GB2489206A

GB2489206A - A pharmaceutical composition comprising forskolin and sodium cholate

Info

Publication number: GB2489206A
Application number: GB1104277.7A
Authority: GB
Inventors: James Terence Fletcher
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-03-14
Filing date: 2011-03-14
Publication date: 2012-09-26
Also published as: GB201104277D0

Abstract

A pharmaceutical composition comprises (a) a compound that induces an increase in intracellular levels of cyclic adenosine monophosphate (cAMP), in particular, forskolin and (b) sodium cholate. Preferably, the formulation is for use in the treatment of male pattern baldness (androgenic alopecia) and may preferably be administered orally in the form of a capsule.

Description

SPECIFICATION

Combinational treatment for male pattern baldness This invention relates to a possible treatment or cure for male pattern baldness (androgenic alopecia).

Male pattern baldness is a condition that affects many men at some point in their lives, there are various treatments available that claim to slow down or stop male pattern baldness but none of them have been proven to be completely effective at stopping the process altogether. The treatments that are currently available offer a temporary solution to slowing or concealing male pattern baldness and do not have a permanent effect on the condition because they do not affect the root cause. A product that offered a permanent solution to treating male pattern baldness would undoubtedly be very much in demand by males that have the condition and it would generate a lot of commercial interest.

The present invention proposes a new way of treating male pattern baldness by affecting the cause of the condition directly with sodium cholate and a compound that induces an increase in intracellular cyclic adenosine monophosphate levels.

The cause of male pattern baldness in broad terms is due to the inhibition of the hormone secretin, this is caused by the over activation of farnesoid x receptor as a consequence of altered concentrations of bile acids in the bile. The farnesoid x receptors increase the activity of small heterodimer partner which then interacts with neuroD, this produces a gene inhibitory effect on secretin. This causes the hormone secretin to not be secreted in the quantities that it should be after receiving stimulation when the pH in the duodenum is low, this leads to the acidic contents of the duodenum not being fully neutralised by sodium bicarbonate. One property of sodium bicarbonate is that it distributes the pH evenly throughout the volume of aqueous solutions. The decreased level of sodium bicarbonate that is present in the plasma during the absorption of the products of digestion is a result of the reduced amount of sodium bicarbonate that is released into the duodenum during digestion. A consequence of the lowered levels of sodium bicarbonate in the blood is that the pH of the blood is no longer distributed evenly throughout its volume. The excess H+ ions that are not effectively distributed by the low levels of bicarbonate migrate to the scalp where they gradually denature the proteins of the region over long periods of time. When this process has been active for an extended period of time the formation and growth of hair are no longer possible due to the essential role of proteins in the hair growth process.

Bile acids are not just used by the body to emulsify fats but they are also ligands for many different receptors that are located in the liver and the intestines. The normal pathway of bile acid synthesis produces cholic acid and chenodeoxycholic acid in roughly the same amounts, the alternative pathway of bile acid synthesis produces primarily chenodeoxycholic acid. An increased concentration of chenodeoxycholic acid in the bile due to the increased activity of the alternative pathway of bile acid synthesis stimulates the suppressive action of small heterodimer partner on the expression of the rate limiting enzyme of the normal pathway of bile acid synthesis, 7a hydroxylase.

The alternative pathway is dependent on reverse cholesterol transport and so reverse cholesterol transport indirectly causes decreased activity of the normal pathway. One of the consequences of the reduction in the normal bile acid synthesis pathway is that the production of cholic acid is reduced, the lowered concentrations of cholic acid in the bile affects the level of stimulation that certain receptors receive. This can cause changes in the expression and activity of the biochemical, hormonal and metabolic pathways that are controlled by those receptors. In the case of increased concentrations of chenodeoxycholic acid, farnesoid x receptor activity increases and consequently the activity of small heterodimer partner also increases. The affects that small heterodimer partner has are to increase beta oxidation of fatty acids by regulating peroxisome proliferator activated receptor, it inhibits secretin gene expression by its interactions with neuroD, it causes the inhibition of 7a hydroxylase and it is also responsible for the inhibition of the SREBP pathway. It is the inhibition of secretin that causes reduced bicarbonate secretion into the bile and is consequently the factor that is responsible for the condition of male pattern baldness.

The invention will now be described with reference to the following drawings.

Fig. 1.: Forskolin is a labdane diterpene and has a molecular formula C22H3407, it is a compound that induces an increase in intracellular levels of cyclic adenosine monophosphate.

Fig.2.: sodium cholate is a detergent and has a molecular formula C24H39NaO5, it dissociates in the gastrointestinal system to form sodium and cholic acid. Cholic acid is a primary bile acid; its exogenous administration can be used to alter the bile acid concentrations of the bile, the hydrophobicity of the bile and the ability of the bile to activate certain nuclear receptors.

Fig.3.: Figure 3 provides a visual display of the cause and treatment of the condition. This visual representation of the problem helps to show the locations at which the interactions between hormones, ligands and their receptors occurs.

Fig.3.: Item 1: The liver Fig.3.: Item 2: The gallbladder Fig.3.: Item 3: The pancreas (used mainly as a reference point in the diagram) Fig.3.: Item 4: The duodenum Fig.3.: ItemS: Hutu-80 cells The cause of the condition and treatment can be more clearly demonstrated by Fig.3. which depicts many of the body parts that are involved in this problem. The liver 1 contains the nuclear receptors farnesoid x receptor which are stimulated by chenodeoxycholic acid, the expression of small heterodimer partner which is also located in the liver 1 is increased by increased stimulation of farnesoid x receptor. Small heterodimer partner interacts with neuroD to produce a gene inhibitory effect on secretin in hutu-80 cells 5. The presence of hydrochloric acid in the duodenum 4 during digestion should stimulate the secretion of secretin from hutu-80 cells 5 but secretin expression is inhibited due to the high activity of small heterodimer partner. If secretin is not secreted from the hutu-80 cells S it cannot activate its receptors in the liver 1, this means that chloride ions and bicarbonate will not be exchanged across the cell membrane and as a result the amount of sodium bicarbonate that is secreted into the bile will be reduced. The hormone CCK stimulates gallbladder 2 contraction during digestion and this causes the bile in the gallbladder 2 to be released into the duodenum 4. The inhibition of secretin does not affect the ability of the bile to emulsify fats but the reduction of sodium bicarbonate released into the duodenum 4 does mean that the acidic contents of the duodenum 4 are not effectively buffered before they are absorbed.

The approach to reducing the inhibiting effect of neuroD on secretin involves the oral administration of a compound that induces an increase in cyclic adenosine monophosphate levels in combination with sodium cholate(shown in Fig.2.). A compound that raises cAMP(cyclic adenosine monophosphate) levels like forskolin(shown in Fig. 1.) can be used to help reactivate the receptors that the hormone sccretin usually binds with. After extended periods of time in which secret in levels are low the receptors that secretin binds with become inactive. The compound forskolin can be used to activate the enzyme adenylyl cyclase which causes the level of cyclic adenosine monophosphate to increase which makes the receptors responsive to secretin binding.

The purpose of the administration of sodium cholate in this combinational treatment is to increase the amount of cholic acid that is present in the bile acid pool. Sodium cholate dissociates in the gastrointestinal system to form sodium and eholic acid. Cholic acid is a bile acid that can be found in the bile of many animals, including homo sapiens and it can be used to alter the composition of the bile. The change in the concentration of cholic acid in the bile acid pool affects the ligand binding potential of certain receptors. The receptors that are affected by higher concentrations of chenodeoxycholic acid and lower concentrations of eholic acid can be returned to their normal level of ligand stimulation. This causes the stimulation of farnesoid x receptor to be reduced, farnesoid x receptor regulates the activity of small heterodimer partner and so as the level of stimulation that farnesoid x receptor receives reduces then the activity of small heterodimer partner decreases. This leads to pathways that are controlled by small heterodimer partner being affected such as beta-oxidation of fatty acids, suppression of the normal pathway of bile acid synthesis and the inhibition of secretin. The most important of these factors in the treatment of the condition is that the normal pathway of bile acid synthesis returns to a normal level of activity and the inhibition of secretin is no longer strongly expressed.

The oral administration of the combination comprising of forskolin and sodium cholate leads to the gene inhibitory effect of neuroD on secretin being reduced and the receptors that secretin interacts with being reactivated. The extent of the reactivation of the receptors that secretin binds with is determined by the dosage of the compound that induces an increase in cyclic adcnosine monophosphate. There is some variability in the result of the treatment depending on the dosage administrated. If a relatively small quantity of forskolin is taken in combination with sodium cholate then the level of secretin activating its receptor during digestion will be increased but not to a level that is sufficient to release enough sodium bicarbonate into the duodenum to effectively buffer its acidic contents. The main point here is that the metabolic and hormonal pathways that are affected by the treatment are not simply switched on' or off' but they can be permanently up regulated or down regulated depending on the dosages of the compounds that are used in this combinational treatment.

After oral administration in sufficient dosages of a compound that induces an increase in the level of intracellular cyclic adenosine monophosphate in combination with sodium cholate secretin is successfttlly secreted from hutu-80 cells when there is stimulation from a pH lower than 4.5 in the duodenum. Secretin is then able to activate its receptors due to the raised levels of cyclic adenosine monophosphate. The chloride ions and bicarbonate can then be exchanged across the cell membrane; as a consequence of this sodium bicarbonate can be released into the bile in a sufficient quantity to effectively buffer the acidic contents of the duodenum before the products of digestion are absorbed.

The combination comprising of forskolin and sodium cholate can be administered orally The two compounds can be consumed at the same time or one of them can be consumed first and then the other one can be consumed within the time frame in which the first compound is still having an effect in the body The doses that produce a positive result could cover a fairly wide range of quantities for both of the compounds although the most reasonable dosages would range somewhere between 500mg -2g for both forskolin and sodium cholate. It is also a requirement of this treatment that no food is consumed within a couple of hours before the treatment and possibly up to 1 hour after the treatment. The reason for this is that the digestion and absorption of food stimulates the release of bile and this could potentially disrupt the mechanism of treatment, although eating something 60 minutes after the treatment could be beneficial due to the stimulatory effect that it would have on secretin secretion. To obtain the best result it would be beneficial to refrain from any exercise from 2 hours before the experiment to 2 hours after. The results of the treatment become clear after only a few hours, after this time sodium bicarbonate will be present in the bile in greater concentrations than it previously would have been and the acidic contents of the duodenum are effectively buffered. This causes sodium bicarbonate levels in the blood around the times of food consumption to be returned to a level which is sufficient to protect the proteins in the scalp from becoming denatured; consequently the disruption of hair growth is slowed down or stopped altogether.

There is no direct interaction between the two compounds and the purpose of their combinational administration is for the complementary effects that they have on affecting the root cause of this problem. There are no unpleasant side effects from this combinational treatment provided that the dosages of both of the compounds stay within the previously stated range. Cholic acid is a naturally occurring bile acid that is present in human bile and the primary effect of forskolin is to induce an increase in the levels of intracellular cyclic adenosine monophosphate, treatment involving the oral consumption of these two compounds is completely safe as long as the dosages stay within the stated range.

I have already performed this treatment on myself very recently and I can say that it has been very effective. I performed the experiment according to the guidelines that I have outlined in the previous paragraph. I used gelatin capsules to contain the sodium cholate, if sodium cholate is put directly into the mouth without the use of some sort of capsule to separate it from the saliva it can cause a painful sensation due to the low pH. The effect that this combinational treatment has had is still present now which indicates that the results are long lasting or even permanent. The regrowth of hair can be noticed from approximately 2 weeks after the treatment.

Claims

Claims 1. A combination comprising of: a) a compound that induces an increase in intracellular levels of cyclic adenosine monophosphate; and b) sodium cholate.
2. A combination according to claim 1 wherein the compound that induces an increase in intracellular levels of cyclic adenosine monophosphate is forskolin.
3. A combination comprising of: a) a mixture that induces an increase in intracellular levels of cyclic adenosine monophosphate; and b) sodium cholate.
4. The use of any one of the combinations according to claims 1-3 for simultaneous, simultaneous separate or sequential use.
5. A combination according to any one of claims 1-3 for use as a treatment or as a cure for the condition of male pattern baldness.
6. A combination according to any one of claims 1-3 for oral administration.