A simple pharmacokinetics subroutine for modeling double peak phenomenon

Double peak absorption has been described with several orally administered drugs. Numerous reasons have been implicated in causing the double peak. DRUG-KNT--a pharmacokinetic software developed previously for fitting one and two compartment kinetics using the iterative curve stripping method--was modified and a revised subroutine was incorporated to solve double-peak models. This subroutine considers the double peak as two hypothetical doses administered with a time gap. The fitting capability of the presented model was verified using four sets of data showing double peak profiles extracted from the literature (piroxicam, ranitidine, phenazopyridine and talinolol). Visual inspection and statistical diagnostics showed that the present algorithm provided adequate curve fit disregarding the mechanism involved in the emergence of the secondary peaks. Statistical diagnostic parameters (RSS, AIC and R2) generally showed good fitness in the plasma profile prediction by this model. It was concluded that the algorithm presented herein provides adequate predicted curves in cases of the double peak phenomenon.     

Mebudipine and dibudipine protect PC12 cells against oxygen–glucose deprivation and glutamate-induced cell death

The protective effect of two new L-type calcium-channel blockers, mebudipine and dibudipine on neurotoxic effects induced by glutamate and oxygen–glucose deprivation (OGD) in PC12 cells was investigated. PC12 cells were intoxicated with two different methods. First, the cells were incubated with glutamate (10 μM/L), glutamate and mebudipine (10 μM/L), dibudipine (10 μM/L) or nimodipine (10 μM/L), on three different treatment schedules (concurrently, pre-3 h and pre-24 h). In the second method PC12 cells were exposed to in vitro oxygen–glucose deprivation for 30 min and 60 min alone or with the drugs in the same time schedules described above. Cellular viability was assessed by MTT assay. Glutamate-induced cell death and OGD-induced cell injury were attenuated significantly by mebudipine, dibudipine in comparison with nimodipine in all three different treatment schedules. Application of MK801 (10 μM/L), an antagonist of NMDA glutamate receptors inhibited PC12 cell death in both methods. Our study suggests that mebudipine and dibudipine, like nimodipine, may have protective effects against glutamate and oxygen–glucose deprivation-induced neurotoxicity.     

Prediction of the Human EP1 Receptor Binding Site by Homology Modeling and Molecular Dynamics Simulation

The prostanoid receptor EP1 is a G-protein-coupled receptor (GPCR) known to be involved in a variety of pathological disorders such as pain, fever and inflammation. These receptors are important drug targets, but design of subtype specific agonists and antagonists has been partially hampered by the absence of three-dimensional structures for these receptors. To understand the molecular interactions of the PGE2, an endogen ligand, with the EP1 receptor, a homology model of the human EP1 receptor (hEP1R) with all connecting loops was constructed from the 2.6 Å resolution crystal structure (PDB code: 1L9H) of bovine rhodopsin. The initial model generated by MODELLER was subjected to molecular dynamics simulation to assess quality of the model. Also, a step by step ligand-supported model refinement was performed, including initial docking of PGE2 and iloprost in the putative binding site, followed by several rounds of energy minimizations and molecular dynamics simulations. Docking studies were performed for PGE2 and some other related compounds in the active site of the final hEP1 receptor model. The docking enabled us to identify key molecular interactions supported by the mutagenesis data. Also, the correlation of r²=0.81 was observed between the Ki values and the docking scores of 15 prostanoid compounds. The results obtained in this study may provide new insights toward understanding the active site conformation of the hEP1 receptor and can be used for the structure-based design of novel specific ligands.     

The life and work of Abu ul-Ala Shirazi (d. 1001): a Persian pioneer in the treatment of malaria, in the style of Rhazes (865-925)

Abu ul-Ala Shirazi, who lived around the 10th century at the Court of Amir Azud ul-Duleh Bueieh (902-951) from the Dailami Dynasty, found that arsenic, known as sam-al-far, could cure malaria. A clinical trial dating from the 10th century demonstrates Abu ul-Ala's intelligence and careful clinical observation, in the tradition of Rhazes' practice based on experimentation and clinical trial.     

Single Tc99m Sestamibi injection,double acquisition gated SPECT after stress and during low-dose dobutamine infusion: a new suggested protocol for evaluation of myocardial perfusion

Background The ability of low dose dobutamine (LDD) has been established in exploiting the reserved contractility of ischemic myocardium. This study was designed to assess the value of a new protocol, with an additional stress imaging during LDD infusion instead of the rest images, for evaluation of coronary artery disease (CAD) and perfusion reversibility. Methods A total of 51 patients (42 men, 9 women; 57.2 ± 11.3 years) were included in the study and underwent three sequential steps of imaging; the first step-stress gated SPECT with Tc-99m sestamibi, immediately followed by the second step-gated SPECT during constant infusion of 7.5 μg/kg/min dobutamine and finally the third step-rest phase scan following trinitroglycerine administration in the next day. The findings were interpreted using the images in three sets of display; first vs. second step-single injection-double acquisition gated SPECT before and during LDD (SIDAGS-LDD), first vs. third step-standard stress/rest protocol, and only first step-gated stress-only SPECT. In all cases, the Visual perfusion index of each protocols were calculated by summating the premeditated 5-point scale (5: normal, 4: completely reversible, 3: partially reversible, 2: nontransmural fixed and 1: transmural fixed defects) of 17 standard myocardial segments. The accuracy as well as the correlation and agreement of protocols for detecting perfusion abnormality and corresponding reversibility were statistically analyzed. Results Calculated sensitivity, specificity, positive predictive value, negative predictive value and accuracy regarding the presence of CAD in both SIDAGS-LDD and standard protocols were 90.9% (40/44), 71.4% (5/7), 95.2% (40/42), 55.6% (5/9) and 88.2% (45/51), respectively. The extent and localization of perfusion abnormality with the new protocol were correlated well with standard method. The estimation of reversibility, however, was considerably improved by SIDAGS-LDD, especially in those with history of previous myocardial infarction (MI). Conclusion Our proposed protocol demonstrates good correlation and agreement with standard method and even is superior in some cases especially for estimation of viability after MI. Regarding no need for the rest phase radiotracer injection and imaging, this protocol can be more convenient (except the need for close monitoring of the patient during LDD infusion), less time-consuming, less expensive and moreover with less radiation burden to the patients and personnel.     

Apoptotic pathway induced by noscapine in human myelogenous leukemic cells

It has been shown that noscapine, an opium-derived phthalideisoquinoline alkaloid that is currently being used as an oral antitussive drug, induces apoptosis in myeloid leukemia cells. The molecular mechanism responsible for the anticancer effects of noscapine is poorly understood. In the current study, the apoptotic effects of noscapine on two myeloid cell lines, apoptosis-proficient HL60 cells and apoptosis-resistant K562 cells, were analyzed. An increase in the activity of caspase-2, -3, -6, -8 and -9, poly(ADP ribose) polymerase cleavage, detection of phosphatidylserine on the outer layer of the cell membrane, nucleation of chromatin, and DNA fragmentation suggested the induction of apoptosis. Noscapine increased the Bax/Bcl-2 ratio with a significant decrease of Bcl-2 expression accompanied with Bcl-2 phosphorylation. Using an inhibitory approach, the activation of the caspase cascade involved in the noscapine-induced apoptosis was analyzed. We observed no inhibitory effect of the caspase-8 inhibitor on caspase-9 activity. In view of these results and taking into consideration that K562 cells are Fas-null, we suggested that caspase-8 is activated in a Fas-independent manner downstream of caspase-9. In conclusion, noscapine can induce apoptosis in both apoptosis-proficient and apoptosis-resistant leukemic cells, and it can be a novel candidate in the treatment of hematological malignancies.     

McCune-Albright syndrome associated with acromegaly and bipolar affective disorder

McCune-Albright syndrome is a rare disorder caused by an activating mutation in the gene (GNAS1) encoding the subunit of the G protein. This syndrome is characterized by polyostotic fibrous dysplasia, café-au-lait pigmentation, and multiple endocrine hyperfunction. A 29-year-old male with polyostotic fibrous dysplasia, café-au-lait pigmentations, and pituitary adenoma is presented in this report. The patient had accompanying bipolar affective disorder, which might have been caused by the underlying genetic abnormality.     

Diabetes-induced changes in the contractility of the aorta and pA2 of nifedipine in the rat

Diabetes-induced changes in the calcium influx and contractile responses of aortic rings to various drugs were investigated in streptozotocin-treated rats. Diabetes is associated with calcium influx into the aortic rings (1.5-and 2.5-fold, respectively, after either KCl or noradrenaline stimulation compared with normal). The maximum KCl-induced contraction of the arorta in diabetic rats was reduced by 38%, but the EC₅₀ of KCl remained unchanged. The pA₂ of nifedipine for inhibiting the contractile response of aorta to KCl decreased one order of magnitude in the diabetic rats (8.26 vs 9.03 for non-diabetic rats). It is concluded that diabetes reduces the sensitivity of aortic tissue to nifedipine and may affect the stimulation-contraction coupling of vascular smooth muscle in such a way that a higher influx of calcium results after stimulation and that this may be responsible for diabetes-induced vascular complications.     

Atypical beta-adrenoceptors of rat thoracic aorta.

The possible existence of atypical beta-adrenoceptors in vascular smooth muscle of rat isolated thoracic aorta was investigated. Isoprenaline (10(-8)-10(-4) M) produced concentration-dependent relaxation of phenylephrine (10(-5) M) precontracted rings of endothelium-denuded rat aorta in vitro. Isoprenaline-induced relaxation was resistant to blockade by atenolol (10(-6) M). But, propranolol (2 x 10(-7) M) caused a non-competitive inhibition and SR 59230A (6.6 x 10(-6) M), a beta3-adrenoceptor selective antagonist, failed to produce additional antagonism in presence of propranolol. BRL 37344 (10(-8)-10(-4) M), a beta3-selective agonist, did not relax ring segments precontracted with phenylephrine (10(-5) M) in the absence of endothelium. The non-conventional partial agonist (-)-cyanopindolol (5 x 10(-6)-10(-4) M) induced a marked relaxation in phenylephrine (10(-5)M) precontracted aortic rings without endothelium. This vasodilation was resistant to blockade by propranolol (2 x 10(-7) M) and SR 59230A (10(-5) M). Salbutamol (10(-8)-10(-4) M) produced concentration-dependent relaxation in isolated endothelium-denuded aortic rings precontracted with phenylephrine (10(-5) M). Propranolol (2 x 10(-7) M), but not atenolol (10(-6) M), inhibited this relaxant response. It is concluded that in endothelium-denuded thoracic aorta, salbutamol acts through beta2-adrenoceptors whereas isoprenaline seems to activate both beta2-adrenoceptors and an atypical beta-adrenergic receptor. This atypical beta-adrenoceptor is distinct from putative beta3-adrenoceptor and maybe resembles the reported fourth cardiac beta-adrenoceptor.