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© Borgis - Postępy Nauk Medycznych 10/2012, s. 794-799
*Małgorzata Latusek1, Ligia Brzezińska-Wcisło2
Wpływ atorwastatyny i perindoprilu na cykl włosowy na modelu zwierzęcym – ryzyko łysienia polekowego u pacjentów kardiologicznych
Impact of atrovastatin and perindopril on the hair cycle in rodent model – risk of drug induced alopecia in patients with heart disease
1Dermatology Department, Independent Public Clinical Hospital of Medical University of Silesia, Katowice
Head of Department: prof. Ligia Brzezińska-Wcisło, MD, PhD
2Dermatology Department, Medical University of Silesia, Katowice
Head of Department: prof. Ligia Brzezińska-Wcisło, MD, PhD
Streszczenie
Wstęp. Ważne zagadnienie z punktu widzenia klinicystów i pacjentów stanowią niepożądane działania polekowe. Obejmują one wiele układów i narządów oraz implikują dalsze postępowanie terapeutyczne. Jednym z nich jest łysienie polekowe, którego mechanizm nie zawsze pozostaje jasny i w wyraźny sposób wiąże się ze stosowanym lekiem. Częstość występowania tego zjawiska u ludzi w skali ogólnej nie jest znana.
Cel pracy. Celem doświadczenia była ocena wpływu atorwastatyny i perindoprilu na przebieg cykli włosowych w wariancie doświadczalnym na zwierzętach laboratoryjnych.
Materiał i metody. Szczury szczepu Wistar podzielono na równe liczebnie grup. Szczury pierwszej grupy (K1) otrzymywały wodę destylowaną, zwierzęta w grupach badanych (G1, G2) otrzymywały po rozpuszczeniu w wodzie destylowanej, sondą dożołądkową wybrane leki.
W trakcie badania dwa razy w tygodniu dokonywano oceny makroskopowej owłosienia oraz wykonywano trichogram. Na podstawie proporcji włosów anagenowych, katagenowych, telogenowych, dystroficznych oraz niesklasyfikowanych wnioskowano o rodzaju łysienia lub jego braku. Dodatkowo wykonano wybrane badania laboratoryjne.
Wyniki. We wszystkich analizowanych cyklach w grupach otrzymujących badane leki stwierdzono przedwczesną inwolucję katagenową i zwiększenie odsetka włosów telogenowych, bądź wzrost liczby telogenowej.
Wnioski. Badane leki wpływają na przebieg cykli włosowych i odpowiadają za rozwój łysienia polekowego, o zmiennym przebiegu zależnym od czasu ekspozycji.
Summary
Introduction. Adverse drug reactions play an important role. Often they are severe, impact many organs and further treatment is always determined by their occurrence. One of them is drug induced alopecia. This side effect mechanism is still unknown. Furthermore drug toxicity is not always evidence. Moreover drug induced alopecia frequency in human is undefined.
Aim. The aim of this study was to asses if atorvastatin and perindopril induce changes in hair cycling in rodent model.
Material and methods. Male Wistar rats were divided into equal groups. Rats in control group (K1) received distilled water. Rats in experimental groups (G1, G2) received orally, via gastric tube selected drugs dissolved in distilled water.
Twice a week macroscopic examination was obtained, followed by microscopic examination of the hair for shaft and root abnormalities. Anagen, katagen, telogen and pathologic types of hair were counted. Depending on telogen count and dystrophic hair appearance the diagnosis was establish. In addiction laboratory test were taken.
Results. Selected drugs induced premature catagen involution and increased the telogen count or only increased telogen count in modified cycles.
Conclusions. Selected drugs influence the hair cycle. Observed drug induced alopecia depends on time of exposure.
INTRODUCTION
In today’s world medical progress is enormous. The pharmaceutical industry introduces a number of therapeutic agents that have many side effects including drug-induced alopecia. It’s mechanism is not always known and clearly associated with the drug. The aging of the population, multidrug therapy, coexisting diseases and the basic factors blur the picture.
Taking into account the mechanisms of hair follicle damage induced by drugs, telogen effluvium is foreground hair loss. It occurs mostly after several months of treatment and sometimes it is difficult to define whether effluvium is the result of the therapy or is associated with an underlying or concomitant disease. In human hair loss usually runs subclinical leading to a loss of less than 50% of hair and mostly affects the scalp.
Classic anagen effluvium, is observed less frequently. It’s pathogenesis is associated with inhibition of mitosis in the hair follicle mainly by chemotherapeutic agents or heavy metals. Runs, always with the clinical manifestations because about 85% of the scalp hair are in anagen phase and stand as potential target for toxic factor.
Sometimes we can also observe mixed alopecia arising in a case of coexistence of both mechanisms.
Atrovastatin is a statin used in the treatment of symptomatic primary and secondary hyperlipidemia caused by: uncontrolled diabetes, alcoholism, renal failure requiring dialysis, obesity, glucocorticoid therapy, nephrotic syndrome, hypothyroidism, cholestasis, diabetes, pregnancy.
One of the statins side effects is hair loss observed in 1-5% of patients. It is usually temporary and affects both the scalp and other body regions (1, 2).
All diseases treated with statins affects the hair condition by themselves therefore these observations require trichologic confirmation (3).
Perindopril belongs to ACE inhibitors and drug-induced hair loss occurs in 1-5% of treated patients. According to available data, it is observed both in adults and children. Hair loss usually affects the scalp, and its mechanism remains unclear (4, 5). This drug is often used in multidrug regimens in the treatment of hypertension or renal dysfunction where other therapeutics often are burdened with negative effects on hair condition. In addition, this drug seems to be interesting because of its immunomodulatory properties and test its application in many diseases.
MATERIAL AND METHODS
The study was conducted in male Wistar rats at the age of 30 days and body weight of 68.35 g+/-9.62, derived from Experimental Medicine Centre of Medical University of Silesia in Katowice. The animals had free access to water (filtered) and feed (standard). Environmental microclimate was characterized by stable parameters: temperature (about 20°C), humidity (60%), air movement and rhythm of light (12:12 hours) with the circulation of 6:00 and 18:00.
During 96 days, the rats in groups G1 and G2 received daily via gastric tube following drugs: G1-atorvastatin (30 mg/kg per day), G2-perindopril (2.0 mg/kg per day). Rats in the control group K1 received distilled water (2 ml/kg per day).
The drug dose was based on available publications, where selected drugs were used in rodent model to achieve therapeutic effects typical for humans. The LD50 (dosis lethalis media) according to the MSDS (Material Safety Data Sheet) and drugs half-lives (T 1/2) were also taken into account.
Three times during the experimental period (day 1,32,64), induced hair cycles (I, II, III) were performed by manual epilation of the 10x10mm field in sacral region in each animal.
Simultaneous in opposite sacral region spontaneous hair cycles I, II and III were observed.
Microscopic evaluation was performed on 1, 4, 8, 11, 15, 18, 22, 25, 29 and a 32 day of the hair cycle, both induced and spontaneous through the trichogram.
Therefore about 100 hair were plucked, embedded in medium, observed under light microscope with 4 x 10 magnification and the number of hair in the different phases of the hair cycle were determined.
The diagnosis of hair loss was establish basing on the proportions of different types of hair.
Macroscopic evaluation carried out in analogous days was based on hair density, thickness, color, gloss and mechanical strength.
Moreover in 1, 48, 96 experimental day blood samples were taken for testing.
After completion of the experiment the rats were euthanized by intraperitoneal administration of sodium pentobarbital at a dose of 200 mg/kg and utilitized.
Microsoft Excel spreadsheet, statistical package STATISTICA and the following statistical tests were used for statistical calculation:
– Kolmogorov-Smirnov test with Lilliefors correction
– nonparametric test U Mann-Whitney
– Wilcoxon sequence test
– parametric analysis of variance, post hoc t tests
In all tests the level of significance α = 0.05.
The study was approved by the Local Ethical Committee for Experiments on Animals Affairs of Medical University of Silesia in Katowice, No. 68/2009 dated 10.09.2009.
RESULTS
To demonstrate the differences and similarities in hair growth, we compared group K1 and G1, G2 (induced and spontaneous cycles (I, II, III)). The surveys included following days: 15 (anagen VI), 25 (catagen) and 32 (telogen).
In addition, statistical analyzes of laboratory results was obtained.
The control group K1
In the control group K1, where animals received distilled water, induced and spontaneous hair cycles I, II, III were correct. Regrowth after epilation was not delayed and all cycles lasted for 32 days.
Comparison of induced cycles within the group, pointed out changes between I and II hair cycles and similarities between II and III hair cycles (tab. 1, 2). It was associated with onset of catagen between compared cycles (day 25 in I hair cycle and 22 in II and III). The observed different time of hair follicles involution was physiological and associated with animals age.
Table 1. Comparison of I and II induced cycle in group K1 (observed probability).
Day Anagen hair (p)Catagen hair (p)Telogen hair (p)Dystrophic
hair (p)
Unclassified hair (p)
15      
25   0.012  
32      
Table 2. Comparison of II and III induced cycle in group K1 (observed probability).
Day Anagen hair (p)Catagen hair (p)Telogen hair (p)Dystrophic hair (p)Unclassified hair (p)
15      
25   0.123 0.686
32   0.180  
Macroscopically animals fur remained fluffy, thick and white throughout the experiment and the rats grew normally.
Laboratory tests were correct.
The tested group G1-atorvastatin

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Piśmiennictwo
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otrzymano: 2012-08-22
zaakceptowano do druku: 2012-09-28

Adres do korespondencji:
*Małgorzata Latusek
Dermatology Department, Independent Public Clinical Hospital of Medical University of Silesia
ul. Francuska 20/24, 40-027 Katowice
tel./fax: +48 (32) 259-16-07
e-mail: gosiapiw@poczta.onet.pl

Postępy Nauk Medycznych 10/2012
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