N-Acetyl-Carnosine Eye Drops

Recently Russian biochemists have been researching an analogue of the di-peptide carnosine called n-acetylcarnosine or NAC which they claim to be efficacious in the treatment of cataract.

N-acetylcarnosine was used in a clinical trial with 96 patients aged 60 and above. All the patients had senile cataract in various stages of maturity. The duration of the disease in these patients ranged between 2 and 21 years. The patients instilled 1 or 2 drops into each eye 3 - 4 times a day, for a range of 3 to 6 months. The results indicated a pronounced effect on primary senile cataract with all patients experiencing an improvement. Of the more mature senile cataract patients (long term cataract) about 80% exhibited improvements. There were no reported side effects in any patients.

Another Russian study using 49 volunteers of average age of 65 was designed to document and quantify the changes in lens clarity over a 6 to 24 month period. All patients suffered from senile cataract of a minimal to advanced opacification. The patients received either the NAC eye-drops or a placebo at a dose of 2-drops twice daily. The patients were then evaluated at 2 and 6-month periods. 6-months - 88.9% of all eyes treated with NAC had an improvement of glare sensitivity. 41.5% of all eyes treated with NAC had a significant improvement of the transmissivity of the lens. Importantly 90% of the eyes treated showed an improvement in visual acuity. The study also showed that at 24-months the NAC treated group maintained the improvement with the continued use of NAC eye-drops. No significant side effects were noted in the 2-year period.

Mechanism of action

Cataract develops when anti-oxidant defence is exhausted and when glycation leads to the cross-linking of crystalline lens proteins resulting in opacification. But, carnosine competes on the molecule for the glycating agent and protects cellular structures against aldehydes. Therefore, carnosine can slow and help to prevent proteins from becoming cross-linked (and in this case from becoming cataract).

When carnosine is delivered in high doses, it can reverse protein-aldehyde cross-linking (this reaction is normally very difficult to reverse). Under these circumstances, carnosine has been shown to have a “rejuvenating” effect on cultured cells.

Regular use of 1% NAC eye-drops, delivers high-dose carnosine through the aqueous humor to the crystalline lens to a level capable of reversing lens cross-linking and elimination of cataract. NAC (n-acetylcarnosine) eye drops do not suffer the same problem as L-carnosine eyedrops which fail to penetrate the cornea / conjunctiva and degrade easily. Once inside the eye’s aqueous humor the NAC provides bioavailable carnosine by transforming into L-carnosine (a process that occurs within 15 to 30 minutes). L-carnosine is an excellent anti-oxidant and is particularly effective against potent free-radicals. It is thought that the super anti-oxidant role of L-carnosine (within the aqueous humor) is a major factor, in the reversal of cataract.

NAC eye-drops appear to act as a universal anti-oxidant, both in the lipid phase of the cellular lens membranes, and in the aqueous environment.

References:

Boldyrev AA, Dupin AM, Bunin Aya, Babizhayev MA, Severin SE “The antioxidative properties of carnosine, a natural histidine containing di-peptide.” Biochem. Inrern., 1987, 15/6, 1105-1113.

Babizhayev MA et al “N-Acetylcarnosine, a natural histidine-containing di-peptide, as a potent ophthalmic drug in treatment of human cataracts.” Peptides (USA) 2001, 22(6): 979-994.

Babizhayev MA, Yermakova VN, Deyev Al, Seguin M-C “Imidazole-containing peptiomimetic NACA as a potent drug for the medicinal treatment of age-related cataract in humans.” J. Anti-Aging Medicine 2000, 2, 43-62.

Babizhayev MA, Yermakova VN, Semiletov yu A, Deyev Al “The natural histidine-containing di-peptide N-acetylcarnosine as an antioxidant for ophthalmic use.” Biochemistry (Moscow), 2000, 65, 588-598.

Babizhayev MA, Yermakova VN, Sakina NL, Evstigneeva RP, Rozhkova EA, Zheltukhina GA “N-Acetycarnosine is a prodrug of L-carnosine in ophthalmic application as antioxidant.” Clin. Chim. Acta., 1996, 254, 1-21.Babizhayev MA, Bozzo Costa E “Composizioni farmaceutiche contenenti N-acetilcarnosina per il trattamento della cataratta.” A61K gruppo 37/00 cap 20122 MI 15.10.1993. Italian patent.

Babizhayev MA, Bozzo Costa E “Pharmaceutical compositions containing N-Acetylcarnosine for the treatment of cataract.” European Patent PCT/EP 94/03340 10.10.1994 Ref. SCB 238 PCT.

Babizhayev MA, Seguin M-C, Gueyene J, Evstigneeva RP, Ageyeva EA, Zheltukhina GA “L-carnosine and carcinine act as natural antioxidants with hydroxyl-radical-scavenging and lipid peroxidase activities.” Biochem J. 304, 509-516.

Babizhayev MA, “Antioxidant activity of L-carnosine, a natural histidine-containing di-peptide in crystalline lens.” Biochem. Biophys. Acta., 1989, 1004, 363-371.

Methylcobalamin (Vitamin B12)

Vitamin B12 deficiencies have been mainly related to blood deficiency diseases, such as macrocytos and pernicious aneamia. Vitamin B12 deficiencies are followed by neurological and psychological disorders, such as disturbed sense of co-ordination, loss of memory, abnormal reflexes, weakness, loss of muscle strength, exhaustion, confusion, low self-confidence, incontinence, impaired vision, frequent need to pass water, psychological deviances.

Deficiencies can be caused by low intestinal B12 uptake (intestinal disorders), low intrinsic factor (a substance essential for its transport to the blood) in the stomach, deficiency of hydrochloric acid in the gastric juices (increasing with old age), regular use of laxatives or medicines like Losec (for treatment of peptic ulcer), low uptake in the central nervous system (CNS) or excessive B12 degradation. Lack of calcium in the food can also reduce the uptake and so can heavy metals.

The transport of vitamin B12 to the brain can be disturbed or interrupted by heavy metals such as inorganic mercury, which affects the blood-brain barrier by causing leakage and hampering the active transport of nutrients. Non-anaemic vitamin B12 deficiencies also play a role in diseases like Multiple Sclerosis, Fibromyalgia, Diabetes and Chronic Fatigue Syndrome. Schizophrenia, a psychotic condition, has been successfully treated with B12 injections in combination with other supplements. There also seems to be a connection between B12 deficiencies and cardiovascular diseases. Methylcobalamin acts as a cofactor for methionine synthase in the conversion of homocysteine to methionine, thus lowering blood levels of homocysteine.  Methylcobalamin acts as a methyl donor and participates in the synthesis of SAM-e (S-adenosylmethionine), a nutrient that has powerful mood elevating properties.

Vitamin B12 comes in many different forms – methylcobalamin, cyanocobalamin, hydroxocobalamin, being the most common. They are freely transformed into each other in the body however, vitamin B12 in the brain and CNS is only present as methylcobalamin. Supplemented Vitamin B12 in its active form, methylcobalamin, gives a much better result than other forms which have to be transformed into methylcobalamin. It is possible that the process of transformation itself is inefficient in many patients.

The uptake from oral methylcobalamin B12 supplementation is usually very low, approx. 1 %. Vitamin B12 is therefore often given intramuscularly. Subbuccal lozenges which is directly absorbed into the blood stream avoiding the need of injections are also available and preferred. Sublingual drops which are placed under the tounge, transdermal creams and nasal sprays are also available however due to its short half life in solution it needs to be used within 14 days of preparation.

Other benefits of methylcobalamin:
Regulate homocysteine

Protect against nerve damage, assist in nerve regeneration and diabetic neuropathy

Increase energy levels

Improve sleep

Reduce stress

Enhance growth and repair of all cells

Aid in metabolism of carbohydrates and fats

Improve protein synthesis

Improve immune function

Increase mental alertness

Special Note: Vitamin B-12 is not recommended in people who have mercury toxicity because it is a “methylator”. A methylator is a chemical that attaches a “methyl” chemical group onto another chemical. Methylation is an important process in the body however in the case of attaching a methyl group (CH-3) onto mercury, elemental mercury becomes methyl mercury (MeHg). MeHg is about 100 times more damaging to the nervous system than elemental mercury. MeHg has an affinity for the nervous system, so it will be attracted to the place where it can do the most damage. Therefore Vit B12 should be avoided in these patients and this may help explain why some patients actually get worse on Vit 12 supplements. If this is the case you should have your mercury levels tested. Vit B12 can be used once mercury has been removed from your system.

Glutathione, Reduced (GSH)

Glutathione (GSH) is classified as a ‘tripeptide’, which means it is composed of three amino acids. The human body produces glutathione from the amino acids Cysteine, Glutamic Acid and Glycine, and it is the key antioxidant compound required for vital functioning of all cells.

Glutathione is a powerful antioxidant essential for alleviating oxidative stress and protecting individual cells and tissues from free radicals. It is also known to enhance healthy growth and activity of immune cells needed for disease resistance and immune protection. In addition it enables the body to rid itself of unwanted toxins and heavy metals, detoxifying the liver, the body’s most concentrated source of glutathione; and protecting the body from today’s environmental pollutants, natural and synthetic toxins, genetically engineered processed foods and toxic waste.

Low levels of glutathione have been implicated in many autoimmune disorders and neurodegenerative diseases such as Parkinson’s, Autism, HIV, MS Rheumatoid Arthritis etc.
Raising the amount of glutathione in the blood, it will help bind the heavy metals and remove them from the body and also help brain and immune development for children with autism. Increasing glutathione levels and effectively improving detoxification of the liver has been found to increase language and awareness for these children.

Glutathione has also been used to help treat Aging, Autism, Cancer, Chemotherapy recovery, Chronic Fatigue Syndrome, for Detoxification, Drug addiction, Emphysema, Fibromyalgia, Glaucoma, Hepatitis, Hypoglycemia, Kydney disease, Liver disease, Liver cancer, Mercury poisoning,Parkinson’s disease, Respiratory problems such as cystic and pulmonary fibrosis, Smoking, Tuberculosis, to name a few.

How to administer GSH 

GSH is a very powerful antioxidant and therefore oxidizes rapidly in the presence of water. Therefore formulations such as nasal sprays should be avoided. Injections should be administered soon after being prepared and creams containing any water should also be avoided. Our laboratory produces a water free oily lotion which contains liposomes to aid transdermal absorption.This lotion bypasses the stomach and liver and thus provides glutathione into the blood stream and throughout the body.

Slow release capsules which minimize the destruction of GSH in the stomach aids absorption and is one of the best ways to concentrate glutathione in the liver for detoxification reactions. If you intend to use it for an overall systemic effect then the lotion, suppositories or nebules would be the preferred option.

Subbuccal lozenges and suppositories, which bypass the stomach and liver, increase levels in the blood to help boost energy levels. As a substantial amount of the lozenges may be swollowed and thus encounter the stomach and liver, therefore the suppositories would be the preferred option.

GSH administered by nebuliser is the best method for increasing GSH levels in the lungs for the treatment of pulmonary conditions. It is also one of the best ways for an overall systemic affect as it is readily absorbed into the blood stream nearly as rapidly as a injection. The dry nebulizer capsule contents are dissolved into 4ml of sterile or boiled water prior to being administered by a nebulizer. Once the capsule contents are dissolved the resulting solution is buffered and isotonic with a pH of about 6 which eliminates the irritation causes by acidic GSH. A 125mg capsule should be nebulized twice daily for maximum benefits.

Human Growth Hormone

Growth Hormone or human growth hormone, also known as hGH or somatotropin, is secreted by the pituitary gland into your blood stream where it stays for only a short time before it is metabolized by the liver into somatomedin-C (insulin like growth factor, IGF-1), which stays in the blood a lot longer and is actually the driving force behind all the remarkable properties of hGH. The highest levels are found in the blood during the first 3 to 4 hours hours of sleep at night.

The production of hGH peaks during adolescence, reaching around 1.5mg/day, and then gradually drops off after the age of 20 to 25 where it averages around 0.35mg/day and continues to decline by approximately 14% each decade for the rest of your life. By the time you are 60 to 70 years of age you only produce about 15% of the amount produced at your peak. The decline in hGH with age is directly associated with many symptoms of aging including wrinkles, grey hair, hair loss, decreased energy, decreased sexual function, loss of muscle mass, increase in body fat, depression, cardiovascular disease, osteoporosis, and overall lower life expectancy.

Low hGH has also been related to elevated cholesterol, elevated apolipoprotein, thin skin, lack of collagen, decreased nail and hair growth, poor thermo-regulation, dehydration, emotional instability, poor memory, reduced energy, hypoglycemia, insulin resistance, abnormal metabolic rates, to name a few. Low levels of hGH cause aging because it is responsible for growth and regeneration of every cell in our bodies.

There is now ample evidence which demonstrates that by replacing hGH levels we can dramatically reverse all of these symptoms. The more closely the scientific evidence is examined the clearer it becomes that everything we associate with aging may be due in part to the decline of hGH in our bodies.

Many of the beneficial effects of supplementing hGH are listed below:

1. Improves lean muscle/body fat ratio – this not only improves strength and vitality in aging people but also for those with muscle wasting disorders such as stroke and recuperation from surgery or long hospitalization.
2. Positive effects on the heart – it improves cardiac impairment, blood pressure and HDL levels while reducing cholesterol, LDL and triglycerides.
3. Osteoporosis – it reverses osteoporosis with a 30 to 40% increase in bone formation in only 12 weeks. It also stimulates cartilage formation which may play a roll in degenerative arthritis.
4. Improved Wellbeing – Most patients report across the board that they suffer less aches and pains, increased strength, better energy levels, hair growth, reduction in wrinkles, increased sexual function, and a general sense of wellbeing.
5. Brain Function – it improves memory, alertness, motivation, and very importantly it restores slow wave sleep paterns.
6. Improves Immune Function – it restores thymus gland function, stimulates the production of antibodies, T and B macrophages, natural killer cells and reduces the risk of certain cancers.

hGH is considered a very safe hormone to administer when it is administered in regular physiological doses which mimic the bodies own natural secretions and should only be used in cases where current levels are shown to be deficient or suboptimal. Therefore it is only used for growth hormone deficiency syndrome and should be monitored by an experienced physician. Deficiencies start to occur when levels IGF-1 levels fall below 33nmol/L in men and 24nmol/L in women. The aim of therapy is to supply the shortfall and bring the level back into the optimal physiological range which is 39 to 46nmol/L in men and 29 to 40nmol/L in women.

Many traditional medical doctors with no experience in hGH supplementation consider hGH therapy unorthodox and usually criticize the idea out of fear of the unknown, however those in the know are well aware of its benefits and restorative properties and its relative safety when used correctly.

Some side effects have been reported, usually when taking larger pharmacological doses. These include water retention in hands and feet, carpet tunnel syndrome, tingling in fingers and nose, hormone imbalances and enlargement of the hands and feet. These side effects are reversible when doses are reduced. 

It is important to monitor your hGH levels to ensure the dose you are taking provides you with a normal physiological level There are several ways to determine hGH levels however most have many drawbacks. A common way is to measure IGF-1 in serum however this is considered unreliable in thyroid disorders, poorly controlled diabetes, liver disease and malnutrition. Research also indicates about 25% of patients on hGH actually experience a decline in IGF-1 levels. Therefore one of the best ways to determine growth hormone levels is a 24hour urine analysis. By closely monitoring your levels you can ensure your dose is appropriate thus maximizing its benefits while minimizing any potential side effects of potentially escalating levels.

Growth Hormone replacement has its drawbacks as it has to be administered as a daily subcutaneous injection. This is the only way hGH will work as nasal sprays, tablets and creams often advertised on the internet are not bioavailable and therefore ineffective. It is also expensive, even though the price has halved in the last few years now costing between $285 to $570 a month depending on the dose being used. The price is expected to continue to decline with pharmaceutical patents running out and more competition.

There are many natural products, proteins, amino acids, herbs, etc on the market reported to increase the bodies own production of growth hormone. We have had experience with many of them and found  them to produce only slight increases in hGH levels which were not significant enough for any  therapeutic effects. None of these products have proven to come even close in comparison to taking the real authentic hormone itself.

GH3 and KH3 - An anti-aging Treatment

In the 1940’s Prof. Anna Aslan, General Director of the State Institute for Geriatric Research and Geriatric Medicine in Bucharest, Romania, after several decades of research, discovered a method that slows down and sometimes reverse the premature decay and aging process. She called it the GEROVITAL GH3 TREATMENT. The original formula she developed consists of 100mg Procaine (a famous dental anesthetic) stabilized with benzoic acid, potassium metabisulfite and disodium phosphate. The Benzoic acid reacted chemically with the procaine forming a double salt. The chemical structure of the double salt protected the procaine from being destroyed in the blood stream by the cholinesterase enzyme thus increasing the half life of the procaine from 0.6 minutes (36 seconds) to over 6 hours. This increased life of the procaine hydrochloride, gave it time to transport into the cells where it is able to cause the cell to rebuild membranes, thus revitalizing the cell function.

Once the procaine is stabilized, ingested and rapidly absorbed it is then broken down to form p-aminobenzoic acid (PABA), diethylaminoethanol (DEAE) and dimethylaminoethanol (DMAE). PABA is essential for certain cellular reactions such as the creation of folic acid. DEAE has a tonic effect on the heart and circulation while DMAE is a mild stimulant and has been used in the treatment of senility, fatigue, mild depression and chronic headaches.

Medical trials show that procaine improves alertness, concentration, recall skills and physical power. It also improves joint stiffness, hearing, has a positive effect on the heart, and can reduce stubbornness. As we grow older the blood circulation in the brain and body decreases causing bad memory, reduced concentration, mental disharmony, dizzy spells, poor skin tone and hearing loss. One way procaine works is by improving circulation in the brain and body thus improving mental and physical function. Procaine also works by increasing cellular oxygen consumption thus stimulating the cells of the body. Cells also become less excitable which can cause feelings of mild stimulation and high spirits. Cellular reactions speed up and protein synthesis increases due to increased DNA levels. Many benefits can be obtained by the regular use of procaine which include: improved circulation, decreased arterial hypertension which prevents heart attack, increased tropism of the skin giving smoothness and normal colouration, favours the growth of hair and its normal pigmentation, stimulation of the endocrine glands, improves reflexes, better hearing, less joint stiffness, activates memory, increases the ability to concentrate and improves fatigue that comes with age.

Later on after GH3 was developed a German company aware of the benefits of GH3 and Prof. Aslan’s work with procaine produced a “knock off” version of GH3 where they used only 50mg of procaine stabilized with hematoporphyrin. This product is known as KH3. There appears to be a lot of confusion as to difference between the two products and hopefully this should clear it up.

Dose - Take one to two capsules daily before breakfast. Treatment should be continued for 5 months, after which a break of 2 to 4 weeks can be used to judge its effectiveness. For long lasting effects the treatment should be repeated several times. Elderly people should take it every day. It is well tolerated and safe to take for long periods of time.

Side Effects - KH3 is very well tolerated and side effects are rare even when taken every day. There have been a few cases of heartburn and headache which dissipate when treatment is terminated.

Contraindications - KH3 should not be taken by children, lactating or pregnant women or if you are allergic to procaine.

Drug Interactions - KH3 should not be taken with sulphonamide drugs as it inhibits their action.

Gamma-Amino Butyric Acid (GABA) - A Natural Relaxant

Gamma-aminobutyric acid (GABA) is both an amino acid and a mood enhancing neurotransmitter. It is formed by glutamic acid in the body with the help of vitamin B6, and prevents nerve cells from firing too much, thus having a claming effect. This results with a relaxed or sedative effect which makes it ideal to calm the mind and body in much the same way as tranquilizer drugs like valium and serepax. These drugs act by inducing the same change in brain chemistry that GABA can perform. The only difference is GABA is entirely safe, is not addictive, will not knock you out and cause many other side effects associated with these drugs. It may be taken right before going to sleep as many people report an improvement in the quality of their sleep and a feeling of well-being upon arising in the morning. Lucid or colorful dreams are also frequently reported. In addition, because of its calming and soothing effects, GABA also lowers blood pressure, helps control hypoglycemia and prevents anxiety.

In addition, GABA has some startling effects on promoting fat loss. GABA stimulates the production of Human Growth Hormone (HGH) which has been found in studies to facilitate the metabolism of fats in the body. Several clinical studies have shown that ingestion of GABA releases growth hormone, especially after exercise, with remarkable effectiveness. Release of growth hormone increases lean body mass. Consequently, it is an invaluable nutritional supplement for body builders, powerlifters, runners, martial artists, and other athletes of all shades.

GABA is best taken before going to sleep on a relatively empty stomach. Empty stomach means approximately 45 minutes after the ingestion of the day’s last meal. Intake of GABA at bed time makes it work with the body’s natural rhythms for increased growth hormone production, which happens roughly 90 minutes after the onset of sleep. The evening intake of GABA correlates with GABA’s effect to induce restful and refreshing sleep.

Even though the effect of GABA varies from individual to individual, the beneficial effects may be discernible within two weeks, but its full impact may be noticed after six to eight weeks.

Dose - 700mg to 1.4g at night on an empty stomach.

Side Effects
Some people have reported tingling on the surface of the skin for a few minutes after the intake of GABA. This may be likened to the well- known “niacin flush.” GABA may also induce a slight shortness of breath, which is also transient and is experienced by a small percentage of people.

Rather rarely, both these sensations may be experienced by a small percentage of people, but they are temporary, and resolve of their own accord. It should be noted that GABA has a slight sedative effect and may cause some drowsiness. If this is the case it should be taken right before retiring for the day.

For more information refer to the Brain Function page on this website.

References

• Satterfield, Neuroscience: Exploring the Brain. Williams & Wilkins, Baltimore
• Hertz, L. 1983. In L. Hertz, Glutamine, Glutamate, and GABA in the CNS. Liss, New York.
• Steardo et al., “Evidence for a GABAergic Control of the Exercise-Induced Rise in GH in Man,” Eur. J. Pharmacol.: 28, 607, 1985.
• Spencer et al., “Neuroendocrine Regulation of Growth Hormone Secretion in Sheep: Effects of GABA,” J. Regul. Peptides: 52, 181, 1994.
• Mergl et al., “Growth Hormone Secretion and Activation of cyclic AMP by Growth Hormone-Releasing Hormone and Gamma-Aminobutyric Acid in the Neonatal Rat Pituitary,” Life Sci.: 56, 579, 1995.

Copyright 2001 Michael Serafin, Ph.D.

Breast Cancer

Recently the media has created a scare campaign against estrogen stating it causes breast cancer. Unfortunately this over simplification on the subject has created much confusion in many women, not to mention their doctors. Estrogen is not evil as it is made out to be by the media. In fact estrogens have over 400 different biological functions in the body such as skin and blood vessel maintenance, prevent bone loss, effects lipid metabolism, protects cardiovascular system, improves blood coagulation, nervous system modulation, controls activity of enzymes and levels of circulating proteins and hormones, increases metabolic rate, aids sleep, prevents cataracts, improves magnesium uptake, maintains collagen and skin moisture content, regulates body temperature, maintains mood and memory functions by influencing neurotransmitter production, to name a few. Therefore it is important that sufficient estrogen levels are maintained for a healthy normal physiological function.

The problem related to breast cancer involves a number of hormonal imbalances which may be responsible for triggering breast cancer formation. The correct balance of the three types of estrogens made by the body and then the balance of these estrogens with progesterone is vital in the prevention and possible treatment of breast cancer. To complicate things even further the correct metabolism of the estrogens is also of vital importance as certain estrogen metabolites have been found to increase the risks of breast cancer. Hypothyroid has also been implicated in breast cancer, not to mention low melatonin and the presence of insulin resistance.

Estrogen Balance
The female body produces three estrogens:
(1) Estriol - 90% of total estrogens produced by a healthy female is estriol. A considerable amount of research on estriol has proven it to be a “good” estrogen. It is a weak estrogen which appears to block many of the effects of other pro-carcinogenic estrogens. The more estriol means less risk of cancer.
(2) Estradiol - About 7% of total estrogens produced by a healthy female is estradiol which is considered a weak pro-carcinogenic estrogen if not correctly balanced by estriol.
(3) Estrone - The remainding 3% of total estrogens in a healthy female is estrone which is also considered a pro-carcinogenic estrogen if not correctly balanced.

What is of importance is not only the absolute amounts of each of these estrogens but also the balance of estriol compared with the sum total of estradiol and estrone - that is your estrogen quotient (EQ). Your EQ is calculated by determining your 24 hour urine levels of the three estrogens and then doing the following maths :

EQ = estriol/(estradiol + estrone)

EQ levels below 1 are considered unfavorable and increase the risk of breast cancer considerably. This means there is not enough estriol to adequately balance out the pro-carcinogen effects of estradiol and estrone, not to mention the other carcinogenic synthetic estrogen mimicking xenoestrogens absorbed from our environment. If your EQ is below 1 then there is a simple solution. Take six to eight drops of a saturated solution of potassium iodide (SSKI) in a glass of water daily for two to three months. The iodine reliably promotes the metabolism of estrone and estradiol into estriol thus increasing your EQ. Retest your EQ after three months to ensure it has increased over 1. If so you can then taper down you dose of SSKI to the smallest amount needed to maintain your EQ above 1. Although SSKI is safe for the majority of people there are a few individuals sensitive to it and with long term use it may suppress thyroid function. Thyroid blood tests are essential to pick up if this occurs.

Traditional HRT such as Premarin is composed of 85% estrone while most other preparations on the market contain estrone or estradiol only. Although there is some interconversion of estrone replacement into estradiol and estriol, and estradiol replacement into estrone and then into estriol in the body it is usually inadequate in order to provide a safe estrogen balance. Therefore there is absolutely no consideration in providing a healthy estrogen balance and therefore it is no suprize that research indicates that these products do indeed increase the risk of breast cancer. It would be far safer for women to supplement with a combination of estriol and estradiol (BIEST), as used in bioidentical replacement, as it mainatains a healthy estrogen balance. Estrone is not recommended as it tends to accumulate in most women and never usually requires any supplementation as it should only ever consist of around 3% of total estrogens.
Estrogen/Progesterone Balance
In healthy women the correct balance of progesterone to estradiol is approximately 200:1. If this balance is reduced due to an estrogen dominant state then the risk of breast cancer is increased. Studies have shown that most women with breast cancer have low progesterone levels. This can be rectified by supplementing progesterone levels with bioidentical progesterone at an appropriate dose to re-establish the correct balance. Estrogen dependent breast cancers would benefit from being treated with progesterone as it inhibits cell proliferation in favor of cell maturation, where as estrogens stimulate cell proliferation and further exacerbate cancer cell growth.

Again most combined estrogen and progestin traditional HRT products on the market do not consider providing an appropriate balance. In addition the synthetic progestins used in these products cannot be tested for so there is no way of knowing if an appropriate estrogen:progesterone balance is maintained! Again this could potentially increase your risk of breast cancer and other conditions such as fibrocyctic breasts, etc.

Estrogen Metabolism
The estrogens in your body are metabolized by your liver into several different metabolites. Estrone is easily converted back and forth into estradiol. These two estrogens are then converted by three different enzyme systems. Over 20 years of research has determined that the 2-hydroxyestrone metabolite is “good” while the 16-hydroxyestrone and 4-hydroxyestrone metabolites promote cancer cell growth. Research indicates that if the ratio of the good estrogen metabolite (2-hydroxyestrone) compared to the bad estrogen metabolite (16-hydroxyestrone) is low then an increased risk of breast cancer results. Both of these metabolites should be measured by urine analysis to determine the ratio (or balance) between the two. A 2/16 ratio below 1 is unfavorable and ideally should be above 2 or greater if possible. If the ratio is found to be below 1 then you should consider using 60mg a day of a natural supplement called diindolylmethane (DIM). It promotes the formation of the good estrogen metabolites which is shown to reduce the risks of breast cancer. A diet rich in brassica vegetables (cabbage, broccoli, cauliflower, bok choy, brussel sprouts) which contain indol-3-carbinol and di-indolylmethane also help promote favorable estrogen metabolism.

The 2 and 4 hydroxyestrone metabolites can be further metabolized into the corresponding quinones. The 4-hydroxyquinone metabolite can cause permanent DNA damage and is associated with increase risk of breast cancer. The use of an antioxidant called glutathione will help “mop up” any 4-hydroxyquinone and thus reduce your risks of breast cancer.

Again traditional HRT does not consider estrogen metabolites and thus may be responsible for an increased risk of breast cancer.

For more detailed information on estrogen metabolism and DIM refer to the article in the blog section - www.custommedicine.com.au/blog/2007/05/01/balancing-estrogens-with-dim/

Hypothyroid
Studies dating back to the 1950’s indicate a low thyroid function predisposes women to breast cancer. When thyroid is low your estrogens are unable to activate appropriate amounts of sex hormone binding globulin (SHBG) in the liver. SHBG in the bloodstream binds to estradiol and estrone preventing too much from entering cells and stimulating growth of tissue in the breast and uterus. Thyroid function tests that include measuring free T3 and T4 levels can determine if a hypothyroid state is present which could be fuelling the cancer or increasing the risks of getting it.

Low Melatonin
Melatonin is a hormone produced by the pineal gland in the brain responsible for our bodies circadian rhythems. Several studies have associated low melatonin levels with an increased risk of breast cancer. It has also been shown to inhibit the growth of human breast cancer cells by up to 75%. Supplementing melatonin may help with the treatment of breast cancer.

Insulin Resistance
The many causes of insulin resistance ultimately results with ongoing high levels of insulin in the bloodstream. High insulin levels cause the pituitary gland in the brain to produce too much luteinizing hormone relative to follicle stimulating hormone which results with dysfunctional estrogen and progesterone production as well as underdeveloped follicles producing excessive amounts of testosterone. It also produces body fat which in turn elevates estrogen levels. This results with an increase risk of breast cancer and also polycystic ovary syndrome. A glucose tollerence test will indicate if insulin resistance is present and if so dietary and lifestyle changes are necessary to rectify the situation.

Listed above are several tests you can perform to estimate your own risks of estrogen-related cancers such as breast and uterine cancer and to help those who already have been diagnosed with these conditions to rebalance their system so they are no longer metabolically in an unfavorable state which only helps feed the cancer further.

Energetic/Emotional Causes of Breast Cancer

The cause of breast cancer from an energetic/emotional point of view is that women in society today have been forced to resort to a more male driven energy to simply win back some form of equality, and in doing so have lost their inner-instincts to self-nurture. This lack of self-nurturing is the actual energetic cause of breast cancer. It should also be noted that if the breasts are effected then so too are the ovaries, which emanate the ‘’light of Femaleness’, and hence they too are suppressed and contracted from their natural way of impulsing. More self love and self nurturing is required to heal this energetic imbalance.

Troches or subbuccal lozenges are fast becoming a very popular method of administering bioidentical hormones in Australian women. Although many women are currently being treated with troches there are much better methods available. In addition there also appears to be a lot of misinformation being publicized about troches.

Troches are being marketed as a new novel method of administering bioidentical hormones that bypass the stomach and first pass metabolism of the liver as they are “supposedly” absorbed directly into buccal circulation. Claims are made that this places less stress on the liver and therefore better for you. In reality more than 50% (and up to 70%) of the total troche dose is actually swallowed by the normal salivation process which will encounter the stomach acids and first pass metabolism while the remainder is absorbed by the buccal mucosa (Int J Pharm Comp., 4, 414-420, 2000). With only 30 to 50% of the dose being absorbed through the mucosa lining in the mouth there appears to be only a minimal reduction in the livers first pass metabolism when compared to capsules. The hormones that are eventually absorbed, weather it is by the buccal mucosa or the gastrointestinal tract, will eventually encounter the liver anyway at some stage through normal circulation so there is no real significant liver sparing effect. Clinical experience shows that the doses required for troches are within the same range as those required for capsules so the overall total load on the body is approximately the same so again no real liver sparing benefit is obtained. Transdermal creams, on the other hand, require lower doses compared to troches and capsules and actually do bypass the stomach and first pass metabolism of the liver so are therefore the only way that actually reduces the overall load on the liver.

Hormones that possess poor oral bioavailability such as progesterone and testosterone (10 to 15% bioavailability) could potentially be good candidates for buccal administration. If successful the dosages for buccal administration should approach those of normal physiological doses e.g. Progesterone 10 to 40mg daily as found with creams. Clinical experience shows that the doses of progesterone needed in troches is usually between 100 to 400mg daily which indicates a great deal of the dose is not being absorbed by the buccal mucosa thus supporting the evidence that a majority of the dose is being swallowed. Perhaps a buccal patch would provide better absorption characteristics than troches but are currently unavailable. In addition, there is no real benefit using buccal administration over oral administration for those hormones such as the estrogens and DHEA which already possess good oral bioavailability (over 90%).

Troches also exhibit poor pharmacokinetic parameters. This means that there are great fluctuations in hormone serum levels after taking a troche dose. Soon after taking a troche serum hormone levels rise rapidly, sometimes to very high levels, and then rapidly fall to low levels within 4 to 5 hours. They therefore require at least twice daily administration or for optimal results three to four times a day to maintain adequate levels longer however compliance becomes a major problem with this type of dosing schedule. This wide fluctuation in hormone levels is not the ideal situation. Creams and slow release capsules release hormones into the blood stream more gradually achieving steadier serum levels for a longer period of time thus generally requiring only once a day dosing.

Another concern with troches (and capsules) is that the estrogens that are actually being swollowed may undergo conversion into estrone in the gastrointestinal tract before being absorbed. Estrone is not a favorable estrogen and can increase the risks of breast cancer if not appropriately balanced. Transdermal estrogen creams do not undergo this conversion into estrone before absorption so may therefore be a safer alternative.
Troches are made from two different types of bases:
(1) Polyethylene glycol (PEG) - PEG bases (hard troches) are well known to cause allergic and chemical sensitivity reactions and can cause the buccal mucosa and gums to become inflamed. PEG base is not recommended for patients with chemical sensitivities or those with a high toxic burden such as leaky gut patients. This appears to be the most common base used in Australia.
(2) Gelatin - Gelatin (soft troche) is a hydrophilic (water loving) base which causes hydrophobic (fat loving) particles such as some bioidentical hormones to aggregate together when made in high doses. This aggregation of particles could possibly further reduce mucosal absorption thus increasing the amount being swallowed. Being the safest of the two bases we recommend gelatin based troches.

Finally there is less patient satisfaction with troches because these bitter tasting hormones need to be held in the mouth for about 30 minutes before they totally dissolve. Surprisingly some compounding chemists are using Aspartame, an artificial sweetener, to mask the bitter taste of these hormones however it has been identified as a possible neurotoxin that can cause brain damage.

In conclusion troches are currently being widely used to successfully administer bioidentical hormones to Australian women however they possess many drawbacks and are not considered the OPTIMAL and safest choice. Transdermal creams should be the first choice as they require lower doses compared to troches and capsules, they also are the only route of administration that truly bypasses the stomach and first pass metabolism. They provide better release parameters providing steady serum levels without wild fluctuations seen with troches. They only require once daily dosing so are more convenient, dosage adjustments are very easy to make, there is no conversion of estrogens into estrone prior to absorption, and finally they are significantly cheaper with a standard formula costing about $30/month. If creams are deemed unsuitable in certain cases then the second choice should be slow release capsules. These capsules provide better release properties than troches, only require once a day dosing, and are fast to administer and no bitter taste. Troches should be reserved in patients where creams are unsuitable and malabsorption syndrome occurs thus making oral administration unsuitable.

Are your cosmetics causing you harm?

Many cosmetic companies including some of the most prestigious brands all contain ingredients that may cause you harm and even potentially cause cancer. To minimalise your exposure to these potentially dangerous ingredients make sure you read the labels and ensure you do not use any product that may contain any of the ingredients listed below:

(1)Confirmed Human Cancer Causing Agents

• Phenylenediamines (Coal tar ingredients)
• Saccharin
• Mineral Oil (Paraffin Oil)
• Petrolatum (soft paraffins)
• FD&C No 1, No 5 and No 6 � artificial colors
• Fragrances that contain benzene, aldehydes or toluene

(2)Hidden Cancer Causing Agents - These ingredients can either (a) form cancerous nitrosamines (b) be contaminated with carcinogenic impurities such as dioxin or nitrosamines or (c) release cancerous formaldehyde.

• Category A - Cocamide DEA, Stearamide DEA, Lauramide DEA, diethanolamine, triethanolamine, Padimate-O.
• Category B - Polyethylene glycols (PEG�s), polysorbates 60 and 80
• Category C - formaldehyde, imidazolidinyl urea, diazolidinyl urea, quaternium-15.

(3)Suspected Cancer Causing Agents

• polyvinylpyrrolidone, fluoride, oxybenzone, benzophenone-3, parabens

(4)Other common problems

• Propylene glycol - produces allergic reactions, hormone disrupter
• Aspartame - artificial sweetener found to be a potent neurotoxin.
• Sodium Benzoate - preservative that causes allergies and asthma.
• Parabens - preservatives with estrogenic activity, hormone disrupter
• Dimethicone - a silicon that is harmful to eyes, skin, and possibly cause lung,
  throat and endocrine cancer.
• Phthalates - solvents that are hormone disrupters
• Waxes/Heavy Oils - clog pores or make the skin feel oily which can cause blemishes
• Sodium Lauryl Sulphate - estrogenic activity, irritant to mucosal membranes

All creams produced by our laboratory are formulated so that they do not contain any of the ingredients listed above thus ensuring their safety. The quality of all ingredients used in our creams are pharmaceutical grade thus ensuring only the purist ingredients are incorporated into our creams. The ingredients included in our standard cream base are: cetyl alcohol, stearyl alcohol (both fatty alcohols made from natural oils), water, glycerine, macadamia oil, stearic acid (fatty acid in vegetable oil), benzyl alcohol (preservative).

New Effective, Innovative Treatments for Neuropathic Pain

Chronic neuropathic pain is the result of actual nerve cell or axonal damage due to inflammation, trauma or degenerative disease. It is characterised by shooting/stabbing pain, as well as sensations of burning, tingling and numbness. Many different types of neuropathic pain share a common pathway of pathophysiology. Diabetic peripheral neuropathy, postherpetic neuralgia, complex regional pain syndrome type 1, fibromyalgia, postsurgical neuropathy, post-trauma neuropathy, visceral neuropathy, xenobiotic neuropathy and the idiopathic neuropathies all share the same pathway of sensory input and central modulation and inhibition.

Mechanism of Pain
Chronic neuropathic pain originates in either the periphery or central compartments, depending on the source of pain (Martin and Hagan, 1997). Noxious stimuli are detected in the periphery by nociceptors which stimulates afferent nerve fibres to process the pain signal to the CNS via the dorsal horn of the spinal chord. These afferent fibres are of two main types: The myelinated, fast A fibres and the unmyelinated, slow C fibres. The constant suffering of patients with neuropathic pain is mostly C-fibre input. Nociceptor sensory input from free nerve endings is also involved but uses afferent nerve fibres as a pathway of input to the CNS. Damage to tissue may directly excite nerve endings by mechanical, thermal, or chemical effects on the nerve membrane. Such damage also sets in process the sequence of events recognised as inflammation. Crucial to the mediation of pain and inflammation at the peripheral pain receptor is the conversion of arachidonic acid, via the enzyme cyclooxygenase, to prostaglandins. These act by lowering the threshold of excitability to other mediators released such as bradykinin, substance P, thromboxanes, leukotrienes, nerve growth factor and histamine. The action of NSAID’s is largely due to their ability to inhibit the action of cyclooxygenase. On the other hand, compounds such as capsaicin cause the release and then deplete stores of substance P leading to analgesia.

The gate control theory of pain explained the modulation of pain signals via a multiplicity of interneurones that synapse with the afferent fibres and descending inhibitory pathway in the dorsal horn (Baumann, 1997). Once the pain signal interfaces the dorsal horn synapse, it reaches the CNS via various pathways for interpretation of pain. The CNS recognition of pain stimulates the descending inhibitory signals with the net result of either resolution, modulation or gain of pain.

Activation of C-fibres induce the release of a number of chemical transmitters at the synapse. Substance P (slow acting) and glutamate (fast acting) are the most important. Glutamate released is able to then activate different types of receptors, most importantly the alpha-amino-3-hydroxy-5-methy-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. The development of hyperalgesia and allodynia states is the result of the activation of NMDA receptors by glutamate (Gibb et al., 1994). Located throughout the brain, dorsal horn and periphery along C-fibres, the NMDA receptors play a crucial roll in the modulation of pain signals, the maintenance of chronic neuropathic pain and the development of hyperalgesia and allodynia (Liu, 1997; Sandkuhler et al., 1998; Yamamoto, 1996). NMDA receptor activation by glutamate in the dorsal horn results with the opening of the calcium channel, by magnesium displacement, allowing calcium to enter the intracellular space. Intracellular calcium stimulates a cascade of events releasing kinase C, arachidonic acid, substance P, endothelium-derived relaxing factor and other inflammatory mediators. These further facilitate the release of glutamate which activates more NMDA receptors causing a wind up effect. Substance P has been particularly implicated in enhancing this wind up and central sensitisation (Carlton et al., 1998B). This process leads to long-term potentiation of NMDA receptors (rather than opioid receptors) at the dorsal horn neurones resulting in hyperalgesia and allodynia (Bloom, 1996; Laughlin et al., 1997).

Evidence exists of sodium channel involvement in NMDA receptor modulation (Eide, 1998). Glutamate activation of the dorsal horn and/or peripheral AMPA receptors, which are located in close proximity to NMDA receptors, causes an intracellular influx of sodium. The result is a delayed calcium rise intracellularly and an increase in excitotoxicity. Intracellular sodium indirectly induces the reduction of the GABA and opioid inhibitory systems increasing excitotoxicity which is a precursor to long-term potentiation. Glutamate antagonists may preventing AMPA receptor activation thus reducing the sensation of pain.
Peripheral insult that stimulates action at the NMDA/AMPA receptors also involve other systems: substance P,  agonists and antagonists, GABA agonists and the free radical system.

Opioid receptor agonists block substance P release and dull the sensation of pain. The opioids do not ameliorate neuropathic pain very effectively when used as monotherapy and also tend to develop tolerance and an array of side effects.

There is evidence to suggest that there is an adrenergic component of cutaneous hyperalgesia in painful peripheral neuropathy. Clinical observations suggest that cutaneous sensitivity to noradrenaline contributes to chronic neuropathic pain. There is extensive, but antidotal, literature reporting the relief of the acute pain of herpes zoster in thousands of patients by local alpha 1 sympathetic blockage (Choi, 1997).The epidermal concentration of alpha 1 adrenergic receptors in hyperalgesic skin when compared to normal skin was found to be significantly greater in patients with neuropathic pain (Drummond et al., 1996).

The alpha 2 adrenergic receptors are located in the periphery and CNS. Topical alpha 2 agonists have also proved to be effective in treating hyperalgesia. Alpha 2 Agonist act by activating prejunctional receptors inhibiting the release of norepinephrine from sympathetic terminals.

GABA agonist action is inhibitory to pain signals. Specifically, the GABAb receptor is a member of the metabotropic (G protein-coupled) complex associated with the NMDA receptor modulation of sensory input (Bloom, 1996). Agents that are GABAb agonists (baclofen) are useful concomitantly with NMDA antagonists to mitigate glutaminergic calcium influx more effectively than either alone.

The involvement of free radicals in excitotoxicity provides evidence for their use in the treatment of neuropathic pain (Schultz et al., 1995).

This brief summary is certainly not inclusive as much yet needs to be learned regarding the pathophysiology of neuropathic pain. It is, however, a more complete basis of understanding than ever before.

Current Pain Management
The treatment of central and peripheral neurogenic pain is difficult. Patients are refractory to nonopioid analgesics, including NSAID’s, and rarely respond to opioids except at very high doses. This usually causes an array of side effects and leads to the rapid development of tolerance. Medication which helps dampen the activity of spontaneously hyperactive nociceptive neurones may help. These include amitriptyline and other tricyclic antidepressants, and anticonvulsants such as carbamazepine. Oral doses are usually titrated in accordance with the clinical response and side effects, which again are numerous.

New Pain Management Treatment
Considering the barriers to effective pain management it is time to consider a different approach to the problem as we enter a new millennium. Therapeutic manipulation has been experimentally achieved by using substances that:

• (a) block the excitatory process, such as NSAID’s and local anaesthetics, or
• (b) enhance the inhibitory response in the cord, such as opioids, alpha 2 agonists, GABA agonists, or
• (c) block the NMDA receptor, eg Ketamine or Dextrometorphan.

Therapeutic application of many of these substances is at a promising, but still experimental phase.

(1) Ketamine - a very effective noncompetitive NMDA antagonist, has been used orally for over 30 years to produce dissociative anaesthesia and more recently to successfully treat chronic neuropathic pain (Hoffmann, 1994). Potential problems with oral dosing is sensory and perceptional illusions, disorientation and vivid dreams at higher doses. Topical ketamine has been used to effectively treat sympathetically maintained pain without any reported side effects (Crowley et al., 1998). Topical application is recommended for localised pain where as low dose oral administration is recommended in cases where pain exists over a large area. Ketamine is now being used by pain specialists in pain clinics throughout Australia with great success where other treatments have failed.
(2) The glutamate antagonist, gabapentin, has also been used orally to treat chronic neuropathic pain (Backonja et al., 1998; Rowbotham et al., 1998). The high oral doses required often cause unwanted side effects which reduces patient compliance. Glutamate receptors have been found to reside at the dermal-epidermal junction so it was hypothesised that topical application could be a form of therapy for pain states either induced or maintained by peripheral primary afferent activity (Davidson et al., 1997). Anecdotal reports confirm that topical application is effective without any side effects.

(3) Topical application of the alpha 2 agonist, clonidine, has also decreased or abolished hyperalgesia in patients with features of reflex sympathetic dystrophy (Davies et al., 1991).

A new approach is now emerging that is able to effectively reduce suffering and side effects by using Low Dose, Combination, Transdermal Pain Therapy (LCTPT). The knowledge of receptor location now provides a different route of administration to avoid oral or systemic doses and their associated side effects. Alpha 1 Receptors and glutamate receptors have been reported to be located in the periphery (Drummond et al., 1996), opioid and alpha 2 receptors are known to exist locally, evidence of NMDA receptors in the epidermal-dermal junction have been reported (Carlton, 1998A; Davidson et al., 1997) and the AMPA receptors are located in close proximity to NMDA receptors. Based on the evidence presented effective pain relief may be achieved using low dose topical administration thus avoiding side effects associated with oral medications.

The theory of LCTPT starts with three medications with complementary modes of action being incorporated into a penetration enhanced topical base. Based on the key roll that the NMDA receptor performs in causing pain and suffering, an NMDA antagonist should be the first primary ingredient. A glutamate/AMPA antagonist second and either an alpha 1-antagonist, alpha 2-agonist, norepinephrine reuptake inhibitor or GABAb agonist, third. If inflammation is implicated a NSAID should also be included. One gram of this starting formula is applied directly to the localised area of pain and to the corresponding dorsal horn area of the involved dermatome. It is applied at eight hour intervals on a regular basis and every two hours in-between, as needed, for breakthrough pain. Dose escalation can occur daily or every other day until pain is relieved or, rarely, if side effects occur. Additional items from the third list should be added (with a different mode of action) after one to two weeks, if required. Again, dose escalation and evaluation should be repeated, if required.

Using the guidelines described above a medication is chosen from each category at the appropriate strength and incorporated into the formula. Ingredients are chosen based on the requirements of each individual thus customising their medication. Ongoing changes to the formula may be necessary until the most effective formula is found. This may involve dosage adjustments or changes to the combinations of the types of medications used.

Several starting formulas have been suggested and may be used as a guide. Their effectiveness has been well established by compounding pharmacies throughout the world (Jones, 2000; Angelle, 2000; Oberlander, 2000; Wood, 2000) Unfortunately, most of the evidence is antidotal as expensive clinical trials have not yet been performed. Pharmaceutical companies are not willing to invest vast amounts of money into this research because they do not stand to profit from it as these treatments are not patentable. It has therefore been left up to pioneering doctors and compounding pharmacists to establish effective and safe dosage protocols. The formulas listed below have been used on thousands of patients world wide and have proven themselves to be very effective in relieving neuropathic pain without any side effects.

1. An effective starting formula for any type of neuropathic pain, especially diabetic neuropathy, may be 10% Ketamine, 6% Gabapentin and 0.2% clonidine. If after one week pain relief is not satisfactory add 2% baclofen and/or 2% amitriptyline. Again, after another week if it is still not successful add 5% loperamide. In addition, 100 to 300mg of alpha lipoic acid should be taken orally three times a day for diabetic neuropathy as numerous studies reveal it is able to reduce associated pain.
2. An effective formula for Herpes Zoster (shingles) contains 5% Acyclovir, 10% lidocaine, 10% Ketoprofen, and 2% amitriptyline. Postherpetic neuralgia is best treated with the first formula listed above.
3. An effective starting formula for more inflammatory pain is 15% ketoprofen, 7% amitriptyline and 5% lignocaine.
4. An effective formula for diabetics with sensory peripheral neuropathy includes 8% Nifedipine and 5% ketamine, in an attempt to prevent the development of diabetic neuropathy from neuronal apoptosis numbness and the resultant high risk of amputation.
5. Another effective starting formula for all types of neuropathic pain is 10% lidocaine, 7% amitriptyline and 7% carbamazepine.
6. An effective formula for severe arthritic pain is 0.075% capsaicin, 2% Ketamine and 10% Ketoprofen.
7. For patients who are unable to apply a cream to the skin due to severe pain may require to pretreat the area with a 5% Ketoprofen and 10% aspirin in ether spray. It is sprayed on the area and allowed to dry for 5 to 10 minutes prior to applying the cream.
8. For patients whom experience pain over a large area low doses of oral ketamine is very effective. Doses between 25 to 100mg three times a day is effective in treating pain with minimal side effects. It is recommended to start low and gradually increase the dose until the desired effect is achieved.

The most important thing to note is that it is possible and preferential to customise a formula to best suite the needs of each individual patient. Changes in medications and their strength may be necessary in order to find the most effective formula. This process will require patience on behalf of the patient and the prescribing doctor, but once the correct formula is found very effective and safe pain management is assured. I encourage patients to contact myself whenever they feel that they require assistance and I closely monitor their progress keeping you, their doctor, up to date. I must emphasise the importance that open communication is maintained between the triad of patient, doctor and pharmacist to ensure a beneficial outcome for the patient.

Preventing Opioid Tollerance
While on the subject of pain management new research indicates that dextromethorphan is capable of attenuating and/or reversing opioid tolerance which is responsible for escalating opioid doses with chronic use (Elliott et al, 1994). The mechanism for this is believed to involve both NMDA receptor-gated and non-NMDA receptor-gated calcium and sodium channels. Dextromethorphan is a noncompetitive NMDA receptor antagonist. Opioid tolerance requires a functional NMDA receptor, and blockage of this receptor prevents developement of opioid tolerance. It also attenuates intracellular Ca influx through NMDA receptor-gated channels as well as voltage-gated Ca channels. It also blocks current through voltage-gated Ca and Na channels (Kane and Glasnapp, 1998). Our laboratory compounds dextromethorphan capsules which may be used in conjunction with opioid therapy to prevent opioid dose escalation.

If you have any queries or requests feel free to contact us as we will do all we can to assist.

Kind Regards
Dr Michael Serafin B.Pharm (Hon) Ph.D. MIACP
Pharmaceutical Chemist/Pharmacist.

References - Most of the original articles are available on request.

• Alley, K.O., Levine, J.D., Multiple receptors involved in peripheral 2, , and A1 antinociception, tolerance, and withdrawal. Soc Neurosci., 17, 735 - 744 (1977).
• Angelle, P., Postherpetic neuralgia. Int J Pharm Comp., 4, 27 - 29 (2000).
  Backonja, M., Baydoun, A., Edwards, K.R., et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: A randomised controlled study. JAMA, 280, 1831 - 1836 (1998).
• Baumann, T. Pain management. Pharmacotherapy: A Pathophysiological Approach. 1259 - 1278 (1997).
• Bloom, F.E. Neurotransmission and the nervous system. Goodman and Gilman�s The pharmacological Basis of Therapeutics, ed 9. 276 - 294 (1996).
• Carlton, S.M., Zhou, S. Attenuation of formalin induced nociceptive behaviours following local peripheral injection of gabapentin. Pain, 76, 210 - 217 (1998A).
• Carlton, S.M., Zhou, S., Coggeshall, R.E., Evidence for the interaction of glutamate and substance P receptors in the periphery, Brain Res., 790, 160 - 169 (1998B).
• Choi, B., Rowbotham, M.C., Effect of adrenergic receptor activation on post-herpatic neuralgia pain and sensory disturbance. Pain, 69, 55 - 63 (1997).
• Crowley, K., Flores, J., Hughes, C., Iacono, R.P., Clinical application of ketamine ointment in the treatment of sympathetically maintained pain. Int J Pharm Comp., 2, 122 - 125 (1998).
• Davies, K.D., Treede, R.D., Raja, S.N., Meter, R.A. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain, 47, 309 - 317 (1991).
  Davidson, E.M., Coggeshall, R.E., Carlton, S.M. Peripheral NMDA and non-NMDA glutamate receptors contribute to nociceptive behaviours in rat formalin test. Neurorepsrt. 8, 941 - 946 (1997).
• Drummond, P.D., Skipworth, S., Finch, P.M. Alpha-1-adrenoreceptors in normal and hyperalgesic human skin. Clin Sci., 91, 73 - 77 (1996).
• Elliott, K., Hynansky, A., Inturrisi, C.E., Dextromethorphan attenuates and reverses analgesic tolerance to morphine. Pain, 59, 361 - 368 (1994).
• Eide, P.K. Pathophysiological mechanisms of ventral neuropathic pain after spinal cord injury. Spinal Cord 36, 601 - 612 (1998).
• Gibb, A.J., Edmonds, B and Silver, R.A. Activation of NMDA receptors. The NMDA receptor, ed 2, Oxford university Press, 219 - 242 (1994).
• Hoffmann, V., Coppejans, H., Verauteren, M. Successful treatment of postherpetic neuralgia with oral ketamine. Clin J Pain, 10, 240 - 242 (1994).
• Jones, M., Chronic neuropathic pain: Pharmacological interventions. Int J Pharm Comp, 4, 6 - 15 (2000).
• Kane, D.L. and Glasnapp, A., Dextromethorphan and opioid tolerance. Int J Comp Pharm., 2, 118 - 119 (1998).
• Laughlin, T.M., Vanderah, T.W., Lashbrook, J et al. Spinal administered dynorphin A produces long-lasting allodynia. Involvement of NMDA but not opioid receptors. Pain, 72, 253 - 260 (1997).
• Liu, X and Sandkuhler, J. Characterisation of long-term potentiation of C-fibre-evoked potential’s in spinal dorsal horn of adult rat. J Neurophysiol., 78, 1973 - 1982 (1997).
  Martin, L.A and Hagen, NA, Neuropathic pain in cancer patients: Mechanisms, syndromes, and clinical controversies. J Pain Symptom Manage, 14, 99 -117 (1997).
• Oberlander, K., Fibromyalgia. Int J Pharm Comp., 4, 21 - 23 (2000).
• Rowbotham, M., Hardin, N., Stacey, B., et al., Gabapentin for the treatment of postherpetic neuralgia: A randomised controlled study. JAMA, 280, 1837 - 1842 (1998).
  Sandkuhler J., Liu, X. Induction of log term potentiation at spinal synapses by noxious stimulation or nerve injury. Eur J Neurosci, 10, 2476 - 2480 (1998).
• Schultz, J.B., Henshaw, D.R., Siwek, D., Involvement of free radicals in excitotoxicity in vivo. J Neurochem., 64, 2239 - 2247 (1995).
• Wood, R.M., Ketamine for pain in hospice patients. Int J Pharm Comp., 4, 253 - 254 (2000).
• Yamamoto, T. NMDA receptor and pain. Masui, 45, 1312 - 1318 (1996).

Copyright 2001 Michael Serafin, Ph.D.