β-Adrenoceptor mediated responses in rat pulmonary artery: putative role of TASK-1 related K channels

The effect of isoprenaline on tone, cyclic adenosine 3′:5′ monophosphate (cAMP), and smooth muscle membrane potential (E _m ) were assessed in rat isolated pulmonary arteries. N^ω-nitro-L-arginine methyl ester (10.0 μM) or removal of endothelium partially inhibited relaxant responses to isoprenaline, but glibenclamide (10.0 μM) and indomethacin (10.0 μM) did not. While Rp-8-Br-cAMP (30.0 μM), tetraethylammonium (0.3 & 1.0 mM), 4-aminopyridine (100 μM), anandamide (10.0 μM), charybdotoxin (0.1 μM), ouabain (100 μM), and barium chloride (100 μM), incompletely blocked relaxation to isoprenaline, cyclopiazonic acid (1.0 μM), apamin (3.0 μM) and zinc acetate (300 μM) were without effect. Increasing extracellular K⁺ ([K⁺]_e) inhibited relaxant responses to isoprenaline, completely abolishing the response at 30 mM [K+]_e. Vasorelaxant effects of isoprenaline were significantly attenuated in buffer pH 6.4, and concomitant presence of Rp-8-Br-cAMP (30.0 μM) in pH 6.4 produced significant additive inhibition when compared to pH 6.4 without Rp-8-Br-cAMP. Isoprenaline increased cAMP turnover (1.55±0.24 fold; mean ± SEM), which was inhibited by propranolol (1.0 μM). Resting E _m of smooth muscle cells was -63.0±0.50 mV, and isoprenaline (1.0 μM) produced hyperpolarisation (−73.3±0.80 mV). While glibenclamide failed to affect isoprenaline-induced hyperpolarisation, ICI 118,551 (1.0 μM), anandamide or buffer pH 6.4 prevented it, and barium chloride and oubain combined caused partial inhibition. Isoprenaline-mediated relaxation seems to arise from several processes, including the generation of nitric oxide, the cAMP-cascade and, more importantly, a hyperpolarisation that is not due to activation of ATP-sensitive K channels but possibly of two-pore domain K channels of the TASK family.     

Hepatic disposition of the cytochrome P450 2E1 marker chlorzoxazone and its hydroxylated metabolite in isolated perfused rat livers

The steady-state disposition of chlorzoxazone (CZX) and its hydroxylated metabolite 6-hydroxychlorzoxazone (HCZX) was determined in a single-pass isolated perfused rat liver (IPRL) model using constant CZX concentrations of 10-200 microM. The concentrations of CZX, HCZX, and/or HCZX glucuronide in the perfusate, bile, and liver tissues were measured and kinetic parameters calculated. Upon an increase in CZX inlet concentrations from 10 to 200 microM, its extraction ratio sharply declined from 0.681 to 0.087. This was associated with a saturable formation of HCZX, which was rapidly and completely metabolized to its glucuronide conjugate. Whereas the biliary excretion of CZX was negligible, that of HCZX was substantial (up to 40% of the generated metabolite). Overall, 79-93% of the CZX dose (10-200 microM) was recovered in our model as CZX and HCZX. Additionally, HCZX accounted for 56% (200 microM) to 71% (10 microM) of the extracted CZX dose. Further, a preliminary study using the preformed HCZX showed a complete (100%) recovery of the metabolite as its conjugate. Therefore, the unrecovered portion of CZX dose in our study (7-21% of the administered dose or 29-44% of the extracted dose at inlet CZX concentrations of 10-200 microM) is most likely due to parallel metabolism of CZX to other metabolites.     

Effects of pressure sensitive adhesives and chemical permeation enhancers on the permeability of fentanyl through excised rat skin

Drug-in-adhesive patches (DIAPs) of fentanyl were formulated using various pressure sensitive adhesives (PSAs) and various chemical permeation enhancers (CPEs). The effects of PSAs and CPEs on skin permeation of fentanyl from DIAPs were evaluated using modified jacketed Franz diffusion cells fitted with excised rat abdominal skin. It was demonstrated that the permeation rate or steady state flux (J(ss)) of the drug through the excised rat skin was dependent on the viscosity and type of acrylic PSA as well as the type of CPE. Among different acrylic PSAs, Duro-Tak 2054 and Duro-Tak 2516 showed the highest J(ss) of 1.95 microg cm(-2) h(-1) and the lowest J(ss) of 1.43 microg cm(-2) h(-1), respectively. Among the various CPEs used, propylene glycol and polyethylene glycol 400 showed 1.61 and 1.18, the highest and the lowest enhancement ratios (ER) of the skin permeation of fentanyl, respectively. Oleic acid and cetyl alcohol moderately increased the skin permeation of fentanyl. It was also shown that increasing the concentration of CPE led to reduction in the adhesion property of PSA as measured by the 180 degrees peeling strength test. Moreover, it was found that the permeation rate increased as the fentanyl loading increased from 1 to 3%. The skin permeation rate of fentanyl did not increase significantly beyond 3% drug loading. It was concluded that propylene glycol as a CPE and cosolvent in 10% (m/m) with 3% fentanyl loading in Duro-Tak 2054 showed an effective monolithic DIAP for the development of a transdermal therapeutic system for fentanyl.     

Inhibition of intraocular fibrin formation after infusion of low-molecular-weight heparin during combined phacoemulsification-trabeculectomy surgery

PURPOSE: To evaluate the effect of intraocular infusion of dalteparin, a low-molecular-weight heparin (LMWH) administered in the infusion fluid to prevent early postoperative fibrin formation in combined phacoemulsification-trabeculectomy surgery (phacotrabeculectomy). SETTING: Farabi Eye Hospital, Tehran, Iran. METHODS: Standard combined phacotrabeculectomy was performed prospectively in a masked fashion in 60 eyes; 35 eyes received 5 IU/mL LMWH in the infusate and 25 eyes served as controls. Masked postoperative examinations assessed visual acuity, intraocular pressure (IOP), anterior chamber cell and flare, and fibrin formation with slitlamp examinations 1, 3, 7, 30, and 90 days after surgery. RESULTS: The rate of intraocular fibrin/membrane formation was significantly lower in the LMWH group than in the control group at each follow-up (P<.001, Student t test) . The amount of IOP was lower in LMWH group at each follow up (P<.01, Student t test). Final visual acuity was better in LMWH group (P = .03, Student t test). The frequency of synechia formation was lower in the LMWH group on day 90 (P = .002, chi-square test). CONCLUSIONS: Infusion of dalteparin, a LMWH, may be an effective inhibitor of postoperative fibrin formation in phacotrabeculectomy surgery. It may reduce the frequency of synechia formation and improve visual acuity. It may not be associated with increased risk for intraoperative or postoperative complications at the tested dose. This drug may be a useful adjunct in combined surgery.     

Estimation of pharmacokinetic parameters based on the patient-adjusted population data

Population pharmacokinetic data, adjusted for patient characteristics, are recommended for the design of initial dosage regimens of some therapeutically monitored drugs in patients for whom patient-specific data are not available. However, despite widespread use by clinicians such as pharmacists, a clear understanding of the principles of population pharmacokinetics, including data collection and analysis and its limitations, is often lacking. This article describes the 2 main methods of obtaining population kinetic data, namely the two-stage method and nonlinear mixed effect model, and their applications to the pharmacokinetic-based design of dosage regimens. Additionally, some numerical examples are provided to assist the reader in understanding the material. The author uses these tools in a pharmacokinetics course taught to PharmD students.     

Role of 5-HT(1A) and 5-HT(2) receptors of dorsal and median raphe nucleus in tolerance to morphine analgesia in rats

Several studies indicate that central serotonergic neurons have important role in morphine analgesia and tolerance. The aim of this study was to investigate possible role of 5-HT(1A) and 5-HT(2) receptors in dorsal and median raphe nucleus on development of tolerance to analgesic effect of morphine using hot plate test. Chronic injection of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino]tetralin) (2, 4 and 8 mug/rat/day) to dorsal raphe nucleus (DRN) delayed tolerance to morphine analgesia, whereas injection of the same doses of 8-OH-DPAT to the median raphe nucleus (MRN) did not alter tolerance to morphine. In addition, chronic administration of ketanserin (1.5, 3 and 6 mug/rat/day), as a 5-HT(2) receptors antagonist, in DRN and MRN did not produce any significant effect. We conclude that 5-HT(1A) receptors of DRN are involved in tolerance to antinociceptive effect of morphine. However, the exact mechanism of interaction between serotonergic and opioidergic systems is not clear and remains to be elucidated.     

Metabolism of 8-aminoquinoline antimalarial agents

Some of the most effective antimalarial agents are derivatives of 8-aminoquinoline. The metabolic products of many of these compounds appear to be toxic to the erythrocytes of certain human subjects, especially those deficient in glucose-6-phosphate dehydrogenase. Although a number of studies have been conducted over many years, the metabolism of most of these compounds has not been determined. These studies are reviewed.     

Diagnosis of an Enteric Duplication with Pertechnetate 99mTc Scanning

A case of enteric duplication is reported in which preoperative pertechnetate ^99mTc scanning demonstrated localized uptake in the region of the anatomic abnormality. This test is recommended for use in the evaluation of lower gastrointestinal bleeding in infants and children.     

Optic nerve sheath meningioma: visual improvement during radiation treatment

PURPOSE: To describe four patients with optic nerve sheath meningioma in whom visual improvement began to occur even before completion of a standard course of radiation therapy. DESIGN: Retrospective case review. METHODS: A review was conducted of 35 patients who received stereotactic three-dimensional conformal radiotherapy for optic nerve sheath meningioma from 1990 to 2005. RESULTS: Four patients with radiographic confirmation of optic nerve sheath meningioma were identified who had neuro-ophthalmologic assessment, which included perimetry, either while radiation treatment was underway or immediately afterwards. All of the patients showed improvement in visual acuity and visual fields. CONCLUSION: A rapid response to radiation therapy may occur in some patients with optic nerve sheath meningioma. In such patients, it may be possible to customize the radiation dose by assessing of visual function during the course of therapy.