| 51. |
- Miller, Frank, et al.
(författare)
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A decision theoretical modeling for Phase III investments and drug licensing
- 2018
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Ingår i: Journal of Biopharmaceutical Statistics. - : Informa UK Limited. - 1054-3406 .- 1520-5711. ; 28:4, s. 698-721
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Tidskriftsartikel (refereegranskat)abstract
- For a new candidate drug to become an approved medicine, several decision points have to be passed. In this article, we focus on two of them: First, based on Phase II data, the commercial sponsor decides to invest (or not) in Phase III. Second, based on the outcome of Phase III, the regulator determines whether the drug should be granted market access. Assuming a population of candidate drugs with a distribution of true efficacy, we optimize the two stakeholders' decisions and study the interdependence between them. The regulator is assumed to seek to optimize the total public health benefit resulting from the efficacy of the drug and a safety penalty. In optimizing the regulatory rules, in terms of minimal required sample size and the Type I error in Phase III, we have to consider how these rules will modify the commercial optimization made by the sponsor. The results indicate that different Type I errors should be used depending on the rarity of the disease.
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| 52. |
- Rao, Komal Umashankar, et al.
(författare)
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A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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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.
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| 53. |
- 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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| 54. |
- 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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| 55. |
- Khoomrung, Sakda, 1978, et al.
(författare)
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Metabolic Profiling and Compound-Class Identification Reveal Alterations in Serum Triglyceride Levels in Mice Immunized with Human Vaccine Adjuvant Alum
- 2020
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3907 .- 1535-3893. ; 19:1, s. 269-278
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Tidskriftsartikel (refereegranskat)abstract
- Alum has been widely used as an adjuvant for human vaccines; however, the impact of Alum on host metabolism remains largely unknown. Herein, we applied mass spectrometry (MS) (liquid chromatography-MS)-based metabolic and lipid profiling to monitor the effects of the Alum adjuvant on mouse serum at 6, 24, 72, and 168 h post-vaccination. We propose a new strategy termed subclass identification and annotation for metabolomics for class-wise identification of untargeted metabolomics data generated from high-resolution MS. Using this approach, we identified and validated the levels of several lipids in mouse serum that were significantly altered following Alum administration. These lipids showed a biphasic response even 168 h after vaccination. The majority of the lipids were triglycerides (TAGs), where TAGs with long-chain unsaturated fatty acids (FAs) decreased at 24 h and TAGs with short-chain FAs decreased at 168 h. To our knowledge, this is the first report on the impact of human vaccine adjuvant Alum on the host metabolome, which may provide new insights into the mechanism of action of Alum. ©
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| 56. |
- Roman, Erika, et al.
(författare)
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Short and prolonged periods of maternal separation and voluntary ethanol intake in male and female ethanol-preferring AA and ethanol-avoiding ANA rats
- 2005
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Ingår i: Alcoholism. - 0145-6008 .- 1530-0277. ; 29:4, s. 591-601
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetic as well as environmental factors can affect the propensity for psychopathology and/or drug dependence. Maternal separation represents an animal experimental model that is useful in studies of effects of early life experiences. The authors have established a protocol for short and prolonged periods of maternal separation to study adult neurochemistry, behavior, and ethanol intake and have previously reported alterations in ethanol intake in Wistar rats and ethanol-preferring rats. The aim of the current study was to more thoroughly study how early life experiences affect an inherited propensity for high and low ethanol intake, respectively, in male and female ethanol-preferring AA (Alko alcohol) and ethanol-avoiding ANA (Alko, Non-Alcohol) rats. METHODS: AA and ANA pups were assigned to one of three different rearing conditions: 15 min (MS15) or 360 min (MS360) of daily maternal separation in litters or normal animal facility rearing (AFR) during postnatal days 1 to 21. In adulthood, voluntary ethanol intake was investigated using the two-bottle free choice paradigm. RESULTS: In male ethanol-preferring AA rats, MS15 resulted in a lower intake and fewer high-preferring animals at 8% and 10% ethanol compared with MS360 rats. The male MS360 rats had a higher ethanol intake at 8% and 10% ethanol in comparison with AFR rats. In contrast, the female AA MS15 and MS360 rats had a lower ethanol intake and a lower preference for the 10% ethanol solution compared with the female AA AFR rats. In male and female ANA rats, no major separation-induced effects were found. CONCLUSIONS: The current results show that genetic inheritance can be affected by environmental manipulations in AA rats with an inherent high ethanol intake. The findings in female ethanol-preferring AA rats give further evidence of a differential outcome of maternal separation in male and female rats, as previously shown.
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| 57. |
- Birnir, Bryndis, et al.
(författare)
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The impact of sub-cellular location and intracellular neuronal proteins on properties of GABA(A) receptors
- 2007
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Ingår i: Current Pharmaceutical Design. - : Bentham Science Publishers Ltd.. - 1381-6128 .- 1873-4286. ; 13:31, s. 3169-3177
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Tidskriftsartikel (refereegranskat)abstract
- Most studies of GABA(A) receptor accessory proteins have focused on trafficking, clustering and phosphorylation state of the channel-forming subunits and as a result a number of proteins and mechanisms have been identified that can influence the GABA(A) channel expression and function in the cell plasma membrane. In the light of a growing list of intracellular and transmembrane neuronal proteins shown to affect the fate, function and pharmacology of the GABA(A) receptors in neurons, the concept of what constitutes the native GABA(A) receptor complex may need to be re-examined. It is perhaps more appropriate to consider the associated proteins or some of them to be parts of the receptor channel complex in the capacity of ancillary proteins. Here we highlight some of the effects the intracellular environment has on the GABA-activated channel function and pharmacology. The studies demonstrate the need for co-expression of accessory proteins with the GABA(A) channel-forming subunits in heterologous expression systems in order to obtain the full repertoire of GABA(A) receptors characteristics recorded in the native neuronal environment. Further studies e.g. on gene-modified animal models are needed for most of the accessory proteins to establish their significance in normal physiology and in pathophysiology of neurological and psychiatric diseases. The challenge remains to elucidate the effects that the accessory proteins and processes (e.g. phosphorylation) plus the sub-cellular location have on the "fine-tuning" of the functional and pharmacological properties of the GABA(A) receptor channels.
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| 58. |
- Eghbali, M, et al.
(författare)
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Hippocampal GABA(A) channel conductance increased by diazepam
- 1997
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 388:6637, s. 71-75
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Tidskriftsartikel (refereegranskat)abstract
- Benzodiazepines, which are widely used clinically for relief of anxiety and for sedation, are thought to enhance synaptic inhibition in the central nervous system by increasing the open probability of chloride channels activated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Here we show that the benzodiazepine diazepam can also increase the conductance of GABAA channels activated by low concentrations of GABA (0.5 or 5 microM) in rat cultured hippocampal neurons. Before exposure to diazepam, chloride channels activated by GABA had conductances of 8 to 53pS. Diazepam caused a concentration-dependent and reversible increase in the conductance of these channels towards a maximum conductance of 70-80 pS and the effect was as great as 7-fold in channels of lowest initial conductance. Increasing the conductance of GABAA channels tonically activated by low ambient concentrations of GABA in the extracellular environment may be an important way in which these drugs depress excitation in the central nervous system. That any drug has such a large effect on single channel conductance has not been reported previously and has implications for models of channel structure and conductance.
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| 59. |
- Lindquist, Catarina, et al.
(författare)
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Extrasynaptic GABA(A) channels activated by THIP are modulated by diazepam in CA1 pyramidal neurons in the rat brain hippocampal slice
- 2003
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Ingår i: Molecular and Cellular Neuroscience. - 1044-7431 .- 1095-9327. ; 24:1, s. 250-257
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Tidskriftsartikel (refereegranskat)abstract
- Single-channel currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cell-attached patches on CA1 pyramidal neurons in the rat hippocampal slice preparation. THIP activated GABA(A) channels after a delay that was concentration-dependent and decreased by 1 muM diazepam. The currents showed outward rectification. Channels activated at depolarized 40 mV relative to the chloride reversal potential had low conductance (<40 pS) but the conductance increased with time, resulting in high-conductance channels (>40 pS). The average maximal-channel conductances for 2 and 100 muM THIP were 59 and 62 pS (-Vp = 40 mV), respectively, whereas in 2 muM THIP plus 1 muM diazepam, it was 71 pS. The results show that in hippocampal neurons THIP activates channels with characteristics similar to those of channels activated by low concentrations (0.5-5 AM) of GABA. The increase in the inhibitory conductance with membrane depolarization permits gradation of the shunt pathway relative to the level of the excitatory input. (C) 2003 Elsevier Science (USA). All rights reserved.
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| 60. |
- Rask-Andersen, Mathias, et al.
(författare)
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Advances in kinase targeting : current clinical use and clinical trials
- 2014
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Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:11, s. 60-76
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Forskningsöversikt (refereegranskat)abstract
- Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec (R)) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.
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