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Hersteller: HEXAL AG Wirkstoff: Isotretinoin
Darreichungsform: Weichkapseln
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Isotret-HEXAL 20mg Kapseln enthalten den Wirkstoff Isotretinoin.
In äußerlichen Zubereitungen (Cremes und Gelen) dient der Wirkstoff zur Behandlung der geringgradig bis mittelstark ausgeprägten entzündlichen und nichtentzündlichen Formen der .
Zum Einnehmen wird Isotretinoin nur bei schweren Formen von Akne verordnet. Solche sind Akneknoten (noduläre Akne), Akne mit zusammenfließenden Entzündungsherden (Acne conglobata) oder Akne mit der Gefahr einer dauerhaften Narbenbildung. Der Einsatz des Wirkstoffs ist nur gerechtfertigt, wenn diese Hautbeschwerden mit äußerlichen Behandlungen und der Standardtherapie mit Antibiotika nicht zu bessern waren.
isotretinoin hexal
Zu folgenden Anwendungsgebieten von Isotretinoin sind vertiefende Informationen verfügbar:
Lesen Sie dazu auch die Informationen zu den Wirkstoffgruppen innerlich anzuwendende Aknemittel, Aknemittel, zu welcher der Wirkstoff Isotretinoin gehört.
Nehmen Sie die Kapseln ein- oder zweimal täglich zusammen mit Nahrung ein.
Die Therapie wird im Allgemeinen mit einer Dosis von 0,5 Milligramm Isotretinoin pro Kilogramm Körpergewicht pro Tag begonnen. Der Behandlungserfolg und auch einige der Nebenwirkungen sind dosisabhängig und unterscheiden sich von Patient zu Patient. Daher ist während der Therapie eine individuelle Dosisanpassung durch den Arzt notwendig. Für diemeisten Patienten liegt die Dosis in einem Bereich von 0,5 bis 1 Milligramm pro Kilogramm Körpergewicht pro Tag. Wie lange die Heilung anhält oder ob Rückfälle eintreten, hängt stärker von der gegebenen Gesamtdosis ab als von der Dauer der Behandlung oder von der Tagesdosis. In Studien zeigte sich, dass es keinen zusätzlichen Nutzen bringt, die angewendete Gesamtdosis über 120 bis 150 Milligramm pro Kilogramm Körpergewicht hinaus zu steigern. Die Behandlungsdauer hängt von der individuellen Tagesdosis ab. Normalerweise ist eine Behandlungsdauer von 16 bis 24 Wochen (ein Behandlungszyklus) ausreichend, um eine Besserung zu erreichen. Bis zu acht Wochen nach dem Ende der Behandlung kann eine weitere Verbesserung der Akne beobachtet werden.
Bei den meisten Patienten wird mit einem einzigen Behandlungszyklus eine vollkommene Heilung der Akne erreicht. Im Falle eines Rückfalls kann ein weiterer Behandlungszyklus mit der gleichen Tages- und Gesamtdosis erfolgen.
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Isotret-HEXAL may be available in the countries listed below.
Isotretinoin is reported as an ingredient of Isotret-HEXAL in the following countries:
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isotretinoin hexal
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Brand name: Isotret Hexal
Active ingredient (generic name): Isotretinoin
Manufacturer: Hexal
Importer: Behestan Darou
Pharmacotherapeutic group: anti-acne
isotretinoin hexal
Pharmaceutical form: 20mg Capsules
Pharmacodynamic:
The exact mechanism of action of isotretinoin has not yet been elucidated in detail, but it has been established that the improvement observed in the clinical picture of severe acne is associated with suppression of sebaceous gland activity and a histologically demonstrated reduction in the size of the sebaceous glands. Furthermore, a dermal anti-inflammatory effect of isotretinoin has been established.
Hypercornification of the epithelial lining of the pilosebaceous unit leads to shedding of corneocytes into the duct and blockage by keratin and excess sebum. This is followed by formation of a comedone and, eventually, inflammatory lesions. Isotretinoin inhibits proliferation of sebocytes and appears to act in acne by re-setting the orderly program of differentiation. Sebum is a major substrate for the growth of Propionibacterium acnes so that reduced sebum production inhibits bacterial colonisation of the duct.
Pharmacokinetic:
The absorption of isotretinoin from the gastro-intestinal tract is variable and dose-linear over the therapeutic range.
In humans little information is available on the distribution of isotretinoin into tissue.
The major metabolite is 4-oxo-isotretinoin with plasma concentrations at steady state that are 2.5 times higher than those of the parent compound.
After oral administration of radiolabelled isotretinoin approximately equal fractions of the dose were recovered in urine and faeces. Following oral administration of isotretinoin, the terminal elimination half-life of unchanged drug in patients with acne has a mean value of 19 hours. The terminal elimination half-life of 4-oxo-isotretinoin is longer, with a mean value of 29 hours.
Therapeutic indication:
Isotretinoin capsules are indicated for the treatment of severe forms of acne (such as nodular or conglobate acne or acne at risk of permanent scarring), resistant to adequate courses of standard therapy with systemic antibacterials and topical therapy.
Dosage and administration:
The capsules should be taken with food once or twice daily.
Isotretinoin therapy should be started at a dose of 0.5 mg/kg daily. The therapeutic response to isotretinoin and some of the adverse effects are dose-related and vary between patients. This necessitates individual dosage adjustment during therapy. For most patients, the dose ranges from 0.5-1.0 mg/kg per day.
Long-term remission and relapse rates are more closely related to the total dose administered than to either duration of treatment or daily dose. It has been shown that no substantial additional benefit is to be expected beyond a cumulative treatment dose of 120-150 mg/kg. The duration of treatment will depend on the individual daily dose. A treatment course of 8-12 weeks is normally sufficient to achieve remission.
In the majority of patients, complete clearing of the acne is obtained with a single treatment course. In the event of a definite relapse a further course of isotretinoin therapy may be considered using the same daily dose and cumulative treatment dose. As further improvement of the acne can be observed up to 8 weeks after discontinuation of treatment, a further course of treatment should not be considered until at least this period has elapsed.
Adverse reaction:
The following symptoms are the most commonly reported undesirable effects with isotretinoin:
Gram positive (mucocutaneous) bacterial infection, anemia, red blood cell sedimentation rate increased, Thrombocytopenia, neutropenia, allergic skin reaction, anaphylactic reactions, hypersensitivity, suicidal ideation, Lymphadenopathy, diabetes mellitus, depression, headache, blurred vision, cataract, Color blindness, colitis, Ileitis, dry throat, gastrointestinal hemorrhage, hemorrhagic diarrhea and inflammatory bowel disease, Nausea, Pancreatitis
Contraindication:
Isotretinoin is contraindicated in women who are pregnant or breastfeeding.
Isotretinoin is contraindicated in women of childbearing potential unless all of the conditions of the Pregnancy Prevention Program are met.
Isotretinoin is also contraindicated in patients with hepatic insufficiency and excessively elevated blood lipid values.
Pharmacokinetic interactions:
Cases of benign intracranial hypertension (pseudotumor cerebri) have been reported with concomitant use of isotretinoin and tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided
Special warnings:
Isotretinoin is contraindicated in women of childbearing potential.
Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception.
Male patients
The available data suggests that the level of maternal exposure from the semen of the patients receiving isotretinoin is not of sufficient magnitude to be associated with the teratogenic effects of isotretinoin.
Male patients should be reminded that they must not share their medication with anyone, particularly not females.
Additional precautions
isotretinoin hexal
Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.
Patients should not donate blood during therapy and for 1 month following discontinuation of isotretinoin because of the potential risk to the foetus of a pregnant transfusion recipient.
Educational material
In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to isotretinoin the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of isotretinoin, to provide advice on contraception before therapy is started and to provide guidance on the need for pregnancy testing.
Full patient information about the teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme should be given by the physician to all patients, both male and female.
Psychiatric disorders
Depression, depression aggravated, aggressive tendencies, mood alterations, psychotic symptoms and, very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with isotretinoin.
Skin and subcutaneous tissues disorders
Acute exacerbation of acne is occasionally seen during the initial period but this subsides with continued treatment, usually within 7-10 days, and usually does not require dose adjustment.
Eye disorders
Dry eyes, corneal opacities, decreased night vision and keratitis usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient to wear glasses during treatment.
Hepatobiliary disorders
Liver enzymes should be checked before treatment, 1 month after the start of treatment, and
Lipid Metabolism
Serum lipids (fasting values) should be checked before treatment, 1 month after the start of treatment, and subsequently at 3 monthly intervals unless more frequent monitoring is clinically indicated.
Gastrointestinal disorders
Isotretinoin has been associated with inflammatory bowel disease (inlcuding regional ileitis) in patients without a prior history of intestinal disorders.
High Risk Patients
In patients with diabetes, obesity, alcoholism or a lipid metabolism disorder undergoing treatment with isotretinoin, more frequent checks of serum values for lipids and/or blood glucose may be necessary. Elevated fasting blood sugars have been reported, and new cases of diabetes have been diagnosed during isotretinoin therapy.
Pregnancy and lactation:
Pregnancy is an absolute contraindication to treatment with isotretinoin .If pregnancy does during treatment with isotretinoin or in the month following, there is a great risk of very severe and serious malformation of the foetus.
Isotretinoin is highly lipophilic, therefore the passage of isotretinoin into human milk is very likely. Due to the potential for adverse effects in the mother and exposed child, the use of isotretinoin is contraindicated in nursing mothers.
Storage temperature:
Room temperature (15-25 C)
Isotretinoin, also known as 13-cis-retinoic acid (and colloquially referred to by its former brand name Accutane or Roaccutane), is a medication primarily used to treat severe acne. Rarely, it is also used to prevent certain skin cancers (squamous-cell carcinoma), and in the treatment of other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. It is a retinoid, meaning it is related to vitamin A, and is found in small quantities naturally in the body. Its isomer, tretinoin, is also an acne drug.
Isotretinoin is primarily used as a treatment for severe acne. The most common adverse effects are a transient worsening of acne (lasting 1–4 months), dry lips (cheilitis), dry and fragile skin, and an increased susceptibility to sunburn. Uncommon and rare side effects include muscle aches and pains (myalgias), and headaches. Isotretinoin is known to cause birth defects due to in-utero exposure because of the molecule’s close resemblance to retinoic acid, a natural vitamin A derivative which controls normal embryonic development. It is also associated with psychiatric side effects, most commonly depression but also, more rarely, psychosis and unusual behaviours. Other rare side effects include hyperostosis, and premature epiphyseal closure, have been reported to be persistent.
In the United States, a special procedure is required to obtain the pharmaceutical. In most other countries, a consent form is required which explains these risks. Women taking isotretinoin must not get pregnant during and for 1 month after the discontinuation of isotretinoin therapy. Sexual abstinence or effective contraception is mandatory during this period. Barrier methods by themselves (e.g., condoms) are not considered adequate due to the unacceptable failure rates of approximately 3%. Women who become pregnant while taking isotretinoin therapy are generally counseled to have an abortion.
It was patented in 1969 and approved for medical use in 1982.[2] It sold well for many years, but in 2009, Roche decided to discontinue manufacturing due to diminishing market share due to the availability of the many generic versions of the drug and in the setting of multiple lawsuits over side effects. It continues to be manufactured worldwide in 2019 as Absorica, Amnesteem, Claravis, Myorisan, Sotret, and Zenatane.[3]
Isotretinoin is used primarily for severe cystic acne and acne that has not responded to other treatments.[4][5][6][7] Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce physical or psychological scarring.[8] Isotretinoin is not indicated for treatment of prepubertal acne and is not recommended in children less than 12 years of age.[9]
isotretinoin hexal
It is also somewhat effective for hidradenitis suppurativa and some cases of severe rosacea.[10] It can also be used to help treat harlequin ichthyosis, lamellar ichthyosis and is used in xeroderma pigmentosum cases to relieve keratoses. Isotretinoin has been used to treat the extremely rare condition fibrodysplasia ossificans progressiva. It is also used for treatment of neuroblastoma, a form of nerve cancer.
Isotretinoin therapy has furthermore proven effective against genital warts in experimental use, but is rarely used for this indication as there are more effective treatments. Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for recalcitrant condylomata acuminata (RCA) of the cervix. In most countries this therapy is currently unapproved and only used if other therapies failed.[11][12]
Isotretinoin is a teratogen; there is about a 20–35% risk for congenital defects in infants exposed to the drug in utero, and about 30–60% of children exposed to isotretinoin prenatally have been reported to show neurocognitive impairment.[13] Because of this, there are strict controls on prescribing isotretinoin to women who may become pregnant and women who become pregnant while taking isotretinoin are strongly advised to terminate their pregnancies.[13]
In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescription by general practitioners and family doctors. In the United Kingdom[14] and Australia,[15][16] isotretinoin may be prescribed only by or under the supervision of a consultant dermatologist. Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious.[17] In New Zealand, isotretinoin can be prescribed by any doctor but subsidised only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner.[18]
In the United States, since March 2006 the dispensing of isotretinoin is run through a website called iPLEDGE. The FDA required the companies marketing the drug in the US, which at the time that iPLEDGE was launched were Roche, Mylan, Barr, and Ranbaxy, to put this website in place as a risk evaluation and mitigation strategy. These companies formed a group called the Isotretinoin Products Manufacturing Group, and it hired Covance to run the website.[19][20] Prescribers, pharmacists, and all people to whom the drug is prescribed need to register on the site and log information into it. Women with child-bearing potential must commit to using two forms of effective contraception simultaneously for the duration of isotretinoin therapy and for a month immediately preceding and a month immediately following therapy. Additionally they must have two negative pregnancy tests 30 days apart and have negative pregnancy tests before each prescription is written.[21][22]
Increasingly higher dosages will result in higher toxicity, resembling vitamin A toxicity. Adverse effects include:[23]
Type of disorders
Very common (≥ 1/10)
Common (≥ 1/100, < 1/10)
Rare (≥ 1/10 000,< 1/1000)
Very rare (≤ 1/10 000)
bacterial infection
and mediastinal
subcutaneous tissues
connective tissue
and tendons)
Isotretinoin may stop long bone growth in young people who are still growing.[7] Premature epiphyseal closure can occur in people with acne receiving recommended doses[24] of Accutane.[25][26][27]
Generally though, premature epiphyseal closure seems to be primarily related to:
Isotretinoin is known to cause meibomian gland dysfunction which causes persistent keratoconjunctivitis sicca (dry eye).[29] Problems with the meibomian and salivary glands are likely due to the non-selective apoptosis of the cells of the exocrine glands.[30] Decreased night vision has been reported to persist in some people after discontinuation of isotretinoin therapy.[31]
The most common side effects are mucocutaneous: dry lips, skin and nose. Other common mucocutaneous side effects are inflammation and chapping of the lips (cheilitis), redness of the skin (erythema), rashes, peeling, eczema (dermatitis), itching (pruritus) and nose bleeds (epistaxis).[32] Absence of dryness of the lips is considered an indication of non-compliance with treatment (not taking the drug as advised), as it occurs in almost all people who take it.[32]
Regular use of lip balm and moisturizer is recommended throughout a course of treatment to reduce these problems. The dose may need to be decreased to reduce the severity of these side effects.[33] The skin becomes more fragile—especially to frictional forces—and may not heal as quickly as normal. Wound healing is delayed. For this reason elective surgery, waxing of hair, tattooing, tattoo removal, piercings, dermabrasion, exfoliation, etc., are not recommended. Treatment of acne scars is generally deferred until 12 months after completion of a course of isotretinoin.
Acne usually flares up 2–3 weeks into the treatment and is usually mild and tolerable. Occasionally this flare-up is severe, necessitating oral antiobiotics such as erythromycin. A short course of oral prednisolone may be required. Some dermatologists favour a few weeks of pre-treatment with oral antibiotics before commencing isotretinoin to reduce the chance of a severe flare. A “stepped” course may also be used to reduce the chance of this initial flare, by which the initial dose is low (e.g. 0.5 mg/kg) and subsequently increased throughout the course.
Isotretinoin use can rarely lead to a more severe form of acne, acne fulminans.
Isotretinoin is a teratogen highly likely to cause birth defects if taken by women during pregnancy or even a short time before conception. A few of the more common birth defects this drug can cause are hearing and visual impairment, missing or malformed earlobes, facial dysmorphism, and abnormalities in brain function. Isotretinoin is classified as FDA Pregnancy Category X and ADEC Category X, and use is contraindicated in pregnancy.[10]
The manufacturer recommends pregnancy be ruled out two weeks prior to commencement of isotretinoin, and women should use two simultaneous forms of effective contraception at least one month prior to commencement, during, and for at least one month following isotretinoin therapy.[34]
In the U.S., around 2000 women became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in abortion or miscarriage. About 160 babies with birth defects were born. After the FDA put the more strict iPLEDGE program in place for the companies marketing the drug in the US, in 2011, 155 pregnancies occurred among 129,544 women of childbearing potential taking isotrentinoin (0.12%).[35]
People taking isotretinoin are not permitted to donate blood during and for at least one month after discontinuation of therapy due to its teratogenicity.[36]
Rare psychological side effects may include depression, worsening of pre-existing depression, aggressive tendencies, irritable mood and anxiety. Very rare effects include abnormal behaviour, psychosis, suicidal ideation, suicide attempts and suicide.[6][37][38][39] In a total of 5577 adverse reactions reported to the UK’s MHRA up to 31 March 2017, the plurality (1207, or 22%) concerned psychiatric effects.[40] There were 85 reports of suicidal ideation, 56 of completed suicide and 43 of suicide attempts.[40]
The association between isotretinoin use and psychopathology has been controversial. Beginning in 1983, isolated case reports emerged suggesting mood change, particularly depression, occurring during or soon after isotretinoin use.[41] A number of studies have been conducted since then of the drug’s effect on depression, psychosis, suicidal thoughts and other psychological effects.[41]
Isotretinoin is the only non-psychiatric drug on the FDA’s top 10 list of drugs associated with depression[38][42] and is also within the top 10 for suicide attempts.[43] A black box warning for suicide, depression and psychosis has been present on isotretinoin’s packaging in the United States since 2005.[42]
In 2012, a systematic review covering all articles in the literature related to isotretinoin, depression and suicide, as well as articles related to class effect, dose response, and biologic plausibility found that the literature reviewed was consistent with an association of isotretinoin administration and depression and with suicide in a subgroup of vulnerable individuals.[37] Following this systematic review, in a 2014 review a group of Australian dermatologists and psychiatrists collaborated on a set of recommendations for safe prescribing of isotretinoin.[44] However, whether isotretinoin use is causally associated with mental illness remains controversial.[44]
Evidence for depression being causally associated with isotretinoin use includes 41 reports of positive challenge/dechallenge/rechallenge with isotretinoin, involving administering isotretinoin, withdrawing the drug and then re-administering it.[37] The majority of these cases had no psychiatric history.[37] There is also a temporal relationship between development of depression and initiation of isotretinoin treatment, with most cases developing after 1–2 months of treatment.[37] Further, higher doses of isotretinoin increases the risk of developing depression, with 25% of people showing depression on a dose of 3 mg/kg/day as compared with 3–4% at normal doses.[37] Studies have uncovered several biological processes which may credibly explain the affective changes induced by isotretinoin.
Isotretinoin has also been linked to psychosis.[23] Many of the side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms.[37] The dopamine hypothesis of schizophrenia and psychosis suggests that an increase in dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms.[45]
It has been suggested that dysregulation of retinoid receptors by retinoids such as isotretinoin may cause schizophrenia.[46][47] The evidence for this is threefold – Transcriptional activation of the dopamine D2 receptor, in addition to serotonin and glutamate receptors, is regulated by retinoic acid,[46] schizophrenia and the retinoid cascade have been linked to the same gene loci[46] and retinoid dysfunction causes congenital anomalies identical to those observed in people with schizophrenia.[46] Further, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid.[48][49]
Isotretinoin has a number of muscoloskeletal effects. Myalgia (muscular pain) and arthralgia (joint pain) are rare side effects.[32] Retinoids, such as high dose etretinate, are well known to cause bone changes, the most common type of which is hyperostotic changes (excessive bone growth), especially in growing children and adolescents.[32] Other problems include premature epiphyseal closure and calcification of tendons and ligaments.[32] The bones of the spine and feet are most commonly affected. Risk factors for skeletal effects include older age, greater dosage and longer course of treatment. Most bone changes cause no symptoms and may only be noticed using X-ray imaging.[32]
isotretinoin hexal
Isotretinoin may cause non-specific gastrointestinal symptoms including nausea, diarrhea and abdominal pain.[32] The drug is associated with inflammatory bowel disease (IBD)—ulcerative colitis, but not Crohn’s disease.[50] There are also reports of people developing irritable bowel syndrome (IBS) and worsening of existing IBS.[51]
Isotretinoin and other retinoids are well known to affect the eyes. Dry eyes are very common during treatment and is caused by isotretinoin’s apoptotic effect on the meibomian glands. Some people develop contact lens intolerance as a result.[32] In some people, these changes are long-lasting or irreversible and represent Meibomian Gland Dysfunction (MGD).[29] Other common effects on the eyes include inflammation of the eyelid (blepharitis), red eye caused by conjunctivitis and irritation of the eye. More rare ocular side effects include blurred vision, decreased night vision (which may be permanent), colour blindness, development of corneal opacities, inflammation of the cornea (keratitis), swelling of the optic disk (papilloedema, associated with IIH), photophobia and other visual disturbances.[6]
Isotretinoin is also associated with sexual side effects, namely erectile dysfunction and reduced libido.[23] In October 2017, the UK MHRA issued a Drug Safety Update to physicians in response to reports of these problems.[52] This was in response to an EU review, published in August 2017, which states that a plausible physiological explanation of these side effects “may be a reduction in plasma testosterone”.[9] The review also stated that “the product information should be updated to include ‘sexual dysfunction including erectile dysfunction and decreased libido’ as an undesirable effect with an unknown frequency”.[53] There have also been reports of spermatogenesis disorders, such as oligospermia. 27 cases of sexual dysfunction report either negative dechallenge or positive dechallenge.[clarification needed][9]
Isotretinoin’s exact mechanism of action is unknown, but several studies have shown that isotretinoin induces apoptosis (programmatic cell death) in various cells in the body. Cell death may be instigated in the meibomian glands,[30][54] hypothalamic cells,[55] hippocampus cells[56][57] and—important for treatment of acne—in sebaceous gland cells.[58][59] Isotretinoin has a low affinity for retinoic acid receptors (RAR) and retinoid X receptors (RXR), but may be converted intracellularly to metabolites that act as agonists of RAR and RXR nuclear receptors.[5]
One study suggests the drug amplifies production of neutrophil gelatinase-associated lipocalin (NGAL) in the skin, which has been shown to reduce sebum production by inducing apoptosis in sebaceous gland cells, while exhibiting an antimicrobial effect on Cutibacterium acnes.[60][61][62] The drug decreases the size and sebum output of the sebaceous glands.[63] Isotretinoin is the only available acne drug that affects all four major pathogenic processes in acne, which distinguishes it from alternative treatments (such as antibiotics) and accounts for its efficacy in severe, nodulocystic cases.[64] The effect of Isotretinoin on sebum production can be temporary,[7] or remission of the disease can be “complete and prolonged.”[63][65][66]
Isotretinoin has been speculated to down-regulate the enzyme telomerase and hTERT, inhibiting “cellular immortalization and tumorigenesis.”[67] In a 2007 study, Isotretinoin was proven to inhibit the action of the metalloprotease MMP-9 (gelatinase) in sebum without any influence in the action of TIMP1 and TIMP2 (the tissue inhibitors of metalloproteases).[68] It is already known that metalloproteases play an important role in the pathogenesis of acne.[69]
A possible biological basis for the case reports of depression involves decreased metabolism in the orbitofrontal cortex (OFC) of the frontal lobe.[37] It has also been found that decreased OFC metabolism was correlated with headaches.[37] People reporting headache as a side effect often report comorbid neuropsychiatric symptoms, especially depression; a statistically significant relationship between headache and depression has been established.[70] It is suggested that people sensitive to isotretinoin-induced CNS effects may also be susceptible to other psychiatric side effects such as depression.[37]
Studies in mice and rats have found that retinoids, including isotretinoin, bind to dopaminergic receptors in the central nervous system.[38][71][72] Isotretinoin may affect dopaminergic neurotransmission by disrupting the structure of dopamine receptors and decreasing dopaminergic activity.[39] The dopaminergic system is implicated in numerous psychological disorders, including depression. Isotretinoin is also thought to affect the serotonergic system – it increases expression of 5-HT1A receptors in the pre-synaptic neuron, which inhibit serotonin secretion.[39] Isotretinoin also directly and indirectly increases the translation of the serotonin transporter protein (SERT), leading to increased reuptake and consequently reduced synaptic availability of serotonin.[39]
Inhibition of hippocampal neurogenesis may also play a role in the development of isotretinoin-induced depression.[37] A further effect of isotretinoin on the brain involves retinoic acid function in the hypothalamus, the hormone regulatory centre of the brain and part of the hypothalamus-pituitary-adrenal axis, a key part of the body’s stress response.[37] Other brain regions regulated by retinoic acid and potentially disrupted by isotretinoin include the frontal cortex and the striatum.[37]
Oral Isotretinoin is best absorbed when taken with a high-fat meal, because it has a high level of lipophilicity.[73] The efficacy of isotretinoin doubles when taken after a high-fat meal compared to when taken without food.[74] Due to Isotretinoin’s molecular relationship to Vitamin A, it should not be taken with Vitamin A supplements due to the danger of toxicity through cumulative overdosing.[75] Accutane also negatively interacts with tetracycline, another class of acne drug, and with micro-dosed (‘mini-pill’) progesterone preparations, norethisterone/ethinylestradiol (‘OrthoNovum 7/7/7’), St. John’s Wort, phenytoin, and systemic corticosteroids.
Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly albumin. Three metabolites of Isotretinoin are detectable in human plasma after oral administration: 4-oxo-isotretinoin, retinoid acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Isotretinoin also oxidizes, irreversibly, to 4-oxo-isotretinoin—which forms its geometric isomer 4-oxo-tretinoin. After an orally-administered, 80 mg dose of liquid suspension 14C-isotretinoin, 14C-activity in blood declines with a half-life of 90 hours.[73] The metabolites of isotretinoin and its conjugates are then excreted in the subject’s urine and faeces in relatively equal amounts.[73] After a single, 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD elimination half-life (t1/2) of isotretinoin and 4-oxo-isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively.[73] After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in people with cystic acne.[73]
The compound 13-cis retinoic acid was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. Experiments completed in 1971 showed that the compound was likely to be ineffective for cancer and, surprisingly, that it could be useful to treat acne. However, they also showed that the compound was likely to cause birth defects, so in light of the events around thalidomide, Roche abandoned the product. In 1975, Gary Peck and Frank Yoder independently rediscovered the drug’s use as a treatment of cystic acne while studying it as a treatment for lamellar ichthyosis, and published that work. Roche resumed work on the drug. In clinical trials, subjects were carefully screened to avoid including women who were or might become pregnant. Roche’s New Drug Application for isotretinoin for the treatment of acne included data showing that the drug caused birth defects in rabbits. The FDA approved the application in 1982.
Scientists involved in the clinical trials published articles warning of birth defects at the same time the drug was launched in the US, but nonetheless isotretinoin was taken up quickly and widely, both among dermatologists and general practitioners. Cases of birth defects showed up in the first year, leading the FDA to begin publishing case reports and to Roche sending warning letters to doctors and placing warning stickers on drug bottles, and including stronger warnings on the label. Lawsuits against Roche started to be filed. In 1983 the FDA’s advisory committee was convened and recommended stronger measures, which the FDA took and were that time unprecedented: warning blood banks not to accept blood from people taking the drug, and adding a warning to the label advising women to start taking contraceptives a month before starting the drug. However use of the drug continued to grow, as did the number of babies born with birth defects. In 1985 the label was updated to include a boxed warning. In early 1988 the FDA called for another advisory committee, and FDA employees prepared an internal memo estimating that around 1,000 babies had been born with birth defects due to isotretinoin, that up to around 1,000 miscarriages had been caused, and that between 5,000 and 7,000 women had had abortions due to isotretinoin. The memo was leaked to the New York Times[76] a few days before the meeting, leading to a storm of media attention. In the committee meeting, dermatologists and Roche each argued to keep the drug on the market but to increase education efforts; pediatricians and the CDC argued to withdraw the drug from the market. The committee recommended to restrict physicians who could prescribe the drug and to require a second opinion before it could be prescribed. The FDA, believing it did not have authority under the law to restrict who had the right to prescribe the drug, kept the drug on the market but took further unprecedented measures: it required to Roche to make warnings yet more visible and graphic, provide doctors with informed consent forms to be used when prescribing the drug, and to conduct follow up studies to test whether the measures were reducing exposure of pregnant women to the drug. Roche implemented those measures, and offered to pay for contraception counseling and pregnancy testing for women prescribed the drug – the program was called the “Pregnancy Prevention Program”.
A CDC report published in 2000[77] showed problems with the Pregnancy Prevention Program and showed that the increase in prescriptions was from off-label use, and prompted Roche to revamp its program, renaming it the “Targeted Pregnancy Prevention Program” and adding label changes like requirements for two pregnancy tests, two kinds of contraception, and for doctors to provide pharmacists with prescriptions directly; providing additional educational materials, and providing free pregnancy tests. The FDA had another advisory meeting in late 2000 that again debated how to prevent pregnant women from being exposed to the drug; dermatologists testified about the remarkable efficacy of the drug, the psychological impact of acne, and demanded autonomy to prescribe the drug; others argued that the drug be withdrawn or much stricter measures be taken. In 2001 the FDA announced a new regulatory scheme called SMART (the System to Manage Accutane Related Teratogenicity) that required Roche to provide defined training materials to doctors, and for doctors to sign and return a letter to Roche acknowledging that they had reviewed the training materials, for Roche to then send stickers to doctors, which doctors would have to place on prescriptions they give people after they have confirmed a negative pregnancy test; prescriptions could only be written for 30 days and could not be renewed, thus requiring a new pregnancy test for each prescription.[citation needed]
In February 2002, Roche’s patents for isotretinoin expired, and there are now many other companies selling cheaper generic versions of the drug. On June 29, 2009, Roche Pharmaceuticals, the original creator and distributor of isotretinoin, officially discontinued both the manufacture and distribution of their Accutane brand in the United States due to what the company described as business reasons related to low market share (below 5%), coupled with the high cost of defending personal-injury lawsuits brought by some people who took the drug.[78] Generic isotretinoin will remain available in the United States through various manufacturers. Roche USA continues to defend Accutane and claims to have treated over 13 million people since its introduction in 1982. F. Hoffmann-La Roche Ltd. apparently will continue to manufacture and distribute Roaccutane outside of the United States.[79]
Among others, actor James Marshall sued Roche over allegedly Accutane-related disease that resulted in removal of his colon.[80] The jury, however, decided that James Marshall had a pre-existing bowel disease.[81]
Several trials over inflammatory bowel disease claims have been held in the United States thus far, with many of them resulting in multimillion-dollar judgments against the makers of isotretinoin.[82]
As of 2017 isotretinoin was marketed under many brand names worldwide: A-Cnotren, Absorica, Accuran, Accutane, Accutin, Acne Free, Acnecutan, Acnegen, Acnemin, Acneone, Acneral, Acnestar, Acnetane, Acnetin A, Acnetrait, Acnetrex, Acnogen, Acnotin, Acnotren, Acretin, Actaven, Acugen, Acutret, Acutrex, Ai Si Jie, Aisoskin, Aknal, Aknefug Iso, Aknenormin, Aknesil, Aknetrent, Amnesteem, Atlacne, Atretin, Axotret, Casius, Ciscutan, Claravis, Contracné, Curacne, Curacné, Curakne, Curatane, Cuticilin, Decutan, Dercutane, Effederm, Epuris, Eudyna, Farmacne, Flexresan, Flitrion, I-Ret, Inerta, Inflader, Inotrin, Isac, Isdiben, Isoacne, Isobest, Isocural, Isoderm, Isoface, IsoGalen, Isogeril, Isolve, Isoprotil, Isoriac, Isosupra, Isosupra Lidose, Isotane, Isotina, Isotinon, Isotren, Isotret, Isotretinoin, Isotretinoina, Isotretinoína, Isotretinoine, Isotretinoïne, Isotrétinoïne, Isotretinoinum, Isotrex, Isotrin, Isotroin, Izotek, Izotziaja, Lisacne, Locatret, Mayesta, Myorisan, Neotrex, Netlook, Nimegen, Noitron, Noroseptan, Novacne, Oralne, Oraret, Oratane, Piplex, Policano, Procuta, Reducar, Retin A, Roaccutan, Roaccutane, Roacnetan, Roacta, Roacutan, Rocne, Rocta, Sotret, Stiefotrex, Tai Er Si, Teweisi, Tretin, Tretinac, Tretinex, Tretiva, Tufacne, Zenatane, Zerocutan, Zonatian ME, and Zoretanin.[1]
As of 2017 it was marketed as a topical combination drug with erythromycin under the brand names Isotrex Eritromicina, Isotrexin, and Munderm.[1]
While excessive bone growth has been raised a possible side effect, a 2006 review found little evidence for this.[83]
The liver is an organ only found in vertebrates which detoxifies various metabolites, synthesizes proteins and produces biochemicals necessary for digestion.[2][3][4] In humans, it is located in the right upper quadrant of the abdomen, below the diaphragm. Its other roles in metabolism include the regulation of glycogen storage, decomposition of red blood cells and the production of hormones.[4]
The liver is an accessory digestive gland that produces bile, an alkaline compound which helps the breakdown of fat. Bile aids in digestion via the emulsification of lipids. The gallbladder, a small pouch that sits just under the liver, stores bile produced by the liver which is afterwards moved to the small intestine to complete digestion.[5] The liver’s highly specialized tissue consisting of mostly hepatocytes regulates a wide variety of high-volume biochemical reactions, including the synthesis and breakdown of small and complex molecules, many of which are necessary for normal vital functions.[6] Estimates regarding the organ’s total number of functions vary, but textbooks generally cite it being around 500.[7]
Terminology related to the liver often starts in hepat- from ἡπατο-, from the Greek word for liver.[8]
No way is yet known to compensate for the absence of liver function in the long term, although liver dialysis techniques can be used in the short term. Artificial livers are yet to be developed to promote long-term replacement in the absence of the liver. As of 2018[update],[9] liver transplantation is the only option for complete liver failure.
The liver is a reddish-brown, wedge-shaped organ with four lobes of unequal size and shape. A human liver normally weighs approximately 1.5 kg (3.3 lb),[10] and has a width of about 15 cm (6 in).[11] It is both the heaviest internal organ and the largest gland in the human body.
Located in the right upper quadrant of the abdominal cavity, it rests just below the diaphragm, to the right of the stomach and overlies the gallbladder.[5]
isotretinoin hexal
The liver is connected to two large blood vessels: the hepatic artery and the portal vein and common hepatic duct. The hepatic artery carries oxygen-rich blood from the aorta via the celiac plexus, whereas the portal vein carries blood rich in digested nutrients from the entire gastrointestinal tract and also from the spleen and pancreas.[9] These blood vessels subdivide into small capillaries known as liver sinusoids, which then lead to lobules.
Lobules are the functional units of the liver. Each lobule is made up of millions of hepatic cells (hepatocytes), which are the basic metabolic cells. The lobules are held together by a fine, dense, irregular, fibroelastic connective tissue layer which extends from the fibrous capsule covering the entire liver known as Glisson’s capsule.[4] This extends into the structure of the liver, by accompanying the blood vessels (veins and arteries), ducts, and nerves at the hepatic hilum. The whole surface of the liver except for the bare area, is covered in a serous coat derived from the peritoneum, and this firmly adheres to the inner Glisson’s capsule.
The liver is grossly divided into two parts when viewed from above – a right and a left lobe, and four parts when viewed from below (left, right, caudate, and quadrate lobes).[12]
The falciform ligament divides the liver into a left and right lobe. From below, the two additional lobes are located between the right and left lobes, one in front of the other. A line can be imagined running from the left of the vena cava and all the way forward to divide the liver and gallbladder into two halves.[13] This line is called “Cantlie’s line”.[14]
Other anatomical landmarks include the ligamentum venosum and the round ligament of the liver (ligamentum teres), which further divide the left side of the liver in two sections. An important anatomical landmark, the porta hepatis, divides this left portion into four segments, which can be numbered starting at the caudate lobe as I in an anticlockwise manner. From this parietal view, seven segments can be seen, because the eighth segment is only visible in the visceral view.[15]
On the diaphragmatic surface, apart from a triangular bare area where it connects to the diaphragm, the liver is covered by a thin, double-layered membrane, the peritoneum, that helps to reduce friction against other organs.[16] This surface covers the convex shape of the two lobes where it accommodates the shape of the diaphragm. The peritoneum folds back on itself to form the falciform ligament and the right and left triangular ligaments.[17]
These peritoneal ligaments are not related to the anatomic ligaments in joints, and the right and left triangular ligaments have no known functional importance, though they serve as surface landmarks.[17] The falciform ligament functions to attach the liver to the posterior portion of the anterior body wall.
The visceral surface or inferior surface, is uneven and concave. It is covered in peritoneum apart from where it attaches the gallbladder and the porta hepatis.[16] The fossa of gall bladder lies to the right of the quadrate lobe,occupied by the gallbladder with its cystic duct close to the right end of porta hepatis.
Several impressions on the surface of the liver accommodate the various adjacent structures and organs. Underneath the right lobe and to the right of the gallbladder fossa are two impressions, one behind the other and separated by a ridge. The one in front is a shallow colic impression, formed by the hepatic flexure and the one behind is a deeper renal impression accommodating part of the right kidney and part of the suprarenal gland.[18]
The suprarenal impression is a small, triangular, depressed area on the liver. It is located close to the right of the fossa, between the bare area and the caudate lobe, and immediately above the renal impression. The greater part of the suprarenal impression is devoid of peritoneum and it lodges the right suprarenal gland.[19]
Medial to the renal impression is a third and slightly marked impression, lying between it and the neck of the gall bladder. This is caused by the descending portion of the duodenum, and is known as the duodenal impression.[19]
The inferior surface of the left lobe of the liver presents behind and to the left the gastric impression.[19] This is moulded over the upper front surface of the stomach, and to the right of this is a rounded eminence, the tuber omentale, which fits into the concavity of the lesser curvature of the stomach and lies in front of the anterior layer of the lesser omentum.
Microscopically, each liver lobe is seen to be made up of hepatic lobules. The lobules are roughly hexagonal, and consist of plates of hepatocytes radiating from a central vein.[20][page needed]The central vein joins to the hepatic vein to carry blood out from the liver. A distinctive component of a lobule is the portal triad, which can be found running along each of the lobule’s corners. The portal triad, misleadingly named, consists of five structures: a branch of the hepatic artery, a branch of the hepatic portal vein, and a bile duct, as well as lymphatic vessels and a branch of the vagus nerve.[21] Between the hepatocyte plates are liver sinusoids, which are enlarged capillaries through which blood from the hepatic portal vein and hepatic artery enters via the portal triads, then drains to the central vein.[20][page needed]
Histology, the study of microscopic anatomy, shows two major types of liver cell: parenchymal cells and nonparenchymal cells. About 70–85% of the liver volume is occupied by parenchymal hepatocytes. Nonparenchymal cells constitute 40% of the total number of liver cells but only 6.5% of its volume.[22] The liver sinusoids are lined with two types of cell, sinusoidal endothelial cells, and phagocytic Kupffer cells.[23] Hepatic stellate cells are nonparenchymal cells found in the perisinusoidal space, between a sinusoid and a hepatocyte.[22]
Additionally, intrahepatic lymphocytes are often present in the sinusoidal lumen.[22]
The central area or hepatic hilum, includes the opening known as the porta hepatis which carries the common bile duct and common hepatic artery, and the opening for the portal vein. The duct, vein, and artery divide into left and right branches, and the areas of the liver supplied by these branches constitute the functional left and right lobes. The functional lobes are separated by the imaginary plane, Cantlie’s line, joining the gallbladder fossa to the inferior vena cava. The plane separates the liver into the true right and left lobes. The middle hepatic vein also demarcates the true right and left lobes. The right lobe is further divided into an anterior and posterior segment by the right hepatic vein. The left lobe is divided into the medial and lateral segments by the left hepatic vein.
The hilum of the liver is described in terms of three plates that contain the bile ducts and blood vessels. The contents of the whole plate system are surrounded by a sheath.[24] The three plates are the hilar plate, the cystic plate and the umbilical plate and the plate system is the site of the many anatomical variations to be found in the liver.[24]
In the widely used Couinaud system, the functional lobes are further divided into a total of eight subsegments based on a transverse plane through the bifurcation of the main portal vein.[25] The caudate lobe is a separate structure that receives blood flow from both the right- and left-sided vascular branches.[26][27] The Couinaud classification of liver anatomy divides the liver into eight functionally independent liver segments. Each segment has its own vascular inflow, outflow and biliary drainage. In the centre of each segment are branches of the portal vein, hepatic artery, and bile duct. In the periphery of each segment is vascular outflow through the hepatic veins.[28] The classification system uses the vascular supply in the liver to separate the functional units (numbered I to VIII), with unit 1, the caudate lobe, receiving its supply from both the right and the left branches of portal vein. It contains one or more hepatic veins which drain directly into the inferior vena cava.[25] The remainder of the units (II to VIII) are numbered in a clockwise fashion:[28]
About 20,000 protein coding genes are expressed in human cells and 60% of these genes are expressed in a normal, adult liver.[29][30] Over 400 genes are more specifically expressed in the liver, with some 150 genes highly specific for liver tissue. A large fraction of the corresponding liver specific proteins are mainly expressed in hepatocytes and secreted into the blood and constitute plasma proteins. Other liver specific proteins are certain liver enzymes such as HAO1 and RDH16, proteins involved in bile synthesis such as BAAT and SLC27A5, and transporter proteins involved in the metabolism of drugs, such as ABCB11 and SLC2A2. Examples of highly liver-specific proteins include apolipoprotein A II, coagulation factors F2 and F9, complement factor related proteins, and the fibrinogen beta chain protein.[31]
Organogenesis, the development of the organs takes place from the third to the eighth week during embryogenesis. The origins of the liver lie in both the ventral portion of the foregut endoderm (endoderm being one of the three embryonic germ layers) and the constituents of the adjacent septum transversum mesenchyme. In the human embryo, the hepatic diverticulum is the tube of endoderm that extends out from the foregut into the surrounding mesenchyme. The mesenchyme of septum transversum induces this endoderm to proliferate, to branch, and to form the glandular epithelium of the liver. A portion of the hepatic diverticulum (that region closest to the digestive tube) continues to function as the drainage duct of the liver, and a branch from this duct produces the gallbladder.[32] Besides signals from the septum transversum mesenchyme, fibroblast growth factor from the developing heart also contributes to hepatic competence, along with retinoic acid emanating from the lateral plate mesoderm. The hepatic endodermal cells undergo a morphological transition from columnar to pseudostratified resulting in thickening into the early liver bud. Their expansion forms a population of the bipotential hepatoblasts.[33] Hepatic stellate cells are derived from mesenchyme.[34]
After migration of hepatoblasts into the septum transversum mesenchyme, the hepatic architecture begins to be established, with liver sinusoids and bile canaliculi appearing. The liver bud separates into the lobes. The left umbilical vein becomes the ductus venosus and the right vitelline vein becomes the portal vein. The expanding liver bud is colonized by hematopoietic cells. The bipotential hepatoblasts begin differentiating into biliary epithelial cells and hepatocytes. The biliary epithelial cells differentiate from hepatoblasts around portal veins, first producing a monolayer, and then a bilayer of cuboidal cells. In ductal plate, focal dilations emerge at points in the bilayer, become surrounded by portal mesenchyme, and undergo tubulogenesis into intrahepatic bile ducts. Hepatoblasts not adjacent to portal veins instead differentiate into hepatocytes and arrange into cords lined by sinudoidal epithelial cells and bile canaliculi. Once hepatoblasts are specified into hepatocytes and undergo further expansion, they begin acquiring the functions of a mature hepatocyte, and eventually mature hepatocytes appear as highly polarized epithelial cells with abundant glycogen accumulation. In the adult liver, hepatocytes are not equivalent, with position along the portocentrovenular axis within a liver lobule dictating expression of metabolic genes involved in drug metabolism, carbohydrate metabolism, ammonia detoxification, and bile production and secretion. WNT/β-catenin has now been identified to be playing a key role in this phenomenon.[33]
At birth, the liver comprises roughly 4% of body weight and weighs on average about 120 g (4 oz). Over the course of further development, it will increase to 1.4–1.6 kg (3.1–3.5 lb) but will only take up 2.5–3.5% of body weight.[35]
In the growing fetus, a major source of blood to the liver is the umbilical vein, which supplies nutrients to the growing fetus. The umbilical vein enters the abdomen at the umbilicus and passes upward along the free margin of the falciform ligament of the liver to the inferior surface of the liver. There, it joins with the left branch of the portal vein. The ductus venosus carries blood from the left portal vein to the left hepatic vein and then to the inferior vena cava, allowing placental blood to bypass the liver.
In the fetus, the liver does not perform the normal digestive processes and filtration of the infant liver because nutrients are received directly from the mother via the placenta. The fetal liver releases some blood stem cells that migrate to the fetal thymus, creating the T-cells or T-lymphocytes. After birth, the formation of blood stem cells shifts to the red bone marrow.
After 2–5 days, the umbilical vein and ductus venosus are completely obliterated; the former becomes the round ligament of liver and the latter becomes the ligamentum venosum. In the disorders of cirrhosis and portal hypertension, the umbilical vein can open up again.
The various functions of the liver are carried out by the liver cells or hepatocytes. The liver is thought to be responsible for up to 500 separate functions, usually in combination with other systems and organs. Currently, no artificial organ or device is capable of reproducing all the functions of the liver. Some functions can be carried out by liver dialysis, an experimental treatment for liver failure. The liver also accounts for about 20% of resting total body oxygen consumption.
The liver receives a dual blood supply from the hepatic portal vein and hepatic arteries. The hepatic portal vein delivers around 75% of the liver’s blood supply, and carries venous blood drained from the spleen, gastrointestinal tract, and its associated organs. The hepatic arteries supply arterial blood to the liver, accounting for the remaining quarter of its blood flow. Oxygen is provided from both sources; about half of the liver’s oxygen demand is met by the hepatic portal vein, and half is met by the hepatic arteries.[36] The hepatic artery also has both alpha- and beta-adrenergic receptors; therefore, flow through the artery is controlled, in part, by the splanchnic nerves of the autonomic nervous system.
Blood flows through the liver sinusoids and empties into the central vein of each lobule. The central veins coalesce into hepatic veins, which leave the liver and drain into the inferior vena cava.[21]
The biliary tract is derived from the branches of the bile ducts. The biliary tract, also known as the biliary tree, is the path by which bile is secreted by the liver then transported to the first part of the small intestine, the duodenum. The bile produced in the liver is collected in bile canaliculi, small grooves between the faces of adjacent hepatocytes. The canaliculi radiate to the edge of the liver lobule, where they merge to form bile ducts. Within the liver, these ducts are termed intrahepatic bile ducts, and once they exit the liver, they are considered extrahepatic. The intrahepatic ducts eventually drain into the right and left hepatic ducts, which exit the liver at the transverse fissure, and merge to form the common hepatic duct. The cystic duct from the gallbladder joins with the common hepatic duct to form the common bile duct.[21] The biliary system and connective tissue is supplied by the hepatic artery alone
Bile either drains directly into the duodenum via the common bile duct, or is temporarily stored in the gallbladder via the cystic duct. The common bile duct and the pancreatic duct enter the second part of the duodenum together at the hepatopancreatic ampulla, also known as the ampulla of Vater.
The liver plays a major role in carbohydrate, protein, amino acid, and lipid metabolism.
The liver performs several roles in carbohydrate metabolism: The liver synthesizes and stores around 100 g of glycogen via glycogenesis, the formation of glycogen from glucose. When needed, the liver releases glucose into the blood by performing glycogenolysis, the breakdown of glycogen into glucose.[37] The liver is also responsible for gluconeogenesis, which is the synthesis of glucose from certain amino acids, lactate, or glycerol. Adipose and liver cells produce glycerol by breakdown of fat, which the liver uses for gluconeogenesis.[37]
The liver is responsible for the mainstay of protein metabolism, synthesis as well as degradation. It is also responsible for a large part of amino acid synthesis. The liver plays a role in the production of clotting factors, as well as red blood cell production. Some of the proteins synthesized by the liver include coagulation factors I (fibrinogen), II (prothrombin), V, VII, VIII, IX, X, XI, factor XII|[XII]], XIII, as well as protein C, protein S and antithrombin. In the first trimester fetus, the liver is the main site of red blood cell production. By the 32nd week of gestation, the bone marrow has almost completely taken over that task. The liver is a major site of production for thrombopoietin, a glycoprotein hormone that regulates the production of platelets by the bone marrow.[38]
The liver plays several roles in lipid metabolism: it performs cholesterol synthesis, lipogenesis, and the production of triglycerides, and a bulk of the body’s lipoproteins are synthesized in the liver.
The liver plays a key role in digestion, as it produces and excretes bile (a yellowish liquid) required for emulsifying fats and help the absorption of vitamin K from the diet. Some of the bile drains directly into the duodenum, and some is stored in the gallbladder.
The liver also produces insulin-like growth factor 1, a polypeptide protein hormone that plays an important role in childhood growth and continues to have anabolic effects in adults.
isotretinoin hexal
The liver is responsible for the breakdown of insulin and other hormones. The liver breaks down bilirubin via glucuronidation, facilitating its excretion into bile.
The liver is responsible for the breakdown and excretion of many waste products. It plays a key role in breaking down or modifying toxic substances (e.g., methylation) and most medicinal products in a process called drug metabolism. This sometimes results in toxication, when the metabolite is more toxic than its precursor. Preferably, the toxins are conjugated to avail excretion in bile or urine. The liver breaks down ammonia into urea as part of the urea cycle, and the urea is excreted in the urine.[20]
The oxidative capacity of the liver decreases with aging and therefore any medications that require oxidation (for instance, benzodiazepines) are more likely to accumulate to toxic levels. However, medications with shorter half-lives, such as lorazepam and oxazepam, are preferred in most cases when benzodiazepines are required in regard to geriatric medicine.
The liver is a vital organ and supports almost every other organ in the body. Because of its strategic location and multidimensional functions, the liver is also prone to many diseases.[40] The bare area of the liver is a site that is vulnerable to the passing of infection from the abdominal cavity to the thoracic cavity.
Hepatitis is a common condition of inflammation of the liver. The most usual cause of this is viral, and the most common of these infections are hepatitis A, B, C, D, and E. Some of these infections are sexually transmitted. Inflammation can also be caused by other viruses in the family Herpesviridae such as the herpes simplex virus. Chronic (rather than acute) infection with hepatitis B virus or hepatitis C virus is the main cause of liver cancer.[41] Globally, about 248 million individuals are chronically infected with HBV (with 843,724 in the U.S.)[42] and 142 million are chronically infected with HCV[43] (with 2.7 million in the U.S.[44]). Globally there are about 114 million and 20 million cases of hepatitis A[43] and hepatitis E[45] respectively, but these generally resolve, and do not become chronic. Hepatitis D virus is a “satellite” of hepatitis B virus (can only infect in the presence of hepatitis B), and co-infects nearly 20 million people with hepatitis B, globally.[46]
Hepatic encephalopathy is caused by an accumulation of toxins in the bloodstream that are normally removed by the liver. This condition can result in coma and can prove fatal.
Other disorders caused by excessive alcohol consumption are grouped under alcoholic liver diseases and these include alcoholic hepatitis, fatty liver, and cirrhosis. Factors contributing to the development of alcoholic liver diseases are not only the quantity and frequency of alcohol consumption, but can also include gender, genetics, and liver insult.
Liver damage can also be caused by drugs, particularly paracetamol and drugs used to treat cancer. A rupture of the liver can be caused by a liver shot used in combat sports.
Budd–Chiari syndrome is a condition caused by blockage of the hepatic veins (including thrombosis) that drain the liver. It presents with the classical triad of abdominal pain, ascites and liver enlargement.[47]
Primary biliary cholangitis is an autoimmune disease of the liver.[48][49] It is marked by slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts (Canals of Hering) affected early in the disease.[50] When these ducts are damaged, bile and other toxins build up in the liver (cholestasis) and over time damages the liver tissue in combination with ongoing immune related damage. This can lead to scarring (fibrosis) and cirrhosis. Cirrhosis increases the resistance to blood flow in the liver, and can result in portal hypertension. Congested anastomoses between the portal venous system and the systemic circulation, can be a subsequent condition.
Many diseases of the liver are accompanied by jaundice caused by increased levels of bilirubin in the system. The bilirubin results from the breakup of the hemoglobin of dead red blood cells; normally, the liver removes bilirubin from the blood and excretes it through bile.
There are also many pediatric liver diseases, including biliary atresia, alpha-1 antitrypsin deficiency, alagille syndrome, progressive familial intrahepatic cholestasis, Langerhans cell histiocytosis and hepatic hemangioma a benign tumour the most common type of liver tumour, thought to be congenital. A genetic disorder causing multiple cysts to form in the liver tissue, usually in later life, and usually asymptomatic, is polycystic liver disease. Diseases that interfere with liver function will lead to derangement of these processes. However, the liver has a great capacity to regenerate and has a large reserve capacity. In most cases, the liver only produces symptoms after extensive damage.
Hepatomegaly refers to an enlarged liver and can be due to many causes. It can be palpated in a liver span measurement.
Liver diseases may be diagnosed by liver function tests–blood tests that can identify various markers. For example, acute-phase reactants are produced by the liver in response to injury or inflammation.
The classic symptoms of liver damage include the following:
The diagnosis of liver disease is made by liver function tests, groups of blood tests, that can readily show the extent of liver damage. If infection is suspected, then other serological tests will be carried out. A physical examination of the liver can only reveal its size and any tenderness, and some form of imaging such as an ultrasound or CT scan may also be needed.[52]
Sometimes a liver biopsy will be necessary, and a tissue sample is taken through a needle inserted into the skin just below the rib cage. This procedure may be helped by a sonographer providing ultrasound guidance to an interventional radiologist.[53]
Axial CT image showing anomalous hepatic veins coursing on the subcapsular anterior surface of the liver.[54]
Maximum intensity projection (MIP) CT image as viewed anteriorly showing the anomalous hepatic veins coursing on the anterior surface of the liver
Lateral MIP view in the same patient
A CT scan in which the liver and portal vein are shown.
The liver is the only human internal organ capable of natural regeneration of lost tissue; as little as 25% of a liver can regenerate into a whole liver.[55] This is, however, not true regeneration but rather compensatory growth in mammals.[56] The lobes that are removed do not regrow and the growth of the liver is a restoration of function, not original form. This contrasts with true regeneration where both original function and form are restored. In some other species, such as fish, the liver undergoes true regeneration by restoring both shape and size of the organ.[57] In the liver, large areas of the tissues are formed but for the formation of new cells there must be sufficient amount of material so the circulation of the blood becomes more active.[58]
This is predominantly due to the hepatocytes re-entering the cell cycle. That is, the hepatocytes go from the quiescent G0 phase to the G1 phase and undergo mitosis. This process is activated by the p75 receptors.[59] There is also some evidence of bipotential stem cells, called hepatic oval cells or ovalocytes (not to be confused with oval red blood cells of ovalocytosis), which are thought to reside in the canals of Hering. These cells can differentiate into either hepatocytes or cholangiocytes. Cholangiocytes are the epithelial lining cells of the bile ducts.[60] They are cuboidal epithelium in the small interlobular bile ducts, but become columnar and mucus secreting in larger bile ducts approaching the porta hepatis and the extrahepatic ducts. Research is being carried out on the use of stem cells for the generation of an artificial liver.
Scientific and medical works about liver regeneration often refer to the Greek Titan Prometheus who was chained to a rock in the Caucasus where, each day, his liver was devoured by an eagle, only to grow back each night. The myth suggests the ancient Greeks may have known about the liver’s remarkable capacity for self-repair.[61]
Human liver transplants were first performed by Thomas Starzl in the United States and Roy Calne in Cambridge, England in 1963 and 1967, respectively.
Liver transplantation is the only option for those with irreversible liver failure. Most transplants are done for chronic liver diseases leading to cirrhosis, such as chronic hepatitis C, alcoholism, and autoimmune hepatitis. Less commonly, liver transplantation is done for fulminant hepatic failure, in which liver failure occurs over days to weeks.
Liver allografts for transplant usually come from donors who have died from fatal brain injury. Living donor liver transplantation is a technique in which a portion of a living person’s liver is removed (hepatectomy) and used to replace the entire liver of the recipient. This was first performed in 1989 for pediatric liver transplantation. Only 20 percent of an adult’s liver (Couinaud segments 2 and 3) is needed to serve as a liver allograft for an infant or small child.
More recently,[when?] adult-to-adult liver transplantation has been done using the donor’s right hepatic lobe, which amounts to 60 percent of the liver. Due to the ability of the liver to regenerate, both the donor and recipient end up with normal liver function if all goes well. This procedure is more controversial, as it entails performing a much larger operation on the donor, and indeed there have been at least two donor deaths out of the first several hundred cases. A recent publication has addressed the problem of donor mortality, and at least 14 cases have been found.[62] The risk of postoperative complications (and death) is far greater in right-sided operations than that in left-sided operations.
With the recent advances of noninvasive imaging, living liver donors usually have to undergo imaging examinations for liver anatomy to decide if the anatomy is feasible for donation. The evaluation is usually performed by multidetector row computed tomography (MDCT) and magnetic resonance imaging (MRI). MDCT is good in vascular anatomy and volumetry. MRI is used for biliary tree anatomy. Donors with very unusual vascular anatomy, which makes them unsuitable for donation, could be screened out to avoid unnecessary operations.
MDCT image. Arterial anatomy contraindicated for liver donation
MDCT image. Portal venous anatomy contraindicated for liver donation
MDCT image. 3D image created by MDCT can clearly visualize the liver, measure the liver volume, and plan the dissection plane to facilitate the liver transplantation procedure.
Phase contrast CT image. Contrast is perfusing the right liver but not the left due to a left portal vein thrombus.
Some cultures regard the liver as the seat of the soul.[63]
In Greek mythology, the gods punished Prometheus for revealing fire to humans by chaining him to a rock where a vulture (or an eagle) would peck out his liver, which would regenerate overnight. (The liver is the only human internal organ that actually can regenerate itself to a significant extent.) Many ancient peoples of the Near East and Mediterranean areas practiced a type of divination called haruspicy or hepatomancy, where they tried to obtain information by examining the livers of sheep and other animals.
In Plato, and in later physiology, the liver was thought to be the seat of the darkest emotions (specifically wrath, jealousy and greed) which drive men to action.[64] The Talmud (tractate Berakhot 61b) refers to the liver as the seat of anger, with the gallbladder counteracting this.
The Persian, Urdu, and Hindi languages (جگر or जिगर or jigar) refer to the liver figurative speech to indicate courage and strong feelings, or “their best”; e.g., “This Mecca has thrown to you the pieces of its liver!”.[65] The term jan e jigar, literally “the strength (power) of my liver”, is a term of endearment in Urdu. In Persian slang, jigar is used as an adjective for any object which is desirable, especially women. In the Zulu language, the word for liver (isibindi) is the same as the word for courage.
Humans commonly eat the livers of mammals, fowl, and fish as food. Domestic pig, ox, lamb, calf, chicken, and goose livers are widely available from butchers and supermarkets. In the Romance languages, the anatomical word for “liver” (French foie, Spanish hígado, etc.) derives not from the Latin anatomical term, jecur, but from the culinary term ficatum, literally “stuffed with figs,” referring to the livers of geese that had been fattened on figs.[66]
Liver can be baked, boiled, broiled, fried, stir-fried, or eaten raw (asbeh nayeh or sawda naye in Lebanese cuisine, or liver sashimi in Japanese cuisine). In many preparations, pieces of liver are combined with pieces of meat or kidneys, as in the various forms of Middle Eastern mixed grill (e.g. meurav Yerushalmi). Well-known examples include liver pâté, foie gras, chopped liver, and leverpastej. Liver sausages such as Braunschweiger and liverwurst are also a valued meal. Liver sausages may also be used as spreads. A traditional South African delicacy, skilpadjies, is made of minced lamb’s liver wrapped in netvet (caul fat), and grilled over an open fire.
Animal livers are rich in iron, vitamin A and vitamin B12; and cod liver oil is commonly used as a dietary supplement. Traditionally, some fish livers were valued as food, especially the stingray liver. It was used to prepare delicacies, such as poached skate liver on toast in England, as well as the beignets de foie de raie and foie de raie en croute in French cuisine.[67]
The Humr, one of the tribes in the Baggara ethnic grouping, native to southwestern Kordofan in Sudan and speakers of Shuwa or Chadian Arabic, prepare a ( non-alcoholic ) drink from the liver and bone marrow of the giraffe which they call umm nyolokh, and which they claim is intoxicating ( Arabic سكران sakran ), causing dreams and even waking hallucinations.[68] Anthropologist Ian Cunnison, who accompanied the Humr on one of their giraffe-hunting expeditions in the late 1950s, notes that:
It is said that a person, once he has drunk umm nyolokh, will return to giraffe again and again. Humr, being Mahdists, are strict abstainers [ from alcohol ] and a Humrawi is never drunk ( sakran ) on liquor or beer. But he uses this word to describe the effects which umm nyolokh has upon him.[69]
Cunnison’s remarkable account of an apparently psychoactive mammal found its way from a somewhat obscure scientific paper into more mainstream literature through a conversation between Dr. Wendy James of the Institute of Social and Cultural Anthropology at the University of Oxford and specialist on the use of hallucinogens and intoxicants in society Richard Rudgley, who considered its implications in his popular work The Encyclopedia of Psychoactive Substances. Rudgley hypothesises that the presence of the hallucinogenic compound DMT might account for the putative intoxicating properties of umm nyolokh. [68]
Cunnison himself, on the other hand, had found it hard fully to believe in the literal truth of the Humr’s assertion that their drink was intoxicating:
I can only assume that there is no intoxicating substance in the drink and that the effect it produces is simply a matter of convention, although it may be brought about subconsciously.[69]
The study of entheogens in general – including entheogens of animal origin ( e.g. hallucinogenic fish and toad venom ) – has, however made considerable progress in the sixty-odd years since Cunnison’s report and the idea that some intoxicating principle might reside in giraffe liver no longer seems as far-fetched as it was in Cunnison’s day, although conclusive proof ( or disproof ) will have to await detailed analyses of the animal organ in question and the drink prepared therefrom.[68]
Certain Tungusic peoples formerly prepared a type of arrow poison from rotting animal livers, which was, in later times, also applied to bullets. Russian anthropologist Sergei Mikhailovich Shirokogorov, revered as one of the greatest scholars of Tungusic studies, notes that :
Formerly the using of poisoned arrows was common. For instance, among the Kumarčen, [ a subgroup of the Oroqen ] even in recent times a poison was used which was prepared from decaying liver. * ( Note ) This has been confirmed by the Kumarčen. I am not competent to judge as to the chemical conditions of production of poison which is not destroyed by the heat of explosion. However, the Tungus themselves compare this method [ of poisoning ammunition ] with the poisoning of arrows.[70]
The liver is found in all vertebrates, and is typically the largest visceral (internal) organ. Its form varies considerably in different species, and is largely determined by the shape and arrangement of the surrounding organs. Nonetheless, in most species it is divided into right and left lobes; exceptions to this general rule include snakes, where the shape of the body necessitates a simple cigar-like form. The internal structure of the liver is broadly similar in all vertebrates.[71]
An organ sometimes referred to as a liver is found associated with the digestive tract of the primitive chordate Amphioxus. Although it performs many functions of a liver, it is not considered a true liver but a homolog of the vertebrate liver.[72][73][74] The amphioxus hepatic caecum produces the liver-specific proteins vitellogenin, antithrombin, plasminogen, alanine aminotransferase, and insulin/Insulin-like growth factor (IGF)[75]
Department of Dermatology, Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
Department of Dermatology, Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
1Department of Dermatology, School of Medicine, Ilam University of Medical Sciences, Ilam, Iran
Department of Dermatology, Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
Department of Dermatology, Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
isotretinoin hexal
2Department of Dermatology Center, Noorand Ali Asghar Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
Department of Dermatology, Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
SAHA (Seborrhea, Acne, Hirsutism and Androgenetic Alopecia) syndrome is a dermatologic disorder, with variant response to treatment. Triad of cutaneous hyperandrogenism included nodulocystic or severe acne, female pattern hair loss and hirsutism.
The aim of this study is to compare the effectiveness of isotretinoin and cyproterone compound in the treatment of nodulocystic acne, in patients with SAHA syndrome or triad of cutaneous hyperandrogenism.
30 female patients with SAHA syndrome were divided randomly into two groups. Group A was treated with cyproterone compound from day 5 of menstrual cycle onwards for 3 weeks and a week without it and group B received isotretinoin, with a dose of 0.75 mg/kg per day from the beginning of menses onwards for 4 months. The results were evaluated by a blind dermatologist using Acne Severity Index (ASI) score at baseline and monthly for 4 months.
Despite a continuous reduction in ASI score in both the groups, according to both physician (P = 0.63) and patient (P = 0.25) assessment, cyproterone compound was not statistically more effective than conventional treatment of nodulocystic acne at the end of the study. Side-effects were reported in patients in both groups, generally being mild and tolerable except in two subjects.
This study indicates that cyproterone compound is not superior to isotretinoin in the treatment of nodulocystic acne in patient with SAHA syndrome or triad of cutaneous hyperandrogenism. Indeed, other studies are needed to evaluate the effect of cyproterone compound (regardless of androgen level) and isotretinoin in subjects with only nodulocystic acne.
Acne as a common dermatologic disorder occurs worldwide. The conventional treatments, such as topical and systemic antibiotics and retinoids, remain the benchmark for the new proposed modalities to be compared with them. Among the common agents, isotretinoin is widely used. However, cyproterone compound plays its role by an antiandrogenic effect in patients with SAHA syndrome.
Clinical manifestations of androgen excess including seborrhea, androgenetic alopecia, hirsutism and acne are very common distressing symptoms in women of reproductive age. SAHA (Seborrhea, Acne, Hirsutism and Androgenetic Alopecia) syndrome is coined for this complex dermatological androgenization syndrome (Seborrhea, Acne, Hirsutism and possibly also, Androgenetic Alopecia).[1,2,3] The development of sudden-onset acne, acne associated with hirsutism or irregular menses, treatment-resistant acne, acne onset as adult, premenstrual acne flare-ups and inflammatory acne on mandibular line and neck may be associated with hyperandrogenism from several different causes.[4] The two most causes of which are polycystic ovarian syndrome (PCOS) and congenital adrenal hyperplasia.[5,6,7] The combination of cyproterone acetate (2 mg) and ethinyl estradiol (35 μg) is of proven efficacy in management of symptoms of androgenic alopecia and hirsutism in females. Cyproterone acetate inhibits gonadotropin-releasing hormone (GnRH) and blocks androgen receptors. Due to menstrual alteration and the threat of male fetus feminization, adding of ethinyl estradiol in the compound form is recommended.[8] After the advent of isotretinoin in the early 1970s, a revolution occurred in the treatment of nodulocystic acne and acne unresponsive to oral antibiotics.[9,10] The aim of this study is to compare the effectiveness of isotretinoin and cyproterone compound in patients with SAHA syndrome or triad of cutaneous hyperandrogenism.
This prospective randomized, double-blinded study was conducted at the department of dermatology, Al-Zahra Hospital in Isfahan, Iran, during April 2012-February 2014. The study was approved by the ethical committee of Isfahan University of Medical Sciences. The research project number was 291042 and it is adhered with the deceleration of Helsinki. We enrolled and assessed the subjects (from 15 to 45 years old) with inflammatory moderate to severe or very severe nodulocystic acne that really need antiandrogens or isotretinoin medico-legally as mild types are not justified to be treated with such therapeutic agents.
Patients with contraindications to receive cyproterone compound including smoking, migraine headaches with aura, and hypertension and contraindications to use isotretinoin including pregnancy, lactation and history of related hypersensitivity were excluded from the study. With regard to type I error (alpha) = 0.05, study power = 80%, and expected difference of 30% in response rate, sample size was calculated as 15 subjects in each group.
The diagnosis was established on the basis of clinical findings. In each group, 15 patients were enrolled. The patients were divided into two different treatment groups, using a table of random numbers to receive either oral isotretinoin or cyproterone compound pills. The patients in group A received cyproterone compound (35 μg ethinyl estradiol and 2 mg cyproterone acetate; Aburaihan pharmaceutical company) from day 5 of menstrual cycle onwards (for 3 weeks on, and a week off) and the patients in group B received isotretinoin (Iso-Tret® Hexal Company, Germany), at a dose of 0.75 mg/kg per day. The latter drug was administered from the beginning of menses onwards. All the recruited patients received azithromycin (250 mg daily for 2 weeks each month for 4 months) plus topical clindamycin 1% solution on routine basis. The duration of treatment was 4 months in both groups. The clinical response was evaluated by a dermatologist blinded to the clinical trial identifications before the initiation of the treatment and monthly for 4 months using Acne Severity Index score (ASI)[11]. According to this method, ASI is calculated as below:
2 × pustules + papules + 1/4 × comedones
In order to perform patient satisfaction surveys, the assessment of the treatment was conducted by patient-based satisfaction at the 16th week of treatment (Patient Global Assessment [PGA]). The improvement was scored from 0 (as no improvement) to 10 (as the best possible improvement).
For isotretinoin users, laboratory tests including serum levels of fasting lipids and liver function (LFT) were performed at the beginning and monthly throughout the course of treatment. The statistical analysis was done by SPSS by using chi-square, repeated measures ANOVA and independent t-test. The significance level was set at a P value of less than 0.05.
The demographic characteristics of our patients are shown in Table 1. At the end of the study two subjects (two from thirty) failed to complete the study. There were one subject with severe nausea and gastrointestinal upset in group A and one subject in group B with severe headaches. We recruited the eligible patients and designed a flow-chart diagram through our study as shown in Figure 1. The remaining (28 from 30) completed the study. The mean age of patients was 25.2±8.1 years in group A and 26.6±6.3 years in group B. The mean ASI score before treatment was not statistically different between the two groups (P = 0.73). A steady decrease in the mean ASI score in both groups was detected. By means of repeated measure ANOVA test, the reduction in ASI values from the base to the end of the study in both group A (P = 0.01) and group B (P = 0.015) was confirmed. By Independent t test, at the end of first month, patients in group A were more likely experienced improvement (P = 0.003), but no statistically significant difference at the end of second month (P = 0.41), third month (P = 0.503) and forth month (P = 0.62) was noted [Table 2]. With regard to the scores from 0 to 10 by the PGA at the end of the study, patients reported scores greater than 5 were 12 (86%) and 10 (71%) subjects in group A and group B, respectively [Table 3]. In addition, nobody in both groups reported satisfaction less than 4 according to PGA score. However, by means of independent t test, patient’s satisfaction survey was compatible with dermatologist evaluation. Side-effects reported in patients in group A were generally mild and tolerable, except one subject with severe nausea and gastrointestinal upset that gave up the study. Other side effects in group A include: Breakthrough and premature bleeding, mild breast tenderness and hardness, headache. In group B, only one subject with severe headache gave up the study and other side effects in this group were generally mild (e.g. cheilitis, xerosis).
Demographic characteristics of patients in two treatment groups
Consort chart of the study
Acne parameters of comparison of cyproterone compound and isotretinoin
Comparison of distribution pattern of PGA between two treatment groups (Significant score level >5)
Our results showed that there were no significant differences between using isotretinoin and cyproterone compounds in the treatment of acne in patients with SAHA syndrome or triad of cutaneous hyperandrogenism. In fact, isotretinoin acts not only by inhibiting the maturation of the basal sebaceous gland cells, but also by normalization of follicular keratinization.[12,13,14,15,16] Hormonal effects on sebum secretion are the key to the pathogenesis of acne. The conjectural role of hormones has been revealed in the pathogenesis of acne by the detection of androgen receptors in the cells of the basal layer of the sebaceous gland and the outer root sheath of the hair follicle.[12] Despite the fact that isotretinoin is widely used as a conventional therapy for nodulocystic acne, the overall outcome remains incomplete and partially effective. Approximately 40-60 of patients demand therapy after a single course of isotretinoin.[4] Amichai et al. showed that isotretinoin 20 mg/day was effective in the treatment of moderate acne, with a low incidence of severe side effects. This study emphasized on the long-term low-dose isotretinoin in the treatment of acne.[17] In another study conducted by Sardana et al., 6 months of treatment with alternate-day isotretinoin 20 mg plus topical 1% clindamycin gel was effective in the treatment of moderate acne.[18] Some clinicians advocate the use of high-dose isotretinoin (>1.3 mg/kg/day) for treatment of severe nodulocystic acne and encourage large, prospective, multicenter studies into this therapeutic approach.[19] In Muhammad Tahir’s study, clinical improvement was 100% at the end of 16 weeks treatment with isotretinoinin 250 ordinary acne patients (without obvious hyperandrogenism signs) but all of the patients (100%) had suffered from some adverse effects.[20] Treatment failures with isotretinoin in female patients are frequently related to endocrinological dysfunctions. Apart from isotretinoin, hormonal interventions are considered as the second-line treatment for female patients with acne, regardless of serum levels of androgens.[12] However, women with identifiable endocrinologic conditions and those with severe acne are the best candidates for hormonal therapy.[21,22,23,24] In addition to inhibiting the secretion of follicle-stimulating hormone and luteinizing hormone, another interesting mechanism by which cyproteronacetate is therapeutic is interfering with the binding of dihydrotestosterone to the androgen receptor due to the possibility of menstrual changes.[8] Despite the earlier reduction in the value of the ASI at the end of first month in the subjects of group A (P value = 0.03), by statistical analysis no significance difference was found between two groups at the end (P value = 0.62).
Despite the fact that hormonal modality is formed the second-line treatment for female patients with acne, in subjects with obvious hyperandrogenism, cyproterone compound makes the same response as the isotretinoin.
In summary, this study shows that cyproterone compound and isotretinoin begin to act from two different ways, meet in the middle and by the end have a nearly similar effect. On one hand, the use of oral isotretinoin should ensure excellent efficacy for acne lesions in patients with triad of cutaneous hyperandrogenism, and on the other hand, it is not necessary to demonstrate androgen excess to achieve the benefit from antiandrogen therapy in acne.
With regard to insignificant and negligible differences between the results of isotretinoin and cyproterone compound trial in the treatment of subjects with acne and hyperandrogenism in our study, it is advisable in future studies to compare cyproterone compound regardless of androgen level verses isotretinoin in subjects with only nodulocystic acne.
The greatest limitation of our study is in the field of case selection as the triad of hyperandrogenism should have been fulfilled clinically before entering into the study. The other one was the cost and also rarity of some brands of the drugs, and the vague public and folkloric view toward side effects of such oral therapy in cases of severe acne that made for us the great responsibility to verifying their recruitment for the trial.
We are very grateful to dear staff of Sadaf dermatology Center of Isfahan for their helpful assistance.
Source of Support: Skin Diseases and Leishmaniasis Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
Conflict of Interest: None declared
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