US20090011047A1 - Pharmaceutical compositions comprising of arsenous acid, its sodium salt and its derivatives intended for the treatment or urogenital cancer and its metastasis - Google Patents
Pharmaceutical compositions comprising of arsenous acid, its sodium salt and its derivatives intended for the treatment or urogenital cancer and its metastasis Download PDFInfo
- Publication number
- US20090011047A1 US20090011047A1 US11/631,962 US63196206A US2009011047A1 US 20090011047 A1 US20090011047 A1 US 20090011047A1 US 63196206 A US63196206 A US 63196206A US 2009011047 A1 US2009011047 A1 US 2009011047A1
- Authority
- US
- United States
- Prior art keywords
- cancer
- carcinoma
- patient
- sodium salt
- arsenous acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Definitions
- Cancer is a significant health problem in the world. Although advances have been made in cancer detection and treatment, no vaccine or other universally successful preventive or therapeutic method is currently available. Management of the disease currently relies on a combination of early diagnosis and aggressive treatment, which may include one or more of a variety of therapies such as surgery, radiotherapy, chemotherapy and hormone therapy. While such therapies provide benefit to many patients, a high mortality continues to be observed for many cancers. The development of improved anti-tumour agents would facilitate cancer prevention and treatment.
- chemotherapeutic agents which possess little or no toxicity, which are inexpensive to obtain or manufacture, which are well tolerated by the patient, and which are easily administered would be a desirable addition to the therapeutic modalities currently available to the oncologist.
- Agents that will selectively sensitise malignant tissue to allow lower doses of radiation or therapy to achieve the same therapeutic effect with less damage to healthy tissues are also desirable.
- agents that prevent cancer from occurring or reoccurring are also desirable.
- the present invention remedies these needs by providing such chemotherapeutic and sensitising agents.
- the technical problem underlying the present invention is to provide alternative or further compounds with anti-cancer activity and methods for the clinical use.
- the compounds of this invention are useful in treating cancer. They are effective in inhibiting survival and/or growth of cancer cells and/or for inhibiting undesirable cell growth in general.
- This invention further provides pharmaceutical and therapeutic compositions which contain a pharmaceutically or therapeutically effective amount of these compounds and therapeutic methods and methods of treatment employing such compounds.
- this invention relates to methods of treating cancer by administration of the oral arsenous acid sodium salt disclosed herein.
- arsenic trioxide in the treatment of cancer as described by several inventors is different from this invention, whereas the role of arsenic (WO 800245; Komipharm International) for the treatment of malignancies was limited to primary tumours.
- kits for inhibiting abnormal cell growth comprising of arsenous acid sodium salt and/or synthetic analogues, modifications and pharmacologically active fragments thereof.
- a “patient” for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In the preferred embodiment the patient is a mammal, and in the most preferred embodiment the patient is human.
- animal refers to an organism with a closed circulatory system of blood vessels and includes birds, mammals and crocodiles.
- the term “animal” used here also includes human subjects.
- angiogenesis refers to the generation of new blood vessels into cells, tissue, organs or tumours.
- tumour refers to the process by which tumour cells are spread to distant parts of the body.
- the term is also used herein to refer to a tumour that develops through the metastatic process.
- contacting is used herein interchangeably with the following: combined with, added to, mixed with, passed over, incubated with, flowed over, etc.
- compounds of present invention can be “administered” by any conventional method such as, for example, parenteral, oral, and topical and inhalation routes as described herein.
- the term “safe and effective amount” refers to the quantity of a component that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
- a “therapeutically effective amount” is an amount of a compound of the present invention effective to yield the desired therapeutic response. This amount for example could be effective in delaying the growth, delaying metastasis inhibiting angiogenesis and/or tolemere and/or causing shrinkage of cancer, either a sarcoma or lymphoma.
- the specific safe and effective amount or therapeutically effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.
- “An anti-angiogenic” amount refer to an amount of a compound or composition effective to depress, suppress or inhibit angiogenesis or result in amelioration of symptoms associated with an angiogenic disease.
- the desired result can be either a subjective relief of a symptom(s) or an objectively identifiable improvement in the recipient of the dosage, a decrease in the vascularisation of endothelial cells or a decrease in the rate of angiogenesis as noted by a clinician or other qualified observer.
- treating cancer refer generally to any improvement in the mammal having the cancer wherein the improvement can be ascribed to treatment with the compounds of the present invention.
- the improvement can be either subjective or objective.
- the patient may note improved vigour or vitality or decreased pain as subjective symptoms of improvement or response to therapy.
- the clinician may notice decrease in tumour size or tumour burden based on physical exam, laboratory parameters, tumour markers or radiographic findings.
- Some laboratory signs that the clinician may observe for response to therapy include normalization of tests such as white blood cell count, red blood cell count, platelet count, erythrocyte sedimentation rate, and various enzyme levels. Additionally, the clinician may observe a decrease in a detectable tumour marker.
- other tests can be used to evaluate objective improvement such as sonograms, nuclear magnetic resonance testing and positron emissions testing.
- “Inhibiting the growth of tumour cells” can be evaluated by any accepted method of measuring whether growth of the tumour cells has been slowed or diminished. This includes direct observation and indirect evaluation such as subjective symptoms or objective signs as discussed above.
- compositions of the invention are administered to cells.
- administered herein is meant administration of a therapeutically effective dose of the candidate agents of the invention to a cell either in cell culture or in a patient.
- therapeutically effective dose herein is meant a dose that produces the effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by those skilled in the art.
- cells herein is meant almost any cell in which mitosis or meiosis can be altered.
- the present invention related to a pharmaceutical anti-cancer composition
- a pharmaceutical anti-cancer composition comprising a therapeutically effective amount of arsenous acid sodium salt represented by the following formula (I):
- the present invention relates to compounds, methods and compositions for the treatment of primary and metastatic neoplastic diseases, including, but not limited to urogenital carcinomas.
- the present invention relates to novel chemotherapeutic compositions of arsenous acid sodium salt methods—novel uses of oral arsenic compounds for treating prostate cancer, primary and metastatic tumours of the urogenital system; and bladder, kidney, testicular and metastatic bone cancer.
- chemotherapeutic drugs are currently developed for intravenous use.
- Oral treatment with anti-cancer agents is now of interest due to the benefits of easy administration, better patient compliance and the reduction in cost and the increase in the quality of life of the patients. For example, patients will be able to undergo oral treatment as outpatients.
- One of the key objectives of the present invention to provide a chemotherapeutic product for the treatment of cancer and which exhibits high bioavailability, enhanced anti-cancer activity and high level of safety following oral administration.
- Genitourinary malignancies are composed of (amongst others) cancers of the prostate, bladder, kidney, and testis.
- the challenges presented by these malignancies parallel those confronting investigators and practicing clinicians in treating all other types of cancers.
- Smoking which is strongly associated with the development of lung cancer, is responsible for one third of bladder cancers, and several studies implicate obesity with an increased risk for colon, breast, and kidney cancers.
- Carcinomas of the urinary tract occur in 90% of the cases directly in the bladder, 8% in the renal pelvis and 2% in the ureter or urethra.
- Bladder cancer is the fourth most common cancer in men and the eighth in women.
- Estimates are that 25% of the bladder cancers in men are related to occupational exposure and 50% to cigarette smoking.
- Smoking is a key determining risk, which persists for up to 10 years after smoking cessation.
- the choice of treatment is based on disease extent: superficial, invasive or metastatic.
- Combination chemotherapy is used to treat metastatic disease.
- Urothelial tumours are chemosensitive, and a number of single agents result in short-term regressions in 20 to 30 percent of cases.
- One regimen is called the MVAC regimen. It consists of combination treatment with methotrexate, vinblastine, adriamycin (doxorubicin) and cisplatin.
- Several drugs are given over a few days with the drugs then being repeated every few
- Renal cell carcinoma accounts for 90 to 95 percent of malignant neoplasm's arising from the kidney. Renal cell carcinoma affects more than 30,000 American annually and is responsible for nearly 12,000 deaths in the United States each year. Renal cell carcinoma occurs most commonly in adults between 50 and 70 years of age, although it has been reported in children as young as 3 years. Renal carcinoma is responsible for approximately 3% of adult malignancies, and the male to female ratio is 1.5:1. A strong correlation exists between cigarette smoking and the development of renal cell carcinoma. Unproven factors that may increase the risk for renal cell carcinoma include polycystic kidney disease, diabetes mellitus, and chronic dialysis.
- renal cell carcinomas Up to 85% of renal cell carcinomas are of the clear cell type; 5% to 15% of renal cell carcinomas are a papillary histologic variant.
- the main type of treatment for cancer of the kidney is surgery although radiotherapy may also be recommended.
- hormonal treatment or biological treatment can be used either after surgery or when a cancer cannot be removed surgically.
- cancer of the kidney will spontaneously improve without any treatment, but this is rare.
- Chemotherapy has not yet been shown to be helpful in treating cancer of the kidney.
- Testicular cancer primarily affects young men in the 20 to 44 year old age group, where it is the most common cancer. Overall, testicular cancer is not very common. Testicular cancer responds particularly well to treatment, and over 9 in 10 patients are cured. Primary germ cell tumours (GCTs) of the testis, arising by the malignant transformation of primordial germ cells, constitute 95 percent testicular neoplasms. This disease is notable for the young age of the afflicted patients, the totipotent capacity for differentiation of the tumour cells and its curability; more than 90 percent of all newly diagnosed patients will be cured, and, since the advent of cisplatin-based chemotherapy about 70 to 80 percent of patients with metastatic disease are cured.
- GCTs Primary germ cell tumours
- Chemotherapy is more often used for non-seminoma testicular cancers, however it is also used for seminoma, which has spread.
- Testicular cancer can be treated with different combinations of drugs with the combination most often used being BEP, Bleomycin, Etoposide and Cisplatin.
- Cancer of the prostate is the most common malignancy in men in the United States and the third most common cause of cancer death in men above the age of 55 (after carcinomas of the lung and colon).
- Surgery is the most common treatment for early-stage prostate cancer with radiation therapy being the second.
- hormonal therapy There are also different forms of hormonal therapy. Prostate cancer cells do not tend to grow rapidly like some other types of cancer. For this reason traditional chemotherapy drugs have not proven to be quite as useful as they have been in some of the other major cancers. Nonetheless, some standard chemotherapies have been shown to be useful—particularly in late-stage prostate cancer. Although there are three chemotherapy drugs approved by the U.S.
- chemotherapeutics approved for other cancers are used on an “off-label” basis for late-stage prostate cancer.
- Chemotherapy is typically utilized in patients with advanced stage prostate cancer who are no longer responding to hormonal-therapy. None of these agents are consistently helpful in the disease.
- the most common sites of metastases in patients with prostate cancer are the bone and lymph nodes. The bone metastases are particularly troublesome in that they can create intense pain for the patient.
- Secondary bone cancer does not start in the bone, but is the result of cancer cells spreading to the bone from the primary tumour. Sometimes only one area of bone is affected, but in other people a number of bone secondaries develop, often in different bones in the body. Although any type of cancer can spread to the bone, the most common types are cancers of the breast, prostate, lung, kidney and thyroid.
- the treatment for a secondary bone cancer depends on the type of primary cancer. For example, prostate cancer cells may have broken away from the prostate gland, traveled in the blood to the bone and begun to grow and multiply there. So the cancer cells in the bone will respond to the same type of treatment as the cancer cells in the prostate.
- a secondary bone cancer can occur in any bone in the body, the most commonly affected bones are those of the spine, ribs, pelvis, skull and the upper bones of the arms and legs.
- Arsenic has been used as a pharmaceutical agent for more than 2400 years to treat a large variety of diseases including cancer, but it is also a poison and carcinogenic agent. With the rapid evolvement of medicine in the 20th century, the use of medicinal arsenic waned rapidly. Interest in arsenic compounds revived when it was shown that daily intravenous administration of arsenic trioxide alone caused complete responses in a large majority of patients with newly diagnosed and relapsed acute promyelocytic leukaemia. Additional trials are underway in patients with haematological malignancies and solid tumours such as prostate and pancreatic cancer. A drawback of arsenic trioxide is that it is administered intravenously daily in 1-4-hr infusion for up to 6 weeks.
- Arsenic exists in both trivalent and pentavalent oxidation states as a chemically unstable sulphide or oxide, or as a salt of sodium, potassium or calcium.
- Trivalent arsenicals comprising sodium arsenite and arsenic trioxide inhibit many enzymes by reacting with biological ligands that possess available sulphur groups.
- Pentavalent arsenic is an uncoupler of mitochondrial oxidative phosphorylation. It is thus not surprising that arsenic trioxide exerts anti-tumour effects by activating apoptosis, induction of reactive oxygen species, inhibition of angiogenesis and in acute promyelocytic leukaemia cells also by degradation of PML-RARA fusion protein. The response depends upon cell type and the form of arsenic.
- arsenic trioxide inhibits growth and promotes apoptosis in many different cancer cell lines and began a research programme to evaluate its clinical activity in haematologic malignancies, such as acute promyelocytic leukaemia, acute myeloid leukaemia, acute lymphocytic leukaemia, chronic myelogenous leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukaemia, myelodysplastic syndrome, and multiple myeloma. It is also supporting research in solid tumours, such as advanced hormone-refractory prostate cancer and renal cell cancer and in cervical cancer and refractory transitional cell carcinoma of the bladder.
- haematologic malignancies such as acute promyelocytic leukaemia, acute myeloid leukaemia, acute lymphocytic leukaemia, chronic myelogenous leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease
- the present invention relates to a pharmaceutical composition intended for the treatment of urogenital diseases and bone metastasis and to a method of treating such diseases.
- the present invention provides a pharmaceutical composition intended for the treatment of urogenital diseases and bone metastasis in a human, wherein said pharmaceutical composition contains an effective amount of arsenous acid alkaline or earth alkaline metal salt and/or a pharmaceutically acceptable adjuvant.
- said alkaline arsenous acid metal salt is sodium meta-arsenite (AsO 2 Na) or potassium meta-arsenite (AsO 2 K).
- the effective amount of arsenous acid alkaline or earth alkaline metal salt is 0.0001-1500 mg/kg, preferably 1-1000 mg/kg, more preferably 1-150 mg/kg, and most preferably 50-100 mg/kg of body weight/day.
- Said pharmaceutical composition preferably occurs in an oral administration form, wherein said oral administration form is e.g. a tablet, capsule, powder and/or solution with a pharmaceutically acceptable carrier, diluent or excipient.
- oral administration form is e.g. a tablet, capsule, powder and/or solution with a pharmaceutically acceptable carrier, diluent or excipient.
- Said urogenital disease comprises essentially cancer of the prostate, bladder, kidney and testis.
- a chemotherapeutic product comprises of arsenous acid sodium salt having the formula (I):
- compositions comprising such products together with a pharmaceutically acceptable carrier or diluent.
- Suitable carriers and diluents are well known, as are the principles of formulation of compositions in unit dosage form and for oral administration.
- the invention includes a method for the treatment of cancer in an animal or human body, the method comprising the simultaneous, separate or sequential administration to the said body of arsenous acid sodium salt.
- arsenous acid sodium salt (As 3+ ), dimethylarsinic acid (As 5+ ) and arsenic acid (As 5+ ).
- arsenous acid sodium salt was the most potent and showed anti-tumour activity in a human tumour model in vivo, reason to develop arsenous acid sodium salt further as a novel arsenic compound.
- Arsenous acid sodium salt surprisingly was more potent in vitro and showed differential activity in leukaemia, melanoma and mammary cancer lines than As 2 O 3 .
- Arsenous acid sodium salt is surprisingly capable of shortening telomeres of human cancer cells, inducing cellular senescence and chromosomal abnormalities, but does not directly inhibit the telomerase activity.
- the effects indicate that arsenous acid sodium salt is a telomere inhibitor.
- Arsenous acid sodium-salt was rapidly absorbed after both i.v. and p.o. administration and remained in the plasma for prolonged periods. Surprisingly the bioavailability of oral arsenous acid sodium salt was approximately 100%. Animal toxicity studies showed that the main target organs were bone marrow and lymphoid organs.
- arsenous acid sodium salt can be administered orally. It might be used in long-term treatment of cancer patients with solid tumours or leukaemia at dose levels below the maximum tolerated dose (MTD), alone or in combination with another treatment modality, maintaining a good quality of life.
- MTD maximum tolerated dose
- This compound (NaAsO 2 ) of the present invention has been developed as novel anti-cancer agent.
- the compound possesses good cytotoxic activity in a panel of 43 human tumour cell lines in vitro with an IC50 value of 0.6 ⁇ M. Pronounced selectivity was observed in tumour cell lines derived from leukaemia, mammary cancer and melanoma.
- arsenous acid sodium salt was surprisingly at least 15-fold more potent than the clinically used agent arsenic trioxide and had also a better differential activity.
- Arsenous acid sodium salt combined with 5-fluoruracil (5-FU) or vinblastine may result in additive effects. Potassium in the arsenite reduced cytotoxic activity.
- arsenous acid sodium salt oral and intraperitoneal was surprisingly borderline active in 2/7 subcutaneously transplanted human tumour xenografts (renal cell carcinoma RXF 944LX and mammary cancer MAXF 401).
- MTD maximum tolerated dose
- the efficacy of the compound was better using daily administrations of 5 or more days compared with intermittent schedules (every 4 days ⁇ 3, weekly ⁇ 3).
- oral arsenous acid sodium salt showed a high therapeutic efficacy in cancer patients suffering from urogenital cancer, mainly prostate and bone metastasis, following treatment with 2.5, 10, 12.5, 15, 17.5 and 20 mg of arsenous acid sodium salt capsules for 14 consecutive days.
- arsenous acid sodium salt the compound of invention, has great therapeutic and safety advantages in comparison to arsenic trioxide.
- Arsenic trioxide As 2 O 3 has been shown to prolong the QT and QT interval corrected for rate (QT c ), which may predispose the patient to potentially fatal aytipical ventricular tachycardia and produce complete atrioventricular block.
- adverse events occurring in 10% or more of patients treated with arsenic trioxide include fatigue, fever, oedema, chest pain, rigors, reactions at the injection site (ie pain, erythema, oedema), weakness, weight gain, nausea, anorexia, decreased appetite, diarrhoea or loose stools, vomiting, abdominal pain, dyspepsia, sore throat, constipation, hypokalemia, hypomagnesemia, increases in serum AST (SGOT) and/or ALT (SGPT), hyperkalemia, hypocalcemia, headache, insomnia, paresthesia, dizziness, tremor, cough, dyspnea, epistaxis, hypoxia, pleural effusion, postnasal drip, wheezing, decreased breath sounds, crepitations, rales, dermatitis, pruritus, ecchymosis, dry skin, erythema, sweating, tachycardia, ECG abnormalities, sinusitis, herpes simplex
- the invention is based, in part, on a dosage regime for the oral administration of a composition comprising of arsenous acid sodium salt. It is also based in part, on the therapeutic efficacy of the arsenous acid sodium salt of the invention against certain cancers.
- This invention includes a method of treating primary solid tumours in a mammal, which involves the administration of a non-lethal and therapeutically effective amount of arsenous acid sodium salt on its own, or in combination with one or more therapeutic agents to the mammal in need of such therapy.
- the invention also includes a method for treating disorders of the blood in mammals, which involves the administration of arsenous acid sodium salt either on its own or in combination with one or more therapeutic agents into the affected mammal.
- arsenic compound of the invention arsenous acid sodium salt
- arsenous acid sodium salt pro-drugs or compounds that are converted in-vivo to biologically active forms of the arsenous acid sodium salt Such pro-drugs may be used to reduce or avoid the toxicity of the usual pharmaceutical agent or to optimise the treatment and efficacy.
- Arsenous acid sodium salt can be synthesised or commercially purchased.
- the arsenous acid sodium salt is prepared in capsules.
- the form of arsenous acid sodium salt to be used should be therapeutically effective without unreasonable toxicity.
- arsenous acid sodium salt may be used in accordance with the present invention including but not limited to oral administration, parenteral administration such as intravenous, subcutaneous, intramuscular and intrathecal and intranasal, rectal or vaginal administration. Administration may also be made directly into the tumour or through transdermal patches or implantation devices (particularly for slow release). Topical administration may also be used.
- compositions to be used may be in the form of sterile physiologically acceptable (aqueous or organic) solutions, colloidal suspensions, creams, ointments, pastes, capsules, caplets, tablets and cachets. It should also be recognised that delayed slow or sustained release forms of administration are also included.
- the arsenic compounds of the present invention may be used against a variety of primary and metastatic neoplastic diseases including, but not limited to, primary and metastatic tumours of the central nervous system, breast, colon, ovaries, kidneys, lung, liver, bladder, prostate and head and neck.
- the present invention relates to a pharmaceutical anti-cancer composition
- a pharmaceutical anti-cancer composition comprising of a therapeutically effective amount of arsenous acid sodium salt represented by the following formula (I)
- the compound of the invention can be administered in a pharmaceutically acceptable formulation.
- the present invention pertains to any pharmaceutically acceptable formulations, such as synthetic or natural polymers in the form of macromolecular complexes, nanocapsules, microspheres, or beads, and lipid-based formulations including oil-in-water emulsions, micelles, mixed micelles, synthetic membrane vesicles, and resealed erythrocytes.
- the pharmaceutically acceptable formulation used in the method of the invention can comprise additional pharmaceutically acceptable carriers and/or excipients.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and anti fungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
- the carrier can be suitable for injection into the blood.
- Excipients include pharmaceutically acceptable stabilizers and disintegrants.
- the pharmaceutically acceptable formulations comprise lipid-based formulations. Any of the known lipid-based drug delivery systems can be used in the practice of the invention.
- multi-vesicular liposomes MLV
- multi-lamellar liposomes also known as multi-lamellar vesicles or MLV
- uni-lamellar liposomes including small uni-lamellar liposomes (also known as uni-lamellar vesicles or SUV) and large uni-lamellar liposomes (also known as large uni-lamellar vesicles or LUV)
- the lipid-based formulation can be a multi-vesicular liposome system.
- the composition of the synthetic membrane vesicle is usually a combination of phospholipids, usually in combination with steroids, especially cholcompoundol. Other phospholipids or other lipids may also be used. Examples of lipids useful in synthetic membrane vesicle production include phosphatidylglycerols, phosphatidylcholines, phosphatidylserines, phosphatidylethanolaminos, sphingolipids, cerebrosides, and gangliosides.
- a suitable biopolymer for the present invention can include also one or more macromolecules selected from the group consisting of collagen, elastin, fibronectin, vitronectin, laminin, polyglycolic acid, hyaluronic acid, chondroitin sulphate, dermatan sulphate, heparin sulphate, heparin, fibrin, cellulose, gelatin, polylysine, echinonectin, entactin, thrombospondin, uvomorulin, biglycan, decorin, and dextran.
- the formulation of these macromolecules into a biopolymer is well known in the art.
- the therapeutic composition is not immunogenic when administered to a human patient for therapeutic purposes.
- a therapeutic composition of the present invention can include pharmaceutically acceptable salts of the components therein.
- Pharmaceutically acceptable salts include the acid addition salts that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, tartaric, mandelic and the like.
- Physiologically tolerable carriers are well known in the art.
- Exemplary of liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline.
- aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, propylene glycol, polyethylene glycol and other solutes.
- Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerine, vegetable oils such as cottonseed oil, organic compounds such as ethyl oleate, and water-oil emulsions.
- a therapeutic composition contains a polypeptide of the present invention, typically an amount of at least 0.1 weight percent of polypeptide per weight of total therapeutic composition. A weight percent is a ratio by weight of polypeptide to total composition. Thus, for example, 0.1 weight percent is 0.1 grams of polypeptide per 100 grams of total composition.
- pharmaceutically acceptable salt refers to those salts of compounds which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, atoluenesulfonic acid, salicylic acid and the like.
- composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonates sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- a pharmaceutical composition may also, or alternatively, contain one or more drugs, which may be linked to a modulating agent or may be free within the composition. Virtually any drug may be administered in combination with a modulating agent as described herein, for a variety of purposes as described below.
- Examples of types of drugs that may be administered with a modulating agent include analgesics, anesthetics, antianginals, antifungals, antibiotics, anti-cancer drugs (e.g., taxol or mitomycin C), antiinflammatories (e.g., ibuprofen and indomethacin), anthelmintics, antidepressants, antidotes, antiemetics, antihistamines, antihypertensives, antimalarials, antimicrotubule agents (e.g., colchicine or vinca alkaloids), antimigraine agents, antimicrobials, antiphsychotics, antipyretics, antiseptics, anti-signalling agents (e.g., protein kinase C inhibitors or inhibitors of intracellular calcium mobilization), antiarthritics, antithrombin agents, antituberculotics, antitussives, antivirals, appetite suppressants, cardioactive drugs, chemical dependency drugs, cathartics, chem
- Formulations for oral use may also be presented as hard gelatin capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate polyvinyl-pyrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial compounds derived from fatty acids and a hexitol such a polyoxyethylene with partial compounds derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
- suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxy-
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent, suspending agent and one or more preservatives Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.
- the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soya bean, lecithin, and compounds or partial compounds derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial compounds with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavouring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above.
- the sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as absolution in 1,3-butane diol.
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- Dosage levels of the order of from about 0.05 mg to about 140 mg per kilogram of body weight per: day are useful in the treatment of the above-indicated conditions (about 2.5 mg to about 7 g per patient per day).
- inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 mg to about 3.5 g per patient per day).
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for the oral administration of humans may vary from about 5 to about 95% of the total composition.
- Dosage unit forms will generally contain between from about 1 mg to about 500 mg of active ingredient.
- the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- the dosage effective amount of compounds according to the invention will vary depending upon factors including the particular compound, toxicity, and inhibitory activity, the condition treated, and whether the compound is administered alone or with other therapies. Typically a dosage effective amount will range from about 0.0001 mg/kg to 1500 mg/kg, more preferably 1 to 1000 mg/kg, more preferably from about 1 to 150 mg/kg of body weight, and most preferably about 50 to 100 mg/kg of body weight.
- the invention relates also to a process or a method for the treatment of the abovementioned pathological conditions.
- the compounds of the present invention can be administered prophylactically or therapeutically, preferably in an amount that is effective against the mentioned disorders, to a warm-blooded animal, for example a human, requiring such treatment, the compounds preferably being used in the form of pharmaceutical compositions.
- Formulation of pharmaceutically-acceptable excipients and carrier solutions is well-known to those of skill in the art, as is the development of suitable dosing and treatment regimens for using the particular compositions described herein in a variety of treatment regimens, including e.g., oral, parenteral, intravenous, intranasal, and intra-muscular administration and formulation.
- compositions disclosed herein may be delivered via oral administration to an animal.
- these compositions may be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard- or soft-shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
- the active compounds may even be incorporated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- the tablets, troches, pills, capsules and the like may also contain the following: a binder, as gum tragacanth, acacia, cornstarch, or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose or saccharin may be added or a flavouring agent, such as peppermint, oil of wintergreen, or cherry flavouring.
- a binder as gum tragacanth, acacia, cornstarch, or gelatin
- excipients such as dicalcium phosphate
- a disintegrating agent such as corn
- the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrup of elixir may contain the active compound sucrose as a sweetening agent methyl and propylparabens as preservatives, a dye and flavouring, such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compounds may be incorporated into sustained-release preparation and formulations.
- these formulations may contain at least about 0.1% of the active compound or more, although the percentage of the active ingredient(s) may, of course, be varied and may conveniently be between about 1 or 2% and about 60% or 70% or more of the weight or volume of the total formulation.
- the amount of active compound(s) in each therapeutically useful composition may be prepared is such a way that a suitable dosage will be obtained in any given unit dose of the compound. Factors such as solubility, bioavailability, biological half-life, route of administration, product shelf life, as well as other pharmacological considerations will be contemplated by one skilled in the art of preparing such pharmaceutical formulations, and as such, a variety of dosages and treatment regimens may be desirable.
- compositions of the present invention may alternatively be incorporated with one or more excipients in the form of a mouthwash, dentifrice, buccal tablet, oral spray, or sublingual orally administered formulation.
- a mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution).
- the active ingredient may be incorporated into an oral solution such as one containing sodium borate, glycerine and potassium bicarbonate, or dispersed in a dentifrice, or added in a therapeutically-effective amount to a composition that may include water, binders, abrasives, flavouring agents, foaming agents, and humectants.
- the compositions may be fashioned into a tablet or solution form that may be placed under the tongue or otherwise dissolved in the mouth.
- compositions disclosed herein parenterally, intravenously, intramuscularly, or even intraperitoneally.
- Solutions of the active compounds as freebase or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
- Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils.
- Proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- a coating such as lecithin
- surfactants for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
- aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
- a sterile aqueous medium that can be employed will be known to those of skill in the art in light of the present disclosure.
- one dosage may be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
- preparations should meet sterility, pyrogenicity, and the general safety and purity standards as required by national or regional offices of biologics standards.
- Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- compositions disclosed herein may be formulated in a neutral or salt form.
- Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
- solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
- the formulations are easily administered in a variety of dosage forms such as injectable solutions, drug-release capsules, and the like.
- carrier includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
- carrier includes any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like.
- the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- compositions that do not produce an allergic or similar untoward reaction when administered to a human.
- pharmaceutically-acceptable refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a human.
- aqueous composition that contains a protein as an active ingredient is well understood in the art.
- injectables either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection can also be prepared.
- the preparation can also be emulsified.
- intranasal sprays, inhalation, and/or other aerosol delivery vehicles may deliver the pharmaceutical compositions.
- delivery of drugs using intranasal microparticle resins and lysophosphatidyl-glycerol compounds are also well known in the pharmaceutical arts.
- the subjects treated will typically comprise of mammals and most preferably will be human subjects e.g. human cancer subjects.
- the compounds of the invention may be used alone or in combination. Additionally the treated compounds may be utilised with other types of treatments.
- the subject compounds may be used with other chemotherapies e.g. tamoxifen, taxol, methothrexate, biologicals such as antibodies, growth factors or lymphokines, radiation etc. Combination therapies may result in synergistic results.
- the preferred indication is cancer especially the cancers identified previously.
- tumours which may be treated by the compositions and methods of the invention, include tumours of an epithelial origin such as, but not limited to: Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesotheliorna; Gastrointestinal: oesophagus (squamous cell carcinoma, adenocarcinoma), gastric carcinoma, colorectal carcinoma; Urogenital tract: kidney (adenocarcinoma, Wilm's tumour [nephroblastoma
- leukaemia refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukaemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic and (3) the increase or non-increase in the number abnormal cells in the blood-leukaemia or aleukaemic (subleukaemic). The P388 leukaemia model is widely accepted as being predictive of in vivo anti-leukaemic activity.
- the present invention includes a method of treating leukaemia, and, preferably, a method of treating acute nonlymphocytic leukaemia, chronic lymphocytic leukaemia, acute granulocytic leukaemia, chronic granulocytic leukaemia, acute promyelocytic leukaemia, adult T-cell leukaemia, aleukaemic leukaemia, a leukocythemic leukaemia, basophylic leukaemia, blast cell leukaemia, bovine leukaemia, chronic myelocytic leukaemia, leukaemia cutis, embryonal leukaemia, eosinophilic leukaemia, Gross' leukaemia, hairy-cell leukaemia, hemoblastic leukaemia, hemocytoblastic leuk
- sarcoma generally refers to a tumour which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
- Sarcomas which can be treated with compound of the invention and optionally a potentiator and/or chemotherapeutic agent include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumour sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's
- melanoma is taken to mean a tumour arising from the melanocytic system of the skin and other organs.
- Melanomas which can be treated with said compounds and optionally a potentiator and/or another chemotherapeutic agent include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma.
- carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
- exemplary carcinomas which can be treated with said compound and optionally a potentiator and/or a chemotherapeutic agent include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoi
- Additional cancers which can be treated with compound according to the invention include, for example, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple mycloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumours, primary brain tumours, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, unary bladder cancer, pre-malignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophagcal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, adrenal cortical cancer, and prostate cancer.
- the present invention provides compositions and methods for enhancing tumour specific immunity in individuals suffering from colorectal cancer metastasised to the liver, in order to inhibit the progression of the neoplastic diseases.
- Preferred methods of treating these neoplastic diseases comprise administering a composition of arsenic, which elicits an immune response against tumour cells.
- the present invention provides compositions and methods for enhancing specific immunity in individuals suffering from hepatocellular carcinoma in order to inhibit the progression of the neoplastic disease and ultimately irradiate all preneoplastic and neoplastic cells.
- the present invention provides hsp compositions and methods for enhancing specific immunity to preneoplastic and neoplastic mammary cells in women.
- the present invention also provides compositions and methods for inhibiting cancer cell proliferation and metastasis. These compositions can be applied alone or in combination with each other or with biological response modifiers.
- ICH-GCP ICH-GCP clinical study with oral arsenous acid sodium salt.
- the patients were suffering from urogenital cancer, mainly prostate cancer and bone metastasis, not amenable to any established methods of therapy and were treated with arsenous acid sodium salt over 7 different dosing levels.
- Arsenous acid sodium salt is thought to act as a telomere poison as it is capable of shortening the telomeres of human cancer cells, which leads to chromosomal abnormalities but doesn't inhibit telomerase activity.
- Arsenous acid sodium salt was taken daily for 14 consecutive days according to the dose level treatment scheme below:
- toxicity profile efficacy
- efficacy liver enzyme parameters (GOT, GPT, ⁇ -GT, AP)
- kidney function haematology functions
- tumour marker evaluations CEA and PSA
- pharmacokinetics of arsenous acid sodium salt were assessed during this study: toxicity profile, efficacy, liver enzyme parameters (GOT, GPT, ⁇ -GT, AP), kidney function, haematology functions, tumour marker evaluations (CEA and PSA) and the pharmacokinetics of arsenous acid sodium salt.
- tumour markers CEA cancer epidermal antigen
- PSA prostate specific antigen
- Histology Advanced, inoperable, solid prostate cancer with infiltration of the rectal mucosal wall, 11, Feb. 2004 Stage: Dukes C, pT 4 Gleason score 6 Therapy
- Dose level one showed a decrease in tumour size from 20 ⁇ 35 mm to 20 ⁇ 34 mm.
- Dose level three also showed a decrease from 20 ⁇ 35 to 20 ⁇ 34 mm while dose level five showed no change in size from 20 ⁇ 34 mm.
- liver transaminases sGPT and sGOT were observed during the intake of arsenous acid sodium salt in dose group III and V (visit 3 and 4). In visit 5 the transaminases almost returned to normal values. This increase seems to be related to the administration of the investigative drug arsenous acid sodium salt.
- Histology Advanced, inoperable, solid prostate cancer with an extraglandular tumour growth Stage: Dukes C, pT 4 Gleason score 4
- this patient also suffered from a renal cell carcinoma (since cured by radical nephrectomy) and a superficial bladder cancer (no tumour recurrence).
- the patient was included in the study due the continued rising of PSA levels after a complete androgen ablation with a LHRH antagonist (one profact s.c injection every 3 months) and an oral antiandrogen (casodex tablets dosage 1 ⁇ 1/d after lunch).
- Dose level one showed a decrease in tumour size from 12.5 ⁇ 65 mm to 0.8 ⁇ 30 mm.
- Dose level three also showed a decrease in the prostate tumour from 60 ⁇ 25 to 50 ⁇ 25 mm while dose level five showed no change in size.
- the secondary parameters showed no clinically significant results at any of the dose levels. Pre-study elevated triglycerides and cholesterol level had been detected which were unchanged during the course of the study. Glucose levels always appeared elevated which could be explained by alimentary reasons since blood probes were always taken in the morning after an opulent breakfast.
- Histology Advanced, inoperable, solid, androgen resistant prostate cancer with an extra-capsular tumour growth. Stage: Dukes C, pT 4 Gleason score 4
- this patient also suffers from rectum cancer. This patient was included because of the advanced and inoperable situation. An androgen ablation with a LHRH antagonist (one profact s.c injection every 3 months) has been performed.
- Dose level one showed a decrease in tumour size from 30 ⁇ 35 mm to 30 ⁇ 30 mm. Dose levels three and five showed no change in size.
- the secondary parameters showed no clinically significant results at any of the dose levels. A reversible and slight increase in sGPT was detected.
- Histology Advanced, inoperable, androgen-resistant solid prostate cancer with an extra-glandular tumour growth. Stage: Dukes C, pT 4 Gleason score 8
- the patient was included in the study due the continued rising of PSA levels after subcapsular orchiectomy for androgen ablation.
- Dose level one showed an increase in tumour size from 30 ⁇ 30 mm to 35 ⁇ 35 mm. Dose levels three and five showed no change from 30 ⁇ 35 mm.
- Histology Local recurrence of a solid prostate cancer after radical prostatectomy (stage pT2C Gleason 6) with bladder neck infiltration, inoperable. Stage: Dukes C, pT 4 Gleason score 6
- tumour lesions was not obtainable by any of the standard measuring means.
- the secondary parameters showed no clinically significant results at any of the dose levels.
- Histology Advanced, inoperable, solid prostate-cancer with an extraglandular tumour growth in the bladder neck and pelvic wall and a dissemination of bone metastases.
- Stage Dukes C, pT 4 Gleason score 9 M2
- the patient was included in the study because of the advanced status of the detected prostate cancer with multiple bone-metastases invading the whole skeleton.
- the secondary parameters showed no clinically significant results at any of the dose levels.
- the patients' quality of life was strongly ameliorated by arsenous acid sodium salt.
- a pre-study elevation of sGGT due to alcohol consumption worsened during the course of the study.
- the hemoglobin concentration increased from 10.0 to 11.1 g/l whereas the PSA decreased from 725 to 3.67 ng/ml.
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EP05076071A EP1721615A1 (en) | 2005-05-09 | 2005-05-09 | Pharmaceutical compositions comprising sodium or potassium arsenite for the treatment of urogenital cancer and its metastasis |
PCT/KR2006/001731 WO2006121280A1 (en) | 2005-05-09 | 2006-05-09 | Pharmaceutical compositions comprising of arsenous acid, its sodium salt and its derivatives intended for the treatment of urogenital cancer and its metastasis |
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US15/077,373 Active US11464859B2 (en) | 2005-05-09 | 2016-03-22 | Pharmaceutical compositions comprising sodium meta arsenite for treatment of multiple myeloma |
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US20170340694A1 (en) * | 2016-05-26 | 2017-11-30 | Stephen N. Pitcher | Composition for promoting metallothionein production |
US11464859B2 (en) | 2005-05-09 | 2022-10-11 | Kominox, Inc. | Pharmaceutical compositions comprising sodium meta arsenite for treatment of multiple myeloma |
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US8945505B2 (en) * | 2007-02-02 | 2015-02-03 | Panaphix, Inc. | Use of arsenic compounds for treatment of pain and inflammation |
US20090246291A1 (en) | 2008-03-27 | 2009-10-01 | Angelika Burger | Method and compositions for treatment of cancer |
US20120045520A1 (en) * | 2008-08-21 | 2012-02-23 | Sang Bong Lee | Pharmaceutical composition comprising arsenite for the treatment of malignancy |
EP2524226A1 (en) * | 2010-01-13 | 2012-11-21 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Promyelocytic leukemia protein as a redox sensor |
RU2602937C2 (ru) * | 2011-01-11 | 2016-11-20 | Универзитет Базель | Комбинация сиросингопина и митохондриальных ингибиторов для лечения рака и для иммуносупрессии |
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KR101309844B1 (ko) * | 2013-03-15 | 2013-09-23 | 박상채 | 항암 활성 증진용 한약재 및 이의 제조방법 |
RU2618405C1 (ru) * | 2015-12-31 | 2017-05-03 | Федеральное государственное бюджетное учреждение "Ростовский научно-исследовательский онкологический институт" Министерства здравоохранения Российской Федерации | Способ определения продолжительности адъювантной химиотерапии при местно-распространенном колоректальном раке с метастазами в регионарные лимфоузлы после радикальных оперативных вмешательств |
KR102487884B1 (ko) | 2016-12-01 | 2023-01-11 | 유파마 피티와이 엘티디 | 비소 조성물 |
EA202092186A1 (ru) * | 2018-03-22 | 2020-12-16 | Комифарм Интернэшнл Австралия Пти Лтд | Фармацевтическая композиция, содержащая метаарсенит, и способ изготовления |
WO2019234112A1 (en) * | 2018-06-05 | 2019-12-12 | Katholieke Universiteit Leuven | Combination treatment of arsenic oxide and antiandrogens |
JP2023513795A (ja) * | 2020-02-16 | 2023-04-03 | コミファーム インターナショナル オーストラリア ピーティーワイ リミテッド | メタ亜ヒ酸塩を使用する治療方法 |
KR20220020635A (ko) * | 2020-08-12 | 2022-02-21 | 이상봉 | 탈모방지 또는 발모촉진용 외용제 조성물 |
KR20220020637A (ko) * | 2020-08-12 | 2022-02-21 | 이상봉 | 항암화학요법이나 방사선요법으로 인한 암 환자의 탈모증을 포함한 탈모증 환자에 대하여 탈모를 방지하고 발모를 촉진하는 메타아르세나이트의 염을 함유하는 경구 투여용 약학적 조성물 |
KR20220020633A (ko) * | 2020-08-12 | 2022-02-21 | 이상봉 | 탈모방지 또는 발모촉진용 주사제 조성물 |
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US11464859B2 (en) | 2005-05-09 | 2022-10-11 | Kominox, Inc. | Pharmaceutical compositions comprising sodium meta arsenite for treatment of multiple myeloma |
US20110059186A1 (en) * | 2009-09-10 | 2011-03-10 | Kominox Usa, Inc. | Cancer stem cell-targeted and drug resistant cancer therapy |
WO2011031890A3 (en) * | 2009-09-10 | 2011-08-25 | Kominox, Inc. | Cancer stem cell-targeted and drug resistant cancer therapy |
JP2013504587A (ja) * | 2009-09-10 | 2013-02-07 | コミノックス・インコーポレイテッド | 癌幹細胞を標的とした薬剤耐性癌治療法 |
KR20150038702A (ko) * | 2009-09-10 | 2015-04-08 | 코미녹스 인코포레이티드 | 암 줄기세포-표적 및 약물 내성 암 치료 |
KR101721009B1 (ko) * | 2009-09-10 | 2017-03-29 | 코미녹스 인코포레이티드 | 암 줄기세포-표적 및 약물 내성 암 치료 |
US20110070314A1 (en) * | 2009-09-18 | 2011-03-24 | Yong Joon Jo | Methods for treating brain tumors |
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CN102753188A (zh) * | 2009-09-18 | 2012-10-24 | 柯密纳克斯公司 | 治疗脑瘤的方法 |
US20170340694A1 (en) * | 2016-05-26 | 2017-11-30 | Stephen N. Pitcher | Composition for promoting metallothionein production |
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