Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates generally to the fields of pharmaceutical chemistry and formulation. More particularly, it concerns the use of an effective amount of riboflavin and amino acids, in any combination, in the alleviation of the nutritional, metabolic and toxic symptoms of cancer and cancer chemotherapy in diagnosed cancer patients.
• TPN total parenteral nutrition
• TPN tumor necrosis factor
• a variety of studies have been conducted since the inception of TPN, with an array of conflicting reports. In some of them, TPN facilitated cancer progression through supply of large quantities of nutrients necessary for cancer growth, suggesting that the broad use of TPN in cancer patients could be deleterious at worst or ineffective at best. While it has been clearly shown that exogenous substrates have a distinct effect on both host and cancer metabolism, the characteristics of the substrates, such as caloric intake and the kind of amino acids used appear to be crucial for a selective response. As a result, fatigue and weakness are currently not indicators for the use of TPN in cancer patients. In spite of such seemingly conflicting reports, several amino acids have indicated promise as nutritional supplements in the treatment of a variety of disorders, including cancer.
• arginine glycine
• ornithine and taurine The amino acid arginine has properties which suggest that it may be of value both nutritionally and immunologically when administered as a dietary supplement. In fact, research has shown that a retardation in tumor growth, tumor regression, decreased tumor incidence, or a combination of all three can be affected by the administration of dietary arginine. Additionally, mixtures which contain arginine as well as a variety of other amino acids, sugars, vitamins, and nucleobases have exhibited potentially cytotoxic effects against several cancer cell lines.
• the non-essential amino-acid glycine has been shown to inhibit hepatocyte proliferation, and may have general anticancer properties as a dietary supplement.
• the present invention provides a method for the treatment or alleviation of cancer chemotherapy toxicity, involving administering to a patient a pharmaceutical composition comprising therapeutically-effective amounts of riboflavin, a component of the urea cycle, and effective amounts of the amino acids alanine, glycine, serine, taurine, threonine, and valine.
• a further aspect of the present invention is to provide a pharmaceutically acceptable agent for the alleviation of the symptoms of fatigue and weakness associated with cancer and cancer cytotoxicity, comprising a therapeutically effective amount of riboflavin, an effector of the urea cycle, and one or more amino acids selected from a group of essential and non-essential amino acids, wherein the latter two constituents are in free form or pharmacologically acceptable salts.
• a preferred composition consists of the six amino acids, alanine, glycine, serine, taurine, threonine, and valine; an effector of the urea cycle selected from L-arginine, L-ornithine, and L- citrulline; riboflavin; and a pharmaceutically acceptable diluent.
• Riboflavin used within the present invention, can be obtained from a commercial source (e.g., Spectrum Laboratory Products, Inc., Gardena, CA) or can be prepared synthetically by any known technique in the art, e.g. by condensation of a ribitylxylidine azo derivative with barbituric acid (Yoneda, F. et al., J. Chem. Soc, Perkin Trans. I, 348 (1978); U.S. Pat. No. 2,807,611).
• riboflavin is preferably obtained from a fermentation process of any number of bacteria, or through a combination of synthetic and biotechnology techniques described in the art (U.S. Pat. No. 6,150,364; U.S. Pat. No. 5,589,355).
• the amino acids used within the present invention can be obtained from a commercial source (e.g., Kyowa Hakko Kogyo Co., LTD., Tokyo, Japan), by fermentation methods, or can be prepared synthetically using any number of techniques in the art, e.g. through the displacement reactions on ⁇ -halo acids.
• the amino acids are preferably prepared synthetically.
• the amino acids used within the present invention are all of the L-(levorotatory), stereochemical series and are all proteinogenic ⁇ -amino acids except for glycine, which does not have optic isomers and taurine, which is an ⁇ -amino acid and does not have optic iosomers.
• the compounds of the present invention can also exist in different stereoisomeric forms by virtue of the presence of one or more asymmetric centers in the compound.
• the present invention contemplates L- stereoisomeric forms of the compounds, as well as mixtures thereof, including racemic mixtures.
• Individual stereoisomers may be obtained commercially, or by methods known in the art, such as the separation of stereoisomers in chiral chromatographic columns.
• the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically-acceptable solvents such as water, ethanol, and the like.
• solvated forms of the compounds are considered to be equivalent to the unsolvated forms for the purposes of the present invention.
• pharmaceutically-acceptable salts means salts which have the biological activity of the parent compound while lacking any toxic activity at the selected administration level. Determination of whether a salt is pharmaceutically-acceptable salt can be determined readily by methods known to those of skill in the art.
• Pharmaceutically acceptable salts include, but are not limited to, organic diethanolamine, cyclohexylamine and amino acid salts, and inorganic sodium, potassium, and ammonium salts.
• amino acid of the invention is meant to refer to glycine, alanine, serine, valine, threonine and/or taurine, in free amino acid form and/or pharmacologically acceptable salt form.
• urea cycle effector includes any of the amino acids comprising the urea cycle wherein such a cycle serves as a metabolic pathway for disposing of cellular breakdown products containing nitrogen. Such effectors are selected from the group comprising arginine, ornithine, and citrulline.
• patient refers to human patients.
• unit dosage form or alternatively “unit dosage levels” as used herein refers to physically discrete units suitable as unitary dosages for human subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier, or vehicle.
• the specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent upon (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic use in humans, as disclosed in this specification, these being features of the present invention.
• suitable unit dosage forms in accordance with this invention are tablets, capsules, troches, powder packets, wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampules, vials, I.V. bags, segregated multiples of any of the foregoing, and other forms as described herein.
• the present invention therefore provides the use of the amino acid(s) of the invention, namely alanine, glycine, serine, taurine, threonine and valine, in combination with riboflavin and an effector of the urea cycle in minimizing the effects of fatigue and weakness in cancer patients resulting from cancer and cancer chemotherapy toxicity; compositions containing the amino acids of the invention in combination with riboflavin and an effector of the urea cycle; the use of the composition of the invention in the manufacture of compositions for minimizing and alleviating the effects of fatigue and weakness in cancer patients resulting from cancer and cancer chemotherapy toxicity; and a method of minimizing and alleviating the effects of fatigue and weakness in cancer patients resulting from cancer and cancer chemotherapy cytotoxicity.
• the amino acid(s) of the invention namely alanine, glycine, serine, taurine, threonine and valine
• compositions contain the selected effector of urea cycle (L-arginine, L-ornithine or L- citrulline) in an amount from about 50 to about 3000 times the molar concentration of riboflavin. Further, each of the amino acids is generally provided in a molar amount from about 0.1 to about 3.0 of the selected effector of the urea cycle.
• AVA One embodiment of the present invention
• AVB An alternative embodiment of the present invention
• Typical formulations are shown below.
• an aqueous solution of L-arginine and riboflavin in about a 500:1 molar ratio is prepared such that the concentration of L-arginine in solution is about 2 mg/mL to about 120 mg/mL.
• the solution also contains the amino acids L-alanine, L-serine, and L-threonine in a 1 :1 molar ratio with L-arginine in a concentration of about 1 mg/mL to about 90 mg/mL; the amino acid glycine in a 1.4:1 molar ratio with L-arginine in a concentration of about 1 mg/mL to about 75 mg/mL; the beta-amino acid taurine in a 0.3:1 molar ratio with L-arginine in a concentration of about 0.5 mg/mL to about 30 mg/mL; and the amino acid L-valine in a 0.6:1 molar ratio with L-arginine in a concentration of about 1 mg/mL to about 50 mg/mL.
• Preparation of the AVA solution can be performed using any technique known to those skilled in the art. It is to be noted that the solution is to be made sterile, and the pH is to be adjusted to a value at or near the physiological pH of 7.4, e.g. 6.8, using sodium hydroxide and hydrochloric acid as needed.
• an aqueous solution of L-ornithine and riboflavin in about a 500:1 molar ratio is prepared such that the concentration of L-ornithine in solution is about 2 mg/mL to about 120 mg/mL.
• the solution also contains the amino acids L-alanine, L-serine, and L-threonine in a 1 :1 molar ratio with L-ornithine in a concentration of about 1 mg/mL to about 90 mg/mL; the amino acid glycine in a 1.4:1 molar ratio with L-ornithine in a concentration of about 1 mg/mL to about 75 mg/mL; the beta-amino acid taurine in a 0.3:1 molar ratio with L-ornithine in a concentration of about 0.5 mg/mL to about 30 mg/mL; and the amino acid L-valine in a 0.7:1 molar ratio with L-ornithine in a concentration of about lmg/mL to about 50 mg/mL.
• Preparation of the AVB solution can be performed using any technique known to those skilled in the art. It is to be noted that the solution is to be made sterile, and the pH is to be adjusted to a value at or near the physiological pH of 7.4, e.g. 6.8, using sodium hydroxide and hydrochloric acid as needed.
• An alternative embodiment of the present invention (AVC) is useful for the prevention of breast, lung and liver cancers as well as for reducing the toxic effects of cytotoxic chemotherapy.
• a pharmaceutical composition AVC according to the present invention typically comprises 0.01- 10 wt % riboflavin, 1-15 wt % arginine, and 1-15 wt % ornithine, 1-15 wt % alanine, 1-15 wt % glycine, 1-15 wt % serine, 1-15 wt % threonine 1-15 wt % valine, and 25-75 wt % 3- phenylacetylamino-2,6-piperidinedione.
• a typical AVC formulation is shown below.
• the sterile pharmaceutical compositions AVA, AVB and AVC should be stored at room temperature (15-30 °C) without refrigeration or freezing. They should be stored in such a manner that they are protected from light until the time of usage.
• the dosage administered of the present composition will be dependent upon a combination of the identity of the neoplastic disease; the type of host involved, including its age, health, and weight; the type of concurrent treatment, if any; the frequency of treatment and the therapeutic ratio.
• typical daily dosage levels of the compounds of the present invention will be in the range of from about 7 mg/kg/d (low end) to about 4000 mg/kg/d (high end) of host body weight.
• Preferred daily doses shall generally be in the range of 1000 mg/kg/d of host body weight. Dosages will depend upon method of administration.
• compositions of the present invention can be prepared for administration to humans in unit dosage forms by a variety of routes, including, but not limited to, oral, subcutaneous, bronchial, pharyngolaryngeal, intranasal and intravenous. Preferred method of administration of
• AVA and AVB is as intravenous solution.
• AVC is particularly suitable for formulation as a solid for encapsulation in gel caps.
• compositions of the present invention are preferably presented for administration to humans in unit dosage forms known to those skilled in the art, such as tablets, capsules, pills, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions and the like, containing suitable quantities of the active ingredients. Examples are given in the following paragraphs.
• One or more ingredients, other than riboflavin, an effector of the urea cycle, and selected amino acids, may be present as diluents, carriers, or excipients in any composition of the present invention.
• the pharmaceutical composition can be formulated as an intravenous solution of sodium salts in water suitable for injection.
• the pharmaceutical composition can be formulated as an intravenous solution of sodium salts in water suitable for injection.
• either solid or fluid unit dosage forms can be prepared.
• Formulation can be as a tablet, capsule, powder, spirit, or elixir, among others.
• Fluid unit dosage forms for oral administration such as in syrups, elixirs and suspensions can be prepared wherein each teaspoonful of composition contains a predetermined amount of active ingredients for administration.
• the water-soluble forms can be dissolved in an aqueous vehicle together with sugar, flavoring agents and preservatives to form a syrup.
• An elixir is prepared by using a hydroalcoholic vehicle with suitable sweeteners together with a flavoring agent.
• Suspensions can be prepared of the insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.
• fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle, water being preferred.
• the active ingredients depending on the form and concentration used, can be either suspended or dissolved in the vehicle.
• the water-soluble active ingredients can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing.
• adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
• Parenteral suspensions are prepared in substantially the same manner except that an active ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
• the active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the active ingredient.
• Powders are prepared quite simply by comminuting the active ingredients to a suitably fine size and mixing with a similarly comminuted dilutent.
• the diluent can be an edible carbohydrate material such as lactose or starch.
• a sweetening agent or sugar is present as well as a flavoring oil.
• Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths.
• a lubricant such as talc, magnesium stearate, calcium stearate and the like is added to the powder mixture before the filling operation.
• Soft gelatin capsules are prepared by machine encapsulation of a slurry of the active ingredients with an acceptable vegetable oil, light liquid petolatum or other inert oil or triglyceride.
• Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and pressing into tablets.
• the powder mixture is prepared by mixing an active ingredient, suitably comminuted, with a diluent or base such as starch, lactose, kaolin, dicalcium phosphate, and the like.
• the powder mixture can be granulated by wetting with a binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage and forcing through a screen.
• a binder such as corn syrup, gelatin solution, methylcellulose solution or acacia mucilage
• the powder mixture can be slugged, i.e. run through a tablet machine and the resultant imperfectly formed tablets broken into pieces (slugs).
• the slugs can be lubricated to prevent sticking to the tablet- forming dies by means of the addition of stearic acid, a stearic salt, talc or mineral oil.
• the lubricated mixture is then compressed into tablets.
• the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac, a coating of sugar and methylcellulose and a polish coating of carnauba wax.
• a fluid unit dosage form is prepared using active ingredients and a suitable pharmaceutical vehicle, preferably P.F. water, wherein a dry powder can be formulated when insufflation is the administration of choice.
• a suitable pharmaceutical vehicle preferably P.F. water
• the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example dichlorofluoromethane, carbon dioxide, nitrogen, propane, and the like, with the usual adjuvants such as cosol vents and wetting agents as necessary or desireable.
• a gaseous or liquified propellant for example dichlorofluoromethane, carbon dioxide, nitrogen, propane, and the like
• adjuvants such as cosol vents and wetting agents as necessary or desireable.
• all compositions according to the present invention can include other agents, such as buffering compounds, glucose, or other sugars, preservatives, and the like suitable for use in pharmaceutical compositions prepared for intravenous administration, as are known in the art.
• a pharmaceutical composition of the present invention can be administered via the appropriate route for its formulation as described above.
• the pharmaceutical compositions of the present invention are preferrably administered intravenously. If it is formulated as an intravenous solution, it shall be administered through a single-channel infusion pump and IV catheter.
• the catheter will be a single-lumen Broviac, Groshong, or equivalent.
• the regimen for injections will vary depending upon age and the concentration of arginine in their plasma, as outlined below. Methods of intravenous administration are widely known in the art.
• neoplastic diseases that are advantageously susceptible to treatment using the disclosed treatment regimen of this invention include carcinoma of the adrenal gland, carcinoma of the bladder, carcinoma of the breast, high grade glioma, glioblastoma multiforme, astrocytoma including anaplastic and low grade astrocytoma, brain stem glioma, primitive neuroectodermal tumors including medulloblastoma and pinealoblastoma, rhabdoid tumor of the central nervous system, oligodendroglioma, mixed glioma, neurofibroma, schwannoma, visual pathway glioma, ependymoma, germ cell tumors, meningioma, carcinoma of the colon and rectum, carcinoma of the esophagus, primary and
• the described treatment regimen is useful for alleviation of symptoms and toxic effects associated with standard chemotherapeutic regimens, as well as for restoring patient nutritional status.
• the duration of the therapeutic regime may be for only as much time as is required in order to alleviate the symptoms and side-effects of the cancer chemotherapy treatment.
• the duration of the therapeutic administration may be for any or all of the length of time following initial cancer treatment.
• a composition comprising a sterile solution of six amino acids, L-arginine, and riboflavin, hereinafter referred to as AVA was tested for its ability to alleviate the symptoms of cancer chemotherapy and improve the nutritional status of a middle-aged cancer patient.
• a fifty-three-year old Caucasian female, diagnosed with adenocarcinoma of the sigmoid colon was treated surgically by lower anterior resection and anastomosis between the descending colon and the rectum. Following recovery, she was started on a daily intravenous administration of AVA. This was followed closely by the initiation of a combination chemotherapy regimen involving intravenous infusions of methotrexate and 5-fluorouracil (5-FU). Following weekly administration of the chemotherapy cocktail for fifty-two weeks, the chemotherapy was discontinued, and shortly thereafter the AVA treatment was discontinued.
• Example 2 Treatment of 70-year old female diagnosed with ductal adenocarcinoma of the breast using AVA formulation.
• a composition comprising a sterile solution of six amino acids, L-arginine, and riboflavin, hereinafter referred to as AVA was tested for its ability to alleviate the symptoms of cancer chemotherapy and improve the nutritional status of an elderly cancer patient.
• the tamoxifen treatment was discontinued due to side effects.
• the patient developed a cancerous nodule behind the left axilla, confirmed by biopsy.
• the patient was started on Taxol and received twenty-one treatments, whereup CT analysis of the chest indicated three nodules in the lungs and one in the liver.
• the patient was then started on daily intravenous infusions of AVA.
• combination chemotherapy was begun with weekly injections of methotrexate and 5-FU in combination with Aromasin.
• the patient showed a gradual improvement in her condition and exhibited an absence of fatigue and weakness and a gradual weight recovery.
• follow-up evaluations involving physical examination, blood count, biochemical profile, urinalysis, electrolyte level tests, and CT scans of the chest and abdomen indicated two pulmonary and one liver lesion; the third pulmonary nodule was no longer visible.
• the two pulmonary lesions one of those still present was larger in size in comparison with the baselines studies, and the second was notably smaller, indicating a remission of two of the lesions.
• the treatment with daily infusions of AVA in combination with a battery of chemotherapeutic agents has resulted in a decrease in the size, as well as the complete disappearance of tumors.
• symptoms such as substantial cytotoxicity and related side effects preventing utilization of a particular therapeutic agent were alleviated and the nutritional status of the cancer patient undergoing the extreme therapeutic regimen was notably improved.
• a composition comprising a sterile solution of six amino acids, L-arginine, and riboflavin, hereinafter referred to as AVA was tested for its ability to alleviate the symptoms of cancer chemotherapy and improve the nutritional status of an elderly cancer patient.
• the low- grade non-Hodgkin's lymphoma had returned to the patient's neck, chest, abdomen and pelvis.
• Treatment was begun using daily intravenous infusions of AVA. The AVA infusions were continued for four months, during which time the patient reported no symptoms typical of the cytotoxicity expected from the chemotherapeutic regimen involved. Shortly afterwards, she began treatment involving subcutaneous injections of Intron-A. Five months later, chemotherapy with Cytoxan was begun, and was continued for five months. During this time, chemotherapy using Rituxan was begun, but soon discontinued.
• AVB formulation comprising a sterile solution of six amino acids, L-ornithine, and riboflavin, hereinafter referred to as AVB was tested for its ability to alleviate the symptoms of cancer chemotherapy and improve the nutritional status of an elderly cancer patient.
• a 72-year-old Caucasian female was diagnosed with transitional cell carcinoma, papillary and invasive, grade 3, within the bladder wall. Due to two lymph nodes out of two being positive for metastatic transitional cell carcinoma of the bladder, cystectomy was not persued.
• the patient underwent urinary diversion and ileal conduit to relieve voiding symptoms, but no radiation therapy or chemotherapy regimen was initiated. Shortly thereafter, the patient was started on intravenous infusions of AVB. One week later, she began combination chemotherapy with methotrexate and 5-FU, the latter of which was given intravenously once a week..
• compositions disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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