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1.
Biomolecules ; 13(7)2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-37509112

RESUMEN

Many people suffer from hair loss and abnormal skin pigmentation, highlighting the need for simple assays to support drug discovery research. Current assays have various limitations, such as being in vitro only, not sensitive enough, or unquantifiable. We took advantage of the bilateral symmetry and large size of mouse whisker follicles to develop a novel in vivo assay called "whisker follicle microinjection assay". In this assay, we plucked mouse whiskers and then injected molecules directly into one side of the whisker follicles using microneedles that were a similar size to the whiskers, and we injected solvent on the other side as a control. Once the whiskers grew out again, we quantitatively measured their length and color intensity to evaluate the effects of the molecules on hair growth and coloring. Several chemicals and proteins were used to test this assay. The chemicals minoxidil and ruxolitinib, as well as the protein RSPO1, promoted hair growth. The effect of the clinical drug minoxidil could be detected at a concentration as low as 0.001%. The chemical deoxyarbutin inhibited melanin production. The protein Nbl1 was identified as a novel hair-growth inhibitor. In conclusion, we successfully established a sensitive and quantitative in vivo assay to evaluate the effects of chemicals and proteins on hair growth and coloring and identified a novel regulator by using this assay. This whisker follicle microinjection assay will be useful when investigating protein functions and when developing drugs to treat hair loss and abnormal skin pigmentation.


Asunto(s)
Minoxidil , Vibrisas , Ratones , Animales , Vibrisas/metabolismo , Minoxidil/metabolismo , Minoxidil/farmacología , Microinyecciones , Cabello , Alopecia/tratamiento farmacológico , Alopecia/metabolismo
2.
Drug Dev Ind Pharm ; 48(9): 457-469, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-36093810

RESUMEN

This work designates EthoLeciplex, a vesicular system consisting of phospholipid, CTAB, ethanol and water, as an innovative vesicular system for cutaneous/transfollicular minoxidil (MX) delivery. MX-loaded EthoLeciplex was fabricated by one-step fabrication process. Formulations were designed to study the effects of drug/phospholipid ratio, CTAB/phospholipid ratio, and ethanol concentration on vesicular size, PDI, surface charge and EE%. The optimized formulation was characterized by in vitro release, drug/excipient compatibility, ex vivo skin permeability and safety. A size of 83.6 ± 7.3 to 530.3 ± 29.4 nm, PDI of 0.214 ± 0.01 to 0.542 ± 0.08 and zeta potential of +31.6 ± 4.8 to +57.4 ± 12.5 mV were observed. Encapsulation efficiency was obtained in its maximum value (91.9 ± 16.2%) at the lowest drug/phospholipid ratio, median CTAB/phospholipid and the highest ethanol concentration. The optimized formulation was consisted of 0.3 as drug/lipid ratio, 1.25 as CTAB/lipid ratio and 30% ethanol concentration and showed responses' values in agreement with the predicted results. Differential scanning calorimetry studies suggested that EthoLeciplex existed in flexible state with complete incorporation of MX into lipid bilayer. The cumulative amount of MX permeated from EthoLeciplex, conventional liposome and ethanolic solution after 12 h were 36.3 ± 1.5 µg/ml, 21 ± 2.0 µg/ml and 55 ± 4.0 µg/ml respectively. Based on the remaining amount, the amount of MX accumulated in different skin layers can be predicted in descending order as follows; EthoLeciplex > conventional liposome > MX solution. EthoLeciplex produced marked disorder in the stratum corneum integrity and swelling with no features of skin toxicity. This new cationic system is a promising carrier for cutaneous/transfollicular drug delivery.


Asunto(s)
Liposomas , Minoxidil , Minoxidil/metabolismo , Liposomas/química , Cetrimonio/metabolismo , Administración Cutánea , Piel/metabolismo , Fosfolípidos/química , Etanol/química , Tamaño de la Partícula
3.
Cells ; 11(13)2022 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-35805177

RESUMEN

Dermal papilla cells (DPCs) are an important element of the hair follicle (HF) niche, widely used as an in vitro model to study hair growth-related research. These cells are usually grown in 2D culture, but this system did not show efficient therapeutic effects on HF regeneration and growth, and key differences were observed between cell activity in vitro and in vivo. Recent studies have showed that DPCs grown in 3D hanging spheroids are more morphologically akin to an intact DP microenvironment. In this current study, global gene molecular analysis showed that the 3D model highly affected cell adhesion molecules and hair growth-related pathways. Furthermore, we compared the expression of signalling molecules and metabolism-associated proteins of DPCs treated with minoxidil (an FDA-approved drug for hair loss treatment) and 3,4,5-tri-O-caffeoylquinic acid (TCQA) (recently found to induce hair growth in vitro and in vivo) in 3D spheroid hanging drops and a 2D monolayer using DNA microarray analysis. Further validations by determining the gene and protein expressions of key signature molecules showed the suitability of this 3D system for enhancing the DPC activity of the hair growth-promoting agents minoxidil and TCQA.


Asunto(s)
Folículo Piloso , Minoxidil , Cabello , Humanos , Minoxidil/metabolismo , Minoxidil/farmacología , Proteómica , Ácido Quínico/análogos & derivados
4.
Adv Healthc Mater ; 11(19): e2200908, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35817085

RESUMEN

The development of painless hair loss therapy without side-effect is challenging. The dermal papilla is the signal center of hair follicles and plays a key role in the regulation of their cycling. Activation of dermal papilla cells (DPCs) would promote hair regeneration. In this study, a separable microneedle patch comprised of chitosan lactate (CL) and exosomes (EXO) from adipose-derived stem cells is fabricated. After insertion of the microneedle into the skin, the hyaluronic acid substrate dissolves fast and the swellable polyvinyl alcohol needles are retained. The EXO sustainedly released from needles can be endocytosed by DPCs and promote cell proliferation via the activation of the Wnt signaling pathway, while the L-lactate released by CL can promote cell growth by activating lactate dehydrogenase. CL and EXO synergetically facilitate hair regeneration through regulating hair follicle cycling. In animal tests, compared with topical administration of minoxidil, the drug-free microneedle patches can more significantly promote hair regeneration within 7 days with lower dosing frequency. Furthermore, the inherent antibacterial properties of CL make it possible to avoid potential infection. Such transdermally administrated drug-free microneedle patches provide a simple, safe, and efficient strategy for hair loss treatment and exhibit great potential in clinical application.


Asunto(s)
Quitosano , Folículo Piloso , Alopecia/tratamiento farmacológico , Alopecia/metabolismo , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Células Cultivadas , Quitosano/farmacología , Cabello , Ácido Hialurónico/farmacología , Lactato Deshidrogenasas/metabolismo , Lactatos/metabolismo , Lactatos/farmacología , Lactatos/uso terapéutico , Minoxidil/metabolismo , Minoxidil/farmacología , Minoxidil/uso terapéutico , Alcohol Polivinílico , Regeneración
5.
Dermatol Ther ; 31(6): e12688, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30295395

RESUMEN

Several studies have established that sulfotransferase enzyme activity in the outer root sheath of plucked hair follicles predicts response to topical minoxidil in the treatment of pattern hair loss. However, the prevalence of this enzyme activity among Indian patients has not been studied. Additionally, no reports in the literature characterize sulfotransferase activity based on sex, age, duration of hair loss, grade of hair loss, and family history. In this study we utilized a sulfotransferase activity assay first reported by Goren et al. We characterize the follicular sulfotransferase activity of 120 pattern hair loss patients visiting a dermatology outpatient clinic in India. Overall, 40.8% of patients with pattern hair loss had low levels of sulfotransferase. Surprisingly, 49.3% of men had low levels of sulfotransferase compared to 26.6% of women. No correlation was found between sulfotransferase activity and age, duration of hair loss, grade of hair loss, or family history. A sub-analysis of patient reported outcomes (PRO) validated previous findings that sulfotransferase enzyme activity is a predictive marker for minoxidil response in pattern hair loss patients.


Asunto(s)
Alopecia/enzimología , Cabello/enzimología , Sulfotransferasas/metabolismo , Adolescente , Adulto , Alopecia/diagnóstico , Alopecia/tratamiento farmacológico , Alopecia/fisiopatología , Biomarcadores/metabolismo , Estudios Transversales , Femenino , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Humanos , India , Masculino , Persona de Mediana Edad , Minoxidil/metabolismo , Minoxidil/uso terapéutico , Medición de Resultados Informados por el Paciente , Resultado del Tratamiento , Adulto Joven
6.
Dermatol Ther ; 31(6): e12741, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30226287

RESUMEN

Topical minoxidil is the only US FDA approved OTC drug for the treatment of androgenetic alopecia (AGA). Minoxidil is a pro-drug converted into its active form, minoxidil sulfate, by the sulfotransferase enzymes in the outer root sheath of hair follicles. Previously, we demonstrated that sulfotransferase activity in hair follicles predicts response to topical minoxidil in the treatment of AGA. In the human liver, sulfotransferase activity is significantly inhibited by salicylic acid. Low-dose OTC aspirin (75-81 mg), a derivative of salicylic acid, is used by millions of people daily for the prevention of coronary heart disease and cancer. It is not known whether oral aspirin inhibits sulfotransferase activity in hair follicles, potentially affecting minoxidil response in AGA patients. In the present study, we determined the follicular sulfotransferase enzymatic activity following 14 days of oral aspirin administration. In our cohort of 24 subjects, 50% were initially predicted to be responders to minoxidil. However, following 14 days of aspirin administration, only 27% of the subjects were predicted to respond to topical minoxidil. To the best of our knowledge, this is the first study to report the effect of low-dose daily aspirin use on the efficacy of topical minoxidil.


Asunto(s)
Alopecia/tratamiento farmacológico , Aspirina/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Folículo Piloso/efectos de los fármacos , Minoxidil/administración & dosificación , Profármacos/administración & dosificación , Sulfotransferasas/antagonistas & inhibidores , Administración Cutánea , Adulto , Alopecia/diagnóstico , Alopecia/fisiopatología , Aspirina/efectos adversos , Interacciones Farmacológicas , Inhibidores Enzimáticos/efectos adversos , Folículo Piloso/enzimología , Folículo Piloso/crecimiento & desarrollo , Humanos , Masculino , Minoxidil/análogos & derivados , Minoxidil/metabolismo , Profármacos/metabolismo , Medición de Riesgo , Sulfotransferasas/metabolismo , Resultado del Tratamiento , Adulto Joven
7.
J Biol Regul Homeost Agents ; 32(4): 937-940, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30043580

RESUMEN

Minoxidil is the only US FDA-approved topical drug for the treatment of female and male pattern hair loss. Previously, it was demonstrated that topical minoxidil is metabolized to its active metabolite, minoxidil sulfate, by sulfotransferase enzymes located in the outer root sheath of hair follicles. The expression of sulfotransferase in the scalp varies greatly between individuals, and this difference in expression explains the varied response to minoxidil treatment. Previously, we have demonstrated the clinical utility of detecting sulfotransferase in plucked hair follicles to predict minoxidil response in pattern hair loss patients. Typically, exogenous exposure to substrates affects the expression of the enzymatic system responsible for their metabolism. For example, Phase I metabolizing enzymes, such as the cytochrome P450 family of enzymes, are known to be up-regulated in the presence of xenobiotic substrates. However, it is not known if Phase II metabolizing enzymes, such as the sulfotransferase family of enzymes, are similarly affected by the presence of substrates. In this study, we recruited 120 subjects and analyzed their sulfotransferase enzymatic activity before and after treatment with topical minoxidil. Adjusting the results for biologic (within subject) variability, we discovered that the sulfotransferase enzymatic system expression is stable over the course of minoxidil treatment. To the best of our knowledge, this is the first study to demonstrate the stability of sulfotransferase, a Phase II metabolizing enzyme, over the course of minoxidil treatment.


Asunto(s)
Folículo Piloso/efectos de los fármacos , Folículo Piloso/enzimología , Minoxidil/metabolismo , Minoxidil/uso terapéutico , Sulfotransferasas/metabolismo , Administración Tópica , Adulto , Alopecia/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad
8.
Eur J Pharm Biopharm ; 117: 60-67, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28377272

RESUMEN

Phytantriol cubosomes loaded with two palmitoyl peptides (Palpepcubes), namely GHKcube and GQPRcube, were prepared using an ultrasonication protocol. The Palpepcubes dimensions were characterized by dynamic light scattering (DLS) and cryo-transmission electron microscopy (cryo-TEM). Small-angle X-ray scattering (SAXS) analyses revealed that the bicontinuous cubic structure remained even at palmitoyl peptide contents as high as 5wt.%, with an increase in the cell parameter from approximately 6.5 to 7.2nm. Isothermal titration calorimetry (ITC) was used to elucidate the interactions between the blank cubosomes and the palmitoyl peptides, revealing an exothermic process of interaction. Moreover, the in vitro release of the palmitoyl peptides from the Palpepcubes was studied using a dialysis method coupled with liquid chromatography-mass spectrometry (LC/MS) technique, in which a sustained release of up to a few days was observed. Finally, the stability of the aqueous solutions of the palmitoyl peptides and the Palpepcubes kept at room temperature and at low temperature (4°C) was studied by LC/MS method, indicating that incorporation into cubosomes increases the peptide stability significantly.


Asunto(s)
Liberación de Fármacos , Alcoholes Grasos/metabolismo , Lipopéptidos/metabolismo , Nanopartículas/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina/química , 2-Hidroxipropil-beta-Ciclodextrina/metabolismo , Interacciones Farmacológicas , Alcoholes Grasos/química , Lipopéptidos/química , Minoxidil/química , Minoxidil/metabolismo , Nanopartículas/química , Dispersión del Ángulo Pequeño , Difracción de Rayos X/métodos
9.
Eur J Pharm Sci ; 96: 411-419, 2017 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-27746266

RESUMEN

Currently marketed minoxidil formulations present inconveniences that range from a grease hard aspect they leave on the hair to more serious adverse reactions as scalp dryness and irritation. In this paper we propose a novel approach for minoxidil sulphate (MXS) delivery based on a solid effervescent formulation. The aim was to investigate whether the particle mechanical movement triggered by effervescence would lead to higher follicle accumulation. Preformulation studies using thermal, spectroscopic and morphological analysis demonstrated the compatibility between effervescent salts and the drug. The effervescent formulation demonstrated a 2.7-fold increase on MXS accumulation into hair follicles casts compared to the MXS solution (22.0±9.7µg/cm2 versus 8.3±4.0µg/cm2) and a significant drug increase (around 4-fold) in remaining skin (97.1±29.2µg/cm2) compared to the drug solution (23.5±6.1µg/cm2). The effervescent formulations demonstrated a prominent increase of drug permeation highly dependent on the effervescent mixture concentration in the formulation, confirming the hypothesis of effervescent reaction favoring drug penetration. Clinically, therapy effectiveness could be improved, increasing the administration interval, hence, patient compliance. More studies to investigate the follicular targeting potential and safety of new formulations are needed.


Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Minoxidil/administración & dosificación , Minoxidil/metabolismo , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Animales , Química Farmacéutica , Folículo Piloso/efectos de los fármacos , Folículo Piloso/metabolismo , Minoxidil/química , Técnicas de Cultivo de Órganos , Absorción Cutánea/fisiología , Porcinos
10.
Dermatol Ther ; 29(5): 330-333, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27356887

RESUMEN

There is yet no consensus among prescribers whether minoxidil (MXD) formulations should be applied on wet/damp or dry scalp and no clear FDA guidelines on the matter. We hypothesized that the use of MXD on damp scalp may lead to higher drug penetration. First, because the drug diffusion and consequent deposition into the hair follicle may be favored when follicle cast is humid. Second, because humidity may also prevent drug crystallization and, therefore, maintain a higher thermodynamic activity for longer periods, which leads to increased penetration. Following in vitro experiments on rat and porcine skin we confirmed the hypothesis, which could markedly improve treatment effectiveness.


Asunto(s)
Folículo Piloso/metabolismo , Minoxidil/administración & dosificación , Cuero Cabelludo/metabolismo , Absorción Cutánea , Agua/química , Administración Cutánea , Animales , Cristalización , Difusión , Minoxidil/química , Minoxidil/metabolismo , Ratas , Solubilidad , Porcinos , Factores de Tiempo
11.
Dermatol Ther ; 27(4): 252-4, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24773771

RESUMEN

Two percent topical minoxidil is the only US Food and Drug Administration-approved drug for the treatment of female androgenetic alopecia (AGA). Its success has been limited by the low percentage of responders. Meta-analysis of several studies reporting the number of responders to 2% minoxidil monotherapy indicates moderate hair regrowth in only 13-20% of female patients. Five percent minoxidil solution, when used off-label, may increase the percentage of responders to as much as 40%. As such, a biomarker for predicting treatment response would have significant clinical utility. In a previous study, Goren et al. reported an association between sulfotransferase activity in plucked hair follicles and minoxidil response in a mixed cohort of male and female patients. The aim of this study was to replicate these findings in a well-defined cohort of female patients with AGA treated with 5% minoxidil daily for a period of 6 months. Consistent with the prior study, we found that sulfotransferase activity in plucked hair follicles predicts treatment response with 93% sensitivity and 83% specificity. Our study further supports the importance of minoxidil sulfation in eliciting a therapeutic response and provides further insight into novel targets for increasing minoxidil efficacy.


Asunto(s)
Alopecia/tratamiento farmacológico , Folículo Piloso/enzimología , Minoxidil/uso terapéutico , Sulfotransferasas/metabolismo , Administración Tópica , Estudios de Cohortes , Femenino , Cabello/crecimiento & desarrollo , Humanos , Minoxidil/administración & dosificación , Minoxidil/metabolismo , Sensibilidad y Especificidad , Resultado del Tratamiento
12.
Dermatol Ther ; 27(3): 171-3, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24283387

RESUMEN

Topical minoxidil is the most common drug used for the treatment of androgenetic alopecia (AGA) in men and women. Although topical minoxidil exhibits a good safety profile, the efficacy in the overall population remains relatively low at 30-40%. To observe significant improvement in hair growth, minoxidil is typically used daily for a period of at least 3-4 months. Due to the significant time commitment and low response rate, a biomarker for predicting patient response prior to therapy would be advantageous. Minoxidil is converted in the scalp to its active form, minoxidil sulfate, by the sulfotransferase enzyme SULT1A1. We hypothesized that SULT1A1 enzyme activity in the hair follicle correlates with minoxidil response for the treatment of AGA. Our preliminary retrospective study of a SULT1A1 activity assay demonstrates 95% sensitivity and 73% specificity in predicting minoxidil treatment response for AGA. A larger prospective study is now under way to further validate this novel assay.


Asunto(s)
Alopecia/tratamiento farmacológico , Arilsulfotransferasa/metabolismo , Folículo Piloso/efectos de los fármacos , Minoxidil/uso terapéutico , Profármacos/uso terapéutico , Alopecia/diagnóstico , Alopecia/enzimología , Biomarcadores/metabolismo , Biotransformación , Femenino , Folículo Piloso/enzimología , Folículo Piloso/crecimiento & desarrollo , Humanos , Masculino , Minoxidil/análogos & derivados , Minoxidil/metabolismo , Selección de Paciente , Valor Predictivo de las Pruebas , Profármacos/metabolismo , Estudios Retrospectivos , Resultado del Tratamiento
13.
Bioanalysis ; 4(23): 2823-32, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23216122

RESUMEN

BACKGROUND: Stabilization of phase II metabolites is an important consideration during bioanalytical method development, method validation and sample analysis. Generic approaches to stabilize these metabolites during storage in liquid-based matrices include pH adjustment of samples prior to storage and/or temperature control; although a variety of other compound-specific stabilization techniques exist. Dried blood spot (DBS) technology is becoming a popular alternative to liquid matrix sampling in many preclinical and clinical applications. However, concerns remain regarding the stability of metabolites stored under ambient conditions using DBS. RESULTS: Experimental data have shown that, under ambient storage conditions, the stability of the glucuronides investigated herein stored as DBS is equivalent to that of liquid samples stored at -80°C. CONCLUSION: The decision to employ DBS technology for a given study needs to be considered on a case-by-case basis with an understanding of compound-specific metabolism characteristics and clinical study design.


Asunto(s)
Antihipertensivos/metabolismo , Pruebas con Sangre Seca , Glucurónidos/metabolismo , Ácido Acético/química , Animales , Antihipertensivos/sangre , Área Bajo la Curva , Ácido Ascórbico/química , Cromatografía Líquida de Alta Presión , Ácido Cítrico/química , Glucurónidos/sangre , Glucurónidos/química , Humanos , Concentración de Iones de Hidrógeno , Ratones , Minoxidil/sangre , Minoxidil/metabolismo , Espectrometría de Masas en Tándem , Temperatura
14.
Org Biomol Chem ; 9(22): 7680-4, 2011 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-21779549

RESUMEN

Minoxidil (2,4-diamino-6-(piperidin-1'-yl)pyrimidine N(3)-oxide; CASRN 38304-91-5) is a bioactive molecule with several nitrosatable groups widely used as an antihypertensive and antialopecia agent. Here the nitrosation of minoxidil was investigated. The conclusions drawn are as follows: (i) In the pH = 2.3-5.0 range, the minoxidil molecule undergoes aromatic C-nitrosation by nitrite. The dominant reaction was C-5 nitrosation through a mechanism that appears to consist of an electrophilic attack on the nitrosatable substrate by H(2)NO(2)(+)/NO(+), followed by a slow proton transfer; (ii) the reactivity of minoxidil as a C-nitrosatable substrate proved to be 7-fold greater than that of phenol, this being attributed to the preferred para- and ortho-orientations of the two -NH(2) groups at positions 2 and 4 of the minoxidil molecule, which activate electrophilic substitution in the C-5 position through their mesomeric effect. The N-nitrosominoxidil resulting from the nitrosation could be potentially harmful to the minoxidil users.


Asunto(s)
Antihipertensivos/química , Minoxidil/química , Nitritos/química , Protones , Alopecia/tratamiento farmacológico , Animales , Antihipertensivos/efectos adversos , Antihipertensivos/farmacología , Cromatografía Liquida , Dimetilnitrosamina/efectos adversos , Dimetilnitrosamina/farmacología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Hipertensión/tratamiento farmacológico , Cinética , Espectroscopía de Resonancia Magnética , Minoxidil/efectos adversos , Minoxidil/metabolismo , Minoxidil/farmacología , Estructura Molecular , Nitritos/metabolismo , Nitrosación , Fenol/química , Ratas , Estereoisomerismo
15.
J Drug Target ; 19(3): 189-96, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20446805

RESUMEN

The aim of this work was to evaluate the ability of Transcutol (Trc) to produce elastic vesicles with soy lecithin (SL) and study the influence of the obtained vesicles on in vitro (trans)dermal delivery of minoxidil. To this purpose, so-called penetration enhancer-containing vesicles (PEVs) were prepared using Trc aqueous solutions (5-10-20-30% v/v) as hydrophilic phase. SL liposomes, without Trc, were used as control. Prepared formulations were characterized in terms of size distribution, morphology, zeta potential, deformability, and rheological behavior. The influence of the obtained PEVs on (trans)dermal delivery of minoxidil was studied by in vitro diffusion experiments through pig skin. Results showed that all prepared PEVs were able to give good entrapment efficiency (E%≈67) similar to that of conventional liposomes. Trc-containing PEVs showed to be more deformable than liposomes only when minoxidil was loaded in 5 and 10% Trc-containing vesicles. Rheological studies showed that PEVs have higher fluidity than conventional liposomes. All PEVs showed a higher stability than liposomes as shown by studying zeta potential and size distribution during three months. Results of in vitro diffusion experiments showed that Trc-containing PEVs are able to deliver minoxidil to deep skin layers without any transdermal permeation.


Asunto(s)
Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Glicoles de Etileno/química , Liposomas/química , Minoxidil/farmacología , Vasodilatadores/farmacología , Administración Cutánea , Animales , Difusión , Estabilidad de Medicamentos , Excipientes/química , Lecitinas/química , Liposomas/metabolismo , Minoxidil/administración & dosificación , Minoxidil/metabolismo , Tamaño de la Partícula , Piel/metabolismo , Porcinos , Vasodilatadores/administración & dosificación , Vasodilatadores/metabolismo
16.
Int J Pharm ; 383(1-2): 277-84, 2010 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-19772905

RESUMEN

Nanocarriers may act as useful tools to deliver therapeutic agents to the skin. However, balancing the drug-particle interactions; to ensure adequate drug loading, with the drug-vehicle interactions; to allow efficient drug release, presents a significant challenge using traditional semi-solid vehicles. The aim of this study was to determine how the physicochemical properties of nanoparticles influenced minoxidil release pre and post dose application when formulated as a simple aqueous suspension compared to dynamic hydrofluoroalkane (HFA) foams. Minoxidil loaded lipid nanoparticles (LN, 1.4 mg/ml, 50 nm) and polymeric nanoparticles with a lipid core (PN, 0.6 mg/ml, 260 nm) were produced and suspended in water to produce the aqueous suspensions. These aqueous suspensions were emulsified with HFA using pluronic surfactant to generate the foams. Approximately 60% of the minoxidil loaded into the PN and 80% of the minoxidil loaded into the LN was released into the external aqueous phase 24h after production. Drug permeation was superior from the PN, i.e. it was the particle that retained the most drugs, irrespective of the formulation method. Premature drug release, i.e. during storage, resulted in the performance of the topical formulation being dictated by the thermodynamic activity of the solubilised drug not the particle properties.


Asunto(s)
Portadores de Fármacos/metabolismo , Hidrocarburos Fluorados/metabolismo , Minoxidil/metabolismo , Nanopartículas , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/metabolismo , Portadores de Fármacos/química , Hidrocarburos Fluorados/química , Minoxidil/química , Nanopartículas/química , Tamaño de la Partícula , Suspensiones
17.
Br J Dermatol ; 150(2): 186-94, 2004 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-14996087

RESUMEN

We have known for over 30 years that minoxidil stimulates hair growth, yet our understanding of its mechanism of action on the hair follicle is very limited. In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans. Minoxidil may also cause prolongation of anagen and increases hair follicle size. Orally administered minoxidil lowers blood pressure by relaxing vascular smooth muscle through the action of its sulphated metabolite, minoxidil sulphate, as an opener of sarcolemmal KATP channels. There is some evidence that the stimulatory effect of minoxidil on hair growth is also due to the opening of potassium channels by minoxidil sulphate, but this idea has been difficult to prove and to date there has been no clear demonstration that KATP channels are expressed in the hair follicle. A number of in vitro effects of minoxidil have been described in monocultures of various skin and hair follicle cell types including stimulation of cell proliferation, inhibition of collagen synthesis, and stimulation of vascular endothelial growth factor and prostaglandin synthesis. Some or all of these effects may be relevant to hair growth, but the application of results obtained in cell culture studies to the complex biology of the hair follicle is uncertain. In this article we review the current state of knowledge on the mode of action of minoxidil on hair growth and indicate lines of future research.


Asunto(s)
Antihipertensivos/farmacología , Cabello/efectos de los fármacos , Minoxidil/farmacología , Alopecia/tratamiento farmacológico , Alopecia/patología , Animales , Antihipertensivos/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Cabello/citología , Cabello/crecimiento & desarrollo , Folículo Piloso/citología , Folículo Piloso/efectos de los fármacos , Folículo Piloso/crecimiento & desarrollo , Humanos , Minoxidil/metabolismo , Canales de Potasio/efectos de los fármacos
18.
Trends Pharmacol Sci ; 21(11): 439-45, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11121575

RESUMEN

K(ATP) channel openers are a diverse group of drugs with a wide range of potential therapeutic uses. Their molecular targets, the K(ATP) channels, exhibit tissue-specific responses because they possess different types of regulatory sulfonylurea receptor subunits. It is well recognized that complex interactions occur between K(ATP) channel openers and nucleotides, but the cloning of the K(ATP) channel has introduced a new dimension to the study of these events and has furthered our understanding of the molecular basis of the action of K(ATP) channel openers.


Asunto(s)
Minoxidil/análogos & derivados , Canales de Potasio/efectos de los fármacos , Adenosina Trifosfato/fisiología , Animales , Sitios de Unión , Cromakalim/metabolismo , Cromakalim/farmacología , Diazóxido/metabolismo , Diazóxido/farmacología , Humanos , Minoxidil/metabolismo , Minoxidil/farmacología , Nicorandil/metabolismo , Nicorandil/farmacología , Pinacidilo/metabolismo , Pinacidilo/farmacología , Canales de Potasio/metabolismo , Canales de Potasio/fisiología
19.
Biochem Biophys Res Commun ; 277(1): 236-45, 2000 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-11027669

RESUMEN

The bioavailability of drugs administered topically or orally depends on their metabolism by epithelial enzymes such as the cytosolic sulfotransferases (SULT). Reverse transcriptase-polymerase chain reaction (RT-PCR) methods were established to detect expression of 8 SULT genes and 4 arylsulfatase (ARS) genes in human tissues of epithelial origin and in cultures of normal and transformed (cancer) cells. The results indicate: (i) SULT 1A1, 1A3, ARSC, and ARSD genes are ubiquitously expressed; (ii) expression is frequently similar between cell lines and corresponding tissues; (iii) SULT gene expression in normal cultured cells is generally comparable to the expression in associated transformed (cancer) cell lines; (iv) SULT 1A1 promoter usage is mainly tissue specific; however, both promoters are frequently used in SULT 1A3 expression; and (v) the expression profile of SULT 1A1, 1A3, 1E1, and 2B1a/b suggests that one or more of these isoforms may be involved in the cutaneous sulfoconjugation of minoxidil and cholesterol.


Asunto(s)
Células Epiteliales/enzimología , Epitelio/enzimología , Perfilación de la Expresión Génica , Sulfatasas/genética , Sulfotransferasas/genética , Disponibilidad Biológica , Transformación Celular Neoplásica/genética , Células Cultivadas , Colesterol/metabolismo , Citoplasma/enzimología , Citoplasma/metabolismo , Cartilla de ADN , Células Epiteliales/citología , Células Epiteliales/metabolismo , Epitelio/metabolismo , Femenino , Regulación Enzimológica de la Expresión Génica , Humanos , Isoenzimas/genética , Masculino , Minoxidil/metabolismo , Proteínas de Neoplasias/genética , Especificidad de Órganos , Regiones Promotoras Genéticas/genética , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
20.
Exp Dermatol ; 8(4): 328-9, 1999 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10439254

RESUMEN

Cytosolic sulfotransferases (ST) catalyze the sulfation of various phenolic agents, catecholamines, thyroid hormones, steroids, drugs, and procarcinogens, usually resulting in the inactivation and subsequent excretion of the compound. My laboratory's efforts have focused on the cloning of the human phenol-sulfating (PST) members of this gene superfamily, implicated in the bioactivation of the hair growth stimulant, minoxidil. At least two major forms of human PST enzymes have been characterized biochemically, the phenol-preferring PST (P-PST), and the catecholamine-preferring PST (M-PST). Various cDNAs have been cloned representing alleles of 3 gene loci termed as STP1, STP2, and STM, which were all mapped precisely to a small region on human chromosome 16p and to the homologous region of mouse chromosome 7. Human cosmid genomic clones have been sequenced to determine the genomic organization for each of the 3 highly-related genes. All contain 7 coding exons, with conserved intron-exon boundaries, and presumptive alternative tissue-specific promoters. At least one of the 3 PST-encoding genes is responsible for forming minoxidil sulfate in the lower outer root sheath of anagen hair follicles. The steroid sulfating genes, STD and STE, have been cloned by other laboratories. The isozyme products of these genes sulfate DHEA and estrogens, respectively. I hypothesize that either STE or STD is involved in the formation of cholesterol sulfate (CS) in epidermal keratinocytes. CS has been demonstrated by other groups to be an activator of keratinocyte Protein Kinase Ceta, which subsequently results in the activation of epidermal transglutaminase and formation of the cornified envelop. STE or STD might also be involved in bioinactivation of estrogens and androgens within skin. Our recent unpublished results have focused on elucidating the patterns of ST gene expression in cultured keratinocytes and fibroblasts derived from human skin using RT-PCR, to understand which of the 5 different ST genes in involved in the regulation of keratinocyte differentiation and minoxidil-induced hair growth.


Asunto(s)
Ésteres del Colesterol/metabolismo , Citosol/enzimología , Minoxidil/análogos & derivados , Familia de Multigenes/genética , Piel/metabolismo , Sulfotransferasas/genética , Animales , Humanos , Minoxidil/metabolismo , Biología Molecular/métodos
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