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Indian Journal of Forensic Medicine & Toxicology, April-June 2021, Vol. 15, No. 2 3241
The Use of Pentoxifylline Topical in the Treatment of Alopecia
in Rats
Raad H. Hassan1, Ahmed H. Jwaid2
1MSc, Holy Karbala Health Department; Karbala; Ministry of Health -Iraq, 2Lecturer Department of
Pharmacology and Toxicology, College of Pharmacy, University of Baghdad; Baghdad-Iraq
Abstract
Hair is the human body’s major esthetic display component, especially in cultural and social interactions.
Hair loss is yet sometimes transient and the patient restore hair growth but have harmful effect on the
psychology of the patient. Throughout this research, the potency of topical pentoxifylline (PTX) in
stimulating regrowth in hair loss caused by cyclophosphamide was established. The study was performed
by treated with PTX topically in male Swiss albino rats. The animals divided into seven groups with six
animals in each group. To induce alopecia Cyclophosphamide used at a dose of (125 mg/kg) intraperitoneal.
Macroscopically pentoxifylline (PTX) treated groups displayed new hair growth. Strong follicular
proliferation was demonstrated by histopathology and gross morphological observations of hair growth in
shaved areas. The blood biochemical cytokine assay revealed a down regulation of pro inflammatory TH1
cytokines TNF-α and INF-g, in addition there is up regulation of TH2 cytokine IL-13. In the study showed
an efficient efficacy on the treatment of alopecia induced by cyclophosphamide.
Key words: chemotherapy induced alopecia, cyclophosphamide, pentoxifylline, TNF-α, INF-γ, IL-13.
Introduction dermal besides hair matrix. The dermal papilla regulates
the quantity of matrix cells, deciding the fiber thickness
Hair is the human body’s major esthetic display
of the hair 2.
part, especially in cultural and social interactions 1
.Hair has several beneficial vital functions, including Within the matrix cells of the hair bulb are
defense from contaminants and sweat-gland dispersion melanocytes that are often responsible for hair color.
substances e.g. pheromones 2 . The hair matrix comprised (inside and outside) medulla,
cortex and hair cuticle. The inner root sheath composed
Is a common term for loss of hair, is a consequence
of the cuticle of the inner root sheath, the sheet of Huxley
of noticeable hair loss. Alopecia is defined as the scalp
and the sheet of Henley (inside to out). The sheath of the
hair loss influencing many men throughout their entire
inner root is solid, and its form defines whether the hair
life and around 30 percent of women. Hair loss is yet
is curled or smooth. And the outer sheath to core 5.
sometimes transient and the patient restore hair growth
but have harmful effect on the psychology of the patient3. The middle part (isthmus), expanding mostly from
opening of the arrector pili muscle to the entrance of the
Hair shaft comprises of three main elements which
sebaceous duct. This section includes the HF’s “bulge,”
are a complex system. The medulla is covered by cortex
in which the epithelial stem cells exist. Disruption to
and cuticle that comprises the innermost component.
the HF bulge leads to persistent alopecia scarring, as is
The hair fiber comes from the follicle in the scalp, which
medically observed with conditions like discoid lupus
when seen in the longitudinal segment consists of several
and lichen planopilaris.The upper part (infundibulum),
major components4.The lowest part, which expands to
which continues to the follicular orifice from the entry
the penetration of the muscle arrector pili from the origin
of the sebaceous duct6.
of follicle, this lower section, in addition, comprises of
many major parts. The hair tube comprises the papilla3242 Indian Journal of Forensic Medicine & Toxicology, April-June 2021, Vol. 15, No. 2
Hair cycle gradually with increasing age in each of these males
and females in populous-based surveys of White people
Through embryogenesis hair follicles (HFs) are
aged 20-70 aged, often utilizing updated classification
developed in humans, but no other HFs are created after
measures, the occurrence of hair loss ranged from 45%
conception. The figuration of the individual follicles
to 90%.In the Hamilton-Norwood classification scale,
will dramatically alter over time, however. During
the incidence of alopecia was approximately 50% 10 .
adolescence, heavier and darker hair replaces thin,
mildly pigmented hairs in the beard. By comparison, Quality of life between subjects with hair loss
dense scalp hairs thereafter turn into delicate, short
In the conventional context, alopecia not considered
hairs. Ironically all reactions take place in reaction to
as an illness. However, psychological and social
a testosterone hormone4.
consequences apparently emerged and affect the quality
The HF redesigns itself through recessionary growth of the life (QOL) of affected the patient.In men as well
cycles. When developed, HFs experience continuous as women, the detrimental psychological influence of
cycles marked by growing phases (anagen), decline alopecia was reported. The relation among hair loss and
(catagen), then resting (telogen), during the last stage psychology consequences in women appears therefore
hair is lost (often recognized as exogen). Around 80 to be greater. However, several researches documented
to 90% of HFs are within the vital stage of growth (the an alopecia has psycho social consequences in males
anagen) at all times. Through anagen phase, the active such as increased self-esteem dissatisfaction and
mitotic matrix cells differentiate and divide into the hair depression. For some trials, the therapy was successful
bulb resulting in an approximate daily hair growth rate with alopecia and QOL -related causes (e.g. psychiatric
of 0.35 mm. around 5-10% of HFs are in the phase of illness, poor self-esteem, lower body confidence, and
dormancy (telogen), whereby all mitosis is halted. The social awareness). These considerations are essential
remainder 1 to 3% is in the involution process Catagen7. when assessing outcomes, for example the medication
effects on the life of patients but may not recognize the
Regeneration of the follicles at the beginning of
influence on QOL of persons with alopecia related to the
the next anagenic period demands that uncommon
extent of alopecia or other health factors11.
circulating epithelial stem cells be triggered from the
fresh follicle matrix during an early phase of anagen Chemotherapy induced alopecia (CIA)
in the permanent follicle Bulge area and the shaft and
While various kinds of chemotherapy occur, the
inner root are extracted from such comparatively in
drug itself can be generally interpreted as a medication
distinguished matrix cells. The descendant of stem cells
that prevents cell division or development. Alopecia
from the initial anagen phase of a new folic matrix and
considered as most severe skin side effects that damages
the shaft of a hair and sheath of inner root originate from
the skin12. Several drugs influence the growth of hair and
these matrix cells. The hair shaft’s height and width are
a few others induce loss of hair, the symptoms of the
relative to the volume of follicle’s hair as well as the
illness of which are important for hair growth as a direct
period of the anagen8.
consequence of drug action on different cells. These
Alopecia inducing factors cells are keratinocytes, hair matrix cells, peri-follicular
blood vessels, in addition those of hair bulbs connective
Alopecia-causing triggers include hormonal
tissues. Keratinocytes considered a first affected cite
disorder, impaired hepatic and liver function, lupus
for environmental or xenobiotic damaging effects. This
erythematosus, heat and chemical injury, conception,
can be attributable to the normal feature that up to 90%
and fungal infection, hereditary predisposition,
from total HFs are in a rapid growth process and the high
chemotherapy, fatigue, diabetics, vicious disorders,
blood flow rate around hair bulbs contributes to a strong
injuries, autoimmune diseases and rheumatoid arthritis 9.
bioavailability of many drugs at these locations13, 14.
Epidemiology of alopecia
There seem to be two kinds of alopecia which
The occurrence of hair loss is reported to increase may induced by chemotherapy telogen effluvium andIndian Journal of Forensic Medicine & Toxicology, April-June 2021, Vol. 15, No. 2 3243
anagen effluvium. Telogen Effluvium considered lesser members have already been detected that vary in their
in severity than anagen Effluvium, typically results in primary structures, affinity for either cAMP or cGMP
substantial thinning, where the patient may lose around , intracellular response, responsiveness to particular
half the hair while receiving cancer treatment. This form inhibitors, and regulatory pathway 18,19,20,21,22 .
of CIA is less visible to the eyes of the public than the
Interruption of these phosphodiesterases, that
anagen effluvium, which also results in alopecia15.
increase levels of intracellular cyclic nucleotide by
As shown by Yeager and Olsen, 15, the anagen blocking hydrolysis of 3, 5-cyclic nucleotides into
effluvium is generally correlated with chemotherapy as 5-nucleotide monophosphates, are an significant number
it is triggered by drugs that affect quickly proliferating of medicines utilized in number of conditions. The
cell groups and destroy neoplastic cells and rapidly xanthine derivatives PTX, theophylline and caffeine
developing normal cells such as anagen hair matrix cells. are non-selective phosphodiesterase inhibitors in this
The phase which is anagen included within the three class. These medicines inhibit all four known families of
phases of hair development that is the process during cAMP and the fifth phosphodiesterase families that are
which productive development takes place. Cancer effective on cGMP, but not cAMP23.
treatment damages the hair’s anchoring to the extent
The pentoxifylline a non-selective antagonist has
where it drops out from scalp or breaks down before it
been utilized medically in a variety of micro-circulatory
hits the upper surface of scalp 15.
disorders for decades, in addition on the dermatologists
For many cancer survivors, alopecia considered a found that the drug is useful in a variety of skin diseases.
traumatic experience. The change in appearance resulted PTX has an action of anti-inflammatory properties.
from alopecia may cause some survivors to encounter While the application and effectiveness of PTX for a
a sense of loss of identity and discomfort as they face number of dermatological diseases has been shown
difficulty to accept their distorted identity. The quickly over a long period of time in multiple trials, the United
growing HFs of cells within the anagen stage suffers from States Food and Drug Administration (FDA) only has
systemic chemical toxins and from premature apoptosis, authorized the usage in intermittent claudication24.
which contributes to earlier catagen beginning16.
Pharmacological actions of pentoxifylline
Pentoxifylline (PTX)
Several documented theories concerning the mode
It is a non-specific promoter of phosphodiesterase of activity of PTX as well as its physiological impact,
enzyme (PDE), which induces numerous physiological based primarily on animal and human research. Which
modifications at cell and molecular rates. Both cyclic involve influences on immunity regulation, opposing
nucleotides cyclic adenosine monophosphate (cAMP) tumor necrosis factor (TNF-α) actions, haemrheological
as well as cyclic guanosine monophosphate (cGMP) are impacts, opposing fibrinolytic effects, and effects on
the second intracellular messengers which play a central endothelial cell line and adhesive molecules24.
function in signal transmission in various physiological
PTX is a recognized drug having many
mechanisms17. The concentrations of the mentioned
pharmacological effects. It is a dimethyl xanthine-
nucleotides intracellularly are tightly controlled at
derivative that raises the levels of cAMP in smooth
both the level of synthesis by receptor with enzymes
muscle of the veins and arteries and is known for its
(such as adenylyl and guanyl cyclases) and also of
vasodilator activity. PTX is sometimes regarded as
the level of degradation through enzymes recognized
a rheological agent because of its action on red blood
as phosphodiesterase (PDEs). Such enzymes act as a
cells. It enhances the resilience of erythrocytes besides
catalyst on adenosine 3’, 5”-phosphodiester hydrolysis,
boosts blood supply in the arteries. Following such
and hence produce the 5’-nucleotides (AMP and GMP)
improvements, blood circulation and oxygen supply was
metabolites form guanosine 3’, 5’-monophosphate
enhanced25.
(cGMP) and adenosine 3’, 5’-monophosphate
(cAMP). PDEs comprise a huge group of structurally
relevant enzymes. At present, eleven PDE gene family3244 Indian Journal of Forensic Medicine & Toxicology, April-June 2021, Vol. 15, No. 2
The anti-thrombotic properties for PTX are linked studies have shown that TNF plays an expanded part
with its activation of prostacyclin production and in multiple diseases. For instance, it appeared that in
suppression of the enzyme PDE. Prostacyclin and studies becomes obvious that TNF is amongst the most
nitric oxide are documented for their strong vasodilator proximal mediators responsible for endotoxin-induced
activity and inhibition of platelet aggregation. PTX shock pathogenesis. At the cellular stage, TNF has
further lowers blood viscosity through its fibrinolytic major pleomorphic influences on cells that are shown
action25. to orchestrate inflammatory mechanisms; involving
endothelial cells, fibroblasts, polymorphonuclear
Immune modulation effect of PTX
leucocytes, blood monocytes and macrophages,
The earlier activity in several inflammatory skin adipocytes, lymphocytes and osteoclasts. The actions
disorders is the production of epidermal and dermal- of TNF on various cell groups put this monokine at the
induced pro-inflammatory cytokines by various stimuli. center of modulating acute and chronic inflammatory
Such triggers could specifically stimulate keratinocytes conditions29.
to manufacture and releases pro-inflammatory cytokines,
PTX was originally shown to clinically supersede
including interleukin (IL)-1a, TNF-α and IL-6. PTX
claudication in individuals with peripheral occlusive
reported originally characterized as inhibiting the
artery disorder. This pharmacological mechanism is
production of TNF-α mRNA-induced liposaccharide
due to decreased prostacyclin (PGI2) from vascular
protein by animal models and humans monocytes and
walls and intracellular cAMP production in platelets,
macrophages. These can be seen to be modified by the
polymorphonuclear leukocytes and monocytes. Since
increase of cAMP. Eventually, Neuner et al. also showed
cAMP may act in intracellular signal translocation
in vivo and in vitro whereby PTX decrease intercellular
and control monokine output, this process can entail
adhesion molecule (I CAM)-1 production on individual
inhibition of TNF development caused by PTX(29).
monocytes controlled by TNF-α inhibition26.
PTX pharmacological activity may have significant
PTX blocked the release of TNF-α that triggered ramifications in medical disease processes where local
by UV light in keratinocytes. This was also observed to and systemic regulation of TNF may be needed to
impede the release of interferon (IFN)-g by leukocytes. regulate particular inflammatory processes 29.
By suppressing the production of pro-inflammatory
The synthesis of TNF-α, a large pro-inflammatory
mediators by keratinocytes and leukocytes, PTX may
mediator with wide spectrum activity and released
eliminate or decrease the initial stage of the inflammatory
mainly by mononuclear cells, is believed to be inhibited
response 27 .
by PTX. PTX also serves as a potent blocker of
PTX also influences immune regulation by previously made TNF-a. In adjuvant-only groups, serum
enhanced leukocyte deformity and chemo taxis, cytokine levels of pro-inflammatory cytokines (TNF-α)
reduced endothelial leukocyte adhesion, decreased were found to be significantly higher than in control29.
degranulation of neutrophil and release of superoxide,
PTX Effects on TH1 and TH2
decreased production of monocyte-derived TNF,
reduced leukocyte susceptibility to interleukin 1 (IL-1) PTX, in addition to inhibiting the synthesis of TNF-α,
and TNF, suppression of T and B lymphocyte activity appears to increase the divergence of the cell secretions
and reduced normal activity of natural killer cell28. more toward the manufacturing of TH 2 cytokines,
suppressing, just from the other hand, cytokines of the
Anti-TNF- α effect of PTX
TH 1 subset, like IFN- γ30.
TNF-α is a mononuclear phagocytic cell-derived
The effectiveness of PTX as an immunomodulation
factor that is identified in a multiple physiological and
as well as anti-inflammatory medicine has been
immunological processes as an essential mediator.
investigated in many animal models of diseases. In the
Systemic actions of TNF-α for its oncolytic action
murine paradigm of allergic pulmonary inflammatory
on solid murine tumors were first described but later
condition, PTX delivery through allergen sensitizationIndian Journal of Forensic Medicine & Toxicology, April-June 2021, Vol. 15, No. 2 3245
contributes to impedance of airway hyper responsive at 2% concentration.
action given the existence of elevated rates of TH 2
Group PTX 3%: the used treatment is PTX at
cytokine IL-13 and reduced amounts of cytokines of
concentration of 3%.
TH1 in the Broncho-alveolar lavage fluid31.
Group standard: the standard treatment (minoxidil
Materials and Methods
2%) was used.
Subjects
Group negative control: no treatment used for this
Wistar albino male rats, their weight range 120- group.
140 gram were brought from animal house in College
of Pharmacy/University of Baghdad. The animals Diagnostic kit
were maintained on normal conditions of humidity, The kits used for measurement of biological
temperature and light/dark cycle. They were fed standard parameters levels are ELIZA kits for the serum levels of
rodent pellet diet and they have free access to water. The TNF-α, INF-g and IL-13 within the study.
animals grouped into seven groups each group with six
animals housed for accommodation for five days before Pentoxifylline topical gel formulation
the induction procedure of the alopecia.
Ultrapure water required was heated to 90 degrees
The protocol utilized for alopecia induction Celsius. Then the powder of HPMC in preheated water
slowly was dispersed. The whole solution of HPMC
The animals clipped at day one of procedure and was mixed till a homogeneous look was achieved.
another clippering in the day six for the stimulation of The mixture then was left in the fridge overnight till
anagen hair growth. The anagen hair follicles are more a transparent gel had been produced. Pentoxifylline-
sensitive for the effect of the cyclophosphamide (CYP). HPMC topical solution mixture was formulated with a
At day nine the animals for groups (2-7) are injected with persistent mixing of pentoxifylline and HPMC gel at
CYP using a dose of 125mg/kg single intraperitoneal room temperature till all pentoxifylline powder became
injection for the inducement of alopecia and group uniformly dispersed32.
control (1) injected only intraperitoneal distilled water.
The animals kept under supervision for the complete Statistical Analysis
effects of the chemotherapy for six days. After six days
The significance of differences between the mean
of intraperitoneal injection of chemotherapy the animals
values was calculated using SPSS version 25 program. P
treated with different formulas for two weeks. At end of
values that is lower than 0.05 were considered significant
treatment the animals authenticated and samples taken
for all data shown.
for analysis1.
Study groups Results
Analysis of variance of the data in figure 1 revealed
The animals in this study were divided into seven
significant increase in mean serum TNF-α comparing
groups; each group with six animals all groups injected
groups that used PTX as treatment with negative control
CYP intraperitoneal at day 9 except control group.
and vehicle groups.
Group control: given no treatment
The serum level of INF-g in figure 2 decreased
Group PTX 1%: in which the treatment is PTX at significantly when treated with PTX topically as
concentration 1%. compared with negative control or vehicle groups.
Group vehicle: the treatment used is the vehicle Examination of means serum levels of the groups
only. in figure 3 exhibited significant decrease in mean serum
TNF-α when compared the values in PTX treated groups
Group PTX 2%: in this group the treatment is PTX with negative control and vehicle groups.3246 Indian Journal of Forensic Medicine & Toxicology, April-June 2021, Vol. 15, No. 2
Figure 1: Comparison of the means ± standard error of means of serum levels of TNF-α of various rat
groups used in the study.
Figure 2: Comparison of the means ± standard error of means of serum levels of INF-g of various rat groups
used in the study
Figure 3: Comparison of the means ± standard error of means of serum levels of IL-13 of various rat groups
used in the study.Indian Journal of Forensic Medicine & Toxicology, April-June 2021, Vol. 15, No. 2 3247
Discussion Effect on serum levels of INF-g
The insufficient insight into the basic mechanism Ito et al. reported that IFN-γ rapidly inhibited hair
leading to alopecia together with therapies that failed to elongation in cultured human anagen hair follicles and
cure it, determined scientists to developed large research induced morphological signs of catagen transformation
programs to overcome hair loss33. after only four days of culture, faster than with other
reported catagen-inducers. Proliferation was inhibited,
As research continues to develop narrowly targeted
apoptosis was increased, and follicular melanogenesis
chemotherapy options, the prevalence and severity
was switched of in hair bulb keratinocytes treated in situ
of chemotherapy-induced alopecia experienced by
with IFN-γ, increasing the possibility of the destruction
patients will hopefully diminish dramatically. Until all
of the hair follicle immune privilege site 35.
chemotherapy becomes so targeted, however, hair loss
will continue to be a side effect dreaded by patients Groups treated with PTX with different
undergoing cancer treatment. Scalp cooling for hair concentrations have showed significant decrease in
loss prevention and 2% topical minoxidil for quicker serum levels of INF-g from negative control or vehicle
regrowth of hair currently are the best-studied and due to the direct effect of PTX on skin, this is consistent
most effective options for treatment. Better therapeutic with previous study of R. Pal et al. 36 . The decrease in
options, however, need to be developed both for the serum levels of INF-g greater in higher concentration
prevention of alopecia and the acceleration of subsequent than in lower concentration of PTX when applied
hair regrowth15. topically due the effect on pro inflammatory cytokine
INF-g as shown in figure 2.
Effect on serum TNF-α
Effect on serum IL-13
TNF-α is a multifunctional proinflammatory
cytokine which has been implicated in the pathogenesis The groups treated with PTX showed a significant
of many infections and inflammatory disorders. increase in serum levels of IL-13 than negative control
However, this cytokine not only acts as mediator of group or vehicle as shown in figure 3. This increased
immunity and inflammation, but also affects not-immune level showed protective effect on HF and there is
responses within tissues such as cell proliferation and observed macroscopic improvement of hair growth and
differentiation. In vitro studies have shown that TNF-α, texture in the groups treated with PTX. The hair growth
along with IL-1α and IL-β, causes vacuolation of matrix improved more with increased levels of serum IL-13 in
cells, abnormal keratinization of the follicle bulb and the groups of PTX 1%, PTX 2%, and PTX 3%.
inner root sheath, as well as disruption of follicular
melanocytes and the presence of melanin granules within Conclusion
the dermal papilla. Experiments in cultured human hair Pentoxifylline showed the ability to prevent damage
follicles showed that TNF-α completely abrogated hair to hair follicles by CYP when administered after CYP
growth, additionally TNF-α induced the formation of a administration and enhanced hair regrowth. Therefore,
club-like hair follicle, similar to catagen morphology of PTX have demonstrated its ability to prevent hair loss
the hair bulb34. and damage to the skin structures caused by CYP to
There is significant decrease in serum levels of rats in CYP induced alopecia. They possibly will be
TNF-α in PTX treated groups from the negative control acting by preventing accumulation of proinflammatory
group, this decrease is due to effect of PTX on serum TH1 cytokines like TNF-α and INF-g, or up regulating
levels of TNF-α as seen in figure 1. These findings are the TH2 cytokines like IL-13. Furthermore the
consistent with the previous study on the action of PTX hemodynamic effect of PTX on blood vessels improve
of Hassan et al.24. When increased the concentration of the blood flow and increase the supply of fresh blood to
PTX there was more decrease in levels of TNF-α. the local area treated with it, and the improvement in the
hair growth may be due to another effect which is the
increased blood flow.3248 Indian Journal of Forensic Medicine & Toxicology, April-June 2021, Vol. 15, No. 2
In this study it was to be concluded that the PTX alopecia. Clin Dermatol (2001); 19–20.
was used to treat the alopecia (a common side effect in 11. Schmidt S. Female alopecia: The mediating effect
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Conflict of Interest: Nil
12. Dunagin WG. Clinical toxicity of chemotherapeutic
Source of Funding: Self agents: dermatologic toxicity. Semin Oncol. (1982);
9(1).
Ethical Clearance: Obtained from Institutional 13. Orafidiya LO, Agbani EO, Adelusola KA, Iwalewa
ethical committee EO, Adebanji OA, Adediran EAF, et al. A study
on the effect of the leaf essential oil of Ocimum
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