Implantable Cardioverter-Defibrillator Efficacy in Patients With Heart Failure and Left Ventricular Dysfunction (from the MADIT II Population) Wojciech Zareba, MD, PhD, Katarzyna Piotrowicz, MD, Scott McNitt, MS, and Arthur J. Moss, MD, for the MADIT II Investigators The Multicenter Automatic Defibrillator Implantation The Multicenter Automatic Defibrillator Trial II
Downloads.hindawi.comHindawi Publishing CorporationISRN PharmacologyVolume 2014, Article ID 575423, 5 pageshttp://dx.doi.org/10.1155/2014/575423 Research Article
Promotive Effect of Topical Ketoconazole, Minoxidil, and
Minoxidil with Tretinoin on Hair Growth in Male Mice
Muhsin A. Aldhalimi,1 Najah R. Hadi,2 and Fadaa A. Ghafil2
1 Department of Dermatology, Kufa College of Medicine, Kufa, Iraq2 Department of Pharmacology and Therapeutics, Kufa College of Medicine, Kufa, Iraq Correspondence should be addressed to Najah R. Hadi; email@example.com Received 2 December 2013; Accepted 23 January 2014; Published 9 March 2014 Academic Editors: R. Thurmond, R. Villalobos-Molina, and S.-N. Wu Copyright 2014 Muhsin A. Aldhalimi et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Recently topical use of 2% Ketoconazole solution has been reported to have a therapeutic effect on androgenic alopecia. Minoxidilis a vasodilatory medication used primarily as antihypertensive drug. It was discovered to have the side effect of hair growth andreversing baldness. Tretinoin is commonly used topically for acne treatment and in the treatment of photoaging. It is used by someas hair loss treatment. Objective. To compare the stimulatory effect of Ketoconazole, Minoxidil, and Minoxidil with Tretinoin on hairgrowth in a mouse model. Materials and Methods. Coat hairs on the dorsal skin of seven weeks old male mice were gently clippedand then stained by using commercial dye. These mice were divided into four groups each of five treated with topical applicationof ethanol 95%, Ketoconazole solution 2%, Minoxidil solution 5%, and Minoxidil with Tretinoin solution 0.1%, respectively. Thedrugs were applied once daily for three weeks, the clipped area was photographed, and the ratio of regrown coat area was calculated.
Results. The results demonstrated that Ketoconazole, Minoxidil, and Minoxidil with Tretinoin had a significant stimulatory effecton hair growth compared with the control group and Minoxidil was the most effective drug among them.
Ketoconazole (KCZ) is an imidazole antifungal agent.
Long term use of 2% KCZ was reported to be effective against Androgenic alopecia is a partial or complete loss of hair that androgenic alopecia in patients without seborrheic dermatitis occurs in a progressive pattern in genetically predisposed and dandruff . Minoxidil is a vasodilatory medication used individuals . A variety of genetic and environmental factors primarily as antihypertensive drug. Minoxidil is a potassium likely play a role in androgenic alopecia, and most of con- channel agonist that has the chemical structure of nitric oxide tributing factors remain unknown.
(NO), a blood vessel dilator, and may be a nitric oxide agonist.
The age at onset of androgenic alopecia differs but occurs This appears to explain its vasodilatory effect  but may also usually in mid-twenties. The prevalence and severity of be linked to Minoxidil's ability to stimulate hair growth and androgenic alopecia increase directly with age . The basis treat hair loss.
of androgenic alopecia is a progressive decrease in the density Tretinoin is the acid form of vitamin A, also known as all of terminal hairs and concurrent increase in density of vellus transretinoic acid (ATRA), helps normalize hyperkeratiniza- hairs . In effect, terminal hairs are turned off and are tion, and has demonstrated significant anti-inflammatory transformed into vellus hairs, and this effect is due to hair effects. It is used by some as hair loss treatment .
follicle miniaturization , which is associated with substan-tial reduction in hair diameter. Although the mechanisms ofthese changes have not been established definitively, male pat- 2. Materials and Methods
tern baldness is known to depend on androgens, in particularthe dihydrotestosterone DHT . DHT is synthesized from 2.1. Animals. The study was conducted on 20 mature male testosterone by 5𝛼-reductase enzyme type-1 and type-2, and Albino-Webster mice, which were housed in the air-con- these enzymes are found on the nuclear membranes .
ditioned animal house of College of Medicine, University of ISRN Pharmacology Table 1: Mean ratio of white color (area showing hair regrowth) tothe ratio of black color (area denuded of hair) after 21 days of treat-ment with KCZ solution 2%, Minoxidil solution 5%, and Minoxidilsolution 5% with Tretinoin solution 0.1%.
Mean ratio of color difference Minoxidil and Tretinoin All data expressed as mean ± SEM.
Figure 1: Mice after clipping of the coat hair.
and then spread by means of swab once daily 6 days/weak for3 weeks.
Group II was treated with Ketoconazole solution 2%, 0.1 mL applied to the denuded skin by a micropipette oncedaily for 3 weeks.
Group III was treated with Minoxidil solution 5%, 0.1 mL applied to the denuded skin by a micropipette once daily for3 weeks.
Group IV was treated with equal amounts of Minoxidil solution 5% + Tretinoin 0.1%, 0.1 mL of each of them appliedby a micropipette once daily for 3 weeks.
The mice were macroscopically observed and photogra- Figure 2: Mice after staining of the dorsal coat hair.
phed every week until the 21st day.
Photographic Data Analysis. Photographic data were analyzed Kufa, with standard animal diet and water. Their ages ranged by a special computer program called Photoshop Visual from 6 to 7 weeks, and their weights ranged from 25 to 30 gm.
Basic-8 program. This program calculated the ratio of the area The design of the study was approved by the local ethical showing hair regrowth (which was represented by the area of committee in the College of Medicine, University of Kufa.
white color) to the ratio of the area denuded of hair (whichwas represented by the area of black color), and this was donefor each mouse in the four groups.
2.2. Methods 2.2.1. Clipping of the Coat Hair of Mice. One day before 2.3. Histological Sections. After completing the treatment the experiment, the mice were anesthetized with diethyl for three weeks, histological sections were obtained. These ether, and the coat hair on the dorsal skin was gently sections were examined microscopically for the hair follicle clipped using an electric shaver to avoid injury. The skin number and diameter, in control and treated groups.
surface of the clipped area of each mouse was observed onthe day when the materials were to be applied to have a 2.4. Statistical Analysis. Statistical analysis was done by using pinkish color, suggesting that it was in the resting phase .
one-way ANOVA test with post hoc test at level of signif- Mice were randomly chosen and put into four groups, each icance 𝛼 = 0.05 to compare between control and treated group included five mice, and they had been photographed groups and then performing multiple comparisons between the treated groups.
Chi-square test had been used to compare between the 2.2.2. Staining. The denuded area of the dorsal skin of each proportion of histological changes in various groups.
mouse was stained by using commercial dye (Hoffmann,2001, 2003) [11, 12]; then it was washed by using alcohol,staining done to find the ratio of area showing hair regrowth 3. Results
(area of white color) to the ratio of area denuded of hair (area There was a significant hair growth (𝑃 value < 0.05) in the of black color). After staining of mice, also they had been groups treated with KCZ, Minoxidil, and Minoxidil with photographed (Figure 2).
Tretinoin as compared with control group (Tables 1 and 2 andFigures 3, 4, 5 and 6).
2.2.3. Study Groups. Group I was considered as a control The histological examination of the specimens showed no group and treated with the vehicle solution (95%), ethanol significant increase in the number of hair follicles (𝑃 value > alcohol, 0.1 mL applied by a micropipette to the denuded skin 0.05) in all treatment groups, while hair follicle diameter has ISRN Pharmacology Figure 4: Mice treated with Minoxidil showing significant hairgrowth after 3 weeks of treatment.
Figure 3: Mice treated with Ketoconazole showing significant hairgrowth after 3 weeks of treatment.
Table 2: Comparison of hair growth among the treated groups after21 days of treatment with KCZ solution 2%, Minoxidil solution 5%,and Minoxidil solution 5% with Tretinoin solution 0.1%.
KCZ-Minoxidil and Tretinoin Minoxidil-Minoxidil and Tretinoin All data expressed as mean ± SEM.
Table 3: The mean number of hair follicles in control and treatedgroups examined under high power field per 10 mm after 21 daysof treatment with KCZ solution 2%, Minoxidil solution 5%, andMinoxidil solution 5% with Tretinoin solution 0.1%. This table shows Figure 5: Mice treated with Minoxidil and Tretinoin showing sig- that hair follicle number increased insignificantly (𝑃 value > 0.05) in nificant hair growth after 3 weeks of treatment.
all treatment groups.
Mean number of hair Minoxidil and Tretinoin All data expressed as mean ± SD.
Figure 6: Mice of control group after 3 weeks of topical alcohol Table 4: The mean diameter (in micrometer) of hair follicles in treatment showing insignificant hair growth.
control and treated groups after 21 days of treatment with KCZsolution 2%, Minoxidil solution 5%, and Minoxidil solution 5% withTretinoin solution 0.1%.
Mean diameter of hair follicles (in 𝜇m) Minoxidil and Tretinoin All data expressed as mean ± SEM.
Figure 7: Histological section from mouse skin in control group been increased significantly (𝑃 value < 0.05) in all treatment (×40) showing normal skin layers and hair follicles.
groups (Tables 3, 4, and 5 and Figures 7, 8, 9, and 10).
ISRN Pharmacology Table 5: Comparison of the diameter (in 𝜇m) of hair follicles amongthe treated groups after 21 days of treatment with KCZ solution 2%,Minoxidil solution 5%, and Minoxidil solution 5% with Retin—Asolution 0.1%. 𝑁 = 5 in each group.
KCZ-Minoxidil and Tretinoin Minoxidil-Minoxidil and Tretinoin All data expressed as mean ± SEM.
Figure 9: Histological section from the skin of mouse treated withMinoxidil (×40) showing normal skin layers and increase in hairfollicle diameter.
Figure 8: Histological section from the skin of mouse treated withKetoconazole (×40) showing normal skin layers and increase in hairfollicle diameter.
Figure 10: Histological section from the skin of mouse treated with This study demonstrated that topical Ketoconazole stimulates Minoxidil and Tretinoin (×40) showing normal skin layers and hair growth significantly. This result is in agreement with increase in hair follicle diameter.
Pi´erard-Franchimont et al. , Khandpur et al. , Jiang etal. , Inui and Itami , and Hugo Perez .
The efficacy of 2% KCZ shampoo in androgenic alopecia In this study there was a significant hair growth in the patients appeared to stem from its antiandrogenic properties group treated with Minoxidil and Tretinoin, and this result [16, 17]. However, our study demonstrated that topical KCZ is in agreement with Bazzano et al. [28, 29].
was effective on the androgen-insensitive coat hairs of mice, Tretinoin is known to alter cell proliferation and differ- so KCZ behaved as an androgen-independent biological res- entiation and may promote vascular proliferation, and these ponse modifier. However, its action on hair growth and hair actions may be important to hair growth and so affect hair follicle diameter is less than that of Minoxidil.
follicle during the various growth and regression phases.
There was a significant increase in hair growth in the Preliminary studies of cRABP levels in whole scalp skin group treated with topical Minoxidil solution. This result is of human subjects with male pattern baldness indicated that, in agreement with Olsen et al. , Weiss et al. , and Mori in the scalp areas not normally affected by alopecia, levels and Uno .
of cRABPs were higher than in areas with alopecia, and the Minoxidil induces rapid relaxation of vascular smooth levels of cRABPs in whole skin were increased by topical muscle induced by its sulphated metabolite, Minoxidil sul- application of retinoic acid .
phate . The conversion of Minoxidil to Minoxidil sulphate It has been found that combining high concentration of is catalysed by sulphotransferase enzyme, which was initially retinoic acid with Minoxidil causes less elongation than at low demonstrated in rat liver  and has since been found in concentration suggested that retinoic acid might increase the human liver , platelets , and mouse vibrissae follicles tissue concentration of Minoxidil in hair follicles .
Tretinoin was reported to increase percutaneous absorp- In scalp skin of stump-tailed macaque, sulphotransferase tion of Minoxidil by increasing the stratum corneum per- activity is largely localized in the hair follicle . Bio- meability . Our study demonstrated that Tretinoin in chemical evidence for Minoxidil sulphation by two phenol combination with Minoxidil caused a significant increase sulphotransferases has been found in human scalp skin .
in hair growth and a significant increase in hair follicle There are individual variations in scalp sulphotransferase diameter. However, in this study the results obtained from activity and this correlates with the level in platelets . In a the combination of Minoxidil with low dose Tretinoin are clinical setting scalp sulphotransferase activity was higher in less than that of Minoxidil alone and this warrants further men who responded to Minoxidil compared with those who studies to evaluate the role of Tretinoin in combination with did not respond .
Minoxidil in the treatment of hair loss.
ISRN Pharmacology Conflict of Interests
 A. W. Rafi and R. M. Katz, "Pilot study of 15 patients receiving a new treatment regimens for androgenic alopecia: the effects of The authors declare that there is no conflict of interests atopy on androgenic alopecia," ISRN Dermatology, vol. 2011, regarding the publication of this paper.
Article ID 241953, 11 pages, 2011.
 E. A. Olsen, M. S. Weiner, E. R. Delong et al., "Topical minox- idil in early male pattern baldness," Journal of the AmericanAcademy of Dermatology, vol. 82, pp. 90–93, 1984.
 R. Sinclair, "Fortnightly review. Male pattern androgenetic alo-  V. C. Weiss, D. P. West, and C. E. Mueller, "Topical minoxidil in pecia," British Medical Journal, vol. 317, no. 7162, pp. 865–869, alopecia areata," Journal of the American Academy of Dermatol- ogy, vol. 5, no. 2, pp. 224–226, 1981.
 J. B. Hamilton, "Patterned loss of hair in man; types and inci-  O. Mori and H. Uno, "The effect of topical minoxidil in the dence," Annals of the New York Academy of Sciences, vol. 53, no.
bald stump tailed macaque," Journal of the American Academy 3, pp. 708–728, 1951.
of Dermatology, vol. 17, pp. 276–281, 1990.
 D. A. Whiting, "Male pattern hair loss: current understanding,"  G. A. Johnson, K. J. Barsuhn, and J. M. McCall, "Sulfation of International Journal of Dermatology, vol. 37, no. 8, pp. 561–566, minoxidil by liver sulfotransferase," Biochemical Pharmacology, vol. 31, no. 18, pp. 2949–2954, 1982.
 D. A. Whiting, "Possible mechanisms of miniaturization during  C. N. Falany and E. A. Kerl, "Sulfation of minoxidol by human androgenetic alopecia or pattern hair loss," Journal of the Amer- liver phenol sulfotransferase," Biochemical Pharmacology, vol.
ican Academy of Dermatology, vol. 45, no. 3, pp. S81–S86, 2001.
40, no. 5, pp. 1027–1032, 1990.
 J. A. Ellis, R. Sinclair, and S. B. Harrap, "Androgenetic alopecia:  G. A. Johnson and C. A. Baker, "Sulfation of minoxidil by hum- pathogenesis and potential for therapy," Expert Reviews in an platelet sulfotransferase," Clinica Chimica Acta, vol. 169, no.
Molecular Medicine, vol. 4, pp. 1–11, 2002.
2-3, pp. 217–227, 1987.
 G. Bartsch, R. S. Rittmaster, and H. Klocker, "Dihydrotestos-  A. E. Buhl, D. J. Waldon, C. A. Baker, and G. A. Johnson, "Mino- terone and the concept of 5𝛼-reductase inhibition in human xidil sulfate is the active metabolite that stimulates hair follicles," benign prostatic hyperplasia," European Urology, vol. 37, no. 4, Journal of Investigative Dermatology, vol. 95, no. 5, pp. 553–557, pp. 367–380, 2000.
 C. Pi´erard-Franchimont, P. De Doncker, G. Camvenbergh, and  C. A. Baker, H. Uno, and G. A. Johnson, "Minoxidil sulfation in G. E. Pierard, "Ketoconazole shampoo: effect of long-term use the hair follicle," Skin Pharmacology, vol. 7, no. 6, pp. 335–339, in androgenic alopecia," Dermatology, vol. 196, no. 4, pp. 474–  R. J. Anderson, P. E. Kudlacek, and D. L. Clemens, "Sulfation of minoxidil by multiple human cytosolic sulfotransferases,"  K. D. Meisheri, L. A. Cipkus, and C. J. Taylor, "Mechanism of Chemico-Biological Interactions, vol. 109, no. 1–3, pp. 53–67, action of minoxidil sulfate-induced vasodilation: a role for increased K+ permeability," Journal of Pharmacology and Exper-imental Therapeutics, vol. 245, no. 3, pp. 751–760, 1988.
 A. E. Buhl, C. A. Baker, A. J. Dietz et al., "Minoxidil sulfotran- sferase activity influences the efficacy of Rogaine topical solu-  N. K. Terezakis and G. S. Bazzano, "Retinoids: compounds imp- tion: enzyme studies using scalp and platelets," Journal of ortant to hair growth," Clinics in Dermatology, vol. 6, no. 4, pp.
Investigative Dermatology, vol. 102, article 534, 1994.
 G. Bazzano, N. Terezakis, H. Attia et al., "Effect of retinoids on  H. Ogawa and M. Hattori, "Regulation mechanisms of hair follicular cells," Journal of Investigative Dermatology, vol. 101, no.
growth," in Normal and Abnormal Epidermal Differentiation, M.
1, pp. 138–142, 1993.
Seiji and I. A. Bernstein, Eds., pp. 159–170, University of TokyoPress, Tokyo, Japan, 1983.
 G. S. Bazzano, N. Terezakis, and W. Galen, "Topical tretinoin for hair growth promotion," Journal of the American Academy  R. Hoffmann, "TrichoScan: combining epiluminescence micro- of Dermatology, vol. 15, no. 4, pp. 880–893, 1986.
scopy with digital image analysis for the measurement of hairgrowth in vivo," European Journal of Dermatology, vol. 11, no. 4,  G. Bazzano, H. Attia, and N. Terezakis, "Cellular retinoic acid pp. 362–368, 2001.
binding protein levels in hair and scalp skin of subjects withalopecia," Clinical Research, vol. 39, article 558A, 1991.
 R. Hoffmann, "TrichoScan: a novel tool for the analysis of hair  S. K. Oh, K. P. Hyun, J. O. Youn et al., "Promotive effect of min- growth in vivo," Journal of Investigative Dermatology Symposium oxidil combined with All- trans retinoic acid (tretinoin) on Proceedings, vol. 8, no. 1, pp. 109–115, 2003.
human hair growth in vitro," Journal of Korean Medical Science,  S. Khandpur, M. Suman, and B. S. Reddy, "Comparative efficacy vol. 22, no. 2, pp. 283–289, 2007.
of various treatment regimens for androgenetic alopecia in  J. J. Ferry, K. K. Forbes, J. T. VanderLugt, and G. J. Szpunar, men," Journal of Dermatology, vol. 29, no. 8, pp. 489–498, 2002.
"Influence of tretinoin on the percutaneous absorption of  J. Jiang, R. Tsuboi, Y. Kojima, and H. Ogawa, "Topical applica- minoxidil from an aqueous topical solution," Clinical Pharma- tion of ketoconazole stimulates hair growth in C3H/HeN mice," cology and Therapeutics, vol. 47, no. 4, pp. 439–446, 1990.
Journal of Dermatology, vol. 32, no. 4, pp. 243–247, 2005.
 S. Inui and S. Itami, "Reversal of androgenetic alopecia by top- ical ketoconzole: relevance of anti-androgenic activity," Journalof Dermatological Science, vol. 45, no. 1, pp. 66–68, 2007.
 B. S. Hugo Perez, "Ketocazole as an adjunct to finasteride in the treatment of androgenetic alopecia in men," Medical Hypothe-ses, vol. 62, no. 1, pp. 112–115, 2004.
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