Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs

Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ^®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18–94 µg/mL.     

Pharmacokinetics of lopromide Liposomes in Rabbits

Purpose. The dose-proportionality of pharmacokinetics of an iodinated contrast medium, iopromide, encapsulated into liposomes was investigated. Methods. Following single intravenous administration of 150 mg iodine/kg (potential diagnostic dose) and a five-fold higher dose in rabbits the pattern of elimination was studied until 7 d and the blood concentrations were monitored up to 72 h after administration. The iodine concentration in the liver was calculated on the basis of the blood concentration and related to the concentration measured in the rabbit liver. Results. The dose-normalized blood concentration-time profiles of the encapsulated iodine were not superimposable. Contrary to the low dose a steady-state concentration of 2.8 mg iodine/mL was observed in blood for 60 min after the high dose administration indicating a saturation of the liposomal liver uptake. For both doses the elimination of iodine occurred predominantly via the kidneys and was complete 7 d after administration. The dose-normalized amounts of iodine excreted with the urine were similar for both dose groups. From the blood data it was calculated that doses up to about 300 mg iodine/kg should result in a dose-proportional increase of liposomal liver uptake before saturation occurs. This was confirmed by the measured iodine liver concentrations after increasing the doses stepwise from 150 to 750 mg iodine/kg. Conclusions. In rabbits for the dose range 150 to 750 mg iodine/kg iopromide liposomes reveal dose-dependent pharmacokinetics due to a saturation in liver uptake which occurs for doses of 300 mg iodine/kg corresponding to 300 mg lipid/kg onwards.     

Assessment of Dose Proportionality,Absolute Bioavailability,and Immunogenicity Response of CTLA4Ig (BMS-188667), a Novel Immunosuppressive Agent,Following Subcutaneous and Intravenous Administration to Rats

Purpose. The objectives of this study were: to delineate the pharmacokinetics of CTLA4Ig in rats after single and multiple intravenous (IV) and subcutaneous (SC) doses; to assess the relationship of the pharmacokinetic parameters of CTLA4Ig vs dose; to calculate the SC absolute bioavailability; and to assess the antibody response of CTLA4Ig. Methods. A total of 48 (24 male and 24 female) Sprague Dawley rats were divided into eight treatments with 3 rats per gender in each group: a single dose of 10, 80, or 200 mg/kg of CTLA4Ig given either IV or SC and a repeated dose of 10 mg/kg (once every other day for 7 doses over 13 days) given either SC or IV. Serial blood samples were collected up to 43 days after single dose administration and up to 50 days following the administration of the last multiple dose on day 13. The serum concentration of CTLA4Ig and anti-CTLA4Ig antibodies were measured using ELISA assays. Results. After single IV doses, C_max and AUC_inf increased in a dose proportional manner; CL appeared to be dose independent, while both V_ss and T_1/2 increased as the administered dose increased. Following single SC doses, C_max and AUC_inf increased in a linear manner but not proportionally; mean T_max values were prolonged but similar among the three dose levels, while T_1/2 increased as the administered dose increased. The absolute SC bioavailability of CTLA4Ig decreased as the dose increased from 10 (62.5%), 80 (55.7%), and 200 mg/kg (41.1%). Comparison of the AUC_tau values between the first and last doses suggested an accumulation (3.1–4.7) of CTLA4Ig. However, regardless of the route of dosing, AUC_tau after the last dose were comparable to AUC_inf values following the single dose. Anti-CTLA4Ig antibodies were detected at the 10 mg/kg dose level after single or multiple doses for both routes of administration. However, regardless of single or multiple doses, antibody titers were relatively greater for the SC compared to the IV administration. Conclusions. The key findings of this study were: (i) the elimination characteristics of CTLA4Ig were comparable between the SC and IV routes; (ii) the repeated dosing did not alter the pharmacokinetics of CTLA4Ig; (iii) the SC absolute bioavailability tended to decrease as the administered dose increased; and (iv) a greater formation of anti-CTLA4Ig antibodies was observed after SC compared to IV at a single 10 mg/kg dose level; however, after multiple dosing, the formation of antibodies from either of the two routes was relatively slower, and (v) during the study period, no antibodies were observed at either the 80 or 200 mg/kg dose levels regardless of the route of administration.     

Population Pharmacokinetics of Tirilazad: Effects of Weight,Gender, Concomitant Phenytoin,and Subarachnoid Hemorrhage

Purpose. Data collected during Phase I and II in the development of tirilazad were pooled and analyzed using nonlinear mixed effects models to assess covariates which might affect tirilazad pharmacokinetics. Methods. Four single dose and five multiple dose studies in normal volunteers were combined with two multiple dose studies performed in patients with subarachnoid hemorrhage (SAH) to identify factors related to intersubject variability in clearance (CL) and central compartment volume (Vc). Data from 253 subjects, which consisted of 7,219 tirilazad concentrations, were analyzed. The effects of weight, gender, patient versus volunteer status, and phenytoin use were evaluated. Results. Relative to male volunteers not receiving concomitant phenytoin, significant effects on clearance included: a 46% increase in volunteers receiving phenytoin, and an 82% increase in clearance associated with SAH patients (all of whom received phenytoin). Significant effects on Vc were: a 26% increase for female volunteers not receiving phenytoin, a 12% decrease for volunteers receiving concomitant phenytoin, a 152% increase for male SAH patients, and a 270% increase for female SAH patients. Incorporating patient covariate effects substantially reduced the interindividual variability (from 27.9% to 24.7% for clearance and from 48.2% to 37.5% for Vc). Residual variability was estimated at 66% coefficient of variation (CV) in SAH patients and at 22–48% CV over the range of predicted concentrations in normal volunteers. Conclusions. The most important factors affecting tirilazad pharmacokinetics are the administration of phenytoin (increased CL) and SAH (increased Vc and residual variability). The effect of gender on tirilazad pharmacokinetics was modest.     

Acute Gastrointestinal Toxic Effects of Suspensions of Unencapsulated and Encapsulated Ibuprofen in Rats

Purpose. The study examined the gastrointestinal (GIT) toxicity effects of suspensions of encapsulated and unencapsulated ibuprofen in male Wistar rats. Methods. Rats were randomly divided into four experimental groups and four control groups, and dosed with suspensions of encapsulated and unencapsulated ibuprofen (17 mg/kg and 44 mg/kg). Bethanechol chloride, a cholinomimetic agent (5 mg/kg), was administered 30 minutes after the dosing, to induce gastric irritation. Blood plasma concentrations were monitored in another set of rats for 12 hours using the encapsulated and unencapsulated systems, to establish drug release and exposure to the mucosa. Results. Evaluation of the upper GI segments after 7 hours revealed that the 44 mg/kg dose of the encapsulated drug significantly reduced the number of lesions present compared to the unencapsulated drug (p < 0.05). At 17 mg/kg, the encapsulated drug reduced toxicity, but not significantly compared to the unencapsulated ibuprofen. Necrosis of the mucosa was observed histopathologically in the unencapsulated drug at both doses, whereas the encapsulated drug treatment revealed preserved mucosa. The encapsulated system had a maximum plasma concentration, Cmax, and time taken to reach Cmax, (Tmax) of 26.7 µg/ml ± 1.5 and 3.6 ± 0.2 hr, respectively. The area under the plasma concentration-time curve, (AUC_0–12), was 158.8 ± 23.5 µg·h/ml, confirming drug release and absorption. Conclusions. Encapsulation of ibuprofen significantly reduced gastrointestinal toxicity especially at the higher dose level and drug was released enough to subject the GI mucosa to irritation, but without the usual toxic effects.     

Oral-Antigen Delivery via a Water-in-Oil Emulsion System Modulates the Balance of the Th1/Th2 Type Response in Oral Tolerance

Purpose. To evaluate the ability of a water-in-oil (W/O) emulsion containing ovalbumin (OVA), a model antigen, to induce oral tolerance and to elucidate the mechanism for the induction of oral tolerance by the emulsion system. Methods. A W/O emulsion containing OVA was prepared and evaluated its ability to induce oral tolerance in mice. Also, the Th1/Th2 balance in the mice tolerized was investigated in terms of the ratios of anti-OVA IgG2a titer to anti-OVA IgG1 titer (IgG2a/IgG1 ratios) and cytokine profiles. Results. Anti-OVA total IgG antibody titer of mice administered OVA in saline was approximately 3.5-fold higher than that of the mice administered OVA in W/O emulsion at a dose of 0.1 mg/mouse/day. Similar total IgG responses were observed between the above two at a dose of 1 mg/mouse/day. The IgG2a/IgG1 ratios decreased as the dose of OVA in W/O emulsion, but not in saline, increased at doses of 0, 0.1, and 1 mg/mouse/day. Interferon- secretion of PLN cells from the mice administered OVA in W/O emulsion decreased, whereas their interleukin-4 secretion remained high. Although interferon- secretion for the mice administered OVA in saline decreased, interleukin-4 secretion did not change. Conclusions. The present study suggests that oral delivery of OVA via the W/O emulsion system may more efficiently enhance the induction of Th2-dominated imbalance than that of OVA in saline.     

Evaluation of the toxicology,anti-lipase,and antioxidant effects of Callistemon citrinus in rats fed with a high fat-fructose diet

ContextCallistemon citrinus Skeels (Myrtaceae) exhibits many biological activities.ObjectiveThis study analyzes for the first time, the toxicity, obesogenic, and antioxidant effects of C. citrinus in rats fed with a high fat-fructose diet (HFFD).Materials and methodsFour studies using male Wistar rats were conducted: (a) 7 groups (n = 3): control (corn oil) and ethanol extract of C. citrinus leaf (single oral dose at 100–4000 mg/kg) for acute toxicity; (b) 2 groups (n = 8): control (corn oil) and C. citrinus (1000 mg/kg/day) for 28 days for subacute toxicity; (c) 3 groups (n = 4) with single oral dose of lipid emulsion: control (lipid emulsion), C. citrinus and orlistat (250 and 50 mg/kg, respectively) for lipid absorption; (d) 4 groups (n = 6): control (normal diet) and 3 groups fed with HFFD: HFFD only, C. citrinus and simvastatin (oral dose 250 and 3 mg/kg, respectively) for 13 weeks. Antioxidant enzymes and biomarkers were evaluated and inhibition of pancreatic lipase was determined in vitro.ResultsToxicological studies of C. citrinus showed no differences in biochemical parameters and lethal dose (LD₅₀) was higher than 4000 mg/kg. C. citrinus inhibited pancreatic lipase activity, with IC₅₀ of 392.00 µg/mL, and decreased lipid absorption by 70%. Additionally, it reduced the body weight 22%, restored the activities of antioxidant enzymes, and reduced the biomarkers of oxidative stress.ConclusionsCallistemon citrinus showed an effect against oxidative stress by reducing biomarkers and induced antioxidant system, without toxic effects.     

水飞蓟宾对高脂诱导非酒精性脂肪肝大鼠的调脂保肝作用

目的 探讨水飞蓟宾对高脂诱导的非酒精性脂肪肝（NAFL）模型大鼠的调脂保肝作用。方法 采用ig高脂乳剂配合高脂饲料制备大鼠NAFL模型,持续4周,对照组给予生理盐水和普通饲料。模型大鼠随机分为模型组、辛伐他汀（阳性药,1.8 mg/kg）组和水飞蓟宾低、中、高剂量（18.9、37.8、75.6 mg/kg）组,第5周在继续造模的基础上ig给药,每天1次,持续8周。末次给药后,称取肝脏质量并计算肝系数;HE染色观察肝组织病理形态;腹主动脉取血,分离血清,试剂盒法检测三酰甘油（TG）、总胆固醇（TC）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）水平。结果 连续治疗8周后,与对照组比较,水飞蓟宾高、中剂量均可明显改善肝组织脂肪变性程度;各剂量组肝系数均显著下降（P<0.05、0.01）;各剂量组均显著降低血清TC、TG、AST、ALT水平（P<0.05、0.01）;高、中剂量组显著降低LDL、升高HDL水平（P<0.01）。结论 水飞蓟宾对NAFL大鼠发挥治疗作用,其作用可能与降脂、保肝有关。     

Extensive Absorption of 2′,3′-Dideoxyinosine by Intratracheal Administration in Rats

Purpose. To evaluate the intratracheal route of administration as an alternative to oral administration for 2,3-dideoxyinosine (ddI). Methods. A ddI dose (40 mg/kg/300 µl or 6.5 mg/kg/50 µl) was instilled into the trachea in female Fisher rats and an intravenous tracer dose (9 µg/kg) of ³H-ddI was administered concomitantly to determine the drug clearance. Plasma concentrations were analyzed for the rate and extent of absorption. Results. ddI was rapidly absorbed from the lungs, with a bioavailability of 63% at 40 mg/kg and 101% at 6.5 mg/kg. By comparison, our previous data showed an oral bioavailability of about 15% (Pharm Res., 9:822, 1992). The distribution of a dye solution instilled intratracheally showed that a fraction of the 300 µL dose spilled over to the gastrointestinal tract, where the entire 50 µL dose was retained in the lungs. The different distribution of the two doses/volumes likely contributed to the different bioavailability, with a fraction of the higher dose/volume degraded in the gastrointestinal tract after the spillover. Absorption of ddI from the airspace of the lung was biexponential, suggesting two absorption processes. Conclusions. These data indicate significantly higher and less variable bioavailability of ddI by the intratracheal route of delivery compared to the oral route. Furthermore, the complete bioavailability at the lower dose/volume indicates no significant pulmonary first pass elimination for ddI.     

Induction of tirilazad clearance by phenytoin

Tirilazad is a membrane lipid peroxidation inhibitor being studied for the management of subarachnoid hemorrhage; phenytoin is used for seizure prophylaxis in the same disorder. The induction of tirilazad clearance by phenytoin was assessed in 12 volunteers (6 male, 6 female). Subjects received phenytoin orally every 8 h for 7 days (200 mg for nine doses and 100 mg for 13 doses) in one phase of a crossover study. In both study phases, 1.5 mg kg⁻¹ tirilazad mesylate was administered by IV infusion every 6 h for 29 doses. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. After the final dose, tirilazad clearance was increased by 91.8% in subjects receiving phenytoin+tirilazad versus tirilazad alone. AUC_0–6 for U-89678 after the last tirilazad dose was reduced by 93.1% by concomitant phenytoin. These effects were statistically significant. The time course of induction was consistent with that of phenytoin's effect on the ratio of urinary 6β -hydroxycortisol to cortisol, a measure of hepatic CYP3A activity. The results show that phenytoin induces metabolism of tirilazad and U-89678 in healthy subjects and that, under these conditions, tirilazad clearance approaches liver blood flow. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetic-Pharmacodynamic Modeling of Ipamorelin,a Growth Hormone Releasing Peptide,in Human Volunteers

Purpose. To examine the pharmacokinetics (PK) and pharmacodynamics (PD) of ipamorelin, a growth hormone (GH) releasing peptide, in healthy volunteers. Methods. A trial was conducted with a dose escalation design comprising 5 different infusion rates (4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg over 15 minutes) with eight healthy male subjects at each dose level. Concentrations of ipamorelin and growth hormone were measured. Results. The PK parameters showed dose-proportionality, with a short terminal half-life of 2 hours, a clearance of 0.078 L/h/kg and a volume of distribution at steady-state of 0.22 L/kg. The time course of GH stimulation by ipamorelin showed a single episode of GH release with a peak at 0.67 hours and an exponential decline to negligible GH concentration at all doses. The ipamorelin–GH concentration relationship was characterized using an indirect response model and population fitting. The model employed a zero-order GH release rate over a finite duration of time to describe the episodic release of GH. Ipamorelin induces the release of GH at all dose levels with the concentration (SC₅₀) required for half-maximal GH stimulation of 214 nmol/L and a maximal GH production rate of 694 mlU/L/h. The inter-individual variability of the PD parameters was larger than that of the PK parameters. Conclusions. The proposed PK/PD model provides a useful characterization of ipamorelin disposition and GH responses across a range of doses.     

Anticestodal Efficacy of Lasia spinosa. Extract Against Experimental Hymenolepis diminuta. Infections in Rats

Abstract

The use of Lasia spinosa. (L.) Thwaites (Araceae) leaves in the treatment of intestinal worm infections is a common ethnobotanical practice in the Naga tribes of India. In the current study, the anticestodal efficacy of L. spinosa. leaf extract was investigated against a tapeworm using Hymenolepis diminuta.–rat animal model. The anticestodal effects of L. spinosa. leaf extract was determined by monitoring the eggs per gram of feces (EPG) counts and percentage worm recovery rates after treatment with leaf extract in single and double doses of 200, 400, 800, and 1600 mg/kg that were given orally for 5 days to the rats harboring immature and mature worms. The effect of plant extract was found to be dose-dependent, and double doses showed better efficacy as compared with single doses. In the case of infections with immature worms, 1600 mg/kg double dose of L. spinosa. leaf extract reduced the fecal egg counts of H. dimunta. by 80.8% and worm recovery rate by 16.7%, respectively. Praziquantel, the standard anticestodal drug given in 5 mg/kg single dose, reduced the fecal egg count by 83.2% and worm recovery rate by 16.7%. In the case of efficacy against mature worms, 1600 mg/kg double dose of leaf extract reduced the fecal egg counts of H. diminuta. by 94.9% and worm recovery rate by 8.5%, respectively. Praziquantel (5 mg/kg, single dose) reduced the fecal egg counts by 95.1% and worm recovery rate by 16.7%. The study suggests that the leaf extract of L. spinosa. possesses significant anticestodal efficacy and supports its use in folk medicine.     

Flavonoid-enriched extract from Hippophae rhamnoides seed reduces high fat diet induced obesity,hypertriglyceridemia, and hepatic triglyceride accumulation in C57BL/6 mice

Context: Flavonoid-enriched extract from Hippophae rhamnoides L. (Elaeagnaceae) seed (FSH) has shown beneficial effects in anti-hypertension and lowering cholesterol level. However, evidence for its efficacy in treating obesity is limited.

Objective: We sought to determine if FSH can reduce body weight and regulate lipid metabolism disorder in high fat diet (HFD)-induced obese mouse model, and to investigate potential molecular targets involved.

Materials and methods: C57BL/6 mice were fed with HFD for 8 weeks to induce obesity. The modeled mice were divided into four groups and treated with vehicle, rosiglitazone (2?mg/kg), low (100?mg/kg) and high (300?mg/kg) dose of FSH, respectively. Normal control was also used. The treatments were administered orally for 9 weeks. We measured the effect of FSH on regulating body weight, various liver and serum parameters, and molecular targets that are key to lipid metabolism.

Results: FSH administration at 100 and 300?mg/kg significantly reduced body weight gain by 33.06 and 43.51%, respectively. Additionally, triglyceride concentration in serum and liver were decreased by 15.67 and 49.56%, individually, after FSH (300?mg/kg) treatment. Upon FSH (100 and 300?mg/kg) treatment, PPARα mRNA expression was upregulated in liver (1.24- and 1.42-fold) and in adipose tissue (1.66- and 1.72-fold). Furthermore, FSH downregulated PPARγ protein level both in liver and adipose tissue. Moreover, FSH inhibited macrophage infiltration into adipose tissues, and downregulated TNFα mRNA expression in adipose tissue (38.01–47.70%).

Conclusion: This effect was mediated via regulation of PPARγ and PPARα gene expression, and suppression of adipose tissue inflammation.     

Gender does not affect the degree of induction of tirilazad clearance by phenobarbital

Objective: Tirilazad mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on tirilazad mesylate pharmacokinetics was assessed in 15 healthy volunteers (7M, 8F). Methods: Subjects received 100 mg phenobarbital orally daily for 8 days in one phase of a two-way crossover study. In both phases, 1.5 mg⋅kg⁻¹ tirilazad mesylate was administered (as a 10 minute IV infusion) every 6 hours for 29 doses. Three weeks separated study phases. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. Results: Phenobarbital had no effect on the first dose pharmacokinetics of tirilazad or U-89678. After the final dose, clearance for tirilazad was increased 25% in males and 29% in females receiving phenobarbital + tirilazad versus tirilazad mesylate alone. These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC_0–6 for U-89678 after the last tirilazad mesylate dose was reduced 51% in males and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction. Conclusion: The results show that phenobarbital induces metabolism of tirilazad and U-89678 similarly in both men and women. Lower levels of tirilazad and U-89678 in SAH patients receiving phenobarbital may adversely impact clinical response. Received: 11 July 1995/Accepted in revised form: 6 October 1995     

Absorption,Metabolism, and Disposition of [14C]SDZ ENA 713, an Acetylcholinesterase Inhibitor,in Minipigs Following Oral,Intravenous, and Dermal Administration

Purpose. SDZ ENA 713 (rivastigmine) is an acetylcholinesterase inhibitor intended for therapeutic use in Alzheimer's disease. The present study compared the pharmacokinetics of [¹⁴C]SDZ ENA 713 after intravenous, oral, and dermal administration to male minipigs, and also examined the effects of dose level and skin abrasion on transdermal absorption. Methods. Four groups of 3 minipigs each received a single intravenous (0.1 mg/kg), single oral (1.0 mg/kg), or topical doses of 18 mg or 54 mg of [¹⁴C]SDZ ENA 713. Topical doses were administered as dermal patches on two occasions 10 days apart. On Study Day 1, test patches were applied to a virgin skin site. Placebo patches were applied to a separate skin site and were replaced daily during Days 1–10. On Study Day 11, test patches were applied to the site on which the placebo patches had been previously applied. After each dose, serial blood and quantitative urine and feces were collected at designated intervals for 7 days. Concentrations of radioactivity, parent drug, and metabolite ZNS 114–666 were measured in whole blood. Radioactivity was also determined in excreta, skin application sites (at study termination), and on used dermal patches (at 24 hr after application). Results. Oral doses of [¹⁴C]SDZ ENA 713 were rapidly (t_max = 0.83 hr) and efficiently (ca. 93%) absorbed, although the bioavailability of the parent drug was low, ca. 0.5%, apparently due to extensive first-pass metabolism. Radioactivity was excreted mainly in the urine (90%) with a half-life of 56 hr, slightly longer than that observed after an intravenous dose, 46 hr. After dermal administration of [¹⁴C]SDZ ENA 713 to a virgin skin site, absorption was 8% at both dose levels investigated. Following daily application of placebo patches for 10 days, absorption from a [¹⁴C]SDZ ENA 713 dermal patch increased by approximately twofold, 17% and 19% of the 18 mg and 54 mg doses, respectively. The increase is possibly due to hydration or abrasion of the skin as a result of repeated application and removal of the adhesive patches. Whereas total absorption from the dermal dose was smaller than that from the oral dose, essentially all of the absorbed drug via the dermal route reached the systemic circulation intact, thus yielding a SDZ ENA 713 bioavailability 20–40 times greater than that of the oral dose. Metabolite ZNS 114–666 was rapidly formed and accounted for <4% of total drug-related material in the systemic circulation. Conclusions. Dermal administration in minipigs provided a markedly greater bioavailability of SDZ ENA 713 than the oral route. The extent of absorption was independent of dose within the range tested, and appeared to be enhanced by hydration or abrasion of the skin application site.     

Effect of GF120918, a Potent P-glycoprotein Inhibitor,on Morphine Pharmacokinetics and Pharmacodynamics in the Rat

Purpose. The objective of this study was to evaluate the effect of a potent P-gp inhibitor, GF120918, on the systemic pharmacokinetics and antinociceptive pharmacodynamics of a single intravenous dose of morphine in rats. Methods. Male Sprague-Dawley rats received either 500 mg base/kg/d GF120918 or vehicle for 4 days by gavage, or no pretreatment. On day 4, morphine was administered as a 1- or 2-mg/kg i.v. bolus. Antinociception, expressed as percent of maximum possible response (%MPR), was evaluated over 300 min after morphine administration. Serial blood samples were collected and analyzed for morphine and morphine-3-glucuronide (M3G) by HPLC. Results. Morphine clearance and distribution volume were not altered significantly by GF120918. M3G AUC in the GF120918-treated rats was approximately 2-fold higher than in vehicle-treated rats. For both morphine doses, %MPR and the area under the effect-time curve at 300 min were significantly higher in the GF120918-treated rats. A pharmacokinetic/pharmacodynamic effect model accurately described the effect-concentration data for the rats that received 1-mg/kg morphine; k_e0 was significantly smaller for GF 120918- vs. vehicle-treated and control rats (0.060 ± 0.028 vs. 0.228 ± 0.101 vs. 0.274 ± 0.026 min^–1, p=0.0023). EC₅₀ and were similar between treatment groups. Conclusions. Pretreatment with GF 120918 enhanced morphine antinociception, as assessed by the hot-lamp tail-flick assay, and elevated systemic M3G concentrations in rats. The differential pharmacologic response to morphine in the GF120918-treated animals could not be attributed to alterations in systemic morphine pharmacokinetics.     

Absorption and Disposition of a Selective Aldosterone Receptor Antagonist,Eplerenone, in the Dog

Purpose. The present study was conducted to characterize the pharmacokinetics of eplerenone (EP), a selective aldosterone receptor antagonist, and its open lactone ring form in the dog. Methods. Pharmacokinetic studies of EP were conducted in dogs following i.v., oral, and rectal dosing (15 mg/kg) and following intragastric, intraduodenal, intrajejunal, and intracolonic dosing (7.5 mg/kg). Results. After oral administration, the systemic availability of EP was 79.2%. Systemic availabilities following administration via other routes were similar to that following oral administration. The half-life and plasma clearance of EP were 2.21 hr and 0.329 l/kg/hr, respectively. Plasma concentrations of the open lactone ring form were lower than EP concentrations regardless of the route of administration. The C-14 AUC in red blood cells was approximately 64% and 68% of the plasma AUC for i.v. and oral doses. Percentages of the dose excreted as total radioactivity in urine and feces were 54.2% and 40.6%, respectively, after i.v. administration, and 40.7% and 52.3%, respectively, after oral administration. The percentages of the dose excreted in urine and feces as EP were 13.7% and 2.5%, respectively, after i.v. administration, and 2.1% and 4.6% after oral administration, respectively. Approximately 11% and 15% of the doses were excreted as the open form following i.v. and oral doses. Conclusions. EP was rapidly and efficiently absorbed throughout the gastrointestinal tract, resulting in a good systemic availability. The drug did not preferentially accumulate in red blood cells. EP was extensively metabolized; however, first-pass metabolism after oral and rectal administration was minimal. EP and its metabolites appear to be highly excreted in the bile.     

Antinociceptive activity of Ligusticum porteri preparations and compounds

Context: The roots and rhizomes of Ligusticum porteri Coulter &; Rose (Apiaceae) are widely used in Mexican folk medicine for several purposes, including painful complaints.

Objective: The main goal of this work was to demonstrate the analgesic action in mice of some preparations and major compounds from L. porteri.

Materials and methods: The extracts, aqueous (AE) and organic (OE), the essential oil (EO) and major compounds (10–316?mg/kg) from L. porteri were evaluated as potential antinociceptive agents using the acetic acid-induced writhing and hot plate tests in ICR mice.

Results: All preparations tested exhibited significant antinociceptive effect in the two animal pain models selected. AE and EO were more effective in the writhing test while OE had a better effect in the hot-plate model. On the other hand, Z-ligustilide (1) provoked an increment in the latency period to the thermal stimuli in the hot-plate test at a dose of 31.6?mg/kg, and a decrease in the number of abdominal writhes at 10?mg/kg. Z-3-butylidenephthalide (2) induced a dose-dependent antinociceptive action in the hot-plate assay; this compound was also effective for controlling the pain provoked by chemical irritation at the doses of 10 and 31.6?mg/kg. Finally, diligustilide (3) inhibited the number of writhing responses at all doses tested but was inactive in the hot-plate model.

Conclusion: The present investigation provides in vivo evidence supporting the use of L. porteri to treat painful conditions in folk medicine.     

Intravenous Lipid Emulsion Given to Volunteers does not Affect Symptoms of Lidocaine Brain Toxicity

Intravenous lipid emulsion has been suggested as treatment for local anaesthetic toxicity, but the exact mechanism of action is still uncertain. Controlled studies on the effect of lipid emulsion on toxic doses of local anaesthetics have not been performed in man. In randomized, subject‐blinded and two‐phase cross‐over fashion, eight healthy volunteers were given a 1.5 ml/kg bolus of 20% Intralipid^® (200 mg/ml) or Ringer's acetate solution intravenously, followed by a rapid injection of lidocaine 1.0 mg/kg. Then, the same solution as in the bolus was infused at a rate of 0.25 ml/kg/min. for 30 min. Electroencephalography (EEG) was recorded, and 5 min. after lidocaine injection, the volunteers were asked to report subjective symptoms. Total and un‐entrapped lidocaine plasma concentrations were measured from venous blood samples. EEG band power changes (delta, alpha and beta) after the lidocaine bolus were similar during lipid and during Ringer infusion. There were no differences between infusions in the subjective symptoms of central nervous system toxicity. Lidocaine was only minimally entrapped in the plasma by lipid emulsion, but the mean un‐entrapped lidocaine area under concentration–time curve from 0 to 30 min. was clearly smaller during lipid than Ringer infusion (16.4 versus 21.3 mg × min/l, p = 0.044). Intravenous lipid emulsion did not influence subjective toxicity symptoms nor affect the EEG changes caused by lidocaine.     

Formulation Development and Antitumor Activity of a Filter-Sterilizable Emulsion of Paclitaxel

Purpose. Paclitaxel is currently administered i.v. as a slow infusion of asolution of the drug in an ethanol:surfactant:saline admixture. However,poor solubilization and toxicity are associated with this drug therapy.Alternative drug delivery systems, including parenteral emulsions, areunder development in recent years to reduce drug toxicity, improveefficacy and eliminate premedication. Methods. Paclitaxel emulsions were prepared by high-shearhomogenization. The particle size of the emulsions was measured by dynamiclight scattering. Drug concentration was quantified by HPLC and invitro drug release was monitored by membrane dialysis. The physicalstability of emulsions was monitored by particle size changes in boththe mean droplet diameter and 99% cumulative distribution. Paclitaxelpotency and changes in the concentration of known degradants wereused as chemical stability indicators. Single dose acute toxicity studieswere conducted in healthy mice and efficacy studies in B16 melanomatumor-bearing mice. Results. QW8184, a physically and chemically stable sub-micronoil-in-water (o/w) emulsion of paclitaxel, can be prepared at high drugloading (8-10 mg/mL) having a mean droplet diameter of <100 nmand 99% cumulative particle size distribution of <200 nm. In vitro release studies demonstrated low and sustained drug release both inthe presence and absence of human serum albumin. Based on singledose acute toxicity studies, QW8184 is well tolerated both in miceand rats with about a 3-fold increase in the maximum-tolerated-dose(MTD) over the current marketed drug formulation. Using the B16mouse melanoma model, a significant improvement in drug efficacywas observed with QW8184 over Taxol^®. Conclusions. QW8184, a stable sub-micron o/w emulsion of paclitaxelhas been developed that can be filter-sterilized and administered i.v.as a bolus dose. When compared to Taxol^®, this emulsion exhibitedreduced toxicity and improved efficacy most likely due to thecomposition and dependent physicochemical characteristics of the emulsion.