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1. WO2011039574 - THE USE OF A HERBAL COMPOSITION FOR THE TREATMENT OF A PERSON INFECTED WITH HIV

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THE USE OF A HERBAL COMPOSITION FOR THE TREATMENT OF A PERSON

INFECTED WITH HIV

THIS INVENTION relates to the treatment of HIV infection and to the prevention of the onset of AIDS.

In particular, the invention relates to the use of a herbal composition in the manufacture of a medicament for the treatment of HIV infection and other diseases and conditions in a subject, to a method of making a herbal composition for the treatment of HIV infection and other diseases and conditions in a subject, to a method of treating a subject with an HIV infection and other diseases and conditions and to dosage forms for the treatment of HIV infection and other diseases and conditions in a subject.

Background

Infection with the human immunodeficiency virus (HIV), a pathogenic retrovirus, can cause acquired immunodeficiency syndrome (AIDS) (Barre-Sinossi, F. et al., 1983). Although macrophage, neuron and other cells can be infected by HIV (Maddon et al., 1986), CD4+ lymphocytes are the major target cells for HIV (Dalgleish, A. et al., 1985), because HIV has strong affinity to the CD4 molecules on the surfaces of CD4+ cells. HIV infection in a human body destroys so many CD4+ lymphocytes that the body begins to lose its immune function, therefore an AIDS patient is highly vulnerable to various infections, neuronal dysfunction, tumors, and so on. In most cases patients eventually die (Levy, J. A. 2000).

With its severe symptoms and high mortality rate, AIDS has become one of the leading causes of death. At present there are about 57,9 million people worldwide who are infected by HIV (WHO Report, 2000). It has also been found that the annual rate of new HIV infections worldwide is not declining. There are 21 ,800,000 people who have died from AIDS in the last decade (WHO Report, 2000). Despite this fact, the rate of death due to AIDS has begun to drop in some nations, including the United States, primarily through the recent use of combination drug therapies against HIV infection.

However, although AIDS incidence and mortality have been decreasing in the United States, it is estimated that 16,000 people worldwide are being infected with HIV each day. In certain African countries, infection rates have reached 25% (Baiter, M. 1998). Treatment success also has been limited by poor tolerance of the treatments by patients and the emergence of resistant strains of HIV. A need thus exists for an effective HIV treatment that is well tolerated and relatively inexpensive.

Currently at least two types of HIV have been identified: HIV-1 (Gallo, R. et. al., 1984) and HIV-2 (Clavel, F. et al., 1986). Each of them has high genetic heterogeneity. For HIV-1 alone, there are at least 1 1 different genotypes (A-J and O subtypes) (Jonassen, T. O. et al., 1997). The E sub-type of HIV-1 is distributed mainly in Central Africa, Thailand, India, Vietnam, Kampuchea, Malaysia, Burma, China, and western hemisphere (WHO Report 1996). The HIV subtypes found in China are mostly B, E, or C subtype (Yu, E. S. et al., 1996). Whereas, as the subtype(s) found in the Middle-East, particularly in the Republic of Yemen is still unknown.

During infection with progressive human immunodeficiency virus type 1 (HIV-1 ), the virus-specific immune responses of an infected subject gradually deteriorate, leading to the development of acquired immunodeficiency syndrome (AIDS). Most infected patients do not exhibit overt clinical manifestations of the disease for six to ten years following initial infection. Reports indicate, however, that approximately 5% of HIV-1 infected persons remain free of disease for ten or more years. (Haynes, 1996; Munoz A and Xu J, 1996; Rinaldo C, et al, 1995; Rowland S. L. et al, 1995; Rowland S. L. et al, 1993; Hoover D. R., et al. 1995; Lifson A. R., et al, 1991 ). Such a person, termed a long-term non-progressor (LTNP), exhibits lower viral loads and stable CD4+ cell counts.

Although great efforts have been dedicated to effective remedial and preventive methods for many years, there is no working vaccine or cure for AIDS yet. An ideal vaccine should be innocuous and capable of inducing neutralizing antibodies as well as persistent immune responses in the mucous membranes and the blood (Levy, J. A., 1988). Many HIV current vaccines are still in the stages of animal trials. Although vaccines against HIV membrane proteins gp 160 and gp120 have already moved into first, second, or third stages of clinical trials, the results of the trials have been disappointing. Moreover, many vaccines that are effective to prevent HIV infection in laboratory animals are not effective in humans (McElrath M. J. et al., 1996). The fact that scientists are making little progress in HIV vaccine research can be attributed amongst others to the complexity and variability of HIV genetic materials (Bloom, B., R., 1996).

The AIDS drugs which have so far been approved can be classified into two categories. These are HIV reverse transcriptase inhibitors (Charles, C. J., et al., 1996; Charles, C. J., et al., 2000) and HIV protease inhibitors (Miles, S. A. et al.,). Both of these categories aim at later stages of HIV infection-transcription and assembly of new viruses. The well-known "Cocktail Therapy" is a combination therapy using both types of inhibitors (Lafeuillade, A., et al., 1997).

Reverse transcriptase inhibitors, including AZT, ddl, ddC, 3TC, d4T and the like sooner or later induce drug resistance. This means that the viruses become less sensitive to the drugs, and the effective inhibition concentration of the drugs rises by several-fold or even ten-fold (Vella, S. and Floridia, M., 1996). This drug-resistance is associated with the high mutation rate of HIV. In a human body, a single HIV virus can produce 108 to 1010 new viruses every day, while the mutation rate is 3x105 per replication cycle. Many Missense Mutations, affecting the expression of amino acids, may happen in the regulatory genes as well as in the envelope proteins. In some HIV strains, the mutation rate could be as high as 40% in the amino acid sequences of certain genes (Myers, G and Montaner, J. G., 1992). As a result, reverse transcriptase inhibitors lead to drug-resistance by facilitating the proliferation of resistant strains that exist before and after the mutations in addition to control sensitive virus strains.

Moreover, all the reverse transcriptase inhibitors have specific toxicity related to their dosage. The symptoms include spinal cord suppression, vomiting, liver dysfunction, muscle weakness, diseases of the peripheral nervous system and pancreatic inflammation. Many patients have to suspend the treatment due to these intolerable side effects (Fischl, M. A., et al., 1987; Lenderking, W. R., et al., 1994).

Drug-resistance is also a major problem for protease inhibitors. Mutations in viral protease gene have caused drug-resistance in all the protease inhibitors presently used

in AIDS treatment (Condra, J. H. et al., 1995). The side effects of protease inhibitors include liver dysfunction, gastrointestinal discomfort, kidney stones, numbness around the mouth, abnormality of lipid metabolism, and mental disorders (Deeks, et al., 1997). However, ARV therapy remains complex, expensive, and not universally effective or available.

New drugs are being developed against new targets in different stages of HIV replication cycle. Recently anti-AIDS drugs which act by a new mechanism have been developed after in-depth research in the field of HIV and AIDS. These drugs include new HIV reverse transcriptase inhibitors and HIV protease inhibitors, as well as new anti-HIV agents aimed at other targets (De, C. E., 2000). For example virus absorbents, such as sodium lauryl sulfate, dextrose sulfate, and heparin can interrupt the cohesion of gp120 on the HIV envelope and the lymphocyte through the action of polyanion groups. However, these absorbents have bad specificity and high toxicity. Some of them can even increase the virus load (Baba, M., et al., 1988). Soluble CD4s are used to prevent gp120 from binding to host cells. Some recombinant soluble CD4s could bind the virus granules before gp120 contact the CD4 molecules on cellular membrane and prevent HIV infection. However, these recombinant soluble CD4s are of no apparent effect on the HIV-1 strains isolated from some patients. Moreover, clinical experiments did not provide any reliable evidence for their antiviral activity (Gomatos, P. J. et al., 1990). Chemokines and their analogs, including RANTES, MIP-1 .alpha., MIP-Lbeta binding with CCR5 and SDF binding with CXCR4, can be used to prevent HIV from entering into host cells. They may not only competitively block the gomphosis between HIV gp120 and cellular chemokine co-receptors but also limit HIV in break points by depressing the expression of this co-receptor on cell. The latest chemokine co-receptor blockers include positive charged small peptides such as ALX40-4C and T22, and compounds such as AMD3100, TAK-779 and trichosanthin. Although soluble CD4-lgG can suppress HIV replication in vitro, it has no reliable antiviral activity in clinical trials. Agents such as 2,2'-dithiobisbenzamides (DIBAs) and azadicarbonamide (ADA) can block the assembly and disassembly of viruses through interactions with NCp7 zinc finger site. A segment of gp41 or its analog can be used as a fusion inhibitor. For example, T-20 is capable of blocking virus entry into the cell (Jiang, S. et al., 1993). Inhibitors of viral mRNA transcriptase, such as CGP64222, fluoroquinolone K-12, and EM2487 can also be used. However, compared with the HIV reverse transcriptase

inhibitors and protease inhibitors currently in clinical use, the advantages of the fusion inhibitor T-20 are better efficacy, lower toxicity, and no drug resistance yet. However, the clinical dosage of T-20 is as high as 200 mg per day is an indication of its bad stability and low anti-fusion valence. In addition, because of such high dosage, T-20 has caused some local responses in some patients (Kilby, J. M. et al., 1998). Inhibitors of integrase, such as derivatives of Carbonyl J [N,N'-bis(2-(5-hydroxy-7-naphthalenesulfonic acid)urea], can prevent HIV from integrating its genome into host lymphocyte genome (Maurer K, et al:, 2000).

Although the use of combination drug therapies against HIV has proven to be effective in many patients, the current drug regimens are far from ideal. Adherence to these combination regimes is remarkably difficult in terms of patient compliance, and the drug combinations are quite expensive. Their use has been further hampered because many HIV infected individuals have been on single drug therapies in the past and are currently infected with HIV viruses that are resistant to one or more inhibitors, thereby greatly reducing the effectiveness of the combination drug therapy. As with the RT inhibitors, resistance to protease inhibitors can also occur. Beyond these issues, a number of undesirable side effects, including lipodystrophy syndromes, have surfaced as a consequence of long-term use of protease inhibitors at current dosage levels. These issues make therapy with existing antiviral agents complicated at best and impossible at worst.

As a result of these problems, there is a need to develop new therapeutic options for HIV/AIDS with improved efficacy. Although several therapies as indicated above are currently available for initial therapy in HIV-infected patients, ongoing research is focused on additions to existing and novel drug classes that might have improved pharmacokinetic and tolerability profiles, as well as on new therapeutic combinations that might result in synergistic activity. To retain activity against resistant strains, novel drugs need to target the numerous critical points in the life cycle of HIV, by inhibiting different enzyme subsets than those affected by antiretroviral agents currently in use. An improvement in patient adherence to therapy is another key objective of efforts in HIV treatment, as suboptimal drug levels are a main determinant of antiretroviral regimen failure.

Herbal medicines

Traditional herbal medicines have been in existence for more than two thousand years and have a proven record of success for curing many kinds of diseases. In many cultures such those of the Arabic speaking countries, China and India a variety of herbs and natural substances have been systemically recorded and incorporated into regular systems of medicine that later became the material-medica of traditional medicine. An effort to heal ailments and to attain vitality and longevity promoted early man to explore his natural surroundings. In this process a number of therapeutic agents mainly from plants were selected and employed. Most ancient cultures have evolved their own medical cures and practices to take care of their health problems.

Until the beginning of the 19th century medical practices were what are now called traditional medicines. Originally medicine was obtained from plants available in the immediate environment and over the millennia the most effective remedies amongst them were selected by trial and error, empirical reasoning and even by experimentation. These then became part of medical tradition. The renaissance period brought great scientific upheavals that began to introduce Cartesian Scientific Materialism into human activities and notably into the theory and practice of health care. Its method was to break up complex phenomena into their component parts and to deal with each one in isolation. This approach resulted in a search for a single cause for the disease and correspondingly modern pharmacological investigations were aimed at finding a single active principle that could be isolated from a medicinal plant.

The introduction of this kind of abstract medicine in the form of basic chemicals and pharmaceutical during the 18th and 19th centuries resulted in methods for bringing quick relief to suffering and this won instant admiration and popularity. This system known as Allopath or Morden Medicine made rapid advances during the 19th and 20th centuries as a result of the advances made in biological, chemical and pharmacological sciences. The world health organisation (WHO) has estimated that 80% of the world population relies on traditional medicine for primary health care. The WHO declaration of health for all by the year 2000 emphasized the importance of traditional medicine in achieving primary health care. According to WHO, the use of plant remedies is increasing even in developed countries. In industrialized countries, consumers are

seeking viable alternatives to medicine with its associated dangers of side effects and over medications. Alternatives to modern medicine are accordingly finding increasing popularity and acceptance in the developed countries. During the last decade, the health assembly of WHO passed a number of resolutions in response to a resurgence in interest in the study and use of traditional medicine.

Detailed description of the invention

The present invention provides a novel herbal composition for the treatment of AIDS and for the suppression of HIV replication at non-toxic concentrations.

According to a first aspect of the invention, there is provided the use of a herbal composition in the preparation of a medicament for the treatment of a subject infected with HIV, the composition comprising an extract of the plant Aucklandia-(Costus Root).

According to another aspect of the invention, there is provided the use of a herbal composition in the preparation of a medicament for the treatment of opportunistic infections associated with AIDS, the composition comprising an extract of the plant Aucklandia-(Costus Root).

According to another aspect of the invention, there is provided the use of a herbal composition in the preparation of a medicament for boosting the immune system of a subject, the composition comprising an extract of the plant Aucklandia-(Costus Root).

According to another aspect of the invention, there is provided the use of a herbal composition in the preparation of a medicament for the treatment of cells infected with HIV without affecting normal or non-infected cells, the composition comprising an extract of the plant Aucklandia-(Costus Root).

According to another aspect of the invention, there is provided the use of a herbal composition in the preparation of a medicament for stimulating bone marrow formation in a subject, the composition comprising an extract of the plant Aucklandia-(Costus Root).

The subject may be an HIV infected subject or a non-HIV infected subject.

According to another aspect of the invention, there is provided the use of a herbal composition in the preparation of a medicament for the treatment of conditions selected from diabetes, liver disease, viral hepatitis, fatty liver, liver cirrhosis, liver cancer, herpes zoster, jaundice and herpes simplex, the composition comprising an extract of the plant Aucklandia-(Costus Root).

The viral hepatitis may be HAV, HBV or HCV.

According to another aspect of the invention, there is provided the use of a herbal composition in the preparation of a medicament for the treatment of a subject having AIDS to improve at least one of the following: sleep, energy level, discomfort, appetite, or mental clarity the composition comprising an extract of the plant Aucklandia-(Costus Root).

The method and composition of the invention also prevent and suppress HIV replication in patients particularly where the extract is prepared from the entire plant. Unlike prior art drugs which are associated with the development of drug resistance, the method and composition of the invention are also characterised by a lack of the development of drug resistance, again particularly where the composition is prepared from the entire plant. The composition of the invention can be used safely for infected pregnant women and also prevents or reduces mother to child transfer of the virus. The composition shows significant efficacy in the eradication of HIV from the bloodstream within a period of between about 4 to 12 weeks of starting therapy. The composition of the invention also increases body weight of HIV infected people and prevents both lipodystrophy and lipoatrophy.

The extract may be an aqueous extract. The extract may be an aqueous extract of the whole plant or of a part of the plant. For example, the extract may be an extract produced from one or more of the roots, leaves, stems or flowers of the plant. Preferably the extract will be prepared from the roots of the plant. The extract will typically be prepared by heating or boiling plant material, for example the whole plant or, more preferably, the sliced or ground roots of the plant, for about an hour. The concentration of the extract will typically will be between about 1000g/t and about 1200g/t. The method may include concentrating the extract (i.e. reducing the volume of the extract). It may include steaming the dried roots.

The method may thus include the step of preparing a first dilute extract and concentrating the first dilute extract to produce a concentrated extract having a concentration of between about 1000g/t and about 1200g/t. Preferably, the concentrate will have a concentration of about 1200g/t.

The extract may, instead, be a dried extract. For example, the aqueous extract may be evaporated or spray-dried to produce a dried extract.

The invention thus extends to an aqueous dosage form, comprising an aqueous extract of the plant Aucklandia-(Costus Root), the dosage form containing between about 1 g and 56g of dissolved material. The invention further extends to a solid dosage form, comprising a dried extract of the plant Aucklandia-(Costus Root) the dosage form containing about 48g.

The dosage form may be formulated for oral administration or for parenteral, eg intravenous or intramuscular, administration. In the case of oral administration, an amount of between about 0.4g per kg body weight per day and about 0.6g per kg body weight per day (for an adult weighing about 60-90 kg) may be administered in three doses. Typically, an amount of about 48g of extract per day is administered to a patient.

According to a further aspect of the invention, there is provided a method of treating a subject infected with HIV, the method including the step of administering to the subject a herbal composition comprising an extract of the plant Aucklandia-(Costus Root) in an amount sufficient to treat the infection.

According to a further aspect of the invention, there is provided a method of treating a subject suffering from opportunistic infections associated with AIDS, the method including the step of administering to the subject a herbal composition comprising an extract of the plant Aucklandia-(Costus Root) in an amount sufficient to treat the opportunistic infections.

According to a further aspect of the invention, there is provided a method of boosting the immune system of a subject, the method including the step of administering to the subject a herbal composition comprising an extract of the plant Aucklandia-(Costus Root) in an amount sufficient to boost the immune system of the subject.

According to a further aspect of the invention, there is provided a method of treating a subject having cells infected with HIV without affecting normal or non-infected cells, the method including the step of administering to the subject a herbal composition comprising an extract of the plant Aucklandia-(Costus Root) in an amount sufficient treat the cells infected with HIV without affecting normal or non-infected cells.

According to a further aspect of the invention, there is provided a method of stimulating bone marrow formation in a subject, the method including the step of administering to the subject a herbal composition comprising an extract of the plant Aucklandia-(Costus Root) in an amount sufficient to stimulate bone marrow formation in the subject.

The subject may be an HIV infected subject or a non-HIV infected subject.

According to a further aspect of the invention, there is provided a method of treating a subject infected with one or more conditions selected from diabetes, liver disease, viral hepatitis, fatty liver, liver cirrhosis, liver cancer, herpes zoster, jaundice and herpes simplex HIV, the method including the step of administering to the subject a herbal composition comprising an extract of the plant Aucklandia-(Costus Root) in an amount sufficient to treat the one or more conditions.

The viral hepatitis may be HAV, HBV or HCV.

The plant Aucklandia-costus (also known as Saussurea lappa) is also referred in

this specification as Iga'az-lll and belongs to the class dicotyledon, the sub-class gamopetalae, the series inferae, the cohort asterales and the family compositae, (alt. Asteraceae). In Siddha medicine, it is known as Kostum. It belongs to the genus saussurea. The botanical name is Saussurea lappa, C.B.Clarke. The pharmaceutical name is radix auklandiae and the common names are auklandia, kostum - CostuslKuth-KushtaM-Saussurea costus and saussurea lappa-(costus). The Indian origin of costus is evident from the Sanskrit term Kushta which means "that which stands in the earth" this word was perhaps used as costus was a root. The properties are pungent, bitter, acrid and warm in nature.

Auklandia costus (saussurea lappa) root comes from a perennial plant [saussurea lappa-costus], that grows to about 2m in height and is native to Northern India, SouthWest China and Pakistan. It has irregular, triangular-shaped leaves and dark blue or black florets, with brownish fruit. Table 1 shows the components which have been found in Aucklandia-(Costus Root).

Table 1

Components present in Auklandia (Costus Root).

Hepatadecatetraene, 12-methoxy-dihydrocostunolide, 22-dihydrostigmasterol, 3-isopropropylpentanoic-acid, 3-methylbutyric-acid, 4-ethyloctanoic-acid, 7-octenoic-acid, Acetic-acid, Alkaloids, Alpha-humulene, Alpha-phellandrene, Alpha-costene, Alpha-amorphenic-acid, Alpha-amyrin-stearate, Alpha-ionone, Aplotaxene Beta-sitosterol beta-selinine, Beta-costene, Beta-ionone, Beta-elemene, Beta-amyrin-stearate, Betulin, Camphene, Caryophyllene, Caryophyllene-oxide, Cedrene, Cedr ol, Cis-dihydroionone, Costic-acid, Costol, Constunolide Costus-acid,Costus-lactone, Dehydrocostus-lactone, Dihydrodehydrocostus-lactone, Dihydroaplotacene, Dihydrocostunolide, Dihydrocostus-lactone, EO, Friedelin, Guaia-3,9,1 1 -triene-12-acid, Heptanoic-acid, Hexanoic-acid, Inulin, Iszaluzanin, Kushtin, Lactones, Linalool, Leupeol, Myrcene, Naphthaline, Octanoic-acid, Oleic-acid, P-cymene, Palmitic-acid, Pentadec-1 -ene, Phellandrene, Resinoids, Saussurine, Stigmasterol, Tannin.

Taraxasterol,Dihydrocostuslactone, dihydrocostunolide and alpotaxene, are the major componants in the herbal composition of the invention.

The applicant is aware of US Patent Publication No. US 2005/0129780 A1 which describes the use of combinations comprising herbal compositions and chelating agents for improving sleep, energy level, discomfort , appetite or mental clarity in persons having AIDS or ARC (AIDS Related Complex). Although Saussurea lappa is mentioned in the publication it is not exemplified nor claimed. The chelating agents include compounds such as 1 ,2-bis(2-aminophenoxy)ethane-N, N, N', N'-tetraacetic acid, ethylenebis(oxyethylenenitrilo)tetraacetic acid, 1 ,2-bis(2-aminophenoxy)ethane-N,N', N'-tetraacetic acid tetrakis(acetoxymethyl ester), trans-1 ,2-diaminocyclohexane-tetraacetic acid, diethylenetriamine-pentaacetic acid, trimethylaminetricarboxylic acid, poly(aspartic acid), poly(glutamic acid), ethylenediamine-Ν,Ν,Ν', N'-tetraacetic acid, and EGTA.

In contrast, the present invention provides a plant extract of Saussurea lappa which is effective in its own right and does not require a chelating agent. This surprising result would not have been expected on a reading of US 2005/0129780 A1 .

The invention is now illustrated, by way of example, with reference to the following non-limiting Examples, the Tables and the Figures, in which

Figures 1 to 5 are graphs showing viral loads;

Figure 6 and 7 are graphs showing CD4 cell populations;

Figure 8 and 9 are graphs showing total white blood (TWB) cell populations.

Example 1

Preparation of the herbal composition

Roots of Aucklandia-(Costus Root) were air dried in direct sunlight until the insides of the roots became black. The dried roots were then sliced before use. The sliced, dried, roots were then ground to a powder. In a variation of this method, the entire dried plant was used. The powdered or sliced plant material (10kg) was boiled in 1 t of water for 1 hour and allowed to cool to room temperature. The cooled mixture was then filtered to remove insoluble material to produce a dilute extract. This dilute extract was optionally concentrated to produce a concentrated extract having a concentration of about 1 .2kg/t. The aqueous concentrated extract was then formulated to produce unit

dosage forms. The unit doses contained between about 24g/0.175t and about 56g/0.175f.

The aqueous extract was optionally spray-dried to produce a granular herbal material. The total mass of the granular material obtained by the spray-drying step was about 1200g from the 10kg of the original dried and powered plant material.

The spray-dried granular material was optionally encapsulated, tabletted or incorporated in sachets. About 48g of the spray dried material was encapsulated tabletted or incorporated in sachets. The material was further optionally processed and formulated in forms suitable for oral administered or parenteral administration. The herbal composition of the present invention was suitable for preparation in a scale typical for pharmaceutical industry as well as for smaller measures. The dosage forms may optionally be packed in bottles, boxes or blister packets.

The dosage of the herbal compositions of the invention will vary depending on factors such as the severity of the condition being treated, age, physical condition and body weight of the patient, diet and the like. However, an advantage of the invention is that the actual dosage is not critical since the compositions of the invention are holistic in nature and represent dietary supplements in their own right. Overdosing is accordingly not a problem. An individual patient with a particular body weight and life style may readily determine a proper dosage by starting out with a general dosage.

As a general guide, patients with a body weight in the range of 60-90 kg would ingest about 72-162g/day of the herbal composition. For example, a patient may ingest between about 0.4g and about 0.6g of the composition per kg of body weight three times per day. However, it is to be understood that these dosage levels are only general guides and the proper dosage level of Aucklandia-(Costus Root) for an individual has been found to be most effective at about 0.53g/kg. Theoretically, a patient weighing 70 kg has about 7x1013 body cells and Aucklandia-(Costus Root) will be useful at a dosage of between about 72g and 162g per day and preferably about 48g three times per day (ie about 144g per day) to protect against viral attack in virus endemic areas. However, any non-toxic dosage may be used if effective. Based on the above data, a dosage of 144g per day is preferred for an adult in the form of 48g per dose three times per day. In another embodiment of the invention the extract is administered in one vial (16g) three times a day. In another embodiment the composition is administered in a dose of about 72-162g, for example 72g per day, per for an adult weighing about 60 kg. Where appropriate, alternative dosages, routes and formulations may be employed and in fact all dosages formulations and routes are contemplated that result in a positive response of the patient to the administration.

Accordingly, it is contemplated that, where appropriate, alternative dosages, routes and formulations may be employed and in fact all dosages formulations and routes are contemplated that result in a positive response of the patient to the administration.

Example 2

Toxicity

Toxicity studies were conducted at the School of Medical Sciences, Pharmacology Department, University of Science and Technology, Sana'a, Republic Yemen. Rabbits (group-A) and guinea-pigs (group-B) were used in the toxicity profile studies. Ten rabbits weighing between 800g and 1300 g and ten guinea pigs weighing between 300g to 900g were used. Both were given different dosages of the herbal composition to investigate the lethal dosage as illustrated in Tables 2 and 3. The herbal solution was prepared as described in Example 1 and administered orally using antistatic at variable dosages to reach the optimum of 16 g/kg, which is a lethal dose according to the international standardisation for the classification of substances. The animals were observed for behaviour continuously for a period of two weeks after such administration. Observation was conducted hourly on day 1 . During the following days, observation was conducted four to six times per day. At the end of the observation period, the animals were sacrificed and dissected to examine the eyes, liver, lung, and spleen for adverse effects.

Table 2

Rabbits dosed with the herbal composition at 16g/kg orally (drug concentration

973.5g/5000ml .

Rabbits No. Rabbits Weight Doses in grams Doses

(Kg) millilitres

1 0.8 12.8 68.2

2 1.4 22.4 119.4

3 1.5 24 127.9

4 1.15 18.4 98.1

5 1.05 16.8 89.5

6 1 16 85.3

7 1.15 18.4 98.1

8 1 16 85.3

9 1.3 20.8 110.9

10 0.9 14.4 76.8

Table 3

Guinea pigs dosed with the herbal composition at 16g/Kg orally (drug concentration

973.5g/5000ml).

Rabbits No. Rabbits Weight Doses in grams Doses

(Kg) millilitres

1 0.3 4.8 25.6

2 0.25 4 21.3

3 0.25 4 21.3

4 0.4 6.4 34.1

5 0.25 4 21.3

6 0.3 4.8 25.6

7 0.25 4 21.3

8 0.25 4 21.3

9 0.5 8 42.6

10 0.5 8 42.6

Results

All of the animals were alive two weeks after receipt of the lethal dosage of 16g/kg. No abnormal behaviour was observed during the observation period. The rabbits showed normal body weight increase during the period. After the sacrifice and dissection, inspection of the eyes, liver, lung, and spleen showed no extraordinary syndromes. The results when compared to a general acute toxicity index were normal and no acute toxicity.

Example 3

Clinical trials on HIV infected patients

Clinical trials were conducted at the University Hospital of Science and Technology in Sana'a, Republic of Yemen to test the effectiveness of the herbal composition of the present invention in treating an HIV-infected patients. Thirty six patients, excluding positive (+Ve) and negative (-Ve) controls, were given the herbal concentration of Example 2 over a period of six months times a day. In selecting the patients the following criteria were used. Firstly, no other drugs were taken less than six weeks prior to the first dose of the herbal composition of the invention. Prior to the commencement of the treatment the patients tested positive to HIV using ELISA and/or Western Blot and the immune functions of the patients were abnormal (i.e., the CD4 to CD8 ration was under 1 , the number of CD4 T cells was under 200/mm3). The average age of the patients was above 7 years, no pregnant women were selected and the patients voluntarily agreed to undergo treatment.

The patients were required to take an ELISA test to indicate the presence of the

HIV virus and underwent testing with monoclonal antibody reagent and flow cytometry (FAC-SCAN) every four weeks before or after treatment to calculate the rate of CD4 to CD8, and the quantity of CD4 (in cm3) as an index to measure the immune function. Complete diagnostic records were kept , including physical signs or appearances, appearance of the tongue and pulse condition.

The criteria for a curative effect were categorised as recovery, evident effect, with effect and no effect. Recovery meant that testing PCR and/or RTPCR was negative, the immune function increased and/or recovered to normal (i.e., ratio of CD4 to CD8 >1

and/or the percentage of the CD4 T cells increased in correlation to the total WBC and there were no symptoms, no physical signs and no opportunity infections. Evident effect meant that HIV appeared negative or undetectable, the immune function improved dramatically (i.e., ratio of CD4 and CD8 >0.2 but the number of CD4 T cells is > 200/mm3).The opportunity infection had basically been removed and the symptoms and physical signs recovered fundamentally back to normal. With effect meant that testing PCR for HIV appeared positive, the immune function was improving (ratio CD4 to CD8>0.2, the quantity of CD4 T cells is beyond 40/mm3), opportunistic infections improved and the symptoms and physical signs were relieved. No effect meant that there were no dramatic changes in the HIV including index of immune function, and there was a decrease of immune function in the treatment.

The strategy of the regime therapy was as follows. A comprehensive analysis of the curative effect according to the immune state and clinical symptoms was made both before and after treatment. The patients included 15 females and 21 males. Infection was confirmed by both ELISA and Quantitative (PCR) RTEAL TIME. The average age of the patients was about 31 .23, with the oldest being 52, and the youngest being 23.

The profile of the patients, including the period of the disease were as follows: Patients Sexuality Age History Diagnosis (7) Females and (3) Male "2 years" AIDS (Phase A3), (4) Females and (3) Male "2 year" AIDS (Phase A3), (2) Females and (3) Males "1 year AIDS" (Phase B2), (1 ) Female and (8) Males "2 year" AIDS (Phase B2), (1 ) Female and (4) Males 34 "Several Months" AIDS (phase A3), 10% weight loss.

The patients were treated with the herbal composition of the invention according to the following regimen. The aqueous herbal composition (125ml containing 7g of the extract) was administered at 8 hourly intervals, before food, for high absorption purposes, for six (6) months. No other medication was administered.

All 36 patients showed common symptoms of weakness, depression, and stegnosis, lost of appetite, weight loss and some patients occasionally developed fever. HIV-infection was confirmed by ELISA with further analysis by quantitative PCR. The patients were divided into five categories (A, B, C, D and E) based on the patients compliance (coherence with the medicine] to the herbal composition. Groups B to E

showed poor compliance for financial reasons as they came from scattered regions. As a result, only Groups A and B were illustrated in respect of CD4 as well as the total WBC. Group B showed an excellent response. Other groups are briefly illustrated to give an indication and supportive data and prediction for Groups A and B.

Blood samples (10ml) were taken from the patients before, during, and after the treatment and further tested for ELISA, Viral Load (VL), CD4, CD8, White Blood cells (WBC) and other screening profiles such as full blood count (FBC), liver function, renal function, fasting lipid profile, blood glucose. Physical examinations including weight record were also performed before, during, and after the treatment. The results are set out in Table 4 and in Figures 1 -5.

Table 4

General results of the patients' screening profile

Pre-Therapy After 4 weeks

Weight Most patients lost weight Gained Weight

Higher WBC - FBC Normal

Within Normal Range

Liver function Normal Normal

Renal Function Normal Normal

Fast Lipid profile Normal

Normal

Blood glucose Normal Normal

Each of the graphs shown in Figures 1 -5 illustrates the monitoring of HIV viral load during the treatment period. Figure 1 represents group A which was followed up six months after treatment period. Figure 1 also illustrates the screening profile of the patients' viral load six months after the end of the treatment. The other Figures represent patients with different coherent status of the therapy. The purpose of showing the results of patients' with bad coherence is to evaluate the efficacy of the invention. In other words, although these patients showed a poor compliance (coherence) the results can be used to predict the efficiency of the herbal composition.

Positive and negative controls were also presented in parallel. However, the results are given for two months after treatment. This is because both the positive and negative controls experienced the same difficulties shown by the other groups, namely financial and coherent problems. Moreover, the positive controls were further showed health deterioration.

Figure 6 illustrates the elevation in the CD4 T cell populations of peripheral blood cells from HIV infected patients upon incubation with the herbal extract within a period of 6 months. It also illustrates the CD4 T cells after six months from which patients stopped the treatment. Figure 7 illustrates the elevation in the CD4 T cell populations of peripheral blood cells from HIV infected patients upon incubation with the herbal extract within a period of 4 months. Figure 8 shows the elevation in the Total White Blood cells population of peripheral blood cells from HIV infected patients upon incubation with the herbal extract within a period of 6 months. It also illustrates the CD4 T cells after six months from which patients stopped the treatment. Figure 9 illustrates the elevation in the total White Blood (WBC) cells population of peripheral blood cells from HIV infected patients upon incubation with the herbal extract within a period of 6 months. It also illustrates the CD4 T cells after six months after patients stopped the treatment.

The results set out below are based on the first group which either completed the treatment program and/or showed an excellent response.

Change of the immune Function:

The ratio of CD4 to CD8 of the first group of patients before and after treatment shows that, in Group A, three patients had an increase in both the CD4 to CD8 ratios as well as an increase in the numbers of CD4 T cells, while the other two showed stability. In Group B, all patients showed a dramatic increased of both parameters i.e. the CD4 to CD8 ratios as well as an increase in the numbers of CD4 T cells.

Evaluating the state of immune function

The immune function was divided into three conditions after treatment, namely improvement, no change and worse. In both groups i.e. A and B, six cases improved, two cases showed no change and none became worse.

Curative effect

According to the criteria of curative effect, it was found that three cases out of five (group A) showed a curative effect. Six cases (as illustrated by group B and C, if they are considered to be a good supportive data) showed that the herbal composition is an effective medication and none showed that the herbal composition was ineffective.

Side effects

In general, none of the cases of the Groups A and B showed side effects except that one case showed symptoms of diarrhoea and tiredness for a short period. However, in all cases the composition continued to be taken in the prescribed quantity. This trial showed that the herbal composition was effective in the suppression of HIV replication as well as its eradication from the blood stream. During the treatment process, all patients showed positive responses with only the side effects described above. However, the symptoms improved after one to two weeks of treatment including alleviation of weakness, depression, and stegnosis. The abdominal region pain and uncomfortable feeling also disappeared. Those patients who lost weight had 2 to 5 kg increase of body weight after two months of treatment.

Overall the herbal composition of the invention was found to be effective in the eradicating of HIV from the blood stream as well as the reduction of symptoms in AIDS patients. To summarise, all of the patients in all of the groups were HIV positive and their conditions were critical. During the treatment, most if not all of the patients showed improvement. Six cases showed immune function improvement as well as an increase in the number of CD4 cells. In Groups A and B the composition was found to be effective in the eradication of the HIV from the patients' bloodstream. This was confirmed after six months when patients stopped taking the medication and screened by Real Time PCR, as shown by group A. The herbal compositions of the invention were found to be highly effective in significantly reducing viral replication within a very short time. Furthermore in Groups C and D, although both groups were not in compliance with the treatment, both still showed a significant declined of the HIV virus to undetectable levels as illustrated in Tables 5 and 6. In general from the above it can be concluded that although the herbal composition proved to be significant in the eradication of HIV from the bloodstream, it shows that it has no direct affect on population of CD4 cells. It also shows that the herbal composition stimulates and

increases WBC in general. In addition because lipodystrophy (fat redistribution) and Iipoatrophy (fat loss) are problems for patients receiving long-term protease inhibitor therapy the herbal composition was found to effective drug in increasing body fat in patients those patients with fat wasting.

Tables 5-14 set out the results of the trial .

Table 5

Group A. PCR results


* means CD4/CD8 ratio increased significantly

Table 6

Group B, PCR results


* means CD4/CD8 ratio increased significantly

Table 7

Group C. PCR results


* means CD4/CD8 ratio increased significantly

Table 8

Group D. PCR results

MP20 MP15 FP13 MP16 FP14 FP15

Pre 4460 1 15000 1060000 121000 219000 2680

M1 2570 923 154 79200 98800 1960

M2 631 1785 1450

Table 9

Group E. PCR results


The CD4 counts of the patients are as follows:

Results of CD4 were more or less stable prior and within the therapy with Iga'az-III. This demonstrated that the Iga'az-lll herbal composition has no affect on such cells.

Table 10

Group A, CD4 "T Cells" % results

FP6 FP7 FP8 MP1 MP2 CIM CIF CHM CHM

Pre 30 10 23 16 3 1 1 21 35 39

M1 25 10 26 18 1 13 19 28 42

M2 26 10 17 21 2 15 21 31 41

M3 32 10 26 35 3

M4 28 10 20 38 1

M5 33 10 32 25 3

Table 1 1

Group B. CD4 "T Cells" % results


The WBC counts of the patients are as follows:

Table 12

Group A, WBC Cells absolute count results


FP6, FP7, FP8, MP2, MP1

Table 13

Group A, WBC Cells absolute count results


Example 4

Clinical trial based on toxicity study on healthy human subjects

The herbal composition used is described in Example 2. The trial was conducted at the University Hospital of Science and Technology in Sana'a, Republic of Yemen to test the effect and safety of the composition of the invention on uninfected healthy human subjects.

Two healthy adult males were treated and examined in parallel with those described in Example 3. The results showed that HIV (VL) levels were negative (i.e. HIV, RNA quantitative (PCR) by Real Time), CD4 and CD8 of both subjects were within normal range 35% and 39% and CD4/CD8 ratios were 2.10 and 2.16. Pathology tests (renal and liver function) as well as other screening profiles such as fast lipid profile, FBC, glucose, and weight as described in Example 3 were all normal. In general the subjects showed no side-effects at all.

Example 5

Case study on HIV-patients

A clinical trial was conducted in the University Hospital of Science and

Technology in Sana'a, Republic of Yemen to test the effectiveness of the herbal composition of the invention in treating an HIV-infected patient. The herbal composition used in the trial is described in Example 2.

Blood samples were taken from the patients before, during, and after the treatment and further tested for ELISA, Viral Load (VL), CD4, CD8, White Blood cells (WBC) and Screening profile (FBC, Liver function, Renal Function, Fasting lipid profile, Blood glucose). Physical examinations, including weight records were also performed before, during, and after the treatment. The patients were a 31 -year old male and a 20-year old female who had been diagnosed with HIV infection complicated by herpes zoster.

The HIV-infection was confirmed by ELISA at the time of the initial diagnosis and further analysis five years later prior treatment was performed by ELISA and quantitative PCR. Prior treatment physical examination showed that both patients had developed an herpetiform rash over the front of the left side of the forehead, check extending over the nick, the shoulder, and the upper left arm. Pathology tests confirmed normal renal function. The functional tests of the liver showed slightly increased levels of serum glutamyl transpeptidase and acetyl glucuronidase. Hepatitis viral tests showed negative for Hepatitis B virus and Hepatitis C virus (HBV-DNA and HCV-RNA). However, Hepatitis G viral test showed positive for HGV-RNA. The immunological studies showed that the .beta. -2 microglobulin level was 2.4-2.5 mg/ml. Haemoglobin and erythrocytes levels of the patient were slightly decreased, while the levels of the leukocyte and platelet were normal. Peripheral blood lymphocytes counts showed that T4 cells were decreased to 1 1 .36 times 10/L (39%) for the male patient and 13.63.times.10/L (38%) for the female patient and the ratio of T4/T8 cell were 0.08 and 0.05, respectively. Thus, the diagnosis was that the patient was infected with HIV complicated by herpes zoster.

After three days of treatment, the signs of herpes zoster and its associated symptoms (such as mental confusion) completely disappeared. Moreover, both patients showed a slight increase in their T4 cells and the ratio of T4/T8 gradually increased to 0.10 after the first month of treatment. The herbal composition was thus effective in reducing symptoms of the herpes zoster within a three days and HIV (VL) was kept

under a detectable level.

In summary, although viral load can be reduced by a variety of treatments, recent studies suggest that many treatment failures occur because the presence of a latent viral reservoir, the development of drug resistance, drug toxicity, pill burden, and compliance problems which are obstacles that impede full eradication of HIV through drug therapy, the invention provides a new antiretroviral herbal therapy (referred to as Igaz-lll). The invention has demonstrated the impact of treatment modality, virus load, and CD4 T cell count on human immunodeficiency virus disease progression.

Aqueous extracts of the roots or the entire plant of Aucklandia-(Costus Root) have been shown to selectively inhibit and eradicate HIV in vivo at concentrations of above 16g with non-toxic side effects. The result is that viruses are prevented from replicating. This effect on the virus allows the body's immune system to reconstitute itself in numbers sufficient to cause clinical remission.

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