Preparation,stability and pharmacokinetics evaluation of lipid microspheres loading a promising antitumor candidate,Timataxel

Timataxel (13-(N-Boc-3-i-butylisoserinoyl-4,10-β-diacetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,13-α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene), used to be called TM-2, is a novel semi-synthetic promising candidate for cancer treatment. However the preformulation study showed that TM-2 was insoluble and chemically instable in water, which would limit its application. This study aimed at the preparation of Timataxel lipid microspheres (TM-2 LMs) and investigated the difference between TM-2 LMs and TM-2 solution in pharmacokinetics. In this work, the final formulation was as follows: 0.10% (w/v) TM-2; 10.00% (w/v) oil phase (long chain triglyceride:media chain triglyceride = 2.50%:7.50%); 1.40% (w/v) phospholipid; 0.02% (w/v) NaH₂PO₄; 2.25% (w/v) glycerin and water to a total volume of 100 ml. The particle size distribution, content and entrapment efficacy were 205.0 ± 43.3 nm, 101.00%, and 99.12%, respectively. TM-2 LMs were stable during storage at 25 °C for 3 months, even under the condition of 60 °C and 4500 lx for 10 d. Phosphatidylethanolamine (PE) in phospholipid may contribute to the stability of TM-2 LMs. The pharmacokinetic parameters for TM-2 LMs were as follows: AUC_(0-∞) 3663.71 µg/l h and the clearance 2.26 l/h/kg. As for solution, these parameters were 1712.52 µg/l h and 4.77 l/h/kg, respectively. The t_1/2 of TM-2 LMs was similar to TM-2 solution. The pharmacokinetic results indicated that the AUC of TM-2 LMs was larger, the clearance was smaller than that of TM-2 solution. In a word, lipid microspheres were a promising drug delivery system for TM-2.     

Regional pharmacokinetics. II. Experimental methods

Regional pharmacokinetics is the study of the drug concentrations in specific regions of the body. It allows greater insight into the mechanisms of drug disposition than the study of systemic blood concentrations. Experimental methods in regional pharmacokinetics and their applications and limitations are reviewed. Post-mortem tissue biopsies give the drug concentrations in highly specific regions of the body, but require a large number of animals. Serial tissue biopsies yield the time-course of drug concentrations in individual animals, but have limited applications. Regional blood sampling in vivo requires catheterization of blood vessels and a measure of regional blood flow, but allows repeated measurements of the time-course of regional drug concentrations in an individual. In contrast, artificially perfused regions allow greater control of perfusate flow and composition, but are less representative of the in vivo situation. These factors can be retained in some animals by surgically transplanting organs to another location to increase access. Tissues slices and cell cultures can examine drug uptake in the absence of perfusion, and tissue homogenates can be used to study the in vitro rates of drug metabolism and tissue drug binding.     

System approaches in pharmacokinetics: II. Applications

Pharmacokinetic system approaches mathematically describe a general property of a pharmacokinetic system without modeling in specific terms the kinetic processes responsible for the general property. Certain applications of the system approach including methods for evaluating drug delivery, drug distribution, drug secretion, and biotransformation in linear and nonlinear pharmacokinetics are presented and discussed. Linear system formulae for various mean time disposition parameters and a disposition decomposition-recomposition system approach for predicting drug levels when the drug clearance changes are presented and discussed. System approaches offer certain advantages over traditional approaches for many practical applications.     

Biphasic release of indomethacin from HPMC/pectin/calcium matrix tablet: II. Influencing variables, stability and pharmacokinetics in dogs

The pectin/calcium interaction, which is the basis for biphasic release of indomethacin from the HPMC/pectin/calcium chloride matrix tablet, is susceptible to influence of a variety of variables that is supposed to be encountered by the oral route. In this study, the effect of influencing variables on biphasic release characteristics, the stability and the pharmacokinetics of the hybrid matrix tablet were investigated. An increasing tendency of the overall release rate was observed from pH 1.2 to 7.4. The power law correlation n values increased with pH, while the release lag time or 10% release time (T_0.1) decreased at pH 6.8 and 7.4. Ionic strength in the release media also influenced the biphasic release significantly at sodium chloride levels of over 0.5%. Obvious increase in overall release rate was observed at sodium chloride level of 0.9% with an n value of 1.20 and a T_0.1 of 3.4 h. At sodium chloride levels of over 2%, the pectin/calcium interaction was disrupted resulting in very fast release of indomethacin. Release in gradient pH media was similar to that in pH 6.8 citrate buffer. When pectinase (Pectinex Ultra SP-L) was added into the release medium in 22.2 pg/ml or over, obvious triggering on drug release was observed. The stress testing showed increased release at extreme relative humidity of 92.5%. Both accelerated testing for 6 m and long-term testing for 12 m affirmed fine stability, especially in release characteristics. Pharmacokinetic study in dogs gave T_max/C_max of 4 h/604 ng/ml and 3 h/1662 ng/ml for HPMC/pectin/calcium and HPMC/pectin tablet, respectively. The plasma indomethacin level of the calcium-containing tablet was maintained at a much lower level for 3 h with a MRT of 7.13 h, longer than 3.97 and 5.61 h for indomethacin crude drug and HPMC/pectin tablet, confirming delayed absorption. The AUC of the HPMC/pectin/calcium tablet was lower than that of the HPMC/pectin tablet and indomethacin crude drug showing incomplete absorption. It is concluded that the HPMC/pectin/calcium matrix tablet is potentially useful for colon-specific drug delivery.     

Heroin addiction: neurobiology, pharmacology, and policy.

The neurobiology of drug addiction is being clarified. Research is revealing the anatomic pathways of primary drug reinforcement (reward) in the brain and the molecular architecture of the receptors on which addictive drugs act. All addictive drugs mimic (or occasionally block) the actions of some neurotransmitter; in the case of heroin or methadone an endogenous opioid, probably beta-endorphin. The groundwork is being laid for understanding Dole and Nyswander's "metabolic disease" concept as a concrete neurochemical abnormality of the endogenous opioid system. Thus, a stronger basis is developing for regarding methadone maintenance as a means of replacing a neurohormonal deficiency. Three practical conclusions that can be drawn from this model are: (1) methadone dosage must be adequate (never less than 50-80 mg); (2) it should be more widely accepted that some patients may require lifelong methadone maintenance; and (3) longer-acting, better stabilizing methadone congeners, such as LAAM and its metabolites, should be brought into general use.     

Hemoglobin niosomes. I. Preparation, functional and physico-chemical properties, and stability

Hemoglobin niosomes. I, Preparation, functional and physical properties and stability. Hemoglobin niosomes (non ionic liposomes) obtained from L'Oréal synthetic lipids by solvents vaporization appear as unilamellar spherical red vesicles, isolated from each other and with heterogeneous size (0.5 to 4 microns). Their suspensions show a visible spectra superimposable to that of free hemoglobin which is incorporated at a rate of 0.3 to 0.5 g per lipid gram. Vesicles are permeable to oxygen and the hemoglobin dissociation curve can be modified similarly to non-encapsulated hemoglobin. Niosomes appear physically stable while hemoglobin undergoes a progressive oxidation to methemoglobin reaching 30% after 5 months at 4 degrees C. Even in the absence of dicetylphosphate (DCP), niosomes possess a negative charge confering to them an electrophoretic mobility. 5% DCP allows to obtain a zeta potential near to that of erythrocytes. The niosomes suspensions are more viscous than red blood cells but their rheological behavior is similar and the vesicles may have some deformability.     

Cold Preparation of Heroin in a Black Tar Market

Background: Black tar heroin is typically prepared for injection with heat which decreases the risk of HIV transmission by inactivating the virus. We received reports that persons who inject drugs (PWID) in Tijuana, Baja California, Mexico, a black tar heroin market, were using only water to dissolve heroin. Objectives: Because Tijuana abuts San Diego County, CA, United States, we undertook the present analyses to determine the prevalence of this practice among PWID in San Diego, California. Methods: PWID completed quarterly behavioral assessments and serological testing for blood-borne viruses. Bivariate and multivariable logistic regression models were constructed to assess for individual, social, and structural correlates of preparing heroin without heat within the preceding 6 months. Results: Nearly half of black tar heroin users (149/305) reported they had prepared heroin without heat within 6 months. In multivariable analysis, cold preparation was independently associated with younger age (10 year decrease; AOR = 1.25; 95% CI 1.03, 1.53), more drug injecting acquaintances (per 5 acquaintance increase; AOR = 1.05; 95% CI 1.01, 1.09) and prefilled syringe use (injecting drugs from syringes that are already filled with drugs before purchase; AOR = 1.86; 95% CI 1.14, 3.02). Conclusions/Importance: To our knowledge, this is the first paper to report that PWID living in a black tar heroin market are preparing heroin without heat. Additional research is needed to determine whether this is an endemic practice or PWID are engaging in new forms of drug preparation in response to changes in the environment.     

姜黄素纳米乳的制备和药动学及药效学研究

目的 探究姜黄素纳米乳在大鼠体内的药动学特性和对大鼠高脂血症的药效作用。方法 建立大鼠血浆中姜黄素的高效液相色谱-质谱联用（HPLC-MS）含量测定方法,考察纳米乳的体内药动学过程。建立SD大鼠高脂血症动物模型,初步考察姜黄素纳米乳对高脂饮食诱导的大鼠高脂血症的药效作用。结果 体内药动学研究结果表明,以姜黄素原料药为参比制剂,姜黄素纳米乳的相对生物利用度为313.47%;以市售片剂为参比制剂,姜黄素纳米乳的相对生物利用度为279.52%。纳米乳组的Cmax为原料药组的201.48%,为片剂组的193.02%,且比原料药组及片剂组具有更高的MRT值（为原料药组的183.52%,是片剂组的154.21%）。药效学研究结果表明姜黄素纳米乳口服给药系统能显著降低模型大鼠的血清总胆固醇（TC）、低密度脂蛋白（LDLc）,缓解高脂饮食给模型大鼠造成的肝脏脂质沉积及肝损伤。结论 姜黄素纳米乳口服给药系统能够有效改善姜黄素的生物利用度,具有良好的降血脂作用,并能够控制高脂血症大鼠体重增长和改善由脂质代谢紊乱造成的肝脏系数变化。     

Preparation,characterization and pharmacokinetics of 10-hydroxy-camptothecin nanosuspension

10-Hydroxycamptothecin (HCPT) is a broad-spectrum anticancer drug, while its low solubility and instability severely limit its application. In this study, HCPT nanosuspension (HCPT-NSP), also known as nanocrystal, was prepared by micro-precipitationcombined with high-pressure homogenization method. This nanosuspension was characterized by size, shape, zeta potential, drug loading efficiency and in vitro drug release behavior. Preferred formulation and process showed that particle size was (129.8±13.9) nm, PDI was 0.20±0.07, and drug loading efficiency was 36.5%±9.5%. Moreover, HCPT nanocrystal concentration reached(1.35±0.2) mg/mL in HCPT-NSP, which was more than 1000-fold higher than that of HCPT. Transmission electron microscopy (TEM) results showed that the nanosuspension was short rod in shape. X-ray powder diffraction (XRD), thermogravimetric analysis (TGA), derivative thermogravimetric analysis (DTA) and differential scanning calorimetry (DSC) further elaborated the crystal state of the HCPT. The drug concentration-time curve of HCPT-NSP in rats was in accordance with the three-compartment model, showing prolonged half-life. Taken together, our data suggested that HCPT-NSP was a promising drug delivery system.     

Enol esters as potential pro-drugs II. In vitro aqueous stability and enzyme-mediated hydrolysis of several enol esters of acetophenone

Several α-acyloxystyrenes were synthesized and evaluated as models of enol esters which might be used in pro-drug design. Their stabilities were evaluated in aqueous buffered solutions at various pH values and temperatures, and in human and rat plasma and tissue homogenates at 37°C. The enol esters studied were relatively stable in neutral aqueous media, but most hydrolyzed rapidly and completely to yield the parent ketone (acetophenone) with the aid of enzymatic catalysis in the biological media used. The aqueous and enzymatic rates of hydrolysis were substantially affected by the nature of the acyl group. The results of this study indicate that enol esters are rather stable yet bioreversible derivatives of ketones and therefore may be useful as pro-drugs of agents containing enolizable carboxyl groups.     

Cremophor-free intravenous microemulsions for paclitaxel II. Stability, in vitro release and pharmacokinetics

Two cremophor-free microemulsion systems LBMW (lecithin:butanol:myvacet:water) and CMW (capmul:myvacet:water), for intravenous (IV) administration of paclitaxel (PAC) were previously developed and characterized. Their chemical stability, in vitro release and pharmacokinetics of PAC were assessed using Taxol (cremophor:ethanol 1:1, 6 mg/ml) as a reference. The shelf-lives of PAC at 25 degrees C in Taxol, LBMW and CMW, in an accelerated stability study, were 71, 57 and 31 days, respectively. The activation energy (Ea) for PAC in Taxol, LBMW and CMW was 23, 16 and 14 kcal/mol, respectively. PAC released from LBMW and CMW using a dialysis technique was significantly slower than that from Taxol. The extents of release of PAC from LBMW and CMW were 25 and 50% of that from Taxol. In vivo pharmacokinetic studies in male Sprague-Dawley rats after IV administration revealed that PAC in LBMW and CMW remained in the systemic circulation five and two times longer and was eight and three times more widely distributed than PAC from Taxol. LBMW and CMW offer a significant clinical advantage in terms of the prolonged half-life and wide tissue distribution, indicating that PAC delivered by these systems intravenously may result in prolonged exposure of PAC to the tumor and subsequently an improved clinical efficacy.     

Amiodarone pharmacokinetics. II. Disposition kinetics following subchronic administration in rats

A 30 mg kg-1 intravenous bolus of 14C-amiodarone (19 microCi kg-1) was given to male Sprague-Dawley rats pretreated with 0 (vehicle), 25 or 100 mg kg-1 day-1 of amiodarone HCl orally for 37-42 days to determine the effects of dose and duration of administration on the disposition kinetics of amiodarone. Serial blood samples and total urine were collected over 48 hours and assayed for 14C-amiodarone by liquid scintillation counting following separation by HPLC. In all three groups, the blood 14C-amiodarone concentration-time curves declined bioexponentially with terminal half-lives (t1/2 beta) ranging from 14-22 hours. No differences in beta, t1/2 beta, or central compartment volume (Vc) were observed between the three groups of rats. In the rats pretreated with 100 mg kg-1 day-1 of amiodarone HCl for 5-6 weeks, amiodarone clearance (CL) and steady state volume of distribution (Vss) were reduced 52 per cent (12.2 to 5.9 ml min-1 kg-1) and 41 per cent (11.73 to 6.97 l kg-1), respectively. At the lower amiodarone daily dose, no changes in CL or Vss were observed. Negligible levels of radioactivity were detected in the urine. Amiodarone accounted for approximately 30-40 per cent of the total radioactivity in each blood specimen. This study demonstrated that CL and Vss were dose-dependent, and that beta, t1/2 beta and Vc were dose-independent. The results further suggested that the disposition kinetics of amiodarone were independent of the duration of drug administration.     

Nonlinearities in amoxycillin pharmacokinetics. II. Absorption studies in the rat.

Most factors influencing amoxycillin oral absorption are, even today, unknown. Since many dosage schedules have been shown to lead to incomplete absorption, it would be desirable to find a suitable animal model where these factors could be studied in depth. In this paper, it is shown that, in the rat, plasma level curves obtained after oral doses of 7 and 28 mg kg-1 are poorly fitted using first-order absorption kinetics and that the best fit is obtained through the use of an input equation combining zero and first-order kinetics. In contrast, plasma level curves found after intraduodenal administration of amoxycillin solutions (7 mg kg-1) are well fitted by first-order input kinetics. It would seem that precipitation of some dose fraction of the orally administered antibiotic may occur in proximal gastrointestinal areas; this plays an important role in absorption profiles and prevents any possible saturation phenomena associated with active intestinal transport of the antibiotic. A comparative study of available human oral data revealed close similarities with those found in rats. As a result, the plasma level curve fitting was greatly improved by the use of the input function described here for the rat. Although oral bioavailability (as assessed from urinary excretion data) is lower in this latter species, the use of suitable correction factors led to superimposable plasma level curves in the two species, as occurred in previously reported disposition studies.