促渗剂对甲睾酮透皮作用的影响

目的:考察各种促渗剂对甲睾酮喷雾剂透皮作用的影响。方法:用改良的Franz透皮扩散池,以离体鼠皮为屏障,制备包含不同种类和浓度的促渗剂的甲睾酮乙醇溶液,高效液相色谱法测定甲睾酮累积渗透量及渗透速率。结果:薄荷素油和月桂氮卓芯酮均可显著促进甲睾酮透皮吸收,其透皮效率为:月桂氮芯卓酮-薄荷油(4%~6%,v/v)>月桂氮卓芯酮-薄荷油(2%~8%,v/v)>10%薄荷素油>10%月桂氮卓芯酮>无促渗剂。结论:薄荷油和月桂氮卓芯酮体积比为6%~4%(v/v)时比使用单一促渗剂时对甲睾酮的乙醇溶液具有更佳的促渗作用。     

透皮促渗剂对甲氧氯普胺的透皮吸收

采用Ｖ－Ｃ水平扩散池研究几种透皮促渗剂对甲氧氯普胺穿透完整小鼠皮肤的作用。实验结果表明：丙二醇、油酸、氮酮与丙二醇混合物均能增加甲氧氯普胺的穿透作用，特别是氮酮与丙二醇混合物使甲氧氯普胺透过小鼠皮肤的穿透系数增加５～６倍。     

Novel Microemulsion Enhancer Formulation for Simultaneous Transdermal Delivery of Hydrophilic and Hydrophobic Drugs

Purpose. Microemulsion (ME) systems allow for the microscopic co-incorporation of aqueous and organic phase liquids. In this study, the phase diagrams of four novel ME systems were characterized. Methods. Water and IPM composed the aqueous and organic phases respectively, whereas Tween 80 served as a nonionic surfactant. Transdermal enhancers such as n-methyl pyrrolidone (NMP) and oleyl alcohol were incorporated into all systems without disruption of the stable emulsion. Results. A comparison of a W/O ME with an O/W ME of the same system for lidocaine delivery indicated that the O/W ME provides significantly greater flux (p < 0.025). The water phase was found to be a crucial component for flux of hydrophobic drugs (lidocaine free base, estradiol) as well as hydrophilic drugs (lidocaine HCl, diltiazem HCl). Furthermore, the simultaneous delivery of both a hydrophilic drug and a hydrophobic drug from the ME system is indistinguishable from either drug alone. Enhancement of drug permeability from the O/W ME system was 17-fold for lidocaine free base, 30-fold for lidocaine HCl, 58-fold for estradiol, and 520-fold for diltiazem HCl. Conclusions. The novel microemulsion systems in this study potentially offers many beneficial characteristics for transdermal drug delivery.     

透皮促进剂对白花前胡甲素体外经皮渗透的影响

目的:考察透皮促进剂对白花前胡甲素(dl-praeruptorin A,Pd-Ia)体外经皮渗透的影响。方法:采用改进的Franz扩散池,以大鼠离体皮肤为渗透屏障,用高效液相色谱法对Pd-Ia进行含量测定,考察月桂氮酮(Azone)及1%Azone与不同浓度丙二醇(PG)混合物对Pd-Ia透皮吸收的影响。结果:使用Azone对Pd-Ia有促透作用,1%Azone效果较好,平均渗透速率达到4.064μg.cm-2.h-1;1%Azone与15%PG合用促透效果最好,平均渗透速率达到4.889μg.cm-2.h-1,且与单用1%Azone有显著性差异(P<0.05)。结论:1%Azone与15%PG合用时,含0.5%Pd-Ia溶液体外渗透具有最大促透效果,体现出协同作用。     

Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement

This study investigated the in vitro nail permeability of penetrants of varying lipophilicity—caffeine (CF, log P −0.07), methylparaben (MP, log P 1.96) and terbinafine (TBF, log P 3.3) and the effect of 2 novel penetration enhancers (PEs), thioglycolic acid (TA) and urea hydrogen peroxide (urea H₂O₂) on their permeation. Studies were conducted using full thickness human nail clippings and ChubTur^® diffusion cells and penetrants were applied as saturated solutions. The rank order of steady-state penetrant flux through nails without PE application (MP > CF > TBF) suggested a greater sensitivity to penetrant molecular weight rather than log P. TA increased the flux of CF and MP 4- and 2-fold, respectively, whilst urea H₂O₂ proved ineffective at enhancing permeability. The sequential application of TA followed by urea H₂O₂ increased TBF and CF flux (19- and 4-fold, respectively) but reversing the application order of the PEs was only mildly effective at increasing just MP flux (2-fold). Both nail PEs are likely to function via disruption of keratin disulphide bonds and the associated formation of pores that provide more ‘open’ drug transport channels. Effects of the PEs were penetrant specific, but the use of a reducing agent (TA) followed by an oxidising agent (urea H₂O₂) dramatically improved human nail penetration.     

复合吸收促进剂对葛根素肠吸收及毒性的影响

目的 考察吸收促进剂配伍对葛根素肠吸收的影响,并进一步观察复合吸收促进剂对肠黏膜的毒性。方法 运用外翻肠囊法,采用 L９（３）４ 正交设计试验考察各吸收 促进剂的协同作用,确定较理想复合吸收促进剂;运用显微形态学观察复合吸收促进剂对肠黏膜的毒性。结果 复合吸收促进剂：1% 壳聚糖、0.02% 白芷挥发油、0.06% 冰片配伍具有协同作用,可显著提高葛根素的肠吸收;复合吸收促进剂无肠黏膜毒性。结论 1% 壳聚糖、0.02% 白芷挥发油、0.06% 冰片配伍可安全有效地促进葛根素的肠吸收。     

GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer

TPA023 and α5IA are structurally related compounds that selectively modulate certain GABA_A receptor subtypes. Hence, TPA023 has weak partial agonist efficacy at the α2 and α3 subtypes whereas α5IA has inverse agonist efficacy at the α5 subtype. These efficacy characteristics translate into novel pharmacological profiles in preclinical species with TPA023 being a nonsedating anxiolytic in rats and primates whereas α5IA enhanced cognition in rats but was devoid of the proconvulsant or kindling liabilities associated with nonselective inverse agonists. In vitro and in vivo metabolic studies showed that TPA023 was metabolized via CYP3A4-mediated t -butyl hydroxylation and N -deethylation whereas α5IA was metabolized to produce the hydroxymethyl isoxazole, the latter of which was highly insoluble and caused renal toxicity in preclinical species. In humans, TPA023 had a half-life in the region of 6–7 h whereas the half-life of α5IA was 2–2.5 h. TPA023 was clearly differentiated from the nonselective agonist lorazepam in terms of saccadic eye movement and unlike lorazepam, it did not impair either postural stability, as judged by body sway, or cognition. The occurrence of the hydroxymethyl isoxazole metabolite of α5IA in human urine precluded the use of α5IA in prolonged dosing studies. Nevertheless, α5IA was evaluated in an alcohol-induced cognitive impairment model in healthy normal volunteers and was found to reverse the memory-impairing effects of alcohol. To date, however, no efficacy data for either TPA023 or α5IA in patient populations has been reported, although at the very least, the preclinical and limited clinical data with TPA023 and α5IA validate the approach of targeting specific GABA_A receptors through subtype-selective efficacy.     

Effects of L-alpha-glycerylphosphorylcholine on the EEG power spectrum in the rat

The effects of L-alpha-glycerylphosphorylcholine (alpha-GPC), a putative acetylcholine precursor, on the EEG power spetrum in rats were investigated. The results show that the oral administration of alpha-GPC (100–300–600 mg/kg) induced a significant decrease in absolute spectral energy in the delta frequency band. A significant increase in absolute spectral energy in the beta frequency band was elicited by alpha-GPC at dose levels of 100 and 300 mg/kg, while the administration of a higher dose (600 mg/kg) of this compound resulted in the loss of response (bell-shaped dose-response curve). No significant changes in the EEG power spectrum were found in rats treated with phosphatidylcholine (PC). The present data, suggesting that the electrocorticographic (ECoG) activation elicited by alpha-GPC may be correlated with its stimulatory effect on brain acetylcholine release, further extend the pharmacological profile of this new cognition enhancer. © 1992 Wiley-Liss, Inc.     

Comparison of the in vivo pharmacological profiles of sabeluzole and its enantiomers

Sabeluzole, a compound with pronounced cognitive enhancing, antihypoxic, and anticonvulsant properties, is the racemic mixture of the enantiomers R 84 439 (R-configuration) and R 84 440 (S-configuration). Sabeluzole and its separate enantiomers were compared in tests evaluating cognitive enhancing, antihypoxic, anticonvulsant, and secondary activity. Only small differences in potency were observed over species (mice, guinea pigs, and rats), routes of administration (i.p., s.c., and p.o.), and time intervals (ranging from 0.5 to 16 hr). R 84 440 was generally slightly more potent (up to 2.6 times) but also slightly shorter acting than R 84 439 (5 vs. 7 hr after s.c. administration in rats). The present data confirm and further extend the pharmacological profile of sabeluzole and indicate that both enantiomers contribute to its biological activity. Selection of one of the enantiomers instead of racemic sabeluzole provides no practical advantage in terms of potency, onset and duration of action, oral absorption, or therapeutic index.