Testosterone skin permeation enhancement by menthol through formation of eutectic with drug and interaction with skin lipids

The aim of this investigation was to elucidate the mechanism of skin permeation enhancement of the lipophilic drug, testosterone, by menthol. Menthol was found to form eutectic mixtures with testosterone, cholesteryl oleate, and ceramides. DSC measurements showed that menthol drastically lowers the Tm of testosterone, from 153.7 to 39.9 degrees C. The decrease in Tm resulted in an increase in the solubility of testosterone in an aqueous ethanol vehicle by 2.8-fold, which caused a corresponding 2.8-fold increase in the flux of testosterone. A further increase in skin flux, to eight times the base line, could be attributed to the effect of menthol on the skin barrier properties. This assumption is supported by DSC results showing that menthol decreases the Tm of cholesteryl oleate and ceramides and modifies the thermogram profile of isolated stratum corneum. The results of this investigation indicate that menthol affects skin permeation by a dual mechanism: by forming a eutectic with the penetrating compound, thereby increasing its solubility, and by altering the barrier properties of the stratum corneum. Moreover, this study indicates that both types of interactions must be taken into consideration when using chemical enhancers and that decreasing the melting temperature of the permeant through formation of a eutectic could be one approach for increasing solubility and permeation rates.     

Membrane potential of mesenteric artery from carvedilol-treated spontaneously hypertensive rats

The effect of current, its magnitude and penetration enhancers (propylene glycol/oleic acid) on the transdermal flux of AZT (Zidovudine) across hairless mouse skin was studied and the results were compared. The in vitro iontophoretic flux from AZT solution increased to about 5-40 fold that obtained by passive diffusion, depending on the magnitude of current density. When the donor side was karaya gum matrix, instead of solution, the flux enhancement effect by iontophoresis was much smaller. Incorporation of penetration enhancers into the matrix increased the passive flux 2-50 fold, depending on the amount of penetration enhancers in the matrix. These enhancers worked synergistically with iontophoresis in the transdermal transport: a much larger flux than that expected from a simple additive effect was observed. Electrical resistance data from our previous work is utilized to further discuss this synergistic effect.     

Antiarrhythmic effect of solvents: propylene glycol, benzyl alcohol

Propylene glycol and benzyl alcohol, the main constituents of most solvent vehicles, display a pronounced antiarrhythmic-antifibrillatory effects, when injected intravenously into animals (dogs, rats) with spontaneous or drug-induced arrhythmias. The antiarrhythmic dose for propylene glycol amounts to 0.2-0.3 ml/kg of a 70 per cent solution and, for benzyl alcohol to 0.2-0.4 ml/kg of a 4 per cent solution in physiologic saline, respectively. Similar effects were also obtained by the combined injection of propylene glycol + benzyl alcohol, in proportions which correspond to the formulae of numerous commercial "solvents" (vehicles): 2 to 20 per cent solutions of benzyl alcohol in 70 per cent propylene glycol (0.05-0.2 ml/kg). The mechanisms which might be responsible for the antiarrhythmic activity of solvents are discussed: lengthening of the effective refractory period, local and general anaesthetic effects, changes of osmolarity. The intravenous injection of propylene glycol and/or benzyl alcohol, in high doses, produces intravascular haemolysis. Clinical investigations are recommended as to the potential, beneficial or toxic effects of drug solvents, especially upon the cardiocirculatory system.     

Solid State Structure and Lyotropic Mesomorphism of Rare-Earth Trisdode-cylsulphates in the Water-Ethylene Glycol System

The phase behaviour of lanthanide(Ⅲ) dodecylsulphates, Ln(C12H25SO4)3, by thermo-optical microscopy using Lawrence penetration technique was investigated. The lyotropic phase behaviour of lanthanide(Ⅲ) dodecylsulphates in ethylene glycol water in mixtures hereof, depends on the composition of the solvent. For pure ethylene glycol and mixtures of ethylene glycol and water three different mesophases are formed, i.e.a lamellar, a cubic and a hexagonal phase, whereas when water is used as solvent no cubic phase is formed. The size of the lanthanide ion has no influence on the mesomorphism of these metallomesogens, although the smaller the lanthanide ion the lower the solubility.     

Ethanol preference and behavioral tolerance in mice: Biochemical and neurophysiological mechanisms.

Determinations were made of ethanol preference and behavioral tolerance in 4 experiments with inbred strains of mice. High- and low-preference strains were compared on neural tolerance to ethanol and metabolic capacity. High preference for ethanol was accompanied by higher behavioral and neural tolerance than that found in low-preference Ss. Differences in metabolism of ethanol between high- and low-preferring Ss were small. However, low-preference Ss did not metabolize acetaldehyde as rapidly as high-preference Ss. Differences in preference for propylene glycol were in the same direction and as extreme as those for ethanol. Both substances are CNS depressants; but unlike alcohol, propylene glycol is not metabolized to a toxic metabolite that might induce a conditioned aversion. This finding in addition to the difference observed in neural tolerance suggests that neural sensitivity may play a part in the acceptance or rejection of ethanol and propylene glycol. (30 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exposure to glycols and their renal effects in motor servicing workers

Ten car mechanics frequently exposed to glycol-based cooling liquids were followed during a workshift. Airborne ethylene and propylene glycol concentrations in the car mechanics' environment were measured. The car mechanics gave urine samples after the workshift and their excretion of ethylene glycol, propylene glycol, oxalic acid, calcium and ammonia was analysed and compared to that of unexposed office workers. Urinary succinate dehydrogenase activity and glycosaminoglycans were also measured in both groups. Airborne ethylene and propylene glycol concentrations in the car mechanics' environment were negligible. Urinary ethylene glycol excretion in exposed workers was significantly higher than that in unexposed workers, but propylene glycol excretion was at the same levels as in controls. In the exposed group, the excretion of the end metabolite of ethylene glycol, oxalic acid (47 +/- 11 mmol/mol creatinine, mean +/- SD, n = 10) differed slightly from that of controls (36 +/- 14 mmol/mol creatinine, mean +/- SD, n = 10). Urinary excretion of ammonia was higher among exposed workers than office workers. The excretion of calcium did not differ from that of controls. A marginally decreased urinary succinate dehydrogenase activity was found in the exposed men. The excretion of glycosaminoglycans was significantly lower in exposed workers. Therefore, it seems that ethylene glycol is absorbed by skin contact. The internal body burden is associated with oxaluria and increased ammoniagenesis typical of chronic acidosis.     

Beneficial effect of vitamin E administration on nitric oxide function in subjects with hypercholesterolaemia

Study of the solubilization of commercial grades of soya phosphatidylcholine (SPC) with different purities by bile salts (BS) indicated that only highly pure grades of SPC are suitable for the preparation of clear solutions of BS/SPC-mixed micelles (BS/SPC-MM). The solubilizing capacity of different BS towards SPC increased in the following order; Sodium cholate (SC) < sodium deoxycholate (SDC) < sodium glycocholate (SGC). Moreover, egg phosphatidylcholine (EPC) was solubilized to a higher extent than SPC. Furthermore, the solubility study of different drugs in the prepared MM showed substantial enhancement of solubility, the extent of which is essentially affected by the chemical nature of the drug and the composition of MM. Benzodiazepine drugs such as clonazepam, tetrazepam, diazepam, and lorazepam displayed higher affinity for MM compared with BS alone, whereas steroidal drugs, such as estradiol, prednisolone and progesterone, compared with benzodiazepines, displayed relatively higher affinity for BS alone. The solubilizing capacity of MM for the different drugs was increased to different degrees by the addition of benzyl alcohol which was comparable to the solubility of the drug in pure benzyl alcohol. The interaction between benzyl alcohol and the drug in MM could be proved by NMR.     

Tonsillar carcinoma: analysis of treatment results

A diffusion cell with an artificial membrane and the single-pass perfused rabbit ear were used to evaluate the percutaneous absorption of clonazepam from various 2-hydroxyethyl acetate (HEA) patches. The influence on drug permeation of the various type of enhancers (isopropylmyristate, lauryl alcohol, propylene glycol and water) in the patches was tested. A comparison between the two types of systems of percutaneous absorption of clonazepam has been done. The results showed that HEA patches produce controlled uniform drug release, modulated by the addition of enhancers.     

Congenital Becker''s nevus with a familial association

Coprecipitates were prepared using different ratios of flutamide with polyvinyl pyrrolidine (PVP), polyethylene glycol (PEG) 4000 and 6000. Drug solubility in carrier solutions, thin layer chromatography (TLC), differential scanning calorimetry (DSC), infra-red spectroscopy (IR), uniformity of drug content, drug dissolution from its respective systems and effect of aging on the physico-chemical parameters of stored flutamide-polymer system were studied. PEG 6000 was found to be the most efficient polymer in increasing both the solubility and the release rate of flutamide. Interaction was found to be complete in certain ratios of drug/polymer systems. The dissolution pattern of flutamide from all the prepared systems appeared to fit a first order mechanism. Physico-chemical parameters of flutamide/carrier systems were not influenced by storage.     

Programmed diffusional release rate from encapsulated cosolvent system

The programmed diffusional release rate of an active agent through a rate-controlling membrane from a cosolvent system is discussed. At initial conditions, the drug is present below saturation in solution in a solvent mixture, enclosed by the rate-controlling membrane; the solvent is composed of the main solvent and a consolvent, which increases the drug solubility in the main solvent. During operation, the active agent and cosolvent diffuse from the capsule at a rate controlled by the membrane. Equations were derived describing the release rate of the active agent as a function of the permeability of the cosolvent and agent, the capsule dimensions, and the system's initial conditions. A great variety of release rate profiles can be programmed from declining to increasing delivery rate patterns as a function of time. Experimental data are presented for the drug progesterone in solution in cyclohexane with methyl, heptyl, or cetyl alcohol as the cosolvent in a polyethylene capsule. The theory qualitatively predicts the theory qualitatively predicts the experimental results.     

Coma in a premature infant associated with the transdermal absorption of propylene glycol

A case of propylene glycol intoxication in a premature infant is reported. The infant went into a state of coma after treatment for burns with antiseptic dressings. Cessation of the topical treatment resulted in complete recovery. An exceptionally high level of the dressings' solvent, propylene glycol, found in the urinary chromatogram, was believed to be the causative agent. It is suggested that topical preparations containing propylene glycol should not be used in premature infants during the first weeks of life.     

Stable nonaqueous pentobarbital sodium solutions for use in laboratory animals

The degradation kinetics of pentobarbital sodium in propylene glycol-based solutions were studied along with the in vivo effects in laboratory animals. The degradation rate constant was directly proportional to the water concentration in propylene glycol-water solvent systems. An activation energy of 23.4 kcal/mole was obtained in propylene glycol-water (1:1). Pentobarbital sodium solutions in anhydrous propylene glycol and 9:1 mixtures of propylene glycol with ethanol, glycerin, or dimethylacetamide gave relatively slow degradation rates at 100 degrees with all projected 25 degrees t 99% values greater than 4.5 years. Intravenous administration of pentobarbital sodium in various anhydrous propylene glycol-based vehicles to rats produced no hemolysis of gross organ damage that would interfere with pathological evaluations. Results of an intraperitoneal sleeptime study indicated that pentobarbital sodium produced consistent hypnotic effect when administered as an aqueous solution or in anhydrous propylene glycol-based vehicles.     

Effect of method of delivery of propylene glycol on plasma metabolites of feed-restricted cattle

Methods of administering propylene glycol to reduce plasma nonesterified fatty acids (NEFA) during feed restriction of cattle were evaluated. Treatments were 1) no propylene glycol supplementation, 2) propylene glycol provided as an oral drench once per day, 3) propylene glycol mixed with concentrate and fed separately from forage, or 4) propylene glycol blended as part of the total mixed ration (TMR). Prior to or during feed restriction at 50% of ad libitum intake, propylene glycol was provided once daily at 2.5 ml/kg of body weight. Prior to feed restriction, administration of propylene glycol as an oral drench or mixed with concentrate was more effective in increasing serum insulin than was feeding propylene glycol as part of the TMR. During feed restriction, administration of propylene glycol as an oral drench or mixed with concentrate resulted in higher serum insulin and lower plasma NEFA concentrations than did feeding propylene glycol as part of the TMR. Propylene glycol decreased the molar percentage of ruminal acetate and the ratio of acetate to propionate. Propylene glycol administered as an oral drench or mixed with concentrate and fed separately from forage appeared to be more effective than feeding propylene glycol as part of the TMR for influencing plasma NEFA in cattle during feed restriction.     

Influence of skin and muscle lesions on the hepatic cytochrome P450 function in 10 and 60 day-old male Wistar rats

In 10 and 60 day-old male Wistar rats skin lesions of different extents and muscle lesions lead to decreases in cytochrome P450 concentrations and monooxygenase activities (ethylmorphine N-demethylation and ethoxycoumarin O-deethylation) at least up to 7 days after operation. The extent of the depression was related to the extent of the lesion and independent of the nature of the tissue involved.     

In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes

Tamoxifen is a highly lipophilic drug that is widely used in breast malignancies and also as a prophylactic therapy in women at high risk for the development of this disease. Recently, the terpenes have been reported to show an enhancement effect on percutaneous drug absorption. The effect of terpenes (e.g. carvone, 1,8-cineole, menthol, and thymol) was studied on the in vitro percutaneous absorption of tamoxifen through porcine epidermis. The above terpenes (5% w/v) in combination with 50% ethanol significantly (P < 0.01) increased the permeability coefficient of tamoxifen in comparison to the control (50% ethanol). The solubility of tamoxifen was determined in the control and enhancer solutions to correct the permeability enhancement by way of fractional solubility adjustment. Binding of tamoxifen to powdered stratum corneum from control and enhancer solutions was also determined. Binding studies reveal that the enhancement in the permeability coefficient of tamoxifen by menthol and thymol is due at least in part, to improvement in the partitioning of the drug to the stratum corneum. In conclusion, terpenes in combination with ethanol can be used to enhance the percutaneous absorption of the highly lipophilic drug tamoxifen.     

In vitro evaluation of a series of N-dodecanoyl-L-amino acid methyl esters as dermal penetration enhancers

A series of N-dodecanoyl-L-amino acid methyl esters (1-10) and n-pentyl N-acetylprolinate (11) were evaluated for dermal enhancement properties using an in vitro diffusion cell technique. Methods of synthesis of these compounds were described. Enhancers were applied 1 h prior to drug treatment. Hydrocortisone was used as the model drug and was applied to excised hairless mouse skin as a saturated suspension in propylene glycol. Enhancement ratios (ER) were determined for permeability coefficient, 24 h diffusion cell receptor concentration (Q24), and 24 h full-thickness skin steroid content. Controls received no enhancer pretreatment of the skin. N-Dodecanoyl-L-proline (10) showed the highest Q24 value for total steroid (ER 13.7) while N-dodecanoyl-L-phenylalanine (5) showed the highest total steroid skin retention (ER 16.5).     

Variables related to the psychological well being of Army wives during the stress of an extended military separation

Ulcer prevention efficacy of orally, rectally and sublingually administered omeprazole was evaluated and compared using ulcer index and percentage inhibition of ulcerogenicity in three different acute gastric ulcer models viz, indomethacin, 0.6N HCl and aspirin (after pylorus ligation) induced ulcers in rats. The ulcer prevention efficacy after oral, rectal and sublingual administration were statistically significant (P < 0.01) in all the models. The differences in ulcer index and percentage inhibition of ulcerogenicity for rectal and sublingual administration were insignificant (P < 0.05) in indomethacin and HCl induced ulcers and were significant (P < 0.05) in aspirin induced ulcers. The ulcer prevention activity was significantly higher (P < 0.05) after rectal and sublingual routes when compared to oral administration in all three models evaluated. Results revealed a faster onset and higher extent of pharmacodynamic activity of omeprazole after rectal and sublingual administration.     

In vivo results with a new device for ultrasonic monitoring of pig skin cryosurgery: the echographic cryoprobe

One of the main difficulties encountered in cryosurgery is the uncertainty in the extent and depth of the tissue effectively treated during the freezing process. The objective of this study was to evaluate in vivo ultrasonic control of skin cryosurgery using a new echographic cryoprobe. An echographic cryoprobe, developed specifically for dermatology applications, combines a high-frequency (20 MHz) miniature ultrasonic transducer and a N2O-driven closed cryoprobe. Knowledge of the ultrasound velocity of frozen skin is a prerequisite for monitoring the iceball formation kinetics. Therefore, in a first study, we estimated the ultrasound velocity of frozen skin specimens. In a second step, the operation of the echographic cryoprobe was assessed, under in vivo conditions similar to those used in human therapeutics, on normal skin of three female "Large-White" pigs under anesthesia. The mean value of ultrasound velocity of frozen skin obtained by pooling the data from all the skin specimens included in this study was 2865 +/- 170 m per s. The average rates of growth (10(-2) mm per s) of the iceballs were found to be 12.2 +/- 1.0 (pig 1), 9.0 +/- 1.0 (pig 2), and 8.4 +/- 0.9 (pig 3). The echographic cryoprobe had a built-in high-frequency ultrasonic transducer that served two functions. It enabled in vivo real-time monitoring of depth penetration of the iceball and it gave important feedback to the operator or to the console relating to the rate of growth of the iceball. Automatic (i.e., operator-independent) detection of the echo signal from the freezing front and calculation of the depth penetration of the iceball was possible.     

DTAB微乳液体系溶水性能研究

研究了阳离子表面活性剂DTAB与不同助表面活性剂、油相形成的微乳液体系的溶水能力,并考察温度、pH对微乳液体系稳定性的影响。分别绘制了不同体系的拟三元相图。结果表明:当DTAB与正丁醇质量比为13∶7,(DTAB+正丁醇)与环己烷质量比为3∶1时,DTAB/正丁醇/环己烷/水微乳液体系具有较大的稳定区域,其最大溶水量在50%左右。该微乳液体系在温度低于80℃时,稳定区域受温度影响较小;pH对该体系稳定性影响不大。     

Penetration, permeation, and resorption of 8-methoxypsoralen. Comperative in vitro and in vivo studies after topical application of four standard preparations

The penetration, permeation, and resorption of radioactively labelled 8-Methoxypsoralen was investigated in human skin. Siultaneously, the effects to time and ointment carrier on the penetration kinetics were ascertained. The carriers tested were: vaseline, aqueous wool-wax alcohol ointment, aqueous hydrophilic ointment and polyethylene glycol ointment. The absolute concentrations of 8-Methoxypsoralen were estimated in the horny layer, epidermis and dermis. With the most advantageous carrier, aqueous wool-wax alcohol ointment, 4-6X10(-5) M and 10(-5) M were attained in the epidermis and dermis, respectively. Moreover, it was shown that the substance penetrates rapidly (10 min) into the epidermis and dermis and the high concentrations reached constant over a period of 16 h. Only with a formulation of aqueous wool-wax alcohols is any accumulation at all achieved in the deeper areas of the horny layer. A uniform decrease in drug concentration with increasing depth of the horny layer is found with the other 3 vehicles, whereby slight variations in concentrations pertain from carrier to carrier. 4 h after local application, 8-Methoxypsoralen can be detected in the urine. Regardless of the ointment base employed, 8-Methoxypsoralen is no longer detectable in the urine 40 h after application. In comparison to the oral therapy, the same magnitude of percutaneous resorption into the central compartment is to be derived from the data, if half the body surface is treated locally.