Bitter leaf-based drugs for diabetes, cancer pass clinical trials, get U.S. patents

  • Monday, August 18, 2008 - Guardian Nigeria
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CAN eating Bitter leaf soup be the cure for the dreaded breast cancer and diabetes? CHUKWUMA MUANYA reports that Bitter leaf-based drugs for diabetes and cancer have passed human clinical trials and received United States patents.

It is bitter, but healthful. Unfortunately, the bitter taste, which contains the healthful punch, is usually removed by boiling or squeezing the leaf of Bitter leaf with running water before it is eaten.

Bitter leaf soup is a popular delicacy in Eastern Nigeria. The soup is made with the leaf of Venomia Amydalina, better known as Bitter leaf, which has been treated to remove the bitter taste, cocoyam paste, palm oil, spices, dry fish and local seasoning.

But researchers say eating more of Bitter leaf soup could be the panacea for diabetes, cancer, liver damage, drug resistant microbial infections; promote safe childbirth, to mention but a few.

Indeed, a Bitter leaf-based herbal anti-diabetic medication has passed human clinical trials and received a United States Patent 6531461 for the treatment of diabetes; even as the Nigeria Institute of Pharmaceutical Research and Development (NIPRD), Abuja, gets set to start a multi-centre human clinical trials of a similar drug, ADI.

Also, a phytochemotherapy (treatment based on plant chemicals) for cancer made from aqueous extracts of leaves of Bitter leaf, collected in Benin City, has received a United States Patent 6849604.

Nigeria researchers have also shown that Bitter leaf protects the liver from drug induced damage. A study published in Journal of Medicinal Food suggests that Bitter leaf elicits hepatoprotectivity (offers protection against liver damage) through antioxidant (prevents cell death) activity on acetaminophen-induced hepatic damage in mice.

The roots and leaves decoction of Bitter leaf has also been shown to increase uterine contraction and motility for safer childbirth. It is traditionally used in western Uganda to treat various ailments such as treatment of painful uterus, inducing uterine contractions, management of retained placenta and post partum bleeding, malaria, induced abortion, antimicrobes (bacterial and fungal infections), infertility, colic pains and treatment of irregular and painful menstruation.

Until now, Bitter leaf is used in Nigerian folk medicine as a tonic and remedy against constipation, fever, high blood pressure, and many infectious diseases.

Scientifically called Vernonia amygdalina, Bitter leaf belongs to the plant family Compositae. In Nigeria, the Edo calls it oriwo; Hausa, chusar doki (a horse tonic food containing the leaves), fatefate/mayemaye (a food prepared from the leaves); Ibibio, atidot; Igbo, onugbu; Tiv, ityuna; and Yoruba, ewuro.

Bitter leaf is a shrub or tree which grows to about five meters high especially around forest-margins and is widely distributed throughout tropical Africa.

The leaves are very bitter. Bitterness can be abated by boiling or in the young leaves by soaking in several changes of water. They are held to be anti-scorbutic and are added to soups or eaten as spinach.

Earlier studies indicated that relevant concentrations of extract from Bitter Leaf inhibits breast cancer and lowers blood glucose levels.

The anticancer invention provides for phytochemotherapeutic compositions produced from aqueous extracts, derived from Vernonia amygdalina leaves. These pharmaceutical compositions inhibit the growth of neoplastic cells, including human breast cancer cells.

Neoplasia (new growth in Greek) is the abnormal proliferation of cells, resulting in a neoplasm. Neoplasia is the scientific term for the group of diseases commonly called tumor or cancer.

The Inventor, Izevbigie Ernest B. claims the instant invention provides phytochemotherapeutic compositions and methods for inhibiting the growth of cancer cells, and specifically for the growth inhibition of human breast cancer cells.

According to an earlier study by Izevbigie, "Discovery of water-soluble anticancer agents (Edotides) from a vegetable found in Benin City, Nigeria," published in the journal Experimental Biology and Medicine, Bitter Leaf may prevent the onset of breast cancer.

The researchers led by Izevbigie wrote: " Treatment of cells with physiologically relevant concentrations of water-soluble Bitter leaf extract potently inhibited DNA synthesis in a concentration dependent fashion, both in the absence and presence of serum. Fractions of Bitter leaf extract separated using preparative reverse-phase chromatography also inhibited DNA (genetic material) synthesis."

The researchers conclude: "These results suggest that the vegetable Bitter leaf, if incorporated in the diet, may prevent or delay the onset of breast cancer."

According to the U.S. Patent report on the anti-diabetic herbal drug, the Bitter leaf extract was orally administered to 26 patients all of whom had been previously diagnosed as suffering from hyperglycemia (high blood glucose, indicative of diabetes). A group of five control subjects were used who maintained diet discipline throughout the trial. The initial extract was dosed to the patient three times daily in 100 mg aliquots for six months.

The blood glucose levels of all 31 subjects were closely monitored. The 26 patients receiving the initial extract no longer required to maintain diet discipline after the first month and examination showed remission of the disease after three months.

15 patients continued to receive medication for the remaining three months of the trial. All volunteers now appear to have recovered from the disease and have returned to their normal life prior to the diagnosis of the disease.

Diabetes is a potentially life threatening condition in mammals brought about by an inability of the mammals to produce insulin. Insulin, a polypeptide hormone produced in the pancreas of the mammal, controls the amounts of glucose present in the blood by stimulating the uptake of glucose by the muscle and adipose tissue.

The production of insulin is ultimately controlled by the brain. Biosynthesised insulin has been the drug of choice for the treatment of diabetes mellitus or hyperglycemia (the term imparted to an excess of glucose in the blood), for many years.

Biosynthesised insulin is manufactured by recombinant DNA technology at a high cost. The administration of biosynthesised insulin to the patient occurs via injection directly into the muscle, since it is partially digested if administered orally. This administration method further elevates costs due to the requirement for needles and furthermore, increases the likelihood of infection and/or contamination.

Recently thiazolidine derivatives, as described in U.S. Patent No.4,387,101, have been introduced for the treatment of hyperglycemia. However, there are some concerns relating to the toxicity of these derivatives.

WO9857636 teaches of an oral anti-diabetic agent, rosiglitazone maleate which when administrated in conjunction with insulin acts primarily by increasing insulin sensitivity.

None of the aforementioned methods of treatment offer any remission for diabetes. The present invention was made from a consideration of this problem.

It was found that the compounds, as isolated from the leaf of Bitter leaf plant and having the general structure `A`, are particularly useful for the treatment of hyperglycemia. Furthermore, the compounds may bring about cell regeneration as trials involving hyperglycemic mammals have resulted in the restoration of complete insulin activity within six months.

It is thought that these compounds enhance insulin sensitisation and may even replace insulin whist initiating beta cell regeneration. Advantageously, the compounds exhibit no known toxicity when administered to either hyperglycemic or non-hyperglycemic mammals.

The compounds may be used in the management of type I and type II diabetes mellitus. The compounds may be in the form of one or more cationic salts, for example sodium, potassium, lithium. The compounds may also be in the form of a hydrate or solvate.

Furthermore, since the compounds are derived from the common Bitter leaf plant, they are easily and cost effectively obtained, particularly when compared with the compounds of the prior art.

According to the U.S. Patent, the compounds may be administered by any convenient route. Preferably, the compounds of the present invention will be administered orally. The dose may be varied depending upon the patient, but will generally be 100 mg, three times daily.

An earlier study carried out by researchers at the University of Jos suggested that Bitter Leaf has an anti-diabetic effect in diabetes mellitus (Type 2 diabetes). The researchers include: Steven S. Gyang of the Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Davou D. Nyam of the Department of Botany, Faculty of Natural Sciences and Elijah N. Sokomba, Department of Pharmacology, Faculty of Pharmaceutical Sciences.

The study published in the Journal of Pharmacy & Bioresources was carried out to evaluate the hypoglycaemic (low blood glucose) effect of the crude chloroform extract of Bitter leaf leaves on blood glucose concentration (BGC) of normoglycaemic (normal blood glucose level) and alloxan-induced hyperglycaemic (high blood glucose level indicative of diabetes) rats.

The study is titled " Hypoglycaemic activity of Vernonia amygdalina (chloroform extract) in normoglycaemic and alloxan-induced hyperglycaemic rats." There was significant lowering of BGCs between one - four hours (for normoglycaemic rats) and one - eight hours (for hyperglycaemic rats). Thus the crude chloroform extract of the leaves of Bitter leaf has a hypoglycaemic activity in both normoglycaemic and alloxan induced hyperglycaemic rats.

This study lends support to the claim by herbalists of Plateau and Nassarawa States that Bitter leaf may have an anti-diabetic effect in diabetes mellitus.

The study on the hepatoprotective and antioxidant activities of Bitter leaf on acetaminophen-induced hepatic (liver) damage in mice was carried out by B.A. Iwalokun, B.U. Efedede, J.A. Alabi-Sofunde and T. Oduala of the Department of Biochemistry, Lagos State University; and O.A. Magbagbeola and A.I. Akinwande Department of Biochemistry, College of Medicine, University of Lagos.

The researchers evaluated the hepatoprotective and antioxidant effects of an aqueous extract of Bitter leaf leaves against acetaminophen-induced hepatotoxicity and oxidative stress in mice in vivo.

The researchers reported that pre-administration of Bitter leaf resulted in a dose-dependent (50-100 mg/kg) reversal of acetaminophen-induced alterations of all the liver function parameters by 51.9-84.9 per cent. Suppression of acetaminophen-induced lipid peroxidation (destruction of fat/protective membranes of cells) and oxidative stress by the extract was also dose-dependent (50-100 mg/kg).

Ugandan researchers have studied the effects of Bitter leaf on the uterine motility. The study titled "Ethno-pharmacological screening of Vernonia amygdalina and Cleome gynandra traditionally used in Childbirth in Western Uganda" was conducted by Maud Kamatenesi-Mugisha, Hannington Oryem-Origa, Olwa-Odyek and Dominic W. Makawiti of the Departments of Botany and Pharmacy, Medical School, Makerere University Kampala, Uganda; and Department of Biochemistry, College of Health Sciences, University of Nairobi, Kenya. The study was published in the NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar.

Rat uterus tissue was used in ethnopharmacological screening because Bitter leaf herbal remedies are used in stimulating childbirth traditionally. The smooth muscle of the rat uterus was the point of contact for these herbal drugs experimentation due to its high sensitivity among other laboratory animals. The aqueous extracts of Bitter leaf contracted and increased the uterine motility.

The aqueous herbal extract of Bitter leaf showed marked rat uterine stimulation (oxytocic) and was further re-screened using the smooth muscle of the rabbit jejunum to confirm the findings. The rabbit jejunum was used because of being a smooth muscle like the uterus and the pronounced pendular movements due to its high sensitivity.

Bitter leaf contracted the jejunum motility. In the interpretation of the results, normal motility is the baseline for that particular tissue.

Standard drugs were used as the controls of the set up. The medicinal plants selected for ethnopharmacological tests were based on the ethnobotanical indigenous knowledge. The fact that traditional healers have been using these plants for ages is a worthwhile reason to investigate their efficacy in the claimed use and matching preparations in the laboratory with indigenous knowledge.

The aqueous herbal extract of Bitter leaf is a strong oxytocic plant. The herbal extract was found to be long acting and when introduced to the rat uterus, it caused contractions that were sustained over 30 minutes. The decoction of Bitter leaf is used for treating malaria irrespective of age, gender, sex and pregnancy in western Uganda, yet the plant is oxytocic as displayed in.

The use of Bitter leaf extract to treat malaria in pregnancy is scientifically dangerous since it increased uterine motility. According to the findings, the plant drug is oxytocic and may cause abortion when used in preterm pregnancy. The aqueous extract of Bitter leaf can cause uterine contractions at lower doses of less than 300 ?g/ml. The usage of Bitter leaf to induce labour can, if due care is not taken; can cause uterine rupture or other complications to the mother and foetus.

The aqueous herbal extract of Bitter leaf caused the contraction of the smooth muscle of the rat uterus and rabbit jejunum. This is an indication that Bitter leaf can hasten childbirth or cause abortion if used in preterm pregnancy.

Ethnobotanical uses elsewhere show that the plant is widely used in Africa. In Malawi, the dried bark of Bitter leaf is used to improve uterine contractions during labour in pregnant women.

The researchers concluded: "However, the aqueous extract was found inactive on the guinea pig uterus. Lactating women who want to increase milk flow drink hot water extract decoction. In Guinea-Bissau and Nigeria, the infusion of leaves of Bitter leaf is used as an abortifacient in women. In Rwanda, the methanolic extract of Bitter leaf showed weak relaxant activity on the smooth muscle of the guinea pig ileum, but caused neither relaxation nor stimulation of the guinea pig uterine muscle. Although the ethnopharmacological experiments else where never proved more effective, it could have been due to the choice of the test animals used since the rat uterus in more sensitive than the pig uterine muscle.

"Thus, the usage of Bitter leaf in hastening childbirth is potentially safe particularly when administered by the traditional birth attendants with long standing experience in childbirths.

"Unlike in the stimulation of abortion, the pregnant women consume large amounts of the plant extracts for some days either intentionally or while treating other diseases such as malaria to cause adverse effects. This would imply that the plant that has shown properties of contracting the uterus is hinged on the dose dependent ratio."

According to a study published in the West African Journal of Pharmacology Drug Res., Bitter Leaf could be effectively used against drug resistant microorganisms._

The study was carried out to determine antibacterial potential of Bitter leaf using a panel multi-drug resistant gram-negative and gram-positive bacteria and standard strains: Eschericia coli ATCC 25922 and Staphylococcus aureus ATCC 25923._

Specifically, the active extract challenge resulted in a decline in the number of viable cells of E.coli, Bacillus and Salmonella by 4logcfu and Shigella, Streptococcus spp and Staphylococcus aureus isolates by 3log cfu within four hours of incubation in the time-kill assay.

The results of this study have scientifically demonstrated the antibacterial activity of Bitter leaf and further suggest its possible exploitation as a source of natural product for future use in the management of multi-drug resistant bacterial infections in Nigeria._

According to the West African Encyclopedia of Medicinal Plants, "the leaves of bitter leaf are widely used for fevers and are known as a quinine-substitute. A leaf-decoction is taken as a laxative. A purgative enema is made by macerating the leaves through a cloth and adding peppers and spices. A cough medicine is made as an expectorant. The leaves are rubbed directly onto the skin for itch, parasitic affections, and ringworm, among others. Cold infusion is applied as a wash. During the puerperium (the time immediately after the delivery of a baby), a mother may take a decoction of the leaves to affect her milk so as to act as a prophylactic against worms in the baby. The leaves are added to horse-feed as a vermifuge (an agent that causes the expulsion of worms or parasites from the body) and to treat internal disorders symptomised by mucal discharge from the nose. Leaves are rubbed onto the breast for weaning infants.

"The wood, most usually from the root after the bark has been removed by scorching, provides one of the common chew-sticks in Nigeria. It is valued as a tooth-cleaner and more especially as a stomachic and appetiser. It has an alleged beneficial effect on dental caries, but no antibiotic activity has been found in material from Ibadan. In Northern Nigeria, the Hausa use these chew-sticks with natron for gastro-intestinal troubles.

Natron is a naturally occurring mixture of sodium carbonate decahydrate (Na2CO3?10H2O, a naturally occurring form of soda ash) and about 17 per cent sodium bicarbonate (also called nahcolite or baking soda, NaHCO3) along with small quantities of household salt (halite, sodium chloride) and sodium sulphate.

"A root-infusion is taken in Nigeria as a worm expeller as well as for intestinal parasitic infections._ The bark of stem and roots is particularly bitter and is more or less astringent. Infusions are commonly taken for fever and diarrhoea. In Nigeria an infusion is used for rheumatism. Dried flowers are used to treat stomach-disorders. The fruit is used as an aphrodisiac, and powdered seeds as worm expeller."

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