| 1. |
- Lesén, Eva, 1982, et al.
(författare)
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Is the level of patient co-payment for medicines associated with refill adherence in Sweden?
- 2014
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Ingår i: European Journal of Public Health. - : Oxford University Press (OUP). - 1101-1262 .- 1464-360X. ; 24:1, s. 85-90
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Tidskriftsartikel (refereegranskat)abstract
- In the Swedish reimbursement scheme, the co-payment is based on the price of the product and decreases in a stepwise manner as the total accumulated co-payment increases. The aim of this study was to analyse how refill adherence in Sweden varies according to patient's co-payment level for medicines, with antiepileptic drug (AED) use as an example.
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| 2. |
- Hedna, Khedidja, 1978, et al.
(författare)
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Clinical relevance of alerts from a decision support system, PHARAO, for drug safety assessment in the older adults
- 2019
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Ingår i: BMC Geriatrics. - : Springer Science and Business Media LLC. - 1471-2318. ; 19:1, s. 164-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPHARAO is a decision support system developed to evaluate the risk for a set of either common or serious side-effects resulting from a combination of pharmacodynamic effects from a patient's medications. The objective of this study was to investigate the validity of the risk scores for the common side-effects generated by PHARAO in older patients.MethodsSide-effects included were sedation, constipation, orthostatic symptoms, anticholinergic and serotonergic effects. The alerts generated by PHARAO were tested in 745 persons 65years old. Dispensed prescriptions retrieved from the Swedish prescribed drug register were used to generate the pharmacological risk scores of patients' medications. Symptoms possibly related to side-effects were extracted from medical records data.ResultsThe PHARAO system generated 776 alerts, most often for the risk of anticholinergic symptoms. The total specificity estimates of the PHARAO system were 0.95, 0.89 and 0.78 for high, intermediate and low risk alerts, respectively. The corresponding sensitivity estimates were between 0.12 and 0.37. The negative predictive value was 0.90 and the positive predictive value ranged between 0.20-0.25.ConclusionsThe PHARAO system had a high specificity and negative predictive value to detect symptoms possibly associated with the of patients' medications, while the sensitivity and positive predictive value were low. The PHARAO system has the potential to minimise the risk of over-alerts in combination with a drug-drug interaction alert system, but should be used in connection with a medical evaluation of the patient.
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| 3. |
- Vicente Carrillo, Alejandro, 1989-
(författare)
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Sperm Membrane Channels, Receptors and Kinematics : Using boar spermatozoa for drug toxicity screening
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 4. |
- Aziz, Abdul Maruf Asif
(författare)
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Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD.The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models.In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced “hangover” anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stress-induced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats. Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol.In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993.In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for motivation to work for alcohol and reinstatement of alcohol-seeking behavior. Treatment with CYM-9840 (10 mg/kg) potently attenuated alcohol SA, progressive ratio responding and stress-induced reinstatement using yohimbine as the stressor, while alcohol cue-induced reinstatement was unaffected. Moreover, a range of control behaviors including taste sensitivity, locomotor and pharmacological sensitivity to the sedative effects of alcohol remained unaffected by CYM-9840 pretreatment, indicating that its effects are specific to the rewarding and motivational aspects of alcohol-intake and related behaviors. CYM-9840 also reversed acute alcohol withdrawal-induced “hangover” anxiety measured in the EPM and reduced alcohol-intake in the 4 hour limited access two-bottle free choice preference drinking model.Finally, in the fourth study (Paper IV), the selective MCH1-R antagonist GW803430 was tested in rat models of escalated alcohol-intake. Pretreatment with GW803430 (effective at 10 & 30 mg/kg) dose-dependently reduced alcohol and food-intake in rats that consumed high amounts of alcohol during IA, while it only decreased food-intake in rats that consumed low amounts of alcohol during IA, likely due to a floor effect. Upon protracted abstinence following IA, GW803430 significantly reduced operant alcohol SA and this was associated with adaptations in MCH and MCH1-R gene-expression. In contrast, GW803430 did not affect escalated alcohol SA induced by chronic alcohol vapor exposure and this was accompanied by no change in MCH or MCH1-R gene expression. Overall, these results suggest that the MCH1-R antagonist affects alcohol-intake through regulation of both motivation for caloric-intake and the rewarding properties of alcohol.In conclusion, our results suggest critical roles for these central neuropeptides in the regulation of anxiety and of alcohol reward, making them potential pharmacological targets in the treatment of AUD.
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| 5. |
- Björnsson, Bergthor, et al.
(författare)
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Digital twins to personalize medicine
- 2020
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 12:1
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Forskningsöversikt (refereegranskat)abstract
- Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.
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| 6. |
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| 7. |
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| 8. |
- Morin, Maxim, et al.
(författare)
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Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 17218-
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Tidskriftsartikel (refereegranskat)abstract
- Skin is easily accessible for transdermal drug delivery and also attractive for biomarker sampling. These applications are strongly influenced by hydration where elevated hydration generally leads to increased skin permeability. Thus, favorable transdermal delivery and extraction conditions can be easily obtained by exploiting elevated skin hydration. Here, we provide a detailed in vivo and in vitro investigation of the skin hydration dynamics using three techniques based on electrical impedance spectroscopy. Good correlation between in vivo and in vitro results is demonstrated, which implies that simple but realistic in vitro models can be used for further studies related to skin hydration (e.g., cosmetic testing). Importantly, the results show that hydration proceeds in two stages. Firstly, hydration between 5 and 10 min results in a drastic skin impedance change, which is interpreted as filling of superficial voids in skin with conducting electrolyte solution. Secondly, a subtle impedance change is observed over time, which is interpreted as leveling of the water gradient across skin leading to structural relaxation/changes of the macromolecular skin barrier components. With respect to transdermal drug delivery and extraction of biomarkers; 1 h of hydration is suggested to result in beneficial and stable conditions in terms of high skin permeability and extraction efficiency.
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| 9. |
- Iredahl, Fredrik, 1988-
(författare)
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Assessment of microvascular and metabolic responses in the skin
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The general aim of this project was to develop experimental in vivo models that allow for minimally invasive investigations of responses in the skin to microvascular and metabolic provocations. The cutaneous microvasculature has emerged as a valuable model and been proposed to mirror the microcirculation in other organs. Dysfunction in the cutaneous microcirculation has thus been linked to systemic diseases such as hypertension and diabetes mellitus. Models for investigating skin responses could facilitate the understanding of pathophysiological mechanisms as well as effects of drugs.In the first study, three optical measurement techniques (laser Doppler flowmetry (LDF), laser speckle contrast imaging (LSCI) and tissue viability imaging (TiVi)) were compared against each other and showed differences in their ability to detect microvascular responses to provocations in the skin. TiVi was found more sensitive for measurement of noradrenaline-induced vasoconstriction, while LSCI was more sensitive for measurement of vascular occlusion. In the second study, microvascular responses in the skin to iontophoresis of vasoactive drugs were found to depend on the drug delivery protocol. Perfusion half-life was defined and used to describe the decay in the microvascular response to a drug after iontophoresis. In the third study, the role of nitric oxide (NO) was assessed during iontophoresis of insulin. The results showed a NO-dependent vasodilation in the skin by insulin. In the fourth study the vasoactive and metabolic effects of insulin were studied after both local and endogenous administration. Local delivery of insulin increased skin blood flow, paralleled by increased skin concentrations of interstitial pyruvate and lactate, although no change in glucose concentration was observed. An oral glucose load resulted in an increased insulin concentration in the skin paralleled by an increase in blood flow, as measured using the microdialysis urea clearance technique, although no changes in perfusion was measured by LSCI.The thesis concludes that when studying skin microvascular responses, the choice of measurement technique and the drug delivery protocol has an impact on the measurement results, and should therefore be carefully considered. The thesis also concludes that insulin has metabolic and vasodilatory effects in the skin both when administered locally and as an endogenous response to an oral glucose load. The vasodilatory effect of insulin in the skin is mediated by nitric oxide.
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| 10. |
- Tjäderborn, Micaela, 1983-
(författare)
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Psychoactive prescription drug use disorders, misuse and abuse : Pharmacoepidemiological aspects
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: There is a widespread and increasing use of psychoactive prescription drugs, such as opioid analgesics, anxiolytics, hypnotics and anti-epileptics, but their use is associated with a risk of drug use disorder, misuse and abuse. Today, these are globally recognized and emerging public health concerns.Aim: The aim of this thesis is to estimate the prevalence of psychoactive prescription drug (PPD) use disorders, misuse and abuse, and to investigate the association with some potential risk factors.Methods: A study using register data from forensic cause of death investigations investigated and described cases of fatal unintentional intoxication with tramadol (Study I). Based on register data on spontaneously reported adverse drug reactions (ADRs) reported cases of tramadol dependence were investigated and summarised (Study II). In a study in suspected drug-impaired drivers with a toxicology analysis confirming the intake of one out of five pre-specified PPDs, the prevalence of non-prescribed use was assessed and associated factors were investigated (Study III). From a cohort of patients initiating prescribed treatment with pregabalin, using data on prescription fills, a study investigated longitudinal utilisation patterns during five years with regards to use of the drug above the maximum approved daily dose (MAD), and factors associated with the utilisation patterns (Study IV).Results: In the first study, 17 cases of unintentional intoxications were identified, of which more concerned men, the median age was 44 years and the majority used multiple psychoactive substances (alcohol, illicit drugs and prescription drugs). The second study identified 104 spontaneously reported cases of tramadol dependence, in which more concerned women, the median age was 45 years, and a third reported a history of substance abuse and 40% of past psychoactive medication use. In the third study, more than half of the individuals suspected of drug-impaired driving used the drug without a recent prescription. Non prescribed use was most frequent in users of benzodiazepines and tramadol, and was more likely in younger individuals and in multiple-substance users. In the last paper five longitudinal utilisation patterns were found in pregabalin users, with two patterns associated with a particularly high risk of doses above the maximum approved dosing recommendation. This pattern of use was associated with male sex, younger age, non-urban residency and a recent prescribed treatment with an antiepileptic or opioid analgesic drug.Conclusions: This thesis shows that psychoactive prescription drug use disorders, misuse and abuse occur and may have serious and even fatal consequences. The prevalence varies between different drugs and populations. Abuse and misuse seem to be more common in young people. Fatal intoxications and misuse of prescribed drugs may be more common in men, while drug use disorders following prescribed treatment may be more common in women and non-prescribed use equally distributed between women and men. Individuals with a history of mental illness, substance use disorder or abuse, or of past use of psychoactive medications are likely important risk groups. In summary, the findings suggest a potential for improvements in the utilisation of psychoactive prescription drugs. The results may be useful in the planning of clinical and regulatory preventive interventions to promote the rational, individualised and safe use of such drugs.
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