| 1. |
- Fredholm, BB, et al.
(författare)
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Consequences of eliminating adenosine A(1) receptors in mice
- 2003
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Ingår i: Drug Development Research (Proceedings of the Seventh International Symposium on Adenosine and Adenine Nucleotides - Part 1). - : Wiley. - 1098-2299 .- 0272-4391. ; 58, s. 350-
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Konferensbidrag (refereegranskat)abstract
- The second coding exon of the adenosine A, receptor gene was eliminated by homologous recombination. The phenotype of mice (mixed C57B6/129OlaHsd background) was studied, using siblings from matings of heterozygous mice. Among the offspring the ratio between+/+, +/-and -/-animals was 1:2:1. Over the first half-year-at least-growth and viability were the same in all genotypes. Binding of A(1) ligands was eliminated in-/-mice and halved in+/-mice. Blood pressure was increased in-/-mice and this was paralleled by an increase in plasma renin. Heart rate was unaffected, as was contractility. Furthermore, the response of the perfused heart to ischemia was similar in+/+and -/-hearts. However, remote preconditioning was eliminated in-/-mouse hearts. Tubuloglomerular feedback in the kidney was also lost in-/-mice. The analgesic response to a non-selective adenosing receptor agonist was lost in-/-mice, which also showed hyperalgesia in the tail-flick test. There was a slight hypoactivity in-/-mice, but responses to caffeine were essentially normal. The inhibition of excitatory neurotransmission in hippocampus by adenosine was lost in-/-mice and reduced in+/-mice. Responses to ATP were affected similarly. Hypoxic depression of synaptic transmission was essentially eliminated in hippocampus and hypoxic decrease in spinal respiratory neuron firing was markedly reduced. These results show that adenosine A, receptors play a physiologically important role in the kidney, spinal cord, and hippocampus and that they are critically important in the adaptive responses to hypoxia. (C) 2003 Wiley-Liss, Inc.
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| 2. |
- Fälker, Knut, et al.
(författare)
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Targeting Platelet G Protein-Coupled Receptors for Antithrombotic Therapy
- 2013
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Ingår i: Drug development research (Print). - : Wiley. - 0272-4391 .- 1098-2299. ; 74:7, s. 440-449
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Tidskriftsartikel (refereegranskat)abstract
- Platelets are small anucleated cells produced by bone marrow megakaryocytes that circulate in the blood as sentinels of vascular integrity. They play a pivotal role in the regulation of vascular homeostasis through adhesion to the injured vessel wall, aggregation, propagation of coagulation, and thrombus formation. Furthermore, platelets are also involved in fibrinolysis and the repair of the blood vessel wall, restoring blood flow and vascular integrity. Under pathophysiological conditions such as atherosclerosis, inappropriate platelet aggregation and clot formation can cause vascular occlusions, resulting in myocardial infarctions or stroke that, according to the World Health Organization, represent with more than 10% of worldwide death a major health risk (http://who.int/mediacentre/factsheets/fs310/en/). Over the last several decades, increasing efforts have been made to elucidate the cellular components, signaling pathways, and risk factors contributing to platelet activation with the main goal of providing a sound basis for the development of antiplatelet drugs and novel therapeutic treatment strategies. The family of seven transmembrane receptors, also designated G protein-coupled receptors (GPCRs), represented by approximately 800 members identified in the human genome represent the largest class of receptors and, hence, the richest source of targets for drug discovery. Here, we here provide an overview of the commonly applied therapies targeting platelet-GPCRs as well as a brief summary of novel approaches.
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| 3. |
- Graf, Fabrice, et al.
(författare)
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Inhibiting conjugation as a tool in the fight against antibiotic resistance
- 2019
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Ingår i: Drug Development Research. - : Wiley. - 0272-4391 .- 1098-2299. ; 80:1, s. 19-23
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 Wiley Periodicals, Inc. (Table presented.). Antibiotic resistance, especially in gram-negative bacteria, is spreading globally and rapidly. Development of new antibiotics lags behind; therefore, novel approaches to the problem of antibiotic resistance are sorely needed and this commentary highlights one relatively unexplored target for drug development: conjugation. Conjugation is a common mechanism of horizontal gene transfer in bacteria that is instrumental in the spread of antibiotic resistance among bacteria. Most resistance genes are found on mobile genetic elements and primarily spread by conjugation. Furthermore, conjugative elements can act as a reservoir to maintain antibiotic resistance in the bacterial population even in the absence of antibiotic selection. Thus, conjugation can spread antibiotic resistance quickly between bacteria of the microbiome and pathogens when selective pressure (antibiotics) is introduced. Potential drug targets include the plasmid-encoded conjugation system and the host-encoded proteins important for conjugation. Ideally, a conjugation inhibitor will be used alongside antibiotics to prevent the spread of resistance to or within pathogens while not acting as a growth inhibitor itself. Inhibiting conjugation will be an important addition to our arsenal of strategies to combat the antibiotic resistance crisis, allowing us to extend the usefulness of antibiotics.
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| 4. |
- Kanders, Sofia H., et al.
(författare)
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A pharmacogenetic risk score for the evaluation of major depression severity under treatment with antidepressants
- 2020
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Ingår i: Drug development research. - : John Wiley & Sons. - 0272-4391 .- 1098-2299. ; 81:1, s. 102-113
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Tidskriftsartikel (refereegranskat)abstract
- The severity of symptoms as well as efficacy of antidepressants in major depressive disorder (MDD) is modified by single nucleotide polymorphisms (SNPs) in different genes, which may contribute in an additive or synergistic fashion. We aimed to investigate depression severity in participants with MDD under treatment with antidepressants in relation to the combinatory effect of selected genetic variants combined using a genetic risk score (GRS). The sample included 150 MDD patients on regular AD therapy from the population‐based Swiss PsyCoLaus cohort. We investigated 44 SNPs previously associated with antidepressant response by ranking them with regard to their association to the Center for Epidemiologic Studies Short Depression Scale (CES‐D) score using random forest. The three top scoring SNPs (rs12248560, rs878567, rs17710780) were subsequently combined into an unweighted GRS, which was included in linear and logistic regression models using the CES‐D score, occurrence of a major depressive episode (MDE) during follow‐up and regular antidepressant treatment during the 6 months preceding follow‐up assessment as outcomes. The GRS was associated with MDE occurrence (p = .02) and ln CES‐D score (p = .001). The HTR1A rs878567 variant was associated with ln CES‐D after adjustment for demographic and clinical variables [p = .02, lower scores for minor allele (G) carriers]. Additionally, rs12248560 (CYP2C19 ) CC homozygotes showed a six‐fold higher likelihood of regular AD therapy at follow‐up compared to minor allele homozygotes [TT; ultrarapid metabolizers (p = .03)]. Our study suggests that the cumulative consideration of pharmacogenetic risk variants more reliably reflects the impact of the genetic background on depression severity than individual SNPs.
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| 5. |
- Lindhagen, Elin, et al.
(författare)
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Pharmacodynamic differences between species exemplified by the novel anticancer agent CHS 828
- 2004
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Ingår i: Drug development research. - : Wiley. - 0272-4391 .- 1098-2299. ; 61:4, s. 218-226
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Tidskriftsartikel (refereegranskat)abstract
- When a candidate drug enters clinical trials, decisions regarding dosing are mainly based on animal data. Occasionally, toxicity problems are faced in the clinic because of unexpected species differences in pharmacokinetics or pharmacodynamics between humans and preclinical species. Fludarabine and topotecan are examples of such drugs. In the first clinical trials of the new agent CHS 828, the maximum tolerated dose was reached earlier than expected from animal data. This paper discusses the issue of species differences in the development of anticancer drugs, and preclinical models for detection and quantification of such differences. Pharmacokinetic and hematological toxicity data of CHS 828 from studies in rats and humans are presented. In vitro sensitivity to CHS 828 and some established cytotoxic agents was measured in lymphocytes from humans and rats and in a panel of human and rodent cell-lines. 10–100 times higher CHS 828 exposure was tolerated by rats than by patients. In both in vitro cell systems, CHS 828 showed higher potency in human cells compared to rodent cells. A species difference was evident also for fludarabine, but not for doxorubicin and cisplatin. CHS 828 pharmacokinetics were similar across species. In conclusion, the lower tolerance of CHS 828 in humans than in rats could be detected in vitro in cultures of peripheral lymphocytes. Preclinical studies of species differences could help the interpretation of in vivo effect studies as well as the choice of starting dose for clinical trials. We suggest peripheral lymphocytes from different species as a potential model system for such studies.
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| 6. |
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| 7. |
- Marshall, Garland R, et al.
(författare)
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Limiting Assumptions in the Design of Peptidomimetics
- 2017
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Ingår i: Drug development research. - : Wiley. - 0272-4391 .- 1098-2299. ; 78:6, s. 245-267
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Forskningsöversikt (refereegranskat)abstract
- Limiting the flexibility of organic compounds to enhance their affinity and selectivity for targeting a macromolecule involved in molecular recognition has become a well-developed paradigm in medicinal chemistry. While the role of reverse-turn motifs as peptidomimetics has received the most attention, β-sheets and helices are also important motifs for protein/protein interactions. The more complicated problem of mimicking the interacting surface of noncontiguous epitopes will not be considered in this review. This limited overview focuses on efforts to use amino acid synthons as secondary-structure mimetics as well as providing examples of peptidomimetic design focused on nonpeptide synthetic chemistry in contrast. In particular, the rationale of optimal design criteria for mimicry and the many naïve violations of those criteria made in its pursuit are emphasized.
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| 8. |
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| 9. |
- Svennebring, Andreas
(författare)
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The connection Between Plasma Protein Binding and Acute Toxicity as Determined by the LD50 Value
- 2016
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Ingår i: Drug development research. - : Wiley. - 0272-4391 .- 1098-2299. ; 77:1, s. 3-11
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Tidskriftsartikel (refereegranskat)abstract
- A dataset of three drug classes (acids, bases, and neutrals) with LD50 values in mice was analysed to investigate a possible connection between high plasma protein binding and acute toxicity. Initially, it was found that high plasma protein binding was associated with toxicity for acids and neutrals, but after compensating for differences in lipophilicity, plasma protein binding was found not to be associated with toxicity. The therapeutic index established by the quotient between mouse LD50 and the defined daily dose was unaffected by both lipophilicity and plasma protein binding.
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| 10. |
- Svennebring, Andreas
(författare)
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Visualization of Plasma and Tissue Binding Using Dose Fractions Parameter
- 2014
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Ingår i: Drug development research. - : Wiley. - 0272-4391 .- 1098-2299. ; 75:7, s. 425-437
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Tidskriftsartikel (refereegranskat)abstract
- A novel concept of dose fractions, based on the distribution of total bioavailable dose between the six combinations of location and binding state in Oie-Tozer's model is suggested as a way to visualize the distribution pharmacokinetics of a drug. The concept of dose fractions provides a sharper terminology in discussions of drug distribution allowing for a more precise description of the state and location of a drug within a system. In medicinal chemistry literature, the free fraction of a drug in plasma is a commonly discussed factor affecting the exposure to free drug while tissue binding is less well addressed. The free dose fraction, defined as the fraction of the bioavailable dose existing in free form, is suggested as a potentially valuable term for such discussions. Presently, drugs with high (>95%) plasma protein binding are viewed with skepticism, the rational behind which is questioned. The plasma protein bound dose fraction defined as the fraction of the total available dose, which is bound to plasma proteins, is suggested as a measure of the risk for problems related to fluctuations in free drug exposure due to variations in the concentration of drug binding plasma protein.
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| 11. |
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| 12. |
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| 13. |
- Wihlborg, Anna-Karin, et al.
(författare)
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2,2 '-nitrophenylisatogen potentiates P2X(1) receptor mediated vascular contraction and blood pressure elevation
- 2003
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Ingår i: Drug Development Research (Proceedings of the Seventh International Symposium on Adenosine and Adenine Nucleotides - Part 2). - : Wiley. - 1098-2299 .- 0272-4391. ; 59:1, s. 82-87
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Konferensbidrag (refereegranskat)abstract
- The objective of this research was to examine the effects of chemical compounds with possible P2 receptor modulating effects and to characterize the potentiating effects of 2,2'-nitrophenylisatogen (NPI) on P2X(1) receptors in vitro and in vivo. Chemical compounds were tested in an in vitro pharmacological assay using vascular segments from the rat mesenteric artery stimulated by P2 receptor-specific agonists. Contractions were expressed as a percentage of 60 mM K+-induced contractions. Blood pressure was evaluated in pithed rats. NPI (30 muM) added 15 min before addition of the P2X(1) receptor-specific agonist alphabeta-MeATP increased the maximum vasoconstriction from 23% to 49% (an increase of 113%). Furthermore, NPI prevented the desensitization of repeated UP-MeATP contractions. Related compounds were examined, and 2-(3-methoxy-phenyl)-1-oxy-indol-3-one (MPI) had similar effects as NPI, but several others lacked effect. NPI had no effect on ADPbetaS (P2Y(1)) or acetylcholine-mediated vasodilatation, nor on UTP (P2Y(2/4)), UDP (P2Y(6)), or noradrenaline-mediated contractions. In pithed rats, the blood pressure response to 50 nmol/kg-infusion of alphabeta-MeATP was increased from 50+/-6 to 63+/-5 mmHg (P < 0.05), but had no effect on basal blood pressure or on the cardiovascular response to preganglionic nerve stimulation. In conclusion, NPI and MPI potentiates P2X(1) receptor vascular contractions in vitro and (NPI) blood pressure effects in vivo. It is possible that the effect is mediated by an inhibition of P2X(1) receptor desensitization. Drug Dev. Res. (C) Wiley-Liss, Inc.
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| 14. |
- Yousif, MHM, et al.
(författare)
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A pharmacological study of bronchodilator properties of NKH477, forskolin, and beta-agonists on guinea pig and ovine isolated bronchioles
- 2000
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Ingår i: Drug development research (Print). - 0272-4391 .- 1098-2299. ; 51:3, s. 169-176
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Tidskriftsartikel (refereegranskat)abstract
- In this study we assessed the relaxant responses of two direct adenylate cyclase activators, NKH477 and forskolin, in comparison with two beta -adrenoceptor agonists, salbutamol and isoprenaline. The possible potentiation effect of NKH477 and forskolin on beta -agonist-induced bronchodilatation was examined. The effectiveness of NKH477 and forskolin in reversing tachyphylaxis development to salbutamol or isoprenaline was also investigated. We tested the in vitro bronchodilator effect of salbutamol, NKH477, and forskolin (10(-9)-10(-4) M) On isolated guinea pig bronchiolar ring segments precontracted with carbachol (3 muM). Salbutamol, NKH477, and forskolin produced a concentration-dependent relaxation. Potency values (pD(2)) were determined from cumulative concentration-response curves. The rank order for their potencies was salbutamol > NKH477 > forskolin (7.3 +/- 0.3, 6.4 +/- 0.3, and 5.4 +/- 0.1, respectively). The bronchodilator effects of salbutamol, isoprenaline, NKH477, and forskolin (10(-9)-10(-4) M) were examined on isolated ovine bronchioles precontracted with carbachol (0.3 muM). Isoprenaline, NKH477, and forskolin produced a concentration-dependent relaxation with pot values of 6.1 +/- 0.2, 5.4 +/- 0.2, and 5.3 +/- 0.2, respectively. Tachyphylaxis to the relaxant effects of salbutamol on guinea pig isolated bronchioles was experimentally induced and the potency of salbutamol was reduced to 5.9 +/- 0.2 after 24 h incubation with salbutamol (10(-5) M). NKH477 and forskolin (10(-6) M) produced a partial reversal of tachyphylaxis to salbutamol-induced relaxation using salbutamol pretreated tissues. The potency of salbutamol was increased to 6.6 +/- 0.2 and 5.9 +/- 0.2 after incubation with NKH477 or forskolin (10(-6) M), respectively Tachyphylaxis to the relaxant effects of isoprenaline resulted in a reduced potency of 5.7 +/- 0.2. Forskolin (10-6 M) Produced a partial reversal of tachyphylaxis, while NKH477 (10(-6) M) produced a complete reversal of tachyphylaxis to isoprenaline-induced relaxation with an pot value of 6.3 +/- 0.1. In conclusion, the guinea pig and sheep isolated bronchioles serve as good models to study the relaxant effects of the bronchodilator agents salbutamol, isoprenaline, NKH477, and forskolin. The beta -agonists examined had higher potencies than NKH477 or forskolin. However, the two adenylate cyclase activators, with greater effectiveness of NKH477, when used in combination with the beta -agonists, could produce an increase in the potency of the beta -agonists. Furthermore, the effectiveness of NKH477 and forskolin in reversing tachyphylaxis to the bronchodilator effects of the beta -agonists, particularly salbutamol, may provide an advantage in long-term use of beta -agonists in bronchial asthma therapy. Drug Dev. Res. 51:169-176, 2000. (C) 2001 Wiley-Liss, Inc.
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| 15. |
- Yousif, MHM, et al.
(författare)
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NKH477 : A novel bronchodilator produces potentiation and tachyphylaxis reversal to salbutamol in isolated guinea pig trachea
- 1999
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Ingår i: Drug development research (Print). - 0272-4391 .- 1098-2299. ; 48:4, s. 154-159
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Tidskriftsartikel (refereegranskat)abstract
- The relaxant responses of the beta(2)-adrenoceptor agonist salbutamol and NKH477, an activator of adenylate cyclase, were compared and the possible potentiating effect of NKH477 on salbutamol-induced bronchodilatation was measured together with the effectiveness of NKH477 in reversing tachyphylaxis development to salbutamol. The in vitro bronchodilator effect of salbutamol and NKH477 (10(-9) - 10(-5) M) was measured on isolated guinea pig tracheal ring segments precontracted with carbachol (10(-6) M). Both salbutamol and NKH477 produced a concentration-dependent relaxation. EC50 values were determined from cumulative concentration-response curves. Salbutamol was more potent than NKH477 in relaxing the tracheal preparations (7.1 +/- 0.1 compared to 6.1 +/- 0.2, respectively). NKH477 produced a significant increase in the salbutamol-induced bronchodilator effect. The potency values recorded for salbutamol were 7.1 +/- 0.1, 7.4 +/- 0.2, 7.6 +/- 0.1, and 8.6 +/- 0.4 in the absence and presence of NKH477 (3 x 10(-8) M, 10(-7) M, and 3 x 10(-7) M, respectively). Reproducible relaxant responses could be elicited to salbutamol and NKH477 after 24 h incubation in Krebs' solution. Tachyphylaxis to the relaxant effects of salbutamol was experimentally induced by 24-h incubation of the preparations in Krebs' solution containing salbutamol (10(-6), 3 X 10(-6) or 10(-5) M). The potency of salbutamol was reduced to 6.9 +/- 0.2, 6.8 +/- 0.2, and 6.0 +/- 0.2 after 24 h incubation with salbutamol 10(-6) M, 3 X 10(-6) M or 10(-5) M, respectively. NKH477 (3 x 10(-7) M) produced a complete reversal of tachyphylaxis to salbutamol-induced relaxation in salbutamol pretreated tissues. The potency of salbutamol was increased to 7.4 +/- 0.2, 7.1 +/- 0.1, and 7.3 +/- 0.1 after the addition of NKH477 (3 x 10(-7) M) to the preparations preincubated (24 h) with salbutamol 10(-6), 3 X 10(-6), or 10(-5) M, respectively. NKH477 shares with salbutamol the ability to relax airway smooth muscle and produces an apparent increase of the bronchodilator effects of salbutamol and reverses tachyphylaxis. Drug Dev. Res. 48:154-159, 1999. (C) 1999 Wiley-Liss, Inc.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Fredholm, BB, et al.
(författare)
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Adenosine (P1) receptor signalling
- 1996
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Ingår i: DRUG DEVELOPMENT RESEARCH. - 0272-4391. ; 39:3-4, s. 262-268
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Fredholm, BB, et al.
(författare)
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Receptor nomenclature
- 1996
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Ingår i: DRUG DEVELOPMENT RESEARCH. - 0272-4391. ; 39:3-4, s. 461-466
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 24. |
- Liguori, L, et al.
(författare)
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Sperm capacitation in adora1 KO mice
- 2002
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Ingår i: DRUG DEVELOPMENT RESEARCH. - 0272-4391. ; 56:4, s. 572-572
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 25. |
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| 26. |
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| 27. |
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| 28. |
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| 29. |
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