Pilocarpine Disposition and Salivary Flow Responses Following Intravenous Administration to Dogs

Oral doses of pilocarpine increase salivary flow rates in patients afflicted with xerostomia (dry mouth). This study examined the pharmacokinetics of and a pharmacodynamic response (salivation) to intravenous pilocarpine nitrate administration in dogs. Disposition was linear over a dose range of 225–600 µg/kg; plasma concentrations were 10–120 µg/L. Elimination was rapid and generally biphasic, with a terminal elimination half-life of approximately 1.3 hr. The systemic clearance of pilocarpine was high (2.22 ± 0.49 L/kg/hr) and its steady-state volume of distribution (2.30 ± 0.64 L/kg) was comparable to that of many other basic drugs. All doses of pilocarpine induced measurable submaxillary and parotid salivary flow rates which could be maintained constant over time. Cumulative submaxillary saliva flow was linearly related to total pilocarpine dose. Plasma pilocarpine concentration was linearly related to both steady-state and postinfusion submaxillary salivary flow rates.     

Rapid Lymph Accumulation of Polystyrene Nanoparticles Following Pulmonary Administration

Purpose

Pulmonary administration of polymeric nanoparticle drug delivery systems is of great interest for both systemic and local therapies. However, little is understood about the relationship of particle size and pulmonary absorption. We investigated uptake and biodistribution of polystyrene nanoparticles (PN) of 50 nm, 100 nm, 250 nm, and 900 nm diameters in mice following administration to lungs via pharyngeal aspiration.

Methods

The amount of PN in tissues was analyzed by gel permeation chromatography (GPC).

Results

At 1 h, larger diameter PN (250 nm and 900 nm) had the highest total uptake at around 15% of administered dose, whereas the smaller diameter PN (50 nm and 100 nm) had uptake of only 5–6%. However, at 3 h, the 50 nm PN had the highest total uptake at 24.4%. For each size tested, the highest nanoparticle deposition was observed in the lymph nodes (LN) as compared to other tissues accounting for a total of about 35–50% of absorbed nanoparticles.

Conclusion

PN size impacts the rate and extent of uptake from lungs and, further, the extent of LN deposition. The extent of uptake and lymph distribution of the model, non-degradable PN lends potential to pulmonary administered, biodegradable polymeric nanoparticles for delivery of therapeutics to regional lymph nodes.     

Pharmacokinetics of Uridine Following Ocular,Oral and Intravenous Administration in Rabbits

The pyrimidine nucleoside uridine has recently been reported to have a protective effect on cultured human corneal epithelial cells, in an animal model of dry eye and in patients. In this study, we investigate the pharmacokinetic profile of uridine in rabbits, following topical ocular (8 mg/eye), oral (450 mg/kg) and intravenous (100 mg/kg) administration. Blood and urine samples were serially taken, and uridine was measured by high-performance liquid chromatography-tandem mass spectrometry. No symptoms were noted in the animals after uridine treatment. Uridine was not detected in either plasma or urine after topical ocular administration, indicating no systemic exposure to uridine with this treatment route. Following a single intravenous dose, the plasma concentration of uridine showed a bi-exponential decay, with a rapid decline over 10 min, followed by a slow decay with a terminal half-life of 0.36 ± 0.05 h. Clearance and volume of distribution were 1.8 ± 0.6 L/h/kg and 0.58 ± 0.32 L/kg, respectively. The area under the plasma concentration-time curves (AUC) was 59.7 ± 18.2 μg·hr/ml, and urinary excretion up to 12 hr was ~7.7% of the dose. Plasma uridine reached a peak of 25.8 ± 4.1 μg/ml at 2.3 ± 0.8 hr after oral administration. The AUC was 79.0 ± 13.9 μg·hr/ml, representing ~29.4% of absolute bioavailability. About 1% of the oral dose was excreted in the urine. These results should prove useful in the design of future clinical and nonclinical studies conducted with uridine.     

Mandibular and Parotid Salivary Levels of Indomethacin Following Intravenous Administration to Rabbits

Indomethacin was measured in mandibular and parotid saliva, obtained from separate cannulas in the salivary ducts, after bolus intravenous administration (15 mg/kg) to male white rabbits that were stimulated for salivation with pilocarpine given subcutaneously. There was a significant correlation between each salivary drug concentration and plasma drug concentration. Saliva to plasma drug concentration ratio (S/P ratio) and pH were higher in mandibular saliva than in parotid saliva. These gland specific differences were in contrast with the previously reported differences in dogs. Matin's equation was found to predict approximately the mean observed S/P ratio of indomethacin for each saliva sample.     

Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract— Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h^?1 kg^?1), distribution volume (4·4 ± 2·0 L kg^?1), mean residence time (9·6 ± 4·1 h) and half-life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg^?1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg^?1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.     

Receptor-Mediated Gene Targeting to Tissues In Vivo Following Intravenous Administration of Pegylated Immunoliposomes

Purpose. Gene therapy has been limited by the immunogenicity of viral vectors, by the inefficiency of cationic liposomes, and by the rapid degradation in vivofollowing the injection of naked DNA. The present work describes a new approach that enables the non-invasive, non-viral gene therapy of the brain and peripheral organs following an intravenous injection. Methods. The plasmid DNA encoding -galactosidase is packaged in the interior of neutral liposomes, which are stabilized for in vivo use by surface conjugation with polyethyleglycol (PEG). The tips of about 1% of the PEG strands are attached to a targeting monoclonal antibody (MAb), which acts as a molecular Trojan Horse to ferry the liposome carrying the gene across the biological barriers of the brain and other organs. The MAb targets the transferrin receptor, which is enriched at both the blood-brain barrier (BBB), and in peripheral tissues, such as liver and spleen. Results. Expression of the exogenous gene in brain, liver, and spleen was demonstrated with -galactosidase histochemistry, which showed persistence of gene expression for at least 6 days after a single intravenous injection of the pegylated immunoliposomes. The persistence of the transgene was confirmed by Southern blot analysis. Conclusions. Widespread expression of an exogenous gene in brain and peripheral tissues is induced with a single intravenous administration of plasmid DNA packaged in the interior of pegylated im- munoliposomes. The liposomes are formulated to target specific receptor systems that enable receptor-mediated endocytosis of the complex into cells in vivo. This approach allows for non-invasive, non-viral gene therapy of the brain.     

Comparison of Simulated and in-Vivo Plasma Levels of Cilastatin Following Intravenous in-Line Drug Administration

The primary objective of this work was to establish a method to simulate the plasma levels of cilastatin, a model drug, following an intravenous in-line delivery scheme. In-vivo data in dogs obtained from this work were used to demonstrate the validity of the proposed approach. The in-line drug delivery system consists of a drug containing device which is placed between a large volume parenteral and a patient. Numerous advantages have been identified for this automatic in-line reconstitution delivery system. The numerical convolution integral algorithm was used in this work to perform plasma profile simulation. The results indicated that the simulated cilastatin plasma profile following in-line delivery closely agreed with the in-vivo data.     

Assessment of Toxicokinetics and Toxicodynamics Following Intravenous Administration of Etoposide Phosphate in Beagle Dogs

The toxicokinetics and toxicodynamics of etoposide phosphate (BMY-40481), a water soluble phosphate ester derivative of etoposide, were investigated in beagle dogs (N = 4) following 5 min i.v. infusion doses equivalent to 57, 114 and 461 mg/m² of etoposide. The doses were administered in sequence starting with the low dose. There was a 28 day wash-out period between the doses. Serial blood samples were collected over 32 hr and the levels of intact BMY-40481 and etoposide in plasma were measured using validated HPLC assays. Hematology profiles were obtained at pre-dose, and twice a week post-dose for 28 days to correlate systemic exposure to etoposide and hematologic toxicity. Following i.v. administration, plasma concentrations of BMY-40481 declined rapidly. For the 3 doses, mean t_1/2 of BMY-40481 ranged from 0.11 - 0.17 hr (6.6-11 min). The mean C_max and AUC values of BMY-40481 ranged from 1.72 - 40.5 µg/ml and 0.16 - 4.14 hr.µg/ml, respectively. Both systemic clearance and steady state volume of distribution of BMY-40481 decreased significantly at the high dose. In contrast, the mean C_max and AUC values of etoposide ranged from 5.46 - 39.4 µg/ml and 2.28 - 22.6 hr.µg/ml, respectively. C_max occurred at the end of infusion (5 min) at all dose levels, indicating that etoposide was rapidly formed from BMY-40481. The apparent systemic clearance (range: 342 - 435 ml/min/m²) and apparent steady state volume of distribution (range: 21.5 - 26.6 1/m²) of etoposide were dose-independent. The AUC of etoposide was significantly correlated with hematologic toxicity, i.e., percent decreases in white blood count (WBC), absolute neutrophil count (ANC) and platelets. The relationship was best described by the sigmoid E_max model for WBC and ANC, and by a simple linear model for platelets. Hemoglobin showed slight decreases which did not correlate with etoposide AUC. In summary, BMY-40481 is rapidly and extensively converted to etoposide; etoposide exhibits linear kinetics; and except for hemoglobin, hematologic toxicity is significantly correlated with etoposide exposure.     

托拉塞米注射液的耐受性和利尿作用研究

目的观察国家二类新药-托拉塞米注射液在中国健康受试者中的安全性、耐受程度及利尿作用,为II期临床试验给药剂量的确定提供依据.方法本研究采用开放、随机的试验设计,将符合入选标准的30名健康中国男性受试者随机分为5组,每组6名,分别注射托拉塞米注射液2.5,10,20,40,80mg,观察临床体征、实验室检查指标的变化及其尿量的变化.结果在静脉注射托拉塞米注射液的所有剂量组,受试者都能耐受.40mg组开始出现药物不良反应,其中2例头晕和1例恶心是中度的,其它均为轻度.80mg组的1例肌肉痉挛是中度的,1例头晕和呕吐是重度的,但持续时间较短,其它均为轻度.在静脉注射托拉塞米注射液10 mg后,已表现出利尿作用,在40mg剂量组达最大,而且与80mg组的利尿作用无显著差异.结论在剂量2.5～80mg范围内的所有剂量显示对健康受试者是安全和耐受的,临床推荐以不超过80mg为宜.     

Metabolism and Pharmacokinetics of Ethylenediamine in the Rat Following Oral, Endotracheal or Intravenous Administration

Metabolism and Pharmacokinetics of Ethylenediamine in the RatFollowing Oral, Endotracheal or Intravenous Administration.Yang, R.S.H. and Tallant, M.J. (1982). Fundam. Appl. Toxicol.2:252-260. Metabolic and pharma-cokinetic studies of ethylenediamine(EDA) in relation to oral, endotracheal and intravenous dosingwere conducted in rats. Male Hilltop Wistar rats were dosedwith ¹⁴C-EDA-2HCl at 5, 50 or 500 mg/kg and the fate of ¹⁴C-EDAand the other radiochemicals was followed for 24 or 48 hours.In all cases, urinary excretion was the primary route of eliminationaccounting for 42 to 65% of the administered radioactivity.Depending on the route of administration and/or the dosage,fecal excretion (5 to 32%) may become an important factor inthe elimination of EDA and its metabolites. Six to 9% of theadministered radioactivity was eliminated via expired air inthe form of ¹⁴CO₂. At the end of the 48-hour experimental period,in all the animals studied, a relatively large portion of theradioactivity (11 to 21%) remained in the various organs andthe carcass. The radioactivity was distributed throughout thebody although thyroid, bone marrow, liver and kidney containedrelatively higher concentrations of radioactivity. Urinary metabolicprofile by AG 50 W cation-exchange column chromatography consistedof 3 to 4 radioactive peaks. Depending on the dosage level,2 to 49% of the radioactivity was unchanged parent compound.N-acetylethylenediamine, a major metabolite, accounted for approximatelyhalf of the urinary radioactivity. The route of administrationdid not appear to change the metabolic profile. As the dosageincreased from 5 to 50 to 500 mg/kg, there was a general patternof accumulation of EDA with a corresponding decrease of metabolite(s)formation. Four pharmacokinetic parameters (bioavailability,total clearance, terminal half-life and area under the curve)were compared among the three dosing routes at the three dosagelevels. There were no significant differences with respect toroute in any of the parameters. Based on this investigation,there is evidence to suggest the equivalency of the fate ofEDA in the rat following oral or endotracheal dosing particularlyat relatively low dosage levels.     

The Pharmacokinetics of Topotecan and Its Carboxylate Form Following Separate Intravenous Administration to the Dog

Purpose. To determine the relationship between topotecan and its ring opened hydrolysis product (SK&F 105992) following intravenous administration of the two agents separately, and to determine the bio-availability of topotecan in female beagle dogs. Methods. The pharmacokinetics of topotecan and SK&F 105992 were determined following separate administration as 30 minute intravenous infusions in a cross-over design. Topotecan was also administered orally to the same dogs. Results. When administered intravenously to dogs, SK&F 105992 underwent interconversion to topotecan. Plasma concentrations of both topotecan and SK&F 105992 appeared to decline multi-exponentially following IV infusion of either compound. A 2-compartment model was found to adequately characterize the data. Conclusions. The clearance of topotecan by other routes proceeded at a faster rate than its interconversion to SK&F 105992, whereas the clearance of SK&F 105992 by other routes was slower than the rate of its interconversion to topotecan. Any SK&F 105992 formed in the GI tract did not appear to be well absorbed following oral administration of topotecan to dogs. The steady-state volume of distribution for topotecan was approximately 8- to 9-fold greater than that for SK&F 105992 in the dog. After intravenous administration of topotecan, the amount of topotecan in the dog was much greater than that of the carboxylate, even though their respective plasma concentrations were similar. The bioavailability of topotecan, calculated from oral topotecan data or from SK&F 105992 data, was approximately 50%.     

小儿口服与静脉给药血清地高辛浓度及中毒反应

测得86例心衰小儿血清地高辛浓度治疗范围(1.9±0.61)μg/L,不同年龄组的治疗浓度无明显差异。20例口服与静脉给药对比,当静脉给药剂量为口服给药的2/3时,前者的血药浓度明显高于后者。血药浓度≥2μg/L时,地高辛中毒的发生率明显增加,且均为心肌疾病患儿。治疗过程中出现心律紊乱或消化道症状不能肯定为地高辛中毒。     

Decline in Exogenous Gene Expression in Primate Brain Following Intravenous Administration Is Due to Plasmid Degradation

Purpose Nonviral gene transfer to the brain of adult Rhesus monkeys is possible with a single intravenous administration of plasmid DNA that is encapsulated in the interior of pegylated immunoliposomes, which are targeted across membrane barriers in vivo with a monoclonal antibody to the human insulin receptor. Methods The present studies measure the rate of decay of luciferase gene expression in the Rhesus monkey with luciferase enzyme assays, Southern blotting, and real-time polymerase chain reaction. Results Luciferase enzyme activity in frontal cortex, cerebellum, and liver decays with a t_1/2 of 2.1 ± 0.1, 2.6 ± 0.2, and 1.7 ± 0.01 days, respectively. Luciferase plasmid in brain and liver was detectable by Southern blotting at 2 days, but not at 7 or 14 days. The concentration of luciferase plasmid DNA in brain and liver was measured by real-time polymerase chain reaction, and decayed with t_1/2 of 1.3 ± 0.3 and 2.7 ± 0.5 days, respectively. Conclusions The maximal concentration of luciferase plasmid DNA in Rhesus monkey brain was 3–4 molecules/cell following an i.v. administration of 12 μg/kg pegylated immunoliposome encapsulated plasmid DNA. These results demonstrate that the rate of loss of exogenous gene expression in the primate in vivo correlates with the rate of DNA degradation of the exogenous plasmid DNA.     

Biodistribution and Excretion of Radiolabeled 40 kDa Polyethylene Glycol Following Intravenous Administration in Mice

The pharmacokinetics, excretion, and tissue distribution of [¹⁴C]-labeled polyethylene glycol–alanine (PEG–Ala) were determined after slow bolus administration into the femoral vein of male CD-1 mice. The pharmacokinetics of PEG–Ala in blood and plasma revealed a biphasic elimination with a terminal half-life of 20 h. Eighty-five percent of the excreted material was voided in the urine and the remaining amount was detected in the feces. PEG–Ala-derived radioactivity was widely distributed with detectable levels of radioactivity observed in all tissues examined. The highest concentration was observed in the kidneys followed by lungs, heart, and liver. Six hours after administration, PEG–Ala levels were significantly reduced in all tissues. Despite a slow prolonged decrease, radioactivity was still detectable after 28 days. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2362–2370, 2013     

达托霉素治疗感染性心内膜炎的快速卫生技术评估研究

摘 要 目的：利用快速卫生技术评估工具对达托霉素霉素治疗感染性心内膜炎进行有效性、安全性、经济性评估,为医院药物遴选提供参考。 方法：通过计算机检索PubMed、the Cochrane Library等英文数据库和中国知网（CNKI）、中国生物医学文献服务系统(SinoMed)、万方数据等中文数据库。2名评价者独立提取数据结果。仅纳入达托霉素治疗感染性心内膜炎的系统评价、Meta分析、卫生技术评估和药物经济学研究,同时采用描述性分析对研究结论进行分类汇总。结果：共纳入3篇文献,1项为系统评价,2项为药物经济学研究。采用达托霉素治疗感染性心内膜炎的有效性和安全性研究结果与对照组（安慰剂、其他阳性对照药单药或联合其他常规用药）比较,差异均无统计学意义,药物经济学研究显示成本效果优于对照组。结论：对达托霉素治疗感染性心内膜炎的评估发现,快速卫生经济技术评估工具可作为一种简洁、快捷、易行的方法,为医院的药物遴选提供参考。     

Adsorption and Leachable Contamination of Flucloxacillin,Cyclosporin and Amiodarone Following Delivery Through an Intravenous Administration Set

Purpose

Interactions between a pharmaceutical drug and its delivery device can result in changes in drug concentration and leachable contamination. Flucloxacillin, amiodarone and cyclosporin were investigated for drug concentration changes and leachable contamination after delivery through an intravenous administration set.

Methods

Flucloxacillin, amiodarone and cyclosporin were delivered through an intravenous administration set and the eluate analysed by HPLC-UV and HPLC-MS.

Results

The average recovery of flucloxacillin was 99.7% and no leachable compounds were identified. The average recovery of cyclosporin was 96.1%, which contrasts previous findings that have reported up to 50% loss of cyclosporin. This is likely due to the use of DEHP-free administration sets in this study, as adsorption of cyclosporin is linearly related to DEHP content. The average recovery of amiodarone was 91.5%. 5-hydroxymethylfurfural was identified in the amiodarone solution following delivery through the administration set as well as the 5% glucose solution used for delivery.

Conclusions

Drug/administration set interactions may modify pharmaceuticals during delivery. In this study, only 90% of the amiodarone was delivered through a generic administration set. Given the growing use of generic administration sets in hospital settings, validation of the suitability of their use is required to ensure patient safety and expected levels of efficacy.

     

High-Dose Daptomycin Is Well Tolerated via 2-Minute IV Push Administration

Background:The purpose of this study was to evaluate the safety of administering high-dose daptomycin (HDD; > 6 mg/kg actual body weight) as a 2-minute intravenous (IV) push (IVP) compared to traditional 30-minute IV piggyback (IVPB) infusion.Methods:Retrospective cohort study comparing patients receiving HDD as an IVP or IVPB infusion. The primary outcome was the proportion of patients with a documented infusion-related reaction (IRR) to daptomycin.Results:Three hundred patients were included in the final analysis, 200 patients received IVP, and 100 patients received IVPB representing a total of 1697 administrations. Median (IQR) daptomycin dose was IVP 700 mg (550-900) and IVPB 700 mg (600-900), with mg/kg doses of 8.2 (7.9-10) and 8.3 (8-10), respectively. After adjudication, IRR occurred in 1% of subjects in each treatment group.Conclusions:This study provides data in more than 1100 administrations of HDD administered via IVP. Infusion-related reactions were documented in 1% of patients regardless of infusion method, suggesting comparable safety to traditional infusion methods. This practice may be useful during fluid shortage and in the outpatient setting.     

儿童静脉滴注阿奇霉素时间与胃肠道反应的相关性分析

目的:探讨儿童静脉滴注阿奇霉素后出现胃肠道反应的情况与用药时间的相关性。方法:选择我院应用阿奇霉素治疗的患儿50例,随机分为试验组和对照组,各25例。试验组在患儿进食后2 h内静脉滴注阿奇霉素,对照组在患儿进食2 h后静脉滴注阿奇霉素。比较2组患儿发生胃肠道反应的发生率及轻、重程度。结果:试验组发生胃肠道反应的程度显著低于对照组,发生率也低于对照组,2组比较差异有统计学意义(P<0.05)。结论:患儿临床应用阿奇霉素时,应注意掌控用药时间,以减少胃肠道不良反应的发生率。     

Pharmacokinetics of Droperidol in Healthy Volunteers Following Intravenous Infusion and Rectal Administration from an Osmotic Drug Delivery Module

Pharmaceutical Research -