Differences In Pharmacological Properties Research Articles

Insights into β3-adrenoceptor agonism through comprehensive in silico investigation

Research onβ3-AR, the new member of the adrenoceptor family, is in its infancy and few β3-AR agonists have been approved for marketing to date. Meanwhile, β3-AR exhibited obvious species differences in pharmacological properties, such as between human and animals, however, the 3D structure of human β3-AR has not been published, which makes it difficult to understand the interaction between human β3-AR and its agonists. Herein, binding patterns of β3-AR agonists are explored starting from the Alphafold predicted structural model, and the obtained model was optimized by using molecular dynamics simulations. Moreover, the human β3-AR and its agonists were subjected to molecular docking, dynamics simulations, binding free energy calculations and pharmacophore modeling to elucidate the characteristics of human β3-AR activity pockets and agonist conformational relationships, including a hydrophobic group, a positively charged group as well as two hydrogen-bonded donors, which provide comprehensive insights into the interactions between human β3-AR and its agonists.

Stoichiometry-Selective Antagonism of α4β2 Nicotinic Acetylcholine Receptors by Fluoroquinolone Antibiotics.

Quinolone antibiotics disrupt bacterial DNA synthesis by interacting with DNA gyrase and topoisomerase IV. However, in addition, they have been shown to act as inhibitors of pentameric ligand-gated ion channels such as GABAA receptors and the α7 nicotinic acetylcholine receptor (nAChR). In the present study, we have examined the effects of quinolone antibiotics on the human α4β2 nAChR, an important subtype that is widely expressed in the central nervous system. A key feature of α4β2 nAChRs is their ability to coassemble into two distinct stoichiometries, (α4)2(β2)3 and (α4)3(β2)2, which results in differing affinities for acetylcholine. The effects of nine quinolone antibiotics were examined on both stoichiometries of the α4β2 receptor by two-electrode voltage-clamp recording. All compounds exhibited significant inhibition of α4β2 nAChRs. However, all of the fluoroquinolone antibiotics examined (ciprofloxacin, enoxacin, enrofloxacin, difloxacin, norfloxacin, pefloxacin, and sparfloxacin) were significantly more potent inhibitors of (α4)2(β2)3 nAChRs than of (α4)3(β2)2 nAChRs. This stoichiometry-selective effect was most pronounced with pefloxacin, which inhibited (α4)2(β2)3 nAChRs with an IC50 of 26.4 ± 3.4 μM but displayed no significant inhibition of (α4)3(β2)2 nAChRs. In contrast, two nonfluorinated quinolone antibiotics (cinoxacin and oxolinic acid) exhibited no selectivity in their inhibition of the two stoichiometries of α4β2. Computational docking studies suggest that pefloxacin interacts selectively with an allosteric transmembrane site at the β2(+)/β2(−) subunit interface, which is consistent with its selective inhibition of (α4)2(β2)3. These findings concerning the antagonist effects of fluoroquinolones provide further evidence that differences in the subunit stoichiometry of heteromeric nAChRs can result in substantial differences in pharmacological properties.

Beta-Adrenergic Blockers’ Supportive and Adverse Role in Hypertension: A Review of Three Generations

ABSTRACT Hypertension causes significant mortality and morbidity around the world. The β-adrenergic blockers are one of the most commonly prescribed hypertension medications. Several β-adrenergic blockers with different pharmacological qualities have been developed, which may be grouped into three generations based on the differences in pharmacological properties. In this narrative review, we addressed evidence-based literature about the role of various types of β-blockers and related adverse drug reactions (ADRs) in hypertension. PubMed, Scopus, Google Scholar, and MEDLINE are used for articles search. The title was examined first, followed by the abstract, and then the entire study. We concluded that the first-generation β-blockers are non-selective and used as antihypertensive however, not recommended for diabetic, asthmatic, and chronic obstructive pulmonary disease patients. The second-generation β-blockers are β1 receptor-selective which are the effective pharmacological option for the treatment of hypertension, with a lower risk of adverse effects associated with antagonism of β2-receptor. Third-generation β-blockers showed improved effects on patients as compared to the previous two generations. This class of β-blockers (labetalol, carvedilol, and nebivolol) has vasodilatory abilities and has an extra beneficial influence with fewer ADRs. However, the effectiveness and benefit of β-blockers as first‐line therapy for hypertension is still controversial. As a result, further accurate screenings, as well as large randomized control clinical trials (RCTs), are needed to investigate the role of all β-blockers in hypertension. Keywords: Hypertension; Beta-Adrenergic Blockers; Blood Pressure; Literature Review.

GABAA Receptors Expressed in Oligodendrocytes Cultured from the Neonatal Rat Contain α3 and γ1 Subunits and Present Differential Functional and Pharmacological Properties.

Oligodendrocytes (OLs) express functional GABAA receptors (GABAARs) that are activated by GABA released at synaptic contacts with axons or by ambient GABA in extrasynaptic domains. In both instances, the receptors' molecular identity has not been fully defined. Furthermore, data on their structural diversity in different brain regions and information on age-dependent changes in their molecular composition are scant. This lack of knowledge has delayed access to a better understanding of the role of GABAergic signaling between neurons and OLs. Here, we used functional, and pharmacological analyses, as well as gene and protein expression of GABAAR subunits, to explore the subunit combination that could explain the receptor functional profile expressed in OLs from the neonate rat. We found that GABAAR composed of α3β2γ1 subunits mimicked the characteristics of the endogenous receptor when expressed heterologously in Xenopus laevis oocytes. Either α3 or γ1 subunit silencing by small interfering RNA transfection changed the GABA-response characteristics in oligodendrocyte precursor cells, indicating their participation in the endogenous receptor conformation. Thus, α3 subunit silencing shifted the mean EC50 for GABA from 75.1 to 46.6 µM, whereas γ1 silencing reduced the current amplitude response by 55%. We also observed that β-carbolines differentially enhance GABA responses in oligodendroglia as compared with those in neurons. These results contribute to defining the molecular and pharmacological properties of GABAARs in OLs. Additionally, the identification of β-carbolines as selective enhancers of GABAARs in OLs may help to study the role of GABAergic signaling during myelination. SIGNIFICANCE STATEMENT: GABAergic signaling through GABAA receptors (GABAARs) expressed in the oligodendroglial lineage contributes to the myelination control. Determining the molecular identity and the pharmacology of these receptors is essential to define their specific roles in myelination. Using GABAAR subunit expression and silencing, we identified that the GABAAR subunit combination α3β2γ1 conforms the bulk of GABAARs in oligodendrocytes from rat neonates. Furthermore, we found that these receptors have differential pharmacological properties that allow specific positive modulation by β-carbolines.

Interaction of Lovastatin with Model Membranes by NMR Data and from MD Simulations

Lovastatin is a drug of the statin group which possesses the ability to decrease low-density lipoprotein cholesterol level by the competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. There is a hypothesis that pharmacological features of statins depend on their location in cell membrane, but to the present day, there is a lack of information in literature on interactions of statins with the surface of the cell membrane in liquid media. Intermolecular complex of lovastatin with dodecylphosphocholine (DPC) and sodium dodecylsulfate (SDS) micelles was investigated by NMR and computational methods. The results of NMR experiments and molecular dynamics (MD) simulation data showed that lovastatin forms intermolecular complexes with models of cell membranes in water solution. Locations of lovastatin on model membranes were established by NOESY NMR data. Distinctions in their positions can explain differences in pharmacological properties of studied compound.

Movement Disorders Associated With Antipsychotic Medication in People With Schizophrenia: An Overview of Cochrane Reviews and Meta-Analysis.

Movement disorders associated with antipsychotic medications are relatively common, stigmatising, and potentially disabling. Their prevalence in people with psychosis who are prescribed second-generation antipsychotics (SGAs) is uncertain, as is their level of recognition by clinicinas. We conducted meta-analyses of randomised controlled trials included in the Cochrane Database of Systematic Reviews on schizophrenia and schizophrenia-like psychoses to estimate the prevalence of new-onset dystonia, akathisia, parkinsonism, and tremor with SGAs (amisulpride, asenapine, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, L-sulpiride, and ziprasidone) approved in Canada and the UK, comparing them with haloperidol and chlorpromazine. We used a random effects model because of the heterogeneity between-studies in drug dosage and method of ascertainment of movement disorders. Our systematic search yielded 37 Cochrane systematic reviews (28 for SGAs), which generated 316 informative randomised controlled trials (243 for SGAs). With respect to SGAs, prevalence estimates ranged from 1.4% (quetiapine) to 15.3% (L-sulpiride) for dystonia, 3.3% (paliperidone) to 16.4% (L-sulpiride) for akathisia, 2.4% (asenapine) to 29.3% (L-sulpiride) for parkinsonism, and 0.2% (clozapine) to 28.2% (L-sulpiride) for tremor. Prevalence estimates were not influenced by treatment duration, the use of a flexible or fixed dosing scheme, or whether studies used validated instruments for the screening/rating of movement disorders. Overall, we found high overlap on the prevalence of new-onset movement disorders across different SGAs precribed for established psychoses. Variations in prevalence figures across antipsychotic medications were observed for the different movement disorders. Differences in pharmacological properties, such as for the dopamine D2 R association rate and serotonin 5-HT2A antagonism, could contribute to this variation.

Neurophysiological effects in cortico-basal ganglia-thalamic circuits of antidyskinetic treatment with 5-HT1A receptor biased agonists

Recently, the biased and highly selective 5-HT1A agonists, NLX-112, F13714 and F15599, have been shown to alleviate dyskinesia in rodent and primate models of Parkinson's disease, while marginally interfering with antiparkinsonian effects of levodopa. To provide more detailed information on the processes underlying the alleviation of dyskinesia, we have here investigated changes in the spectral contents of local field potentials in cortico-basal ganglia-thalamic circuits following treatment with this novel group of 5-HT1A agonists or the prototypical agonist, 8-OH-DPAT. Dyskinetic symptoms were consistently associated with 80 Hz oscillations, which were efficaciously suppressed by all 5-HT1A agonists and reappeared upon co-administration of the antagonist, WAY100635. At the same time, the peak-frequency of fast 130 Hz gamma oscillations and their cross-frequency coupling to low-frequency delta oscillations were modified to a different extent by each of the 5-HT1A agonists. These findings suggest that the common antidyskinetic effects of these drugs may be chiefly attributable to a reversal of the brain state characterized by 80 Hz gamma oscillations, whereas the differential effects on fast gamma oscillations may reflect differences in pharmacological properties that might be of potential relevance for non-motor symptoms.

Chlorido and bromido oxaliplatin analogues as potential agents for CRC treatment: Solution behavior, protein binding and cytotoxicity evaluation

Despite the widespread use of platinum drugs in the treatment of colorectal cancer (CRC), due to the heavy side effects and to intrinsic or acquired Pt resistance, new and more efficient drugs are urgently needed. Starting from the encouraging results obtained for the complex PtI2(DACH), we summarise here our recent advances, reporting data on the synthesis and the chemical and biological features of two oxaliplatin analogues i.e. PtBr2(DACH) and PtCl2(DACH). The comparative approach of these studies reveals how these analogues possess interesting and differential pharmacological properties as well as some peculiar features that may be conveniently exploited to shed light in the mechanistic aspects involved in the pharmacological action of the parent drug oxaliplatin. Furthermore, these findings may inspire the design of more effective Pt-based anticancer drugs to be used in CRC treatment.

Perioperative management and monitoring of antiplatelet agents: a focused review on aspirin and P2Y12 inhibitors.

Platelets play pivotal roles in hemostasis as well as pathological arterial thrombosis. The combination of aspirin and a P2Y12 inhibitor has become the mainstay therapy in the ageing population with cardiovascular conditions, particularly during and after percutaneous coronary intervention. A number of novel P2Y12 inhibitors has become available in the recent years, and they markedly vary in pharmacokinetic and pharmacodynamic properties. Perioperative physicians today face a challenge of preventing hemorrhage due to platelet inhibitors, while minimizing thrombotic risks. There are several point-of-care platelet function tests available in the peri-procedural assessment of residual platelet aggregation. However, these platelet function tests are not standardized in terms of sample processing, agonist type and potency as well as methods of detecting platelet activity. Understanding the differences in pharmacological properties of antiplatelet agents, principles of platelet function tests, and pertinent hemostatic strategies may be useful to anesthesiologists and intensivists who manage perioperative issues associated with antiplatelet agents. The objectives of this review are: 1) to discuss clinical data on aspirin and P2Y12 inhibitors relating to perioperative bleeding, 2) to outline different features of point-of-care platelet function tests, and 3) to discuss therapeutic options for the prevention and treatment of bleeding associated with antiplatelet agents.

Interaction of different statins with model membranes by NMR data

Hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins reduce the amount of low-density lipoprotein (LDL) cholesterol, which is known as a well-established risk factor for atherosclerosis. Despite the fact that statins have a common pharmacologic target essential to sterol biosynthesis, their efficacy, safety, and potential non-LDL actions vary significantly for different statins. There is a hypothesis that pharmacological features of statins depend on their location in cell membrane, but to the present day there is a lack of information in literature on interactions of statins with the surface of the cell membrane in liquid media. The results of NMR experiments showed that all studied statins form intermolecular complexes with models of cell membranes (dodecylphosphocholine micelles) in water solution. Locations of pravastatin, simvastatin, fluvastatin and cerivastatin on model membranes were established by NOESY NMR data. Distinctions in their positions can explain differences in pharmacological properties of studied compounds.

Iodinated benzimidazole PARP radiotracer for evaluating PARP1/2 expression in vitro and in vivo

BackgroundPARP inhibitors (PARPi) have the potential to impact cancer therapy in a selective patient population; however, despite current patient selection methods clinical trials have shown mixed response rates. It is therefore clinically useful to determine which patients will respond prior to receiving PARPi therapy. One essential biomarker is to measure the level of PARP enzyme expression in tumors. Small molecule radiotracers have been developed to accurately quantify PARP-1 expression in vitro and in vivo. [125I]KX-02-019 is the first report of a radioiodinated analogue of the benzimidazole class of PARPi. Herein, we studied the pharmacological properties of [125I]KX-02-019 as well as the in vivo biodistribution. Methods[125I]KX-02-019 was evaluated in both cancer and non-cancer cell lines. We evaluated the pharmacologic properties of [125I]KX-02-019 in live cells by measuring enzyme association and dissociation kinetics, saturation, and specificity. In addition, competitive inhibition experiments were carried out with commercially available PARPi. Protein expression was analyzed by Western blot to compare PARP-1 and PARP-2 expression across cell lines studied. The biodistribution was studied in a mouse EMT6 tumor model at time points of 0.5, 1, 2, 4 and 6h. Results[125I]KX-02-019 showed subtle differences in pharmacological properties in the absence of PARP-2. In addition, [125I]KX-02-019 was competitively displaced by clinical PARPi. In vivo biodistribution studies showed an increasing tumor to muscle ratio over 6h as well as fast clearance from healthy tissues. Conclusion[125I]KX-02-019 has binding sites in both PARP1 KO cells as well as PARP2 KO cells showing higher affinity for PARP-2. This observation is supported by a decrease in binding affinity in PARP2 KO cells compared to PARP1 KO cells. The pharmacologic and biological properties of [125I]KX-02-019 studied in vitro and in vivo showed that this analogue may be useful in determining pharmacokinetic and pharmacodynamic properties of clinical PARPi.

MK-801-induced deficits in social recognition in rats: reversal by aripiprazole, but not olanzapine, risperidone, or cannabidiol.

Deficiencies in social activities are hallmarks of numerous brain disorders. With respect to schizophrenia, social withdrawal belongs to the category of negative symptoms and is associated with deficits in the cognitive domain. Here, we used the N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) for induction of social withdrawal in rats and assessed the efficacy of several atypical antipsychotics with different pharmacological profiles as putative treatment. In addition, we reasoned that the marijuana constituent cannabidiol (CBD) may provide benefit or could be proposed as an adjunct treatment in combination with antipsychotics. Hooded Lister rats were tested in the three-chamber version for social interaction, with an initial novelty phase, followed after 3 min by a short-term recognition memory phase. No drug treatment affected sociability. However, distinct effects on social recognition were revealed. MK-801 reduced social recognition memory at all doses (>0.03 mg/kg). Predosing with aripiprazole dose-dependently (2 or 10 mg/kg) prevented the memory decline, but doses of 0.1 mg/kg risperidone or 1 mg/kg olanzapine did not. Intriguingly, CBD impaired social recognition memory (12 and 30 mg/kg) but did not rescue the MK-801-induced deficits. When CBD was combined with protective doses of aripiprazole (CBD-aripiprazole at 12 : or 5 : 2 mg/kg) the benefit of the antipsychotic was lost. At the same time, activity-related changes in behaviour were excluded as underlying reasons for these pharmacological effects. Collectively, the combined activity of aripiprazole on dopamine D2 and serotonin 5HT1A receptors appears to provide a significant advantage over risperidone and olanzapine with respect to the rescue of cognitive deficits reminiscent of schizophrenia. The differential pharmacological properties of CBD, which are seemingly beneficial in human patients, did not back-translate and rescue the MK-801-induced social memory deficit.

Impact of Antidepressant Drugs on Sexual Function and Satisfaction

Pleasurable sexual activity is important in many human relationships and can provide a sense of physical, emotional and social well-being. Depressive symptoms and depressive illness are associated with impairments in sexual function and sexual dissatisfaction in untreated and treated patients. Most currently available antidepressant drugs are associated with development or worsening of sexual dysfunction in a substantial proportion of patients. Sexual difficulties during antidepressant treatment often resolve as depression lifts, but can persist over long periods, reducing self-esteem and affecting mood and relationships adversely. Sexual difficulties during antidepressant treatment typically have many possible causes but the incidence and nature of dysfunction varies between drugs. Many interventions can be considered when managing sexual dysfunction associated with antidepressants but no approach is 'ideal'. Because treatment-emergent sexual difficulties are less frequent with certain drugs, presumably related to differences in pharmacological properties, and since current interventions are suboptimal, a lower incidence of sexual dysfunction is a relevant tolerability target when developing novel antidepressants.

Differential effects of opioid-related ligands and NSAIDs in nonhuman primate models of acute and inflammatory pain

Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates. The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs). Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception. Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.

Differential Pharmacologic Properties of the Two C75 Enantiomers: (+)‐C75 Is a Strong Anorectic Drug; (−)‐C75 Has Antitumor Activity

C75 is a synthetic compound described as having antitumoral properties. It produces hypophagia and weight loss in rodents, limiting its use in cancer therapy but identifying it as a potential anti-obesity drug. C75 is a fatty acid synthase (FAS) inhibitor and, through its coenzyme A (CoA) derivative, it acts as a carnitine palmitoyltransferase (CPT) 1 inhibitor. Racemic mixtures of C75 have been used in all the previous studies; however, the potential different biological activities of C75 enantiomers have not been examined yet. To address this question we synthesized the two C75 enantiomers separately. Our results showed that (-)-C75 inhibits FAS activity in vitro and has a cytotoxic effect on tumor cell lines, without affecting food consumption. (+)-C75 inhibits CPT1 and its administration produces anorexia, suggesting that central inhibition of CPT1 is essential for the anorectic effect of C75. The differential activity of C75 enantiomers may lead to the development of potential new specific drugs for cancer and obesity.

Nicotine-, tobacco particulate matter- and methamphetamine-produced locomotor sensitisation in rats

Repeated nicotine exposure produces a weak and transient sensitised locomotor response in rats. Since tobacco smoke contains thousands of non-nicotine chemical constituents, these could alter the sensitised response. This study aims to compare the magnitude, persistence and spatial distribution of locomotor sensitisation produced by repeated doses of nicotine, aqueous tobacco particulate matter (TPM) and a positive methamphetamine control. Male Sprague-Dawley rats received five nicotine (0.0, 0.2 or 0.4mg/kg), TPM (containing 0.2 or 0.4mg/kg nicotine) or methamphetamine (0.5mg/kg) injections every second day, followed by a 4-day withdrawal before the first challenge (Challenge 1, C1). The animals were re-challenged again at 15days post C1 to test for the persistence of sensitisation (Challenge 2, C2). There were no major differences in sensitisation profile between nicotine and TPM. At the lowest 0.2mg/kg nicotine/TPM dose, however, small differences emerged on select test days. The results indicated that the non-nicotinic agents in TPM did not greatly impact the nicotine-produced locomotor-sensitised response. These findings might suggest that the differential pharmacological properties of TPM do not have major clinical significance. Alternatively, the locomotor model might not expose effects of non-nicotinic constituents, and furthermore, might not closely relate to human tobacco dependence. Different reward-related behavioural models should also be utilised to assess potential effects of non-nicotinic constituents before a role in dependence is discounted.

Lack of Response of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) to Decitabine After Failure of Azacitidine

AbstractAbstract 3858 Background:Standard therapy for high-risk MDS consists of one of two FDA-approved demethylating agents, azacitidine or decitabine. AML patients considered unfit for intensive chemotherapy are also frequently treated with one of these agents, both of which have activity in AML and an acceptable toxicity profile. These agents are not considered curative, and responses are of variable duration. When azacitidine or decitabine is not effective, or is no longer effective, few options are available. In view of differences in pharmacological properties between these two agents, it is not uncommon to switch demethylating agents after failure of initial demethylating agent therapy. To date, only two small studies have addressed the outcome of this intervention, with conflicting results. In a study of 14 MDS patients treated with decitabine following failure of, or progression on, azacitidine, 4 patients (28%) responded (Borthakur et al, Leuk Lymph 2008), while a subgroup analysis of 10 evaluable patients treated with decitabine following azacitidine failure demonstrated no complete or partial responses (Prebet et al, J Clin Oncol 2011). Here we report outcomes in a retrospective analysis of 22 MDS and AML patients who received decitabine after azacitidine. Methods:Charts of 22 MDS or AML patients who were evaluated at the University of Maryland Greenebaum Cancer Center between January 1, 2008 and March 31, 2012 and who received decitabine after azacitidine were reviewed. Results:Patient and disease characteristics for 13 MDS patients and 9 AML patients are shown in Table 1. All patients were initially treated with azacitidine before being switched to decitabine following lack of response to initial therapy or disease progression after initial response. Five of 9 AML patients received azacitidine as frontline therapy, while four received it after other induction chemotherapy regimens.Disease responses following azacitidine 75mg/m2 for 5–7 days in 28-day cycles were variable as shown in Table 1. The median number of courses of azacitidine to disease response for MDS and AML patients who responded was 5 (range, 2–10), median disease-free survival (DFS) was 6.1 months (range, 2.3–16), and median number of courses of azacitidine received was 9 (range, 1 to 17). All 22 MDS and AML patients were refractory to, or progressed after, subsequent decitabine therapy after receiving a median of 2 courses (range, 1–6). Conclusions:Our study population represents the largest to date and the first in which AML disease responses to decitabine after failure of azacitidine have been studied. All MDS and AML patients were refractory to decitabine therapy following initial treatment with azacitidine. Thus this approach should generally not be employed. New therapies are needed for patients for whom demethylating agent therapy is, or becomes, ineffective, and these patients should be enrolled on clinical trials whenever possible. [Display omitted] Disclosures:Baer:Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding.

Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination

Drugs containing one or more chiral centres exist in stereoisomeric molecular forms. Most commonly, drugs containing a single asymmetric carbon atom exist in two enantiomeric forms, designated as eutomer (the more potent) and distomer (the less potent). As well as differences in potency and other pharmacodynamic properties, most members of enantiomeric pairs commonly differ also in their pharmacokinetic profiles. This article reviews factors underlying differences in pharmacological properties of enantiomers. The relevance of such differences for studies designed to evaluate the bioequivalence of products containing chiral drugs is also reviewed.

Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo–keto reductase superfamily

Human ketosteroid reductases of the aldo–keto reductase (AKR) superfamily, i.e. AKR1C1–4, are implicated in the biotransformation of synthetic steroid hormones. Norethynodrel (NOR, 17α-ethynyl-17β-hydroxy-estra-5(10)-en-3-one), the progestin component of the first marketed oral contraceptive, is known to undergo rapid and extensive metabolism to 3α- and 3β-hydroxymetabolites. The ability of the four human AKR1C enzymes to catalyze the metabolism of NOR has now been characterized. AKR1C1 and AKR1C2 almost exclusively converted NOR to 3β-hydroxy NOR, while AKR1C3 gave 3β-hydroxy NOR as the main product and AKR1C4 predominantly formed 3α-hydroxy NOR. Individual AKR1C enzymes also displayed distinct kinetic properties in the reaction of NOR. In contrast, norethindrone (NET), the Δ4-isomer of NOR and the most commonly used synthetic progestogen, was not a substrate for the AKR1C enzymes. NOR is also structurally identical to the hormone replacement therapeutic tibolone (TIB), except TIB has a methyl group at the 7α-position. Product profiles and kinetic parameters for the reduction of NOR catalyzed by each individual AKR1C isoform were identical to those for the reduction of TIB catalyzed by the respective isoform. These data suggest that the presence of the 7α-methyl group has a minimal effect on the stereochemical outcome of the reaction and kinetic behavior of each enzyme. Results indicate a role of AKR1C in the hepatic and peripheral metabolism of NOR to 3α- and 3β-hydroxy NOR and provide insights into the differential pharmacological properties of NOR, NET and TIB.

Effects of captopril and angiotensin II receptor blockers (AT1, AT2) on myocardial ischemia–reperfusion induced infarct size

The renin–angiotensin system (RAS) plays a major role in regulating the cardiovascular system, and disorders of the RAS contribute largely to the cardiac pathophysiology, including myocardial ischemia–reperfusion (MI/R) injury. Two subtypes of angiotensin II (Ang II) receptors have been defined on the basis of their differential pharmacological properties. The current study was undertaken to address the question as to whether the inhibition of the angiotensin converting enzyme (ACE) by captopril and the AT1 and AT2 receptor blockers losartan and PD123319 modulate MI/R-induced infarct size in an in vivo rat model.To produce necrosis, a branch of the descending left coronary artery was occluded for 30min followed by two hours of reperfusion. ECG changes, blood pressure, and heart rate were measured during the experiment. Captopril (3mg/kg), losartan (2mg/kg), and PD123319 (20μg/kg/min) were given in an IV 10min before ischemia and were continued during the ischemic period. The infarcted area was measured by TTC staining. The volume of infarct and the risk zone was determined by planimetry.Compared to the control group (55.62±4.00%) both captopril and losartan significantly reduced the myocardial infarct size (30.50±3.26% and 37.75±4.44%), whereas neither PD123319 nor PD123319+losartan affected the infarct size volume (46.50±3.72% and 54.62±2.43%).Our data indicates that captopril and losartan exert cardioprotective activity after an MI/R injury. Also, infarct size reduction by losartan was halted by a blockade of the AT2 receptor. Therefore, the activation of AT2 receptors may be potentially protective and appear to oppose the effects mediated by the AT1 receptors.