Sildenafil citrate (Viagra)

Sildenafil citrate, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type V (PDE V), initially designated as compound 92-480-10 by Pfizer, was studied in the late 1980s as an antianginal. An unexpected side effect of the early clinical investigations was improved erectile function among the men studied. This serendipitous finding has transformed the field of erectile dysfunction therapy (1-3). The novelty of this compound is its oral route of delivery and efficacy across a broad range of etiologies.     

Sildenafil citrate (Viagra) complexes with bivalent ions

The interaction of Ca(2+)-ions with sildenafil citrate (Viagra) leads to the precipitation of a new polymorph variety of sildenafil base. Under the same conditions, Mg(2+), Zn(2+), and Cd(2+) ions form structurally related crystalline complexes of the composition Me(2+)C(28)H(34)N(6)O(11)S. Lattice parameters have been determined showing that magnesium compound belongs to an orthorhombic system, while the zinc and cadmium compounds are its monoclinic distortions. All three compounds are thermally stable, undergoing decomposition above 175 degrees C with the consequent formation of carbonates Me(2+)CO(3) and oxides.     

Pharmacokinetics of mitoxantrone in patients after 2 h and 24 h intra-arterial administration

The pharmacokinetic parameters of mitoxantrone in patients with liver metastasis after intra-arterial 2 h and 24 h infusion (dosage 12 mg/m2) were investigated. Peak plasma concentrations were 305 +/- 60 ng/ml at 2 h infusion and 244 +/- 89 ng/ml at 24 h infusion. These peak plasma concentrations occurred at 0.9 +/- 0.8 h during 2 h infusion and 5.5 +/- 3.4 h during 24 h infusion. No significant difference between both intra-arterial administrations in elimination half-life (50-223 h at 2 h infusion, 58-246 h at 24 h infusion) and area under the plasma concentration-time curve (AUC0-72 = 11.6 micrograms/ml.h for 2 h infusion, AUC0-72 = 11.2 micrograms/ml.h for 24 h infusion) could be found. The results indicate that no change of availability in the central compartment at infusion of mitoxantrone over a period of 24 h could be achieved. The 2 h infusion lead to sufficient plasma levels with pharmacokinetic parameters of mitoxantrone similar to 24 h infusion and showed a good clinical picture with mild toxicity.     

No effect of route of exposure (oral; subcutaneous injection) on plasma bisphenol A throughout 24h after administration in neonatal female mice

Route of administration of chemicals in adults is an important factor in pharmacokinetics of chemicals such as bisphenol A (BPA), the monomer with estrogenic activity used to make polycarbonate plastic products and to line food and beverage cans. Based on findings in adults it has been proposed (CERHR, 2007) that non-oral routes of administration in newborn rodents would also lead to high exposure relative to oral administration. However, in fetuses and neonates, the enzyme that conjugates BPA (UDP-glucuronosyltransferase) is expressed at low levels, suggesting that there may be no differences in pharmacokinetics between oral and non-oral dosing. We thus conducted an analysis of plasma concentrations of unconjugated ³H-BPA after HPLC separation in postnatal day 3 female mice throughout the 24 h after administering ³H-BPA orally or via subcutaneous injection at doses above and below the current EPA reference dose. We found no significant difference in plasma BPA based on route of administration in neonatal mice at either dose. However, compared to data from other studies conducted with adults, there was a markedly higher plasma BPA level after oral administration of BPA in newborn mice. This finding sets aside the belief that non-oral administration of BPA renders data as not suitable for consideration of the hazard posed by low-dose exposure to BPA during neonatal life. Therefore the large numbers of BPA studies that used non-oral administration at very low doses during the neonatal period should not be dismissed by scientists or the regulatory community based on route of administration.     

Pharmacokinetics of ambenonium chloride in dogs after intravenous and oral administration

Plasma concentrations of ambenonium chloride (Mytélase) were studied, using a high pressure liquid chromatographic technique, in 11 dogs, after intravenous or oral administration of the drug. The results found suggest a complex multi-compartment storage with several periodical releases in general circulation.     

雷公藤甲素在Beagle犬体内毒代动力学研究

目的：探索性研究雷公藤甲素在犬体内的毒代动力学特征,并观察其毒性反应,为雷公藤甲素毒性机制的深入研究提供研究数据.方法：25只Beagle犬随机分为5组,分别为灌胃给药A组（高剂量,0.1 mg/kg）、B组（中剂量,0.08 mg/kg）、C组（低剂量,0.05mg/kg）,静脉给药D组（0.08 mg/kg）和空白对照组E组,连续给药14d,于给药第1、7和14天采集血样或组织样本供毒代动力学研究及毒性检查（血常规、血生化、病理切片）;14 d给药过程中进行临床症状观察.结果：雷公藤甲素给药后第1天和第14天,静注和口服药代参数均有所变化,静注AUC0-从145.86增加到276.24 ng· h·mL-1,CL从548.45降到301.89mL·h^-1·kg^-1;口服高剂量 AUC0-∞从 151.54 增加到289.98 ng·h·mL^-1,Cmax从44.49增加到75.26 ng/mL;口服中剂量AUC0-∞从37.78增加到61.65 ng· h·mL^-1,Cmax从44.49增加到75.26 ng/mL;口服低剂量AUC0-∞从67.92增加到143.98 ng·h·mL^-1,Cmax从24.05增加到38.07 ng/mL.MRT、T1/2延长.毒性观察结果显示,毒性呈剂量和时间相关性,均出现不同程度的胃肠道反应,肝功能受损,白细胞降低等.结论：本文探索性研究了雷公藤甲素在犬体内的毒代动力学的性质,提示胃肠道和肝脏可能是两个主要的毒性靶器官,同时研究发现给药途径对雷公藤甲素的安全性有较大影响.     

Effect of oral ketoconazole on first-pass effect of nifedipine after oral administration in dogs

The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans.     

Metformin induces cardioprotection against ischaemia/reperfusion injury in the rat heart 24 hours after administration

The UK Prospective Diabetes Study demonstrated that the hypoglycaemic drug metformin is associated with a reduction in cardiovascular events in a group of obese type 2 diabetes patients. The energy sensing enzyme AMP-activated protein kinase (AMPK) has been indicated to play an important protective role in the ischaemic heart and is activated by metformin. The aim of this study was to determine whether a single dose of metformin protects the myocardium against experimentally induced ischaemia 24 hr after the administration, and furthermore to determine whether a single dose of metformin results in an acute increase in myocardial AMPK activity. Wistar rats were given either a single oral dose of metformin (250 mg/kg body weight), or a single oral dose of saline. After 24 hr, the hearts were Langendorff-perfused and subjected to 45 min. of coronary artery occlusion. Infarct size was determined by staining with triphenyltetrazoliumchloride (TTC) and Evans Blue and expressed as a percentage of the risk zone (IS/AAR %). Isoform specific AMPK activity was measured 2 hr after administration of metformin or saline. Infarct size was significantly reduced in the metformin treated (I/R: 19.9 +/- 3.9%versus 36.7 +/- 3.6%, P < 0.01, n = 8-14) compared to the control group. A single oral dose of metformin resulted in an approximately ~2-fold increase in AMPK-alpha2 activity 2 hr after administration (P < 0.015, n = 10). In conclusion, a single dose of metformin results in an acute increase in myocardial AMPK activity measured 2 hr after administration and induces a significant reduction in myocardial infarct size 24 hr after metformin administration. Increased AMPK activity may be an important signal mediator involved in the mechanisms behind the cardioprotective effects afforded by metformin.     

Postprandial pancreatic exocrine secretion in dogs after oral administration of pirenzepine dihydrochloride

The effect of orally administered 1,5-dihydroxy-11-(4-methyl-1-piperazinyl)- acetyl-6H-pyrido[2,3-b]-1,4-benzodiazepin-6-one dihydrochloride (pirenzepine dihydrochloride, LS-519 Cl, Gastrozepin) on the postprandial secretion of pancreatic juice and the duodenal pH was studied in conscious dogs. An inhibition of the normal increase of the postprandial pancreatic secretion was observed. A possible indirect role of endogenous secretin and a cholinergic enteropancreatic reflex was discussed.     

Pharmacokinetics of aminolevulinic acid after oral and intravenous administration in dogs.

The purpose of these studies was to examine the pharmacokinetics, oral bioavailability, and systemic side effects of aminolevulinic acid (ALA) in beagle dogs after oral and i.v. administration. Oral and i.v. doses of ALA (128 mg of ALA hydrochloride, equivalent to 100 mg of ALA) were administered to four animals using a crossover design. Animals were allowed a 2-week washout period between doses. Plasma ALA concentrations were determined using precolumn fluorescent derivatization and reversed-phase HPLC. Plasma concentrations after i.v. administration declined rapidly with a terminal half-life of 19.5 +/-2.5 min (mean +/- S.D.). Total body clearance and volume of distribution at steady state averaged 6.79+/-1.77 ml/min/kg and 259+/- 128 ml/kg, respectively. Peak plasma concentrations of ALA after oral administration ranged from 1.27 to 9.42 microgram/ml. Oral bioavailability in these animals averaged 41.2+/-14.8% (range, 23.5-58.5%). These studies demonstrate that oral administration may provide a convenient and efficient route of delivery of ALA for photodynamic therapy in patients.     

Pharmacokinetics of Huperzine A after transdermal and oral administration in beagle dogs

Comparison of single and multiple dose pharmacokinetics between patches and conventional tablets of Huperzine A (Hup-A) was performed in beagle dogs to evaluate the patches' controlled drug release characteristics in vivo, a newly developed transdermal system for treatment of Alzheimer disease. Results showed that transdermal administration of Hup-A prolonged T(max) value (24h vs. 3h, P<0.01), lowered C(max) value (3.4+/-0.2 ng mL(-1) vs. 9.8+/-1.0 ng mL(-1), P<0.01), and produced a relatively constant serum concentration within 84 h after a single transdermal dose of 4 mg/20 cm(2) Hup-A patches. Following application of the patches, Hup-A serum concentrations increased for approximately 12-24h, reaching an average C(max) of 3.4+/-0.2 ng mL(-1). Thereafter, a serum concentration of at least 2.1 ng mL(-1) was maintained for up to 84 h. The serum concentration was maintained within the range of 2.4-4.3 ng mL(-1) during 2-week wearing period after multiple dosing, and the degree of fluctuation at the steady state of td and po administration was significantly different (0.51 vs. 1.99, P<0.01). This study indicates that Hup-A patches exhibited good controlled-release properties in vivo, maintained a relatively constant serum concentration within 3.5 d after wearing, and are suitable for twice-weekly application.     

Excretion and biotransformation of cisapride in dogs and humans after oral administration

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after a single po dose of [14C]cisapride in dogs and humans. The excretion of radioactivity amounted to 97% within 4 days after a 1 mg/kg dose in dogs (72% in feces and 25% in urine). After a 10-mg dose in humans, 44% was excreted in the 0-24-hr urine and 37% in the 0-35-hr feces; excretion was complete within 4 days. Excretion of the parent drug was greater in dogs (0.4-1.3% of the dose in urine, 23% in feces) than in humans (0.2% in urine, 4-6% in feces). This was due, at least in part, to a larger proportion of amine glucuronidation and sulfation in dogs. N-Deal-kylation at the piperidine nitrogen resulting in the main urinary metabolite, norcisapride, and aromatic hydroxylation of the 4-fluorophenyl ring were major metabolic pathways in both species. Norcisapride excretion accounted for 14% of the dose in dogs and 41-45% in humans. Minor metabolic pathways were O-dealkylation at the 4-fluorophenoxy group and piperidine oxidation. Peak plasma levels and AUC values of norcisapride in humans were 8-9 times lower than those of cisapride. Apart from more amine conjugation in dogs, the biotransformation of cisapride was similar in dogs and humans.     

Absolute bioavailability of glimepiride (Amaryl) after oral administration

Twelve healthy fasting male volunteers received a single 1.0 mg dose of glimepiride either as an intravenous injection over one minute or as a tablet. Blood and urine samples were taken before drug administration and afterwards for up to 24 hours (blood) and 48 hours (urine) to determine serum and urinary concentrations of glimepiride and its hydroxy- and carboxy-metabolites (M1 and M2). There were no statistically significant differences between mean serum pharmacokinetic parameters for the oral and intravenous formulations either with glimepiride or M1. Mean urinary recovery of M1 plus M2 was 50% of the dose for the glimepiride tablet and 51% for the intravenous injection. The absolute bioavailability of the tablet formulation was 107% (AUDC(glimepiride)), 109% (AUDC(M1)) and 97% (urinary recovery). The tablet formulation of glimepiride is completely bioavailable and was safe and well tolerated in healthy volunteers.     

Pharmacokinetics of butofilolol (CAFIDE) after repeated oral administration in man

The pharmacokinetics of butofilolol, a new beta-blocking drug, was studied in 6 healthy subjects. Plasma concentrations and urinary excretion of the unchanged drug were determined after a single 100-mg oral administration, and also during chronic treatment (100 mg/day for a week) and after the last dose. Maximum plasma concentrations were observed 2 to 3 h after drug administration and varied between the subjects (120 to 430 ng/ml). The apparent volumes of distribution were large, ranging between 200 I and 500 I, and the apparent clearances of elimination appeared to be intermediate between 40 and 70 l/h. Drug elimination in the urine (about 4% of administered dose) occurred by filtration, tubular secretion and pH-sensitive reabsorption following a non-linear process. However, pharmacokinetic parameters remained constant during chronic treatment, since urinary elimination of the parent drug was too low to influence its pharmacokinetic profile. In addition, a high correlation was found between plasma levels of butofilolol and the effect of the drug on resting heart rate, while a slight effect on diastolic blood pressure could be discerned.     

Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration

Summary Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol levels declined multiphasically with a mean clearance after intravenous administration of 352±40 ml/min. A two-compartment open model appeared to describe the decline adequately. Comparison of the areas under the plasma concentration-time curves (AUC) indicated that oral bioavailability increased from 0.63±0.02 after 500 mg, to 0.89±0.04 and 0.87±0.08 after 1000 mg and 2000 mg, respectively. As a consequence of the incomplete bioavailability of paracetamol, as well as its multicompartmental distribution, accurate estimates of its distribution volume and clearance cannot be obtained if the drug is given orally. However, an estimate of its total plasma clearance may be derived from the AUC after a 500 mg oral dose.     

Startle response during smoking and 24 h after withdrawal predicts successful smoking cessation

RATIONALE: The startle response is thought to reflect changes in attentional processes in humans. The startle response shows a number of forms of plasticity, of which prepulse inhibition (PPI) refers to the attenuation of the startle response to a strong sensory stimulus (pulse), when such a pulse is preceded by a stimulus of lower intensity (prepulse). Recent studies have shown that nicotine modulates startle and PPI of the startle reflex in humans and animals. The present study examined individual differences in cognitive benefits obtained from smoking as indexed by startle response and PPI. OBJECTIVES: We investigated, using a within-subjects design, the effects of cigarette smoking via a comparison of baseline and withdrawal measures of startle and PPI in 18 subjects wishing to quit cigarette smoking. The relapse of five of these subjects enabled a between-group comparison of these measures with the successful quitters. METHODS: Startle and PPI were measured on three separate occasions: before quitting, 24 h after quitting and 1 month after quitting. RESULTS: The presence of a high startle response amplitude while subjects were still engaged in their normal smoking patterns (baseline) and the occurrence of a significant drop of startle amplitude in withdrawal relative to baseline factors were found to be predictive of an individual's ability to quit smoking. Changes in PPI were found to reflect these changes in startle amplitude. CONCLUSIONS: The observed response patterns are discussed in terms of individual differences in commitment to quitting and self-dosing to manipulate attentional mechanisms as measured by the acoustic startle response. Furthermore, it is suggested that these specific response profiles may be predictive of the ability to quit smoking.     

Metabolism and excretion of centbutindole (neuroleptic) in rats after oral administration

The metabolism and excretion of centbutindole was studied in Sprague-Dawley rats after oral administration. The percentage of dose excreted was monitored over 4 days. Efforts were also directed towards evaluating the stability of centbutindole in various in-vitro biomatrices. Centbutindole was found to be metabolised in rats and only a negligible amount of parent drug was excreted. The percentage of the dose excreted in bile and faeces was 0.2% and 0.6%, respectively. No drug was found in urine after oral administration, but after an intravenous dose only 0.0012% of the dose was eliminated through urine. Two metabolites, dealkylated metabolite and hydroxy metabolite, were identified by ion spray LC/MS/MS, using a combination of parent ion and product ion scanning techniques. The major routes of metabolism of centbutindole include reduction of the carbonyl functional group in the butyrophenone side chain and N-dealkylation of the butyrophenone side chain attached to the pyrazinopyridoindole ring nitrogen at position 2. The hydroxy metabolite was excreted negligibly in bile, although it was present in the form of glucuronide conjugates more in comparison to its free form.     

常规12导心电图与24h动态心电图对起搏器植入术后患者心律失常的诊断比较

目的 对比常规12导心电图与24 h动态心电图(DCG)诊断起搏器植入患者心律失常检出率的差异。方法 选取2011年3月到2014年3月于我院就诊的永久性起搏器置入术后患者共50例,患者均同时采用常规12导心电图和24 h DCG监测和诊断,比较其心律失常阳性检出率差异。结果 24 h DCG检出心律失常患者50例,其检出率为100.0%,常规12导心电图检出心律失常患者22例,检出率为44.0%,检出差异有统计学意义(P <0.05)。24 h DCG在心房早搏、室性早搏等检出率明显高于常规12导心电图,差异有统计学意义(P <0.05)。结论 24 h DCG诊断起搏器植入患者心血管事件心律失常的敏感性和特异性均优于常规12导心电图,能为永久性起搏器植入术后临床随访提供准确的依据。