the most difficult parts in forensic toxicology is to interpret obtained drug concentrations. Was it therapeutic, toxic or even lethal to the particular individual that the blood sample was drawn from? Concentrations of opioid drugs are especially difficult to interpret, because of large interindividual differences in innate and acquired tolerance.Tramadol is a complex drug. Not only is it an opioid, it is also a racemic drug with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. Further, it is metabolized by polymorphic enzymes, which may affect the amounts of metabolites formed and possibly the enantiomer ratios of the parent compound and its metabolites. It has been speculated that particularly the (+)/(-)-enantiomer ratio of O-desmethyltramadol is related to the risk of adverse effects, and it has been shown that the ratio is affected by CYP2D6 genotype.The overall aim of the thesis was to evaluate if forensic interpretations of tramadol, regarding toxicity and time since drug administration, may be improved by the use of genotyping and enantioselective concentration determination of tramadol and its three main metabolites.To simultaneously quantify the enantiomer concentrations of tramadol, Odesmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol in whole blood, a liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed and validated. Genetic variation in CYP2D6, CYP2B6, CYP3A4 (encoding the tramadol metabolizing enzymes), ABCB1 (encoding a transport protein) and OPRM1 (encoding the μ-opioid receptor) was investigated, using pyrosequencing, xTAG, and TaqMan analysis. The methods were applied to the blood samples of two study populations; 19 healthy volunteers administered a therapeutic, single tramadol dose, and 159 tramadol positive autopsy cases.The most important finding was the positive correlations between all four enantiomer ratios and time since tramadol administration in the healthy volunteers. All enantiomer ratios except the one of tramadol was also affected by the CYP2D6 genotype, which was apparent among the autopsy cases as well. Genetic variation in CYP2D6 and possibly CYP2B6 was shown to have an impact on tramadol pharmacokinetics, although no association to neither drug related symptoms nor tramadol related causes of death was found. Tramadol intoxications were predominantly characterized by low age (median 26 years) and male sex, often with a history of substance abuse and with other drugs (at fairly low concentrations) detected in blood.In conclusion, enantiomer concentration determination combined with genotyping seems promising regarding estimations of time since drug administration, although is of low value concerning interpretations of toxicity in autopsy cases.
  • Söderberg, Carl, et al. (författare)
  • Antipsychotics - Postmortem fatal and non-fatal reference concentrations
  • 2016
  • Ingår i: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 266, s. 91-101
  • Tidskriftsartikel (refereegranskat)abstract
    • Making the diagnosis fatal intoxication is a challenging task for the forensic pathologist and toxicologist, particularly when the cases involve substances where reference information is scarce or not at all available. This study presents postmortem femoral blood concentrations for 24 antipsychotic substances, based on samples collected and analyzed from 4949 autopsy cases in Sweden during 1992-2010. In addition our study provides information about the prevalence of different antipsychotics in accidental, suicidal, homicidal and uncertain deaths.The data have been selected and evaluated according to strict inclusion and exclusion criteria as well as a manual, multi-reviewer, case-by-case evaluation. The reference information is subdivided into intoxications by one specific substance only (group A, n = 259), multi-substance intoxications (group B, n = 614) and postmortem controls, consisting of deaths not involving incapacitation by substances (group C, n = 507). Moreover, the results are compared with data based on therapeutic drug monitoring, and data collected from driving under the influence cases.Median concentrations in group A were significantly higher than in group C for all substances evaluated. For 17 of 24 substances, the median concentrations in group B were significantly higher than in group C. In general, the therapeutic drug monitoring and driving under the influence concentrations were similar to, or lower than, the concentrations in group C.
  • Vicente Carrillo, Alejandro, 1989- (författare)
  • Sperm Membrane Channels, Receptors and Kinematics : Using boar spermatozoa for drug toxicity screening
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Internal fertilization usually implies that a spermatozoon, with intact attributes for zygote formation, passes all hurdles during its transport through the female genitalia and reaches the oocyte. During this journey, millions to billions of other spermatozoa perish. Spermatozoa are highly differentiated motile cells without synthetic capabilities. They generate energy via glycolysis and oxidative phosphorylation to sustain motility and to maintain the stability and functionality of their plasma membrane. In vivo, they spend their short lifespan bathing in female genital tract fluids of different origins, or are in vitro exposed to defined media during diverse sperm handling i.e. extension, cryopreservation, in vitro fertilization, etc. Being excitable cells, spermatozoa respond in vivo to various stimuli during pre-fertilization (capacitation, hyperactivation, oocyte location) and fertilization (acrosome reaction, interaction with the oocyte) events, mediated via diverse membrane ion-conducting channels and ligand-gated receptors. The present Thesis has mapped the presence and reactivity (sperm intactness and kinematics) of selected receptors, water and ion channels in ejaculated boar spermatozoa. The final aim was to find a relevant alternative cell type for in vitro bioassays that could ease the early scrutiny of candidate drugs as well as decreasing our needs for experimental animals according to the 3R principles. Spermatozoa are often extended, cooled and thawed to warrant their availability as fertile gametes for breeding or in vitro testing. Such manipulations stress the cells via osmotic variations and hence spermatozoa need to maintain membrane intactness by controlling the exchange of water and the common cryoprotectant glycerol, via aquaporins (AQPs). Both AQPs-7 and -9 were studied for membrane domain changes in cauda- and ejaculated spermatozoa (un-processed, extended, chilled or frozen-thawed). While AQP-9 maintained location through source and handling, thawing of ejaculated spermatozoa clearly relocated the labelling of AQP-7, thus appearing as a relevant marker for non-empirical studies of sperm cryopreservation. Alongside water, spermatozoa interact with calcium (Ca2+) via the main Ca2+ sperm channel CatSper. Increments in intracellular Ca2+ initiate motility hyperactivation and the acrosome reaction. The four subunits of the CatSper channel were present in boar spermatozoa, mediating changes in sperm motility under in vitro capacitation-inducing conditions (increased extracellular Ca2+ availability and bicarbonate) or challenge by the CatSper antagonists mibefradil and NNC 55-0396. Uterine and oviduct fluids are richest in endogenous opioids as β-endorphins during mating and ovulation. Both μ- and δ- opioid receptors were present in boar spermatozoa modulating sperm motility, as in vitro challenge with known agonists (μ: morphine; δ: DPDPE and κ: U 50488) and antagonists (μ: naloxone; δ: naltrindole and κ: nor-binaltrorphimine) showed that the μ-opioid receptor maintained or increased motility while the δ-opioid receptor mediated decreased motility over time. Finally, boar spermatozoa depicted dose-response effects on sperm kinematics and mitochondrial potential following in vitro challenge with 130 pharmacological drugs and toxic compounds as well as with eight known mito-toxic compounds. In conclusion, boar spermatozoa expressing functional water (AQPs-7 and -9) and ion (CatSper 1-4) channels as well as μ- and δ-opioid receptors are able to adapt to stressful environmental variations, capacitation and pharmacological compounds and drug components. Ejaculated sperm suspensions are easily and painlessly obtained from breeding boars, and are suitable biosensors for in vitro drug-induced testing, complying with the 3R principles of reduction and replacement of experimental animals, during early toxicology screening.
  • Ekqvist, David, et al. (författare)
  • Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin : a study protocol of a phase II clinical trial (HighShort-RP)
  • 2022
  • Ingår i: BMJ Open. - : BMJ. - 2044-6055 .- 2044-6055. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Increased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical trial aims to explore safety and pharmacokinetics-pharmacodynamics of a high-dose pyrazinamide-rifampicin regimen.Methods and analysis: Adult patients with pulmonary TB admitted to six hospitals in Sweden and subjected to receive first-line treatment are included. Patients are randomised (1:3) to either 6-month standardised TB treatment or a 4-month regimen based on high-dose pyrazinamide (40 mg/kg) and rifampicin (35 mg/kg) along with standard doses of isoniazid and ethambutol. Plasma samples for measurement of drug exposure determined by liquid chromatography tandem-mass spectrometry are obtained at 0, 1, 2, 4, 6, 8, 12 and 24 hours, at day 1 and 14. Maximal drug concentration (C-max) and area under the concentration-time curve (AUC(0-24h)) are estimated by non-compartmental analysis. Conditions for early model-informed precision dosing of high-dose pyrazinamide-rifampicin are pharmacometrically explored. Adverse drug effects are monitored throughout the study and graded according to Common Terminology Criteria for Adverse Events V.5.0. Early bactericidal activity is assessed by time to positivity in BACTEC MGIT 960 of induced sputum collected at day 0, 5, 8, 15 and week 8. Minimum inhibitory concentrations of first-line drugs are determined using broth microdilution. Disease severity is assessed with X-ray grading and a validated clinical scoring tool (TBscore II). Clinical outcome is registered according to WHO definitions (2020) in addition to occurrence of relapse after end of treatment. Primary endpoint is pyrazinamide AUC(0-24h) and main secondary endpoint is safety.Ethics and dissemination: The study is approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. Informed written consent is collected before study enrolment. The study results will be submitted to a peer-reviewed journal.
  • Al-Adwani, S., et al. (författare)
  • Studies on citrullinated LL-37: detection in human airways, antibacterial effects and biophysical properties
  • 2020
  • Ingår i: Scientific Reports. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Arginine residues of the antimicrobial peptide LL-37 can be citrullinated by peptidyl arginine deiminases, which reduce the positive charge of the peptide. Notably, citrullinated LL-37 has not yet been detected in human samples. In addition, functional and biophysical properties of citrullinated LL-37 are not fully explored. The aim of this study was to detect citrullinated LL-37 in human bronchoalveolar lavage (BAL) fluid and to determine antibacterial and biophysical properties of citrullinated LL-37. BAL fluid was obtained from healthy human volunteers after intra-bronchial exposure to lipopolysaccharide. Synthetic peptides were used for bacterial killing assays, transmission electron microscopy, isothermal titration calorimetry, mass-spectrometry and circular dichroism. Using targeted proteomics, we were able to detect both native and citrullinated LL-37 in BAL fluid. The citrullinated peptide did not kill Escherichia coli nor lysed human red blood cells. Both peptides had similar α-helical secondary structures but citrullinated LL-37 was more stable at higher temperatures, as shown by circular dichroism. In conclusion, citrullinated LL-37 is present in the human airways and citrullination impaired bacterial killing, indicating that a net positive charge is important for antibacterial and membrane lysing effects. It is possible that citrullination serves as a homeostatic regulator of AMP-function by alteration of key functions. © 2020, The Author(s).
  • Marwaha, Sania, et al. (författare)
  • N-acylated derivatives of sulfamethoxazole and sulfafurazole inhibit intracellular growth of Chlamydia trachomatis
  • 2014
  • Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 58:5, s. 2968-2971
  • Tidskriftsartikel (refereegranskat)abstract
    • Antibacterial compounds with novel modes of action are needed for management of bacterial infections. Here we describe a high-content screen of 9,800 compounds identifying acylated sulfonamides as novel growth inhibitors of the sexually transmitted pathogen Chlamydia trachomatis. The effect was bactericidal and distinct from that of sulfonamide antibiotics, as para-aminobenzoic acid did not reduce efficacy. Chemical inhibitors play an important role in Chlamydia research as probes of potential targets and as drug development starting points.
  • Rao, Komal Umashankar, et al. (författare)
  • A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy
  • 2021
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.
  • Eroli, Francesca, et al. (författare)
  • Chronic polypharmacy impairs explorative behavior and reduces synaptic functions in young adult mice
  • 2020
  • Ingår i: Aging. - 1945-4589 .- 1945-4589. ; 12:11, s. 10147-10161
  • Tidskriftsartikel (refereegranskat)abstract
    • A major challenge in the health care system is the lack of knowledge about the possible harmful effects of multiple drug treatments in old age. The present study aims to characterize a mouse model of polypharmacy, in order to investigate whether long-term exposure to multiple drugs could lead to adverse outcomes. To this purpose we selected five drugs from the ten most commonly used by older adults in Sweden (metoprolol, paracetamol, aspirin, simvastatin and citalopram). Five-month-old wild type male mice were fed for eight weeks with control or polypharmacy diet. We report for the first time that young adult polypharmacy-treated mice showed a significant decrease in exploration and spatial working memory compared to the control group. This memory impairment was further supported by a significant reduction of synaptic proteins in the hippocampus of treated mice. These novel results suggest that already at young adult age, use of polypharmacy affects explorative behavior and synaptic functions. This study underlines the importance of investigating the potentially negative outcomes from concomitant administration of different drugs, which have been poorly explored until now. The mouse model proposed here has translatable findings and can be applied as a useful tool for future studies on polypharmacy.
  • Wallerstedt, Susanna Maria, 1970, et al. (författare)
  • Long-term use of proton pump inhibitors and prevalence of disease-and drug-related reasons for gastroprotection-a cross-sectional population-based study
  • 2017
  • Ingår i: Pharmacoepidemiology and Drug Safety. - 1053-8569 .- 1099-1557. ; 26:1, s. 9-16
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose To analyse the prevalence of long-term use of proton pump inhibitors (PPI) with respect to underlying diseases and drugs, and to find predictors for such treatment when an evident rationale for the PPI treatment is lacking. Methods The study cohort consisted of individuals, >= 65 years in 2010, residing in the Region Vastra Gotaland during 2005-2010. For individuals with and without long-term use of PPI in 2010, we investigated the prevalence of an underlying diagnosis, that is, an acid-related disease during the five preceding years, as well as concomitant long-term use of antiplatelet agents or cyclooxygenase inhibitors. Results In all, 278 205 individuals (median age: 74 years; 55% female; median 3 drugs per person; 5% nursing home residents, 11% with multi-dose drug dispensing) were included in the analyses, 32 421 (12%) of whom were on long-term treatment with PPI in 2010. For 12 253 individuals (38%) with such treatment, no underlying rationale was found. In individuals without a disease-or a drug-related reason for PPI use, nursing home residence, number of drugs, female sex, but not multi-dose drug dispensing, were associated with long-term use of PPI; adjusted odds ratios (95% confidence interval): 1.63 (1.49; 1.78), 1.27 (1.26; 1.28), 1.24 (1.19; 1.29), and 0.94 (0.88; 1.01), respectively. Conclusions Long-term use of PPI occurs in one out of nine individuals in the older population. For four out of ten of these, no reason for PPI use can be identified. Nursing home residence, female sex, and greater number of drugs predict non-rational long-term use of PPI.
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