can you put up sum links w info please
oh im sorry.
well i was reading threads in hairloss forums.
but here is some info.
Chromoglycate
A compound called disodium cromoglycate, or also known simply as cromoglicic acid or chromoglycate, has been shown to be highly effective in inhibiting mast cell production and release of various prostaglandins, including prostaglandin D2[1].
PGD2 and Baldness
In 2012, Garza and Cotsarelis implicated prostaglandin D2 as a primary or main causative factor in male pattern baldness (androgenic alopecia)[2]. Prostaglandin D2 is an inflammatory prostaglandin (read more here:
PGD2 Inhibitor Family) found throughout the body and with multiple convergent roles, including immune function, inflammation, and central nervous system functions such as sleep and circadian rhythms [3]. Prostaglandin D-synthase or PGDS is an enzyme that has been shown to convert arachidonic acid (AA) into prostaglandin (PGs).
L-PGDS vs H-PGDS
Two known types of PGDS have been discovered that are functionally convergent, meaning that they have a similar function (to convert AA into PGD2) but developed through evolutionary mechanisms independently of one another to act in separate physiological niches [4]. Lipocalin-type PGDS or L-PGDS exists primarily in the central nervous system and acts to upregulate levels of PGD2 for purposes of sleep regulation [3]. Hematopoetic-type PGDS or H-PGDS is found in the skin, blood, skeletal system, and in smooth and skeletal muscle, and is involved in immune response and inflammation [4].
Al-Waili et al write:
[it is] hypothesized that… the overproduction of PGs is responsible for immunosuppression and secondary anemia in conditions associated with increased PG synthesis, such as pathologic inflammation, malignancy, trauma, and injury, and (2) that PG inhibitors reverse immunosuppression and secondary anemia, thereby enhancing the immune response. [5]
It is unlikely that disodium cromoglycate reduces physiological L-PGDS, CNS-involved prostaglandins, or interferes with the CNS or circadian rhythm roles of PGD2.
MPB as Inflammatory/Autoimmune Disorder
H-PGDS appears to be the main or only PGDS that could potentially play a role in the generation of local prostaglandins and induce androgenic alopecia. H-PGDS acts within a specialized type of immune cell called a mast cell to convert the downstream product of arachidonic acid (PGH2) into PGD2:
PGD(2) is formed from arachidonic acid by successive enzyme reactions: oxygenation of arachidonic acid to PGH(2), a common precursor of various prostanoids, catalyzed by cyclooxygenase, and isomerization of PGH(2) to PGD(2) by PGD synthases (PGDSs). PGD(2) can be either pro- or anti-inflammatory depending on disease process and etiology[6]
Mast cells exist in red blood cells, skin, the gastrointestinal tract, and the vascular system. Functioning mast cells are part of a normal, health immune system and also play roles in wound healing, but overactive mast cells are implicated in various immunological or inflammatory disorders as well as other diseases; PGD2 is a key component in some of these conditions:
Prostaglandin (PG)D(2) is a key mediator in various inflammatory diseases including allergy and asthma. It is generated by activated mast cells after allergen exposure and subsequently orchestrates the recruitment of inflammatory cells to the tissue. PGD(2) induces the chemotaxis of Th2 cells, basophils and eosinophils, stimulates cytokine release from these cells and prolongs their survival, and might hence indirectly promote IgE production. PGD(2) mediates its biologic functions via 2 distinct G protein-coupled receptors, D-type prostanoid receptor (DP), and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) [7]
If Cotsarelis and Garza’s findings that PGD2 is a causative factor in human male pattern baldness are replicated, male pattern baldness may come to be regarded as an inflammatory or autoimmune disorder.
Indomethacin
It works by inhibiting the production of prostaglandins (can't find the links right now)
Cortexolone 17-alpha propionate (CB-03-01): Peripherally Selective Anti-Androgen - 30ml in solution, ethanol / propylene glycol 1:1, 1% by volume.
Cortexolone 17-alpha propionate, also called CB-03-01, is a derivative of 11-deoxycortisone[1] with peripheral, selective anti-androgen activity. Published data demonstrate that cortexolone 17α-propionate possesses therapeutic potential as a topical anti-androgen for skin disorders such as acne, as well as androgenic alopecia (male pattern baldness). Cortexolone boasts equal or greater safety and potentially greater efficacy compared to retinoids used to treat acne, as well as a more localized and therefore potentially safer and more effective mechanism as compared to systemic 5-alpha reductase drugs such as finasteride and dutasteride. Though not currently FDA-approved, if FDA approval is granted cortexolone 17-alpha propionate will be the first commercially available topical anti-androgen[1].
Background and Timeline of Development
According to the manufacturer, Italian company Cosmo Pharmaceuticals, cortexolone “tightly mimics the profile of an ideal anti-androgen for topical use”[1]. The stated objective of the manufacturer is “to create a product for topical application to treat acne, male pattern baldness, and seborrhoea that does not have the side effects of products currently being taken in tablet form”[1] which presumably would include oral isotretinoin (Accutane) and antibiotics for acne, and 5-AR inhibitors such as dutasteride (Avodart) and finasteride (Propecia) for male pattern baldness.
Five clinical trials assessing the safety and efficacy of cortexolone 17-alpha propionate in European markets have been completed with favorable results, and non-clinical early data supporting the IND (investigational new drug) application was also deemed promising[2].
Per US FDA code, each individual disease or disorder claimed to be treated by a drug will require separate applications for the drug approval process. According to Cosmo, an IND application for acne was granted by FDA in the first quarter of 2012, with phase II escalating dose trials in process at the time of this writing[1]. While the future appears bright for cortexolone 17-alpha propionate as an alopecia drug, the IND process has not been initiated at this time; the manufacturer has stated their intent to apply for an IND for androgenic alopecia in 2014[1].
Anti-inflammatory and Anti-Androgenic Mechanism and Safety Profile and Rationale
Due to a common androgenic pathway between inflammatory acne and androgenic alopecia, cortexolone 17-alpha propionate is considered a promising drug for both disorders[3]. What is unique about cortexolone 17-alpha propionate is the peripheral and selective mechanism.
Cortexolone has good penetrative properties, making it suitable for topical use, and while effective locally it is metabolized into a harmless, inactive parent compound prior to circulating systemically:
“CB-03-01’s mechanism of action is based on the competitive activity between testosterone and DHT for androgen-receptors in the skin. CB-03-01 is devoid of systemic anti-androgenic activity, in as far as it does not inhibit gonadotropins hypersecretion, and has a moderate anti-inflammatory effect. In preclinical studies, CB-03-01 was shown to be rapidly metabolized by the skin to the parent compound cortexolone, which is a physiological steroid lacking anti-androgen activity and is completely safe. CB-03-01 has also been shown to have good penetration through the skin, making it the first anti-androgen suitable for topical application.”(emphasis added)[3]
The primary supporting study around which Cosmo bases their claims regarding safety and efficacy of topical anti-androgen therapy for acne was published in the British Journal of Dermatology in 2011.[4]
There are effective anti-androgens currently available, but they are not suitable for topical use and act in a systemic manner which, due to the pervasiveness of androgen activity and androgen receptors in physiological function throughout the body, results in a poor safety profile. As Cosmo CEO Mauro Ajani states, “drugs available for the treatment of acne are either not very effective or have substantial negative side effects”[3].
The recent manufacturer-funded studies and internal data are abundant, but there is also early peer-reviewed data that is illustrative of the comparative potency, and safety rationale, of cortexolone (CB-03-01) compared to other drugs:
“The aim of this study was to investigate the antiandrogenic activity of a new monoester of cortexolone, cortexolone 17alpha-propionate (CAS 19608-29-8, CB-03-01). Although the compound displayed a strong local antiandrogenic activity… it did not exhibit antiandrogenic activity in rats after subcutaneous injection, nor did it affect gonadotropins hypersecretion… As topical antiandrogen, the steroid resulted about 4 times more active than progesterone (CAS 57-83-0) and, when compared to known antiandrogen standards, it was about 3 times more potent than flutamide (CAS 13311-84-7), about 2 times more effective than finasteride …Its pharmacological activity seemed to be primarily related to its ability to antagonistically compete at androgen receptor level.”[5]
Androgen-Receptor-mediated Acne Mechanisms
The pathogenesis of acne vulgaris involves multiple factors, but local mechanisms mediated by androgens are known to play a significant role in the development of lesions:
“Acne is a chronic inflammatory disease of the pilosebaceous unit resulting from androgen-induced increased sebum production, altered keratinisation, inflammation, and bacterial colonisation of hair follicles on the face, neck, chest, and back by Propionibacterium acnes.”[15]
The consensus is that each factor of acne vulgaris pathogenesis is involved in a complex interplay, and the resulting dysfunction often requires a multi-prong treatment approach:
“The multifactorial nature of the pathogenesis of acne includes increased sebum production, alteration of the quality of sebum lipids, inflammatory processes, interaction with neuropeptides and dysregulation of the hormone microenvironment, follicular hyperkeratinization and inflammation maintained by Propionbacterium acnes products within the follicle”[16]
The four primary factors – altered keratinization, bacterial colonization by P. acnes, increased sebum production, and inflammation – are often treated separately using different drugs; for example, oral isotretinoin to reduce sebum production, exogenous hormones (usually in women) to reduce androgen-receptor-mediated effects, topical retinoids or other drugs with anti-inflammatory properties, and systemic antibiotics for reduction of P. acnes colonization.
According to Lee et al, new data that shows that cultured sebum cells product inflammatory cytokines through an androgen-mediated pathway, suggesting that “DHT may not only be involved in sebum production but also in production of proinflammatory cytokines in acne” [17].
Comparative Efficacy
In Treatment of Acne
In order to quantify the efficacy of cortexolone in treatment of acne, it was compared directly with tretinoin (Retin-A) 0.05% w/v in a randomized three-arm double-blinded controlled study with parallel treatment groups[3].
The trial entailed application of either compound (or control) to the facial region of sufferers of acne vulgaris, and lasted for ten weeks and compared total counts of two types of lesions, as well as overall severity of the acne using a standardized index[3]. Evaluations of each outcome were performed every other week[3].
According to the manufacturer’s website, “preliminary data of the trial showed that CB-03-01 met all clinical end points and was clinically superior to placebo and to Retin-A® in the treatment of facial acne vulgaris after 8 weeks of drug application” (emphasis added) [3]. The fact that cortexolone 17-alpha propionate not only took effect faster, but was more clinically effective than Retin-A in a large controlled trial demonstrates that its safety and efficacy profiles, taken together, are unprecedented.
The mechanism of action of cortexolone 17α-propionate is unique and suggests an exceptional safety profile compared to systemically dosed 5-AR inhibitory drugs currently used to treat androgenic alopecia.
Cortexolone 17-alpha propionate, Androgen Receptors, and AR-Targeted Treatment of Alopecia
Compared to the recently-demonstrated PGD2 mechanism, knowledge of the effects of androgen receptor agonism is not cutting-edge; the mechanism was first mentioned in published literature in the late 1980s [7], and early off-label use of 5-alpha reductase (5AR) inhibitor drugs finasteride (then Proscar, now also Propecia) and Dutasteride (Avodart) existed in the 1990s [8] prior to the approval of finasteride labeled for treatment of alopecia in 1997[9]. 5AR inhibitors prevent the local enzymatic conversion of testosterone into dihydrotestosterone, which is 2.4-10 times more potent in its action at the androgen receptor than testosterone depending on tissue and action examined [10]. However, they also reduce serum DHT levels, sometimes drastically, resulting in potentially undesirable effects[11].
5AR inhibitors are effective to prevent hair shedding when taken long-term by men with androgenic alopecia (AGA). However, lately there have been increasing concerns as to the short-term and long-term safety profiles of these drugs, both in civil courts and in the published literature:
“Men who suffered ongoing erectile dysfunction after taking prescription drugs to treat prostate problems and male pattern baldness will be able to pursue a class-action lawsuit against the drug maker, a B.C. judge has ruled.”[12]
“The significant reduction in DFI within 3 months of finasteride cessation and continued improvement suggests a causal link between finasteride and sperm DNA damage. We hypothesize that low-dose finasteride may exert a negative influence on sperm DNA integrity, resulting in increased pregnancy losses. We suggest that in infertile men using finasteride, sperm DFI should be measured in addition to semen parameters, and a trial of discontinuation of finasteride may be warranted.”[13]
The likely primary mechanism of most or all reported side-effects not due to nocebo-type effect is systemic action of 5-alpha reductase. When taken orally, 5AR drugs have systemic action and are in no way confined in their action to the peripheral (local) area of effect, namely the scalps of balding men. Topical applications of finasteride preparations may reduce systemic circulation, but will not prevent this issue, since, unlike cortexolone, the finasteride gel that absorbs into the dermal layer can still be circulated systemically in its active form[14].
The androgen-receptor-mediated mechanism is upstream of PGD2, meaning that it is hypothetically possible to reduce PGD2 levels to treat baldness without interfering with androgen levels. On the other hand, since PGD2 is likely associated in a general sense with inflammation, modulation of the androgen pathway may be an insufficient way to address baldness in some men if PGD2 elevation is caused by a pathway other than androgen receptor binding by DHT. Without more published PGD2 data, though, it is impossible to predict how future PGD2 inhibitor drugs may change the treatment landscape for AGA patients.
It is reasonable to state that the androgen receptor pathway of baldness is well-demonstrated, well-studied, and is an effective target for drug development in the interest of treating androgenic alopecia. Cortexolone, with a distinct yet similar mechanism (competitive inhibition/receptor inactivation, preventing DHT-binding) is a major step forward in addressing the major downside to 5AR inhibition as a baldness treatment because, if approved, it may be as effective as systemic, orally-dosed 5AR inhibitors, and would almost certainly be safer.
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