Selective intraperitoneal biochemical modulation of methotrexate by dipyridamole.

1989 ◽  
Vol 7 (2) ◽  
pp. 262-269 ◽  
Author(s):  
R Goel ◽  
S M Cleary ◽  
C Horton ◽  
F M Balis ◽  
S Zimm ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Intraperitoneal Administration ◽  
Biochemical Modulation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Drug Concentrations ◽  
The Mean ◽  
Chemical Peritonitis ◽  
Selective Increase ◽  
Dose Limiting Toxicity

Dipyridamole increases the toxicity of methotrexate in a concentration-dependent manner. We hypothesized that concurrent intraperitoneal administration of both drugs would result in high peritoneal concentrations with much lower plasma concentrations, permitting a selective increase in the activity of methotrexate against intraperitoneal tumors without enhancing systemic toxicity. Initially, 2.16 mg/m2/d methotrexate and 12 mg/m2/d dipyridamole were delivered together as a constant intraperitoneal infusion for 48 hours. With escalation of chemotherapy, eventually 4.32 mg/m2/d methotrexate was administered for 168 hours. Forty-seven courses were administered to 18 patients. The mean peritoneal to plasma concentration ratios of methotrexate and non-protein bound dipyridamole were 71.6 +/- 34.8 and over 2,300, respectively. Chemical peritonitis was the dose-limiting toxicity. Three patients had some evidence of a response (two with decreasing tumor markers, and the third with a reduction in ascites). We conclude that the drug concentrations are in an appropriate range for selective intraperitoneal biochemical modulation of methotrexate, and that it is feasible to expose tumors confined to the peritoneal cavity to these drugs for long periods of time.

Effect of Intravenous Anesthetics on Inward Rectifier Potassium Current in Rat and Human Ventricular Myocytes 

1997 ◽  
Vol 87 (2) ◽  
pp. 327-334 ◽  
Author(s):  
Cynthia A. Carnes ◽  
William Muir ◽  
David R. Van Wagoner
Keyword(s):  
Potassium Current ◽  
Ventricular Myocytes ◽  
Plasma Concentrations ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Pipette Solution ◽  
Rat Ventricular Myocytes ◽  
Ventricular Cells ◽  
Drug Concentrations

Background Inhibition of the inward rectifying potassium current (I(K1)) may cause cardiac dysrhythmias by decreasing resting membrane potential or prolonging action potential. Methods The effects of thiopental, ketamine, and propofol on I(K1) conductance were evaluated in rat ventricular myocytes. The effect of thiopental on I(K1) conductance was also evaluated in human ventricular myocytes. Currents were recorded using the nystatin-perforated whole-cell patch-clamp technique (holding potential, -50 mV; test potentials, -140 to -40 mV). Pipette solution contained 130 mM KCl, 5 mM MgCl2, 5 mM HEPES, and 5 mM EGTA,pH 7.2. Bath solution (32 degrees C) contained 134 mM NaCI, 4 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 0.3 mM CdCl2, 5 mM HEPES, and 5 mM d-glucose,pH 7.4. Drug concentrations examined encompassed the range of clinically relevant unbound plasma concentrations. Currents were normalized for cell capacitance. Conductance was calculated as current density/delta mV from -140 to -100 mV. Analysis of variance was used to test for changes in conductance as a function of drug concentration. Results Thiopental reduced I(K1) conductance in a concentration-dependent manner (P < 0.0001). Thiopental-induced changes in I(K1) conductance in rat ventricular myocytes were fit to an inhibitory E(max) model, with a median inhibitory concentration of 10.5 microM. The effect of thiopental on I(K1) conductance in human ventricular cells was comparable to that observed in rat ventricular myocytes. Neither ketamine nor propofol altered I(K1) conductance. Conclusions Thiopental reduces I(K1) conductance in a concentration-dependent manner at clinically relevant concentrations in both rat and human ventricular myocytes.

scholarly journals Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes
Keyword(s):  
Steady State ◽  
High Performance ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

scholarly journals Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

2001 ◽  
Vol 45 (2) ◽  
pp. 382-392 ◽  
Author(s):  
Zeruesenay Desta ◽  
Nadia V. Soukhova ◽  
David A. Flockhart
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Cost Effective ◽  
Competitive Inhibitor ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Specific Substrate ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
The Mean

ABSTRACT Isoniazid (INH) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH on the activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at its Km value with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 μM INH (∼6.86 μg/ml), the activities of these isoforms decreased by ∼40%. INH did not show significant inhibition (<10% at 50 μM) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (Ki values) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The meanKi values (± standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 ± 6.2 and 13 ± 2.4 μM, respectively. INH showed potent noncompetitive inhibition of CYP3A (Ki = 51.8 ± 2.5 to 75.9 ± 7.8 μM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (Ki = 110 ± 33 μM) and a competitive inhibitor of CYP2D6 (Ki = 126 ± 23 μM), but the mean Ki values for the inhibition of CYP2C9 and CYP1A2 were above 500 μM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylators of INH may be at greater risk for adverse drug interactions, as the degree of inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact.

The Role of β2-Glycoprotein I in the Clearance of Platelet Microvesicles.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 145-145
Author(s):  
Hanan Abdel-Monem ◽  
Swapan Kumar Dasgupta ◽  
Anhquyen Le ◽  
Anthony Prakasam ◽  
Perumal Thiagarajan
Keyword(s):  
Plasma Proteins ◽  
Plasma Concentrations ◽  
Major Protein ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Anionic Phospholipid ◽  
Concentration Dependent Manner ◽  
Glycoprotein I

Abstract Abstract 145 The physiological function of β2-glycoprotein I is unclear and several studies suggest a role in the clearance of anionic phospholipid containing membranes. Anionic phospholipid containing liposomes are cleared rapidly from the circulation by the reticuloendothelial cells. In rats, uptake of liposomes by Kupffer cells requires that the liposomes bind to plasma proteins. In mice, the clearance of liposomes from the circulation is related to their ability to interact with plasma proteins. β2-glycoprotein I was identified as a major protein associated with rapid clearance of liposomes and pretreating the mice with antiβ2- glycoprotein I antibodies was found to significantly increase the half-life of the liposome. In vitro, β2-glycoprotein I was also shown to promote the phagocytosis of phosphatidylserine containing liposomes and apoptotic tumor cells. In conditions associated with increased microvesicles generation such as disseminated intravascular coagulation, plasma levels of β;2-glycoprotein I was reduced presumably due to its consumption. Antibodies to β2 glycoprotein I are frequently seen in patients with systemic lupus erythematosus and at times, in otherwise normal individuals. A subset of these antibodies prevents the assembly of the prothrombinase and the tenase complexes on phospholipid membrane, leading to the lupus anticoagulant effect. The presence of these antibodies is clinically very significant, as individuals harboring these antibodies are at risk for thromboembolic manifestations. We studied the role of β-glycoprotein I in the clearance of procoagulant platelet microvesicles and the effect of the auto antibodies in the phagocytosis of platelet microvesicles. We labeled β2-glycoprotein I with BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene)-hydrazide and β2-glycoprotein I incorporated 1.8 mole of BODIPY /mole. Labeling of β2-glycoprotein I with BODIPY did not change the binding efficacy of β2-glycoprotein I to cardiolipin as determined by Elisa assay. Binding of BODIPY-β2-glycoprotein I to platelet microvesicles was analyzed by flow cytometry. BODIPY- β2-glycoprotein I bound to phosphatidylserine-expressing platelet microvesicles in a concentration-dependent manner. Binding was inhibited by 50 fold molar excess of unlabeled β2-glycoprotein I, annexin A5 and the phosphatidylserine-binding C1C2 fragment of lactadherin. β2-glycoprotein I also promoted the phagocytosis of platelet microvesicles by THP-1 derived macrophages in vitro at physiological plasma concentrations with a half maximal effect at ∼10 ug/ml. β2-glycoprotein I-mediated phagocytosis was inhibited by annexin V and the C1C2 fragment of lactadherin. Furthermore, immunoaffinity purified β2-glycoprotein I-dependent antiphospholipid antibodies from 5 patients inhibited the phagocytosis in a concentration dependent manner. These studies suggest β2-glycoprotein I binding to phosphatidylserine-expressing procoagulant platelet microvesicles promotes their clearance by macrophages and autoantibodies to β2-glycoprotein I inhibit the process. The predictive value of antiβ-2 glycoprotein I for thrombosis is highly variable but the correlation is stronger in patients with lupus. In lupus, there is impaired clearance of procoagulant apoptotic cells. β2-glycoprotein I may have a significant role in their clearance and antibodies to β2-glycoprotein I may causally related to the thrombosis in these patients by inhibiting the clearance. Disclosures: No relevant conflicts of interest to declare.

Phagocytosis of platelet microvesicles and β2– glycoprotein I

2010 ◽  
Vol 104 (08) ◽  
pp. 335-341 ◽  
Author(s):  
Anhquyen Le ◽  
Anthony Prakasam ◽  
Hanan Abdel-Monem ◽  
Swapan Dasgupta ◽  
Perumal Thiagarajan
Keyword(s):  
Antiphospholipid Syndrome ◽  
Antiphospholipid Antibodies ◽  
Binding Capacity ◽  
Plasma Concentrations ◽  
Physiological Role ◽  
Maximal Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Phospholipid Binding ◽  
Glycoprotein I

SummaryThe majority of the antiphospholipid antibodies, present in patients with antiphospholipid syndrome, are directed against conformational epitopes in β2-glycoprotein I. β2-glycoprotein I is an anionic phospholipid- binding 50-kDa plasma protein whose physiological role is not clear. Here we investigate the role of β2-glycoprotein I in the phagocytosis of phosphatidylserine-expressing platelet microvesicles and the effect of autoantibodies to β2-glycoprotein I on this process. We labelled the glycans of β2-glycoprotein I with BODIPY (4,4-difluoro- 4-bora-3a,4a-diaza-s-indacene)-hydrazide without affecting its phospholipid binding capacity. BODIPY-β2-glycoprotein I bound to platelet microvesicles in a concentration-dependent manner and promoted the phagocytosis of platelet microvesicles by THP-1 derived macrophages in vitro at physiological plasma concentrations with a half maximal effect at ∼10 μg/ml. β2-glycoprotein I-stimulated phagocytosis was inhibited by annexin A5 and the phosphatidylserine-binding C1C2 fragment of lactadherin. Furthermore, immunoaffinity purified β2-glycoprotein I-dependent antiphospholipid antibodies from five patients with antiphospholipid syndrome inhibited the phagocytosis in a concentration- dependent manner. These studies suggest that the binding of β2-glycoprotein I to phosphatidylserine-expressing procoagulant platelet microvesicles may promote their clearance by phagocytosis and autoantibodies to β2-glycoprotein I may inhibit this process to induce a procoagulant state.

Effects of local anesthetics on Na+ channels containing the equine hyperkalemic periodic paralysis mutation

1998 ◽  
Vol 275 (2) ◽  
pp. C389-C400 ◽  
Author(s):  
Rajan L. Sah ◽  
Robert G. Tsushima ◽  
Peter H. Backx
Keyword(s):  
Local Anesthetics ◽  
Time Course ◽  
Slow Component ◽  
Periodic Paralysis ◽  
Dependent Manner ◽  
Wild Type ◽  
Hyperkalemic Periodic Paralysis ◽  
Concentration Dependent Manner ◽  
Drug Concentrations ◽  
Recovery From Inactivation

We examined the ability of local anesthetics to correct altered inactivation properties of rat skeletal muscle Na+channels containing the equine hyperkalemic periodic paralysis (eqHPP) mutation when expressed in Xenopusoocytes. Increased time constants of current decay in eqHPP channels compared with wild-type channels were restored by 1 mM benzocaine but were not altered by lidocaine or mexiletine. Inactivation curves, which were determined by measuring the dependence of the relative peak current amplitude after depolarization to −10 mV on conditioning prepulse voltages, could be shifted in eqHPP channels back toward that observed for wild-type (WT) channels using selected concentrations of benzocaine, lidocaine, and mexiletine. Recovery from inactivation at −80 mV (50-ms conditioning pulse) in eqHPP channels followed a monoexponential time course and was markedly accelerated compared with wild-type channels (τWT= 10.8 ± 0.9 ms; τeqHPP= 2.9 ± 0.4 ms). Benzocaine slowed the time course of recovery (τeqHPP,ben = 9.6 ± 0.4 ms at 1 mM) in a concentration-dependent manner. In contrast, the recovery from inactivation with lidocaine and mexiletine had a fast component (τfast,lid = 3.2 ± 0.2 ms; τfast,mex = 3.1 ± 0.2 ms), which was identical to the recovery in eqHPP channels without drug, and a slow component (τslow,lid = 1,688 ± 180 ms; τslow,mex = 2,323 ± 328 ms). The time constant of the slow component of the recovery from inactivation was independent of the drug concentration, whereas the fraction of current recovering slowly depended on drug concentrations and conditioning pulse durations. Our results show that local anesthetics are generally incapable of fully restoring normal WT behavior in inactivation-deficient eqHPP channels.

Pharmacological Evidence for Two Types of Postsynaptic Glycinergic Receptors on the Mauthner Cell of 52-h-Old Zebrafish Larvae

1997 ◽  
Vol 77 (5) ◽  
pp. 2400-2415 ◽  
Author(s):  
P. Legendre
Keyword(s):  
Relative Proportion ◽  
Relative Weight ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
M Cell ◽  
Open Probability ◽  
Concentration Dependent Manner ◽  
Mauthner Cell ◽  
Zebrafish Larvae ◽  
The Mean

Legendre, P. Pharmacological evidence for two types of postsynaptic glycinergic receptors on the Mauthner cell of 52-h-old zebrafish larvae. J. Neurophysiol. 77: 2400–2415, 1997. The presence of homooligomeric and heterooligomeric glycine receptors (GlyRs) on the Mauthner (M) cell in the isolated medulla of 52-h-old zebrafish larvae was investigated by analysis of the effects of picrotoxin on glycine-gated channels and on glycinergic miniature inhibitory postsynaptic currents (mIPSCs). Two functionally different GlyRs have been previously described on the M cell. The effects of picrotoxin on these two GlyRs were first analyzed by measuring the relative change in their total open probability ( NP o) with picrotoxin concentration. Picrotoxin had no significant effect on the glycine channel with a single conductance level of 40–46 pS. In contrast, picrotoxin application decreased the NP o of the GlyR with multiple subconductance levels. On this GlyR, picrotoxin decreased in a concentration-dependent manner the occurrence of the 80- to 86-pS substate (median inhibiting concentration = 0.89 μM) and had no apparent effect on the 40- to 46-pS opening probability. Opening frequency and the mean open times of the 80- to 88-pS main conductance state were reduced in the presence of 10 μM picrotoxin, but their relative weight remained unchanged. These effects of picrotoxin were not voltage dependent. Picrotoxin also modified 40- to 46-pS kinetics. At 100 μM, picrotoxin evoked voltage-independent flickering during channel openings. Short and long mean open times were significantly decreased, whereas the relative proportion of long mean open times was increased. The medium closed time was decreased, whereas medium burst duration was increased. The burst frequency remained unchanged. Spontaneous glycinergic mIPSCs were recorded in the presence of 1 μM tetrodotoxin + 25 μM bicuculline (holding potential = −50 mV). Application of 10 μM picrotoxin did not change the frequency of the synaptic activity, whereas it decreased the amplitude of large mIPSCs. No effect was observed on the time to peak (0.8 ms) or the mean decay time constant (τd = 7.7 ms). Increasing picrotoxin concentration to 100 μM resulted in a decrease of mIPSC frequency (35.6%), amplitude (39.8%), and τd (from 7.7 to 5 ms). These results suggest that these two functionally different GlyRs correspond to α1 homooligomeric-like and α1/β-heterooligomeric-like GlyRs, and that both are synaptically activated. Variation in the proportions of GlyR subtypes from one synapse to another could partly account for the broad amplitude distribution of mIPSCs recorded from the zebrafish M cell.

Abstract 3218: Pharmacokinetics, Pharmacodynamics, and Safety of an Anti-von Willebrand Factor Therapeutic Aptamer, ARC1779, in Healthy Volunteers

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
James C Gilbert ◽  
Tia DeFeo-Fraulini ◽  
Renta M Hutabarat ◽  
Christopher J Horvath ◽  
Patricia G Merlino ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Platelet Function ◽  
Therapeutic Potential ◽  
Controlled Study ◽  
Terminal Phase ◽  
Dependent Manner ◽  
Double Blind ◽  
Concentration Dependent Manner ◽  
Platelet Receptor ◽  
The Mean

Background: The prominent role played by vWF in arterial thrombogenesis suggests that vWF inhibition may offer an effective adjunct therapy to PCI in ACS patients. ARC1779 is a PEG-conjugated aptamer that blocks platelet activation through inhibition of vWF A1 domain binding to platelet receptor GPIb. Design: This was an ascending-dose, double-blind, placebo-controlled study in 47 healthy volunteers at doses of 0 (placebo, n = 6) or 0.05 to 1.0 mg/kg ARC1779 (n = 41) given via IV push, “slow bolus” IV infusion over 15 minutes, or “slow bolus” followed by 4-hour IV infusion. PK parameters were estimated from plasma ARC1779 concentrations determined with a validated assay. PD effects were measured by an ELISA for free vWF A1 binding sites and by a platelet function analyzer, the PFA-100 ® . PK: The concentration-time profiles for ARC1779 after IV push or slow bolus appeared monophasic, though the terminal phase may not have been fully captured. The C max and AUC values were dose-proportional. The highest exposure was observed after 1.0 mg/kg slow bolus, with mean C max of 21.15 μg/mL and AUC (0-∞) of 80.92 μ g·hr/mL. The mean apparent elimination half-life (t 1/2β ) was ~2 hours and mean residence time (MRT) was ~3 hours. The mean apparent volumes of distribution (V z and V ss ) were ~1/2 of the blood volume, suggesting that ARC1779 distribution is in the central compartment. The mean clearance (CL) values ranged from ~10% to 21% of GRF, suggesting that renal filtration may not be a major mechanism of clearance of ARC1779. PD: Inhibition of vWF A1 binding was achieved in a dose- and concentration-dependent manner, with respective EC 50 and EC 90 values of 0.22 μ g/mL (17 nM) and 1.98 μg/mL (151 nM). Platelet function inhibition (PFA-100 ® closure time) was achieved, with respective EC 50 and EC 90 values of 0.75 μ g/mL (57 nM) and 2.57 μg/mL (196 nM). vWF activity returned in a dose- and concentration-dependent manner. Safety: ARC1779 was generally well tolerated and no bleeding was observed. Adverse events tended to be minor and not dose related. One volunteer had a hypersensitivity reaction to IV push administration, but no such reactions occurred at higher doses given by slow bolus or infusion. Conclusion: The PK, PD and safety profile of ARC1779 supports its therapeutic potential for use in ACS.

Evidence for voltage-dependent Cl− permeability in mouse pancreatic β-cells

1987 ◽  
Vol 7 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Janove Sehlin
Keyword(s):  
Dependent Manner ◽  
Β Cells ◽  
Efflux Rate ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Concentration Dependent Manner ◽  
Cell Plasma ◽  
Voltage Dependent ◽  
The Mean ◽  
Cl Permeability

Microdissected β-cell-rich pancreatic islets from ob/ob-mice were used in studies of transmembrane36Cl− efflux. The mean rate coefficient for36Cl− efflux was stable at 0.158 min−1 during the initial 10 min. Depolarization of the β-cell plasma membrane by acute increases in extracellular K+ (5–130mM) stimulated the36Cl− efflux in a concentration-dependent manner. Glucose-induced (20mM) and K+-induced increases in36Cl− efflux were largely overlapping, but even at 135.9 mM K+, glucose slightly further enhanced the36Cl− efflux rate. The data suggest (1) that pancreatic β-cells are equipped with a voltage-dependent Cl− permeability, (2) that glucose-induced increase in Cl− permeability may, at least partly, be mediated by primary membrane depolarization, and (3) that glucose in addition may activate other mechanisms for β-cell Cl− transport.

Comparison of Plasma Concentrations for Two Amiodarone Products

2002 ◽  
Vol 36 (11) ◽  
pp. 1682-1685 ◽  
Author(s):  
Shari C Sauro ◽  
Douglas D DeCarolis ◽  
Gordon L Pierpont ◽  
Charles C Gornick
Keyword(s):  
Steady State ◽  
Medical Center ◽  
Plasma Concentrations ◽  
Veterans Affairs ◽  
Brand Name ◽  
Drug Concentrations ◽  
Pharmacokinetic Properties ◽  
Before And After ◽  
The Mean ◽  
State Plasma

BACKGROUND: A generic formulation of amiodarone was recently approved by the Food and Drug Administration based on single-dose equivalence data. Because amiodarone has complex pharmacokinetic properties, a narrow therapeutic range, and a significant adverse effect profile, concern about equivalency persists. OBJECTIVE: To compare steady-state plasma concentrations of the brand-name reference product Cordarone with the AB-rated generic formulation, Pacerone, in patients exposed to both products. METHODS: A retrospective analysis was performed at the Minneapolis Veterans Affairs Medical Center on 138 patients who were taking a stable dose of amiodarone before and after an amiodarone generic product substitution. RESULTS: Seventy-seven patients had steady-state plasma concentrations documented for each product at the same dose. The mean steady-state plasma concentrations of amiodarone were not significantly different for Cordarone compared with Pacerone (1.07 ± 0.48 vs. 1.19 ± 0.66 μg/mL, respectively); similarly, the concentrations of the active metabolite (desethylamiodarone) did not differ (0.95 ± 0.30 vs. 0.96 ± 0.49 μg/mL, respectively). However, the variability in plasma drug concentrations between products was increased as compared to variability within each product. CONCLUSIONS: This study indicates that comparable steady-state concentrations can be achieved with a change in formulation from Cordarone to Pacerone. However, individual responses vary, suggesting that monitoring of plasma concentrations is prudent 1–3 months after any change from one product to another.

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