Jonathan R. Matias

The Possibility of Lidocaine Ion Pair Absorption Through Excised Hairless Mouse Skin

The purpose of the present research was to test the ion pair absorption hypothesis with respect to the topical route of drug delivery. The experiment consisted of preparing various lidocaine-n-alkanoate ion pairs, then characterizing them by proton magnetic resonance spectroscopy, elemental analysis and conductivity. Percutaneous absorption studies through excised hairless mouse skin were carried out using ethanolic solution of radiolabeled 14C-lidocaine-octanoate, 14C-lidocaine-decanoate and 14C-lidocaine-dodecanoate. Studies were conducted under steady-state conditions using Bronaughs flow-through apparatus and normal saline as the receptor fluid. Ethanolic solution of a lidocaine base served as a control. The apparent differences in flux between lidocaine and the various ion pairs were statistically significant (p less than 0.05). The differences among the fluxes of the various ion pairs were not statistically significant (p greater than 0.05), nor were the differences in lag times (p greater than 0.05). The difference between the flux values of lidocaine-1-14C-dodecanoate and 14C-lidocaine-dodecanoate infers that lidocaine-dodecanoate did not cross the excised, full-thickness, hairless mouse skin as an intact 1:1 ion pair. The formation of weakly associated ion pairs was suggested by the apparent low-association constants (Ka = 15-17 liters/mol) obtained at 25 degrees C in methanol by conductometric analysis.

Local Inhibition of Sebaceous Gland Growth by Topically Applied RU 58841

The biological activity of a series of nonsteroidal, pure androgen receptor inhibitors was compared using the Syrian hamster ear skin sebaceous gland model. RU 58841, RU 56187, RU 38882 and cyproterone acetate were applied topically for 4 weeks on the ventral ear pinna of sexually mature male Syrian hamsters. Their order of efficacy was as follows: RU 58841 > RU 56187 > RU 38882 > cyproterone acetate. Maximal reduction of 60% in the size of the sebaceous glands was observed in hamsters treated with RU 58841 at a dose of 10 micrograms per day. This degree of inhibition occurred without any systemic side effects as shown by the absence of inhibition on the contralateral untreated ear pinna. Longer treatment did not produce greater inhibition since extending the treatment period from 4 weeks to 12 weeks showed similar data. The effect of RU 58841 was reversible since the inhibited sebaceous glands returned to normal size within 4 weeks after the cessation of the topical applications. The potent localized inhibition of sebaceous glands by RU 58841 demonstrates the excellent potential of this compound as a topical drug for the treatment of acne and other androgen-mediated disorders.

The effect of testosterone, cyproterone acetate, and minoxidil on hair loss in the androchronogenetic alopecia mouse

Abstract The work of Montagna, Uno, and others 1–4 using the stumptailed macaque as a nonhuman baldness model has contributed to further advancement of our understanding of hair loss by providing a model to test various therapeutic modalities; however, the small number of macaques available and the high cost of maintaining these animals unfortunately limit their use in hair research. Although mutations for hair loss occur frequently in laboratory rodents, to the best of our knowledge, androgen-mediated alopecia has never been described. This report demonstrates a mutation in our mouse colony in which the onset of alopecia is dependent upon the presence of androgens. Because alopecia in this mutation parallels that of baldness in man, we propose the use of this animal as an alternative model for studying the mechanism or mechanisms controlling the balding phenomenon and for screening of compounds that may be of therapeutic value.

Studies on the efficacy of methyl esters of n-alkyl fatty acids as penetration enhancers

The efficacy of the methyl esters of medium chain n-alkyl fatty acids as penetration enhancers was evaluated in vitro using various animal and human skins with minoxidil as the test drug. Both methyl nonanoate and methyl caprate at a 10% concentration were found to be effective penetration enhancers for a 2% solution of minoxidil in alcohol USP. The percent of the applied radioactive dose of minoxidil penetrated after 17 h was 5-8 times greater for methyl non-anoate and methyl caprate enhanced solutions than for a 2% solution of minoxidil in alcohol USP alone or with the addition of 10% Azone, dimethylsulfoxide (DMSO) or N,N-diethyl-m-toluamide (DEET). The penetration enhancing activity of methyl caprate was effective for human, mouse, and hamster skins. Methyl caprate also enhanced the penetration of vitamin D3, erythromycin, triamcinolone acetonide, testosterone, and hydrocortisone.

A Comparative Study of the Effects of Percutaneously Administered 5α‐Reductase and Androgen Receptor Inhibitors on Hamster Sebaceous Glands

There is a need for the development of potent and locally active antiandrogens because the presence of side effects makes the systemic administration of antiandrogens unacceptable for the treatment of acne, hirsutism, and male pattern baldness. The antagonistic activities of these compounds in the skin are expressed through the inhibition of the metabolic conversion of testosterone to dihydrotestosterone (DHT) or the prevention of DHT binding to specific receptor proteins. Although the relative potencies of systemically administered 5a-reductase and androgen receptor blockers have already been intensively studied, there is little data concerning their relative potencies when applied topically. In this study, the topical antiandrogenic activity of progesterone (P), a potent 5a-reductase inhibitor, and two receptor antagonists, namely cyproterone acetate (CA) and spironolactone (SL), were compared using the androgen-sensitive ear skin sebaceous glands of the Syrian hamsters.’.’

Effects of 13‐cis‐Retinoic Acid (Isotretinoin) on Hamster Hepatic Heme Biosynthetic Enzymes

13-cis-Retinoic acid ( 1 3-CRA), isotretinoin, is a synthetic retinoid that has been demonstrated to effectively reduce the activity of the sebaceous glands. It is currently being used for systemic treatment of severe recalcitrant cystic acne. Although the clinical effects and pharmacokinetics of 13-CRA have been extensively investigated, there is a paucity of information regarding the effects of this compound on the hepatic heme synthetic enzymes. In this study, we examined the effects of the oral administration of 13-CRA on several heme synthetic enzymes using the Syrian hamster as a model system.