drug literature

ANTI- NEOPLASTIC AGENTS:

ALKYLATING AGENTS:

Melphalancommonly use brand name:alkeranCategory: Anti-neoplasticPharrmacolgy/pharmacokenetics:

Mechanism of action:Melphalan is an alkylating agent of the nitrogen mustard type. Melphalan is a bifunctional alkylating agent and is cell cycle–phase nonspecific. Activity occurs as a result of formation of an unstable ethylenimmonium ion, which alkylates or binds with many intracellular molecular structures including nucleic acids. Its cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein synthesis.

Absorption:Variably and incompletely absorbed from the gastrointestinal tract. Absorption is decreased in the presence of food.

Distribution:Apparent volume of distribution (steady-state: 0.5 liter per kg of body weight

Protein binding:Moderate to high (60 to 90%), primarily to albumin and alpha 1-acid glycoprotein irreversibly bound to plasma proteins

Biotransformation:Deactivated in plasma by hydrolysis

Half-life:Distribution—Approximately 10 minutes Terminal—Approximately 90 minutes; the average terminal half-life of melphalan in the perfusion circuit during regional hyperthermic perfusion is 26 to 53 minutes.

Elimination: Primarily nonrenal. In dialysis—Not removable by hemodialysis or hemoperfusion

Precaution to consider:Cross-sensitivity and/or related problemsPatients sensitive to chlorambucil may also be sensitive (in form of skin rash) to melphalan Carcinogenicity/MutagenicitySecondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The risk may increase with increasing dose and duration of therapy. In one study, the 10-year risk of developing secondary acute leukemia or myeloproliferative syndrome was less than 2% for cumulative doses under 600 mg, but 19.5% for cumulative doses of 730 to 9652 mg Although information is limited, available data seem to indicate that the highest carcinogenic risk is with the alkylating agents.Melphalan produces chromosomal aberrations in human cells both in vitro and in vivo

Pregnancy/reproduction: Fertility:Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking melphalan. These effects may be related to the dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.

Pregnancy:Adequate and well-controlled studies in humans have not been done. However, melphalan is believed to be potentially harmful to the fetus

Breast feeding:It is not known whether melphalan is distributed into breast milk. Breast-feeding is not recommended while melphalan is being administered, because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity)

Pediatrics:Appropriate studies on the relationship of age to the effects of melphalan have not been performed in the pediatric population. Safety and efficacy in pediatric patients have not been established

Geriatics:No information is available on the relationship of age to the effects of melphalan in geriatric patients. However, geriatric patients are more likely to have age-related renal function impairment, which may require adjustment of dosage Dental:The bone marrow depressant effects of melphalan may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.Melphalan may cause stomatitis, especially when high doses are used.Drug interactions: Bone marrow depressants, other (see Appendix II ) orRadiation therapy (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively) Carmustine (intravenous melphalan may be synergistic with carmustine in causing lung toxicityCimetidine (reduced serum concentration of melphalan may result, perhaps due to decreased absorption Cyclosporine increased risk of nephrotoxicity Interferons, alpha (increased elimination of melphalan may occur, perhaps due to fever induced by alpha interferons)Nalidixic acid (increased incidence of hemorrhagic necrotic enterocolitis in pediatric patients)Vaccines, killed virus (because normal defense mechanisms may be suppressed by melphalan therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year) Vaccines, live virus (because normal defense mechanisms may be suppressed by melphalan

therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the melphalan therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. Oral poliovirus vaccine should not be administered to persons in close contact with the patient, especially family members)

With physiology/laboratory test valuesUric acid concentrations in blood and urine (may be increased)Urinary 5-hydroxyindoleacetic acid (5-HIAA) concentrations (may be increased, possibly as a result of tumor cell destruction with accompanying release of metabolites)

Patient monitoring:The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):Blood counts, complete (CBC), includingHematocritHemoglobinPlatelet count (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to the patient's condition, the dose of melphalan administered, and other drugs being administered concurrently Blood urea nitrogen (BUN) concentrations andSerum creatinine concentrations (recommended prior to initiation of therapy and at periodic intervals during therapy)Serum uric acid concentrations (recommended prior to initiation of therapy and at periodic intervals during therapy)

Side/Adverse effect:Those indicating need for medical attentionNeutropenia, with or without infection (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic; uncommon after limb perfusionthrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomaticIncidence less frequent or rare:Hypersensitivity reactions, including anaphylaxis (fast or irregular heartbeat; shortness of breath; sudden skin rash or itching; troubled breathing)hyperuricemia or uric acid nephropathy (joint pain; lower back or side pain; swelling of feet or lower legs)mucositis (diarrhea; difficulty in swallowing)—dose-relatedpulmonary fibrosis (shortness of breath)skin or soft tissue injurY (redness and/or soreness in arm or leg)—with isolated limb perfusionstomatitis (sores in mouth and on lips)vasculitis, severe, recurrent} (redness and/or soreness at the infusion site)Nausea and vomitingdose-relatedThose indicating the need for medical attention if they occur after medication is discontinuedBone marrow depression (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising)

Note: Cumulative myelosuppression may occur with repeated dosing.Overdose:For specific information on the agents used in the management of melphalan overdose, see the Colony Stimulating Factors (Systemic) monograph.For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).Clinical effect of overdose:The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:Acute and chronicAnemia (unusual bleeding or bruising; unusual tiredness or weakness)colitis (abdominal cramping and pain)mucositis, severe (difficulty in swallowing; diarrheastomatitis (painful sores in the mouth)Supportive carePatient consulation:As an aid to patient consultation, refer to Advice for the Patient, Melphalan (Systemic) . Consider advising the patient on the following ( = major clinical significance):Carcinogenicity—Increased risk of secondary malignanciesPregnancy—Advisability of using contraception; telling physician immediately if pregnancy is suspectedBreast-feeding—Not recommended because of the potential risk to the infantOther medications, especially other bone marrow depressants and live virus vaccines, or previous cytotoxic drug therapy or radiation therapy within 3 to 4 weeksOther medical problems, epecially bone marrow depression, chickenpox or recent exposure, herpes zoster, infection, or renal function impairmentParenteral Dosage FormsUpper extremity:Arterial infusion, by hyperthermic isolated limb perfusion technique, 1 mg per kg of body weight, not to exceed 80 mg, in three equally divided doses at five-minute intervals orLower extremity:Arterial infusion, by hyperthermic isolated limb perfusion technique, 1.5 mg per kg of body weight, not to exceed 120 mg, in three equally divided doses at five-minute intervals .Packaging and storage:Store between 15 and 30 ºC (59 and 86 ºF). Protect from light.Preparation of dosage form:For intravenous infusion Reconstitute the vial of melphalan with 10 mL of the diluent supplied by the manufacturer, for a concentration of 5 mg per mL (mg/mL). Immediately dilute the dose to be administered in 0.9% sodium chloride injection, USP, to a final concentration no greater than 0.45 mg/mLFor isolated limb perfusionReconstitute the vial of melphalan with 10 mL of the diluent supplied by the manufacturer, for a concentration of 5 mg per mL (mg/mL).Stability:Melphalan reconstituted as directed to a concentration of 5 mg/mL is stable for up to two hours at 30 ºC (86 ºF). The reconstituted solution should not be refrigerated because refrigeration will cause a precipitate to form Incompatibilities:Melphalan 0.1 mg per mL (mg/mL) in 0.9% sodium chloride injection is incompatible for Y-site administration with amphotericin B, chlorpromazine hydrochloride, daunorubicin hydrochloride, idarubicin hydrochloride, lorazepam, methylprednisolone sodium succinate, and prochlorperazine edisylate. Auxiliary labeling:

Do not refrigerate. Protect from light.

Ifosfamide: Generic Names: Asta Z 4942; I-Phosphamide; Ifosfamid; Ifosfamide Sterile; Ifsofamide; Iphosphamid; Iphosphamide; Isofosfamide; Isophosphamide. Trade Names: Cyfos; Holoxan 1000; IFEX; Ifex/Mesnex Kit; Ifosfamide/Mesna Kit; Isoendoxan; Mitoxana; Naxamide

PharmGKB Accession Id: PA449964

Description: Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent.

Indications: For third line chemotherapy of germ cell testicular cancer. It should ordinarily be used in combination with a prophylactic agent for hemorrhagic cystitis, such as mesna.

ATC Therapeutic category: L01AA: Nitrogen mustard analogues

Mechanism of action: After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein synthesis.

Pharmacology: Ifosfamide selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of ifosfamide-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.

Absorption,Distribution,Metabolism,elimination,&toxicity: Biotransformation: Primarily hepatic

Protein binding: Minimal

Toxicity: LD (mouse) = 390-1005 mg/kg, LD (rat) = 150-190 mg/kg. Side effects include nausea, vomiting and myelosuppression. Toxic effects include central nervous system toxicity (confusion, hallucinations) and urotoxic effects (cystitis, blood in urine).

Chlorambucil:

Generic Names: Chlocambucil; Chloraminophen; Chloraminophene; Chlorbutin; Chlorbutine; Chloroambucil; Chlorobutin; Chlorobutine; Phenylbutyric Acid Nitrogen Mustard

Trade Names: Ambochlorin; Amboclorin; Ecloril; Elcoril; Leukeran; Leukeran Tablets; Leukersan; Leukoran; Linfolizin; Linfolysin; Pepstatin


Description: A nitrogen mustard alkylating agent used as antineoplastic for chronic lymphocytic leukemia, Hodgkin's disease, and others. Although it is less toxic than most other nitrogen mustards, it has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (Merck Index, 11th ed)

Indication: For treatment of chronic lymphatic (lymphocytic) leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease

ATC Therapeutic category: L01AA:Nitrogen mustard analogues

Mechanism of action: Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.

Pharmacology: Chlorambucil is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

Food interaction: Drink liberally.Food reduces bioavailability.Take on an empty stomach. Protein binding: 99% Chemical Properties: Isometric smile c1cc (ccc1CCCC (=O) O) N (CCCl) CCCl

Generic Names: cyclophosphamide

Trade Names: ASTA; Asta B 518; CP; CPA; CTX; CY; Clafen; Claphene; Cyclophosphamid; Cyclophosphamide Monohydrate; Cyclophosphamide Sterile; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphoramide; Cyclostin; Cyklofosfamid; Cytophosphan; Cytoxan; Cytoxan Lyoph; Endoxan; Endoxan R; Endoxan-Asta; Endoxana; Endoxanal; Endoxane; Enduxan; Genoxal; Hexadrin; Lyophilized Cytoxan; Mitoxan; Neosar; Procytox; Rcra Waste Number U058; Revimmune; Semdoxan; Sendoxan; Senduxan; Zyklophosphamid PharmGKB Accession Id: PA449165 Description: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It has been used in the treatment of lymphoma and leukemia. Its side effect, alopecia, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.

Indication:For management of malignant lymphomas, multiple myeloma,leukemias, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma and carcinoma of the breast

ATC therapeutic category: L01AA: Nitrogen mustard analogues ;L01DB:Anthracyclines and related substances


Pharmacology: Cyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

Food interaction: Drink liberally- 2 to 3 liters/day.Take with food to reduce irritation. Biotransformation: hepatic Protein binding:>60% Absorption-90-100% Toxicity:infection, myelosuppression, and cardiac toxicity

Chemical properties: C1CN [P@](=O)(OC1)N(CCCl)CCCl

Generic Names: Estramustin Sodium Phosphate; Estramustina [INN-Spanish]; Estramustine Sodium Phosphate; Estramustinum [INN-Latin]

Trade Names: Emcyt; Estracyt


Description: A Nitrogen mustard linked to estradiol, usually as phosphate; used to treat prostatic neoplasm; also has radiation protective properties.

Indication: For the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate

ATC therapeutic category: L01XX:Other antineoplastic agents

Pharmacology,Interaction,and Contraindication:

Mechanism of action: The precise mechanism of action of estramustine is unknown.

Pharmacology: Estramustine is an antineoplastic agent indicated in the palliative treatment of patients with metastatic and/or progressive carcinoma of the prostate. Estramustine is a combination of estradiol with nornitrogen mustard. The precise mechanism of action of estramustine is unknown. Unlike other alkylating agents, estramustine does not directly damage DNA.

Food interaction: Do not take with milk or milk products.Take on an empty stomach.

Chemical properties: Isomeric smileC1CN [P@](=O)(OC1)N(CCCl)CCCl

NITROSOUREAS AGENTS:

Generic Names:

BCNU; Bischlorethylnitrosourea; Bischlorethylnitrosurea; Carmustin

Trade Names:

Becenun; Bi CNU; BiCNU; Carmubris; Gliadel; Gliadel Wafer; Nitrumon


Description: A cell-cycle phase nonspecific alkylating antineoplastic agent. It is used in the treatment of brain tumors and various other malignant neoplasms. (From Martindale, The Extra Pharmacopoeia, 30th ed, p462) This substance may reasonably be anticipated to be a carcinogen according to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (From Merck Index, 11th ed)

Indications:

For the treatment of brain tumors, multiple myeloma, Hodgkin's disease and Non-Hodgkin's lymphomas.

ATC therapeutic category: L01AD: Nitrosoureas Pharmacology,interaction,and contraindication:

Mechanism of Action: Carmustine causes cross-links in DNA and RNA, leading to the inhibition of DNA synthesis, RNA production and RNA translation (protein synthesis). Carmustine also binds to and modifies (carbamoylates) glutathione reductase. This leads to cell death.

Pharmacology: Carmustine is one of the nitrosoureas indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Although it is generally agreed that carmustine alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.

Absorption,Distribution,metabolism,elimination,&toxicity Biotransformation:Hepatic and rapid with active metabolites. Metabolites may persist in the plasma for several days.

Protein binding: 80% Absorption: 5 to 28% bioavailability

Toxicity:The oral LD ~50~s in rat and mouse are 20 mg/kg and 45 mg/kg, respectively. Side effects include leukopenia, thrombocytopenia, nausea. Toxic effects include pulmonary fibrosis (20-0%) and bone marrow toxicity.

Chemical properties: Isomeric smile (CCl) NC(=O)N(CCCl)N=O

Lomustine: Commonly used brand name(s): CeeNU. Category: anti-neoplastic

Indications: Tumors, brain, primary (treatment);Carcinoma, colorectal (treatment)]Carcinoma, lung, non-small cell (treatment)] or;Carcinoma, breast (treatment)]—Lomustine is indicated for treatment of both primary and metastatic brain tumors, in patients who have already received appropriate surgical or radiotherapeutic procedures. It is also indicated for treatment of colorectal carcinoma, non–small-cell lung carcinoma, and advanced breast carcinoma after conventional therapy has faile.Lymphomas, Hodgkin's (treatment)—Lomustine is indicated for treatment of Hodgkin's disease, as secondary therapy in combination with other drugs in patients who relapse while being treated with primary therapy or in patients who fail to respond to primary therapy. Lomustine is also indicated for treatment of multiple myeloma and malignant melanoma. Pharmacology/PharmacokineticsPhysicochemical characteristics:Molecular weight— 233.70Mechanism of action/Effect:Lomustine is an alkylating agent of the nitrosourea type. Lomustine (and/or its metabolites) interferes with the function of DNA and RNA. It is cell cycle–phase nonspecific. Lomustine also acts to inhibit DNA synthesis by inhibiting key enzymatic processes.Absorption: Well and rapidly absorbed from the gastrointestinal tract.Distribution: Crosses the blood-brain barrier.Protein binding: Moderate (50%; metabolites).Biotransformation: Hepatic; rapid and complete (active metabolites).Half-life:Biologic—Approximately 94 minutes.Chemical—Approximately 15 minutes.Metabolites—Prolonged; 16 to 48 hours.Elimination: Renal (totally as metabolites); some enterohepatic circulation is believed to occur.Fecal (less than 5%); Respiratory (10%). Precautions to Consider:Carcinogenicity/MutagenicitySecondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.Long-term use of nitrosoureas in humans has been reported to be possibly associated with development of secondary malignancies (acute leukemia) and bone marrow dysplasias Lomustine is carcinogenic in rats and mice at the approximate clinical dose and, like other alkylating agents, is probably carcinogenic in humans. Pregnancy/ReproductionFertility—Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian

function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents. Pregnancy—Adequate and well-controlled studies in humans have not been done.

Breast-feeding:Lomustine is distributed into breast milk. Breast-feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).Pediatrics: Appropriate studies on the relationship of age to the effects of lomustine have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medication in children are not expected.

Geriatrics: No information is available on the relationship of age to the effects of lomustine in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving lomustine.

Dental: The bone marrow depressant effects of lomustine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problemsThe following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):Blood dyscrasia–causing medications (leukopenic and/or thrombocytopenic effects of lomustine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of lomustine, if necessary, should be based on blood counts) Bone marrow depressants,

Patient monitoring:Alanine aminotransferase (ALT [SGPT]) values, serum andAspartate aminotransferase (AST [SGOT]) values, serum andBilirubin values, serum andLactate dehydrogenase (LDH) values, serum (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)

» Blood urea nitrogen (BUN) concentrations and» Creatinine concentrations, serum (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)

» Hematocrit or hemoglobin and» Leukocyte count, total and, if appropriate, differential and» Platelet count (determinations recommended prior to initiation of therapy and at periodic intervals

during and after therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently).

Streptozocin: Antineoplastic agent; a nitrosourea-derivative alkylating antibiotic.

Uses: Pancreatic islet cell carcinoma; Carcinoid Tumor and Syndrome; Pancreatic adenocarcinoma

Dosage: Optimize results and minimize adverse effects by basing dosage on clinical, renal, hematologic, and hepatic responses and tolerance of the patient.

Consult published protocols for dosages of streptozocin and other chemotherapeutic agents and for method and sequence of administration. Do not administer repeat course until renal, hematologic, and hepatic functions are within acceptable limits.

Caution and Precaution: Highly toxic, with low therapeutic index; therapeutic response not likely to occur without some evidence of toxicity ;Renal toxicity occurs in 25–75% of patients. Dose limiting and cumulative; may be severe or fatal. Renal toxicity may manifest as azotemia, anuria, proteinuria, hypophosphatemia, hyperchloremia, and proximal renal tubular acidosis (possibly associated with Fanconi-like syndrome [e.g., glycosuria, acetonuria, aminoaciduria]). Hypokalemia and hypocalcemia also have occurred. Hypophosphatemia or mild proteinuria may be earliest sign of nephrotoxicity and may indicate impending further deterioration of renal function. Increased BUN and Scr may occur later if streptozocin is continued.

Common adverse effect: Severe nausea and vomiting, nephrotoxicity, myelosuppression.

Pharmacokenetics: Absorption: Poorly absorbed following oral administration. Not active orally; must be administered IV.

Distribution: Following IV or intraperitoneal administration in animals, rapidly distributed into liver, kidneys, intestine, and pancreas; lower concentrations in skeletal muscle, spleen, lungs, heart, and thymus. Does not appear to cross the blood-brain barrier; however, metabolites readily distribute into CSF. Readily crosses the placenta in monkeys. Not known whether streptozocin crosses the placenta or is distributed into milk in humans.

Elimination: Extensively metabolized, probably in the liver and kidneys. Elimination route: Excreted principally in urine as unchanged drug (10%) and metabolites (60–70%). May be excreted in expired air (5%) or in feces (<1%).

Half- life: Biphasic terminal half-life is approximately 35–40 minutes for streptozocin or >40 hours for metabolites.

Storage: Powder for Injection 2–8°C; protect from light, Store in carton. Reconstituted or diluted solution (i.e., diluted with 5% dextrose and 0.9% sodium chloride injection to final concentration of 2 mg/mL) stable for 48 hours at room

temperature or for ≥96 hours at 2–8°C. However, because product contains no preservatives, manufacturer recommends discarding reconstituted or diluted solution within 12 hours after preparation.

Alkylating like-agent:

Dacarbazine:

Generic Names: Biocarbazine R; DIC; DTIC; DTIE; Dacarbazino [INN-Spanish]; Dacarbazinum [INN-Latin]; Dtic-Dome; ICDMT; ICDT; Imidazole Carboxamide

Trade Names: Deticene


Description: An antineoplastic agent. It has significant activity against melanomas. (from Martindale, The Extra Pharmacopoeia, 31st ed, p564)

Indication: For the treatment of metastatic malignant melanoma. In addition, DTIC-Dome is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other effective agents

ATC Therapeutic category: L01AX: Other alkylating agents

Pharmacology,Interaction,and contraindications:

Mechanism of action: Possibly blocking the formation of inosinic acid.

Pharmacology: After intravenous administration of DTIC-Dome, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours. 1 The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in 6 hours. 1 DTIC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations DTIC is not appreciably bound to human plasma protein.

Absorption,Distribution,metabolism,elimination,&toxic

Biotransformation:Hepatic

Protein binding:Less than 5%

Absorption: Erratic, slow and incomplete

Toxicity: LD 50=350mg/kg (orally in mice)

Chemical category: isomeric smiles CN(C)N=Nc1c(nc[nH]1)C(=O)N

Cisplatin: Generic Names: CACP; CPDC; CPDD; Cis-DDP; Cis-Diaminedichloroplatinum; Cis-Diamminedichloroplatinum; DDP; DDPT; Diamminedichloroplatinum; Platinum Ammine Chloride; Platinum Ammonium Chloride; Platinum Diamine Dichloride; Trans-DDP; Trans-Diaminedichloroplatinum; Trans-Diamminedichloroplatinum; Trans-Dichlorodiammine Platinum; Trans-Platinumdiammine Dichloride Trade Names: Abiplatin; Biocisplatinum; Briplatin; Carboquone; Cis Pt II; Cismaplat; Cisplatine; Cisplatyl; Citoplationo; Lederplatin; Neoplatin; Plastin; Platamine; Platiblastin; Platidiam; Platinex; Platinol; Platinol-AQ; Platinoxan; Randa PharmGKB Accession Id: PA449014 Description: Cisplatin, cisplatinum or cis-diamminedichloroplatinum(II) (CDDP) is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumors. It was the first member of its class, which now also includes carboplatin and oxaliplatin. Indication: For the treatment of metastatic testicular tumors, metastatic ovarian tumors and advanced bladder cancer. ATC Therapeutic Category: L01XA: Platinum compounds

Pharmacology,Interaction and contraindication:


Pharmacology: Cisplatin is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

Absorption,Distribution,metabolism,elimination,&toxicity:

Protein binding: Greater than 90%.

Chemical properties: Isomeric smile [NH3][Pt]([NH3])(Cl)Cl

Thiotepa:

Antibiotic anti-neoplastic drugs:

Doxurubicin:

Generic Names: Doxorubicin HCl; Doxorubicin Hydrochloride; Doxorubicina [INN-Spanish]; Doxorubicine [INN-French]; Doxorubicinum [INN-Latin]; doxorubicin

Trade Names: ADM; Adriablastin; Adriamycin; Adriamycin PFS; Adriamycin RDF; Adriamycin Semiquinone; Adriblastin; Adriblastina; Caelyx; DM2; Doxil; Doxo; Myocet; RDF Rubex; Resmycin; Rubex


Description: Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of daunorubicin.

Indication: For the treatment of Koposi's sarcome connected to AIDS.

ATC Therapeutic category: L01DB: Anthracyclines and related substances Pharmacology,interactions,and contraindications

Mechanism of action: Doxorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Doxorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.

Pharmacology: Doxorubicin is an antineoplastic in the anthracycline class. General properties of drugs in this class include: interaction with DNA in a variety of different ways including intercalation (squeezing between the base pairs), DNA strand breakage and inhibition with the enzyme topoisomerase II. Most of these compounds have been isolated from natural sources and antibiotics. However, they lack the specificity of the antimicrobial antibiotics and thus produce significant toxicity. The anthracyclines are among the most important antitumor drugs available. Doxorubicin is widely used for the treatment of several solid tumors while daunorubicin and idarubicin are used exclusively for the treatment of leukemia. Doxorubicin may also inhibit polymerase activity, affect regulation of gene expression, and produce free radical damage to DNA. Doxorubicin possesses an antitumor effect against a wide spectrum of tumors, either grafted or spontaneous. The anthracyclines are cell cycle-nonspecific.

Food interaction: Liberal fluid intake to increase urine output and help the excretion of uric acid. Absorption, Distribution, Metabolism, Elimination & Toxicity

Protein binding: 70% Toxicity: LD 50=21800 ug/kg (rat, subcutaneous) Chemical properties:Isomeric smile

Mitomycin:

Generic Names: 7-Amino-9α-methoxymitosane; MMC; Mitamycin

Trade Names: Ametycin; Ametycine; Mit-C; Mito-C; Mitocin-C; Mitomycin (TN); Mitomycin C; Mitomycin-C; Mitomycinum; Mitomycinum C; Mitomycyna C [Polish]; Mitozytrex; Muamycin; Mutamycin; Mytomycin; Mytozytrex PharmGKB Accession Id: PA450524

Description: An antineoplastic antibiotic produced by Streptomyces caespitosus. It is one of the bi- or tri-functional alkylating agents causing cross-linking of DNA and inhibition of DNA synthesis.

Indications: For treatment of malignant neoplasm of lip, oral cavity, pharynx, digestive organs, peritoneum, female breast, and urinary bladder.

ATC therapeutic category: L01DC:Other cytotoxic antibiotics pharmacology,interaction,and contraindications: Mechanism of Action: Mitomycin is activated in vivo to a bifunctional and trifunctional alkylating agent. Binding to DNA leads to cross-linking and inhibition of DNA synthesis and function. Mitomycin is cell cycle phase-nonspecific.

Pharmacology: Mitomycin is one of the older chemotherapy drugs, which has been around and in use for decades. It is an antibiotic which has been shown to have antitumor activity. Mitomycin selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Mitomycin has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFa, and IL-2.

Absorption,distribution,metabolism elimination and toxicity:

Mechanism of action: Primarily hepatic, some in various other tissues.

Absorption: Erratic.

Toxicity: Oral, mouse: LD 50 = 23 mg/kg; Oral, rat: LD 50 = 30 mg/kg. Symptoms of overdose include nausea and vomiting.

Chemical properties: isomeric smileCC1=C(C(=O)C2=C(C1=O)[N@@]3C[C@H]4[C@@H]([C@@]3([C@@H]2COC(=O)N)

Bleomycin: Brand Name: Blenoxane

Category:anti-neoplastic Indications: Carcinoma, head and neck (treatment)Carcinoma, laryngeal (treatment) Bleomycin is indicated for treatment of Hodgkin's and non-Hodgkin's lymphomas Pharmacology/PharmacokineticsPhysicochemical characteristics: Hygroscopic; inactivated in vitro by agents containing sulfhydryl groups, hydrogen peroxide, and ascorbic acid.Mechanism of action/Effect: Bleomycin is classed as an antibiotic but is not used as an antimicrobial agent. Although bleomycin is effective against both cycling and non-cycling cells, it seems to be most effective in the G 2 phase of cell division. Its exact mechanism of antineoplastic action is unknown but may involve binding to DNA, inducing lability of the DNA structure, and reduced synthesis of DNA, and, to a lesser extent, RNA and proteins.Absorption: Approximately 45% of a dose is absorbed into the systemic circulation following intrapleural or intraperitoneal administration.Protein binding: Very low (1%).Biotransformation: Unknown; probably by enzyme degradation in tissues (based on animal studies). Tissue enzyme activity varies, which may determine toxicity and antitumor effect of bleomycin; enzyme activity is high in the liver and kidneys, as well as in bone marrow and lymph nodes, but is low in the skin and lungs. It is not known if any metabolites are active Half-life: Creatinine clearance greater than 35 mL per minute—115 minutes.Creatinine clearance less than 35 mL per minute—Increases exponentially as creatinine clearance decrease.Elimination: Renal, 60 to 70%, largely as unchanged drug ,markedly reduced in renal failure. In dialysis—probably not dialyzable. Precautions while using this medication Importance of close monitoring by physician Caution if any kind of surgery (including dental surgery) or emergency treatment is requiredSide/adverse effects:Signs of potential side effects, especially fever and chills, pneumonitis, pulmonary fibrosis, mild stomatitis due to mucocutaneous toxicity, idiosyncratic reaction, hepatic toxicity, pleuropericarditis, renal toxicity, or vascular toxicity, including cerebral arteritis, cerebrovascular accident, myocardial infarction, and/or thrombotic microangiopathy;Possibility of hair loss; normal hair growth should return after treatment has ended (may take several months);Pulmonary toxicity more likely in smokersIt is recommended that bleomycin be administered to patients under supervision of a physician experienced in cancer chemotherapy. It is also recommended that equipment and medications (including epinephrine, oxygen, diphenhydramine, and intravenous corticosteroids) necessary for treatment of a possible anaphylactic reaction be readily available at each administration of bleomycin.

For treatment of adverse effects: Treatment of the idiosyncratic reaction is symptomatic and may consist of volume expansion, pressor agents, antihistamines, and corticosteroids Packaging and storage: Store between 2 and 8 °C (36 and 46 °F).Preparation of dosage form:Sterile bleomycin sulfate may be prepared for intramuscular or subcutaneous use by dissolving the contents of the vial (15 Units [base]) in 1 to 5 mL of sterile water for injection, 0.9% sodium chloride

for injection, or bacteriostatic water for injection.

Plicamycin: Brand name: Mithracin Pharmacologic class: Crystalline compound produced by Streptomyces plicatus Therapeutic class: Antibiotic antineoplastic Pregnancy risk category X :Drug is for I.V. use only. Due to risk of severe reactions, give only to hospitalized patients under supervision of qualified physician experienced in use of cancer chemotherapy, where laboratory resources are available for necessary tests. Severe thrombocytopenia, hemorrhagic tendency, and even death may occur. Severe toxicity is more likely in patients with far-advanced disease or who otherwise are poor risks for therapy. However, serious toxicity also may occur in patients in relatively good condition. Before therapy starts, clinician must weigh potential benefits against toxicity risk and thoroughly review data regarding drug use in treating testicular tumors and hypercalcemic or hypercalciuric conditions linked to advanced cancers.

Action: Unknown. Thought to form complex that causes cross-linking of DNA strands, inhibiting cellular RNA and enzymatic RNA synthesis.

Availability:Injection: 2.5-mg vials ⊘Indications and dosages : Testicular cancer Adults: 25 to 30 mcg/kg/day I.V. over 4 to 6 hours for 8 to 10 days, unless significant adverse effects or toxicity occur. Treatment course exceeding 10 daily doses not recommended. Hypercalcemia and hypercalciuria related to advanced cancer Adults: 25 mcg/kg/day I.V. over 4 to 6 hours for 3 to 4 days; may repeat weekly until adequate response occurs Dosage adjustment: Renal failure Contraindication: Hypersensitivity to drug;Thrombocytopenia, thrombocytopathy Bone marrow depression; Coagulation disorders or increased risk of bleeding Females of childbearing potential; Pregnancy or breastfeeding Precautions: Use cautiously in: renal or hepatic disease, electrolyte imbalances. Adminstration: Follow facility policy for preparing, handling, and administering carcinogenic, mutagenic, or teratogenic drugs. Don't let drug touch skin or mucous membranes.Give antiemetic before plicamycin, as prescribed, to reduce nausea and vomiting.Dilute with 4.9 ml of sterile water for injection. Shake vial to dissolve. Further dilute in 1,000 ml of dextrose 5% in water or normal saline solution. Infuse I.V. over 4 to 6 hours. Discard unused portion.

Route Onset Peak Duration

I.V. 1-2 days 3 days 3-15 days

Adverse reactions:CNS: headache, malaise, drowsiness, asthenia, lethargy, depressionCV: phlebitis GI: nausea, vomiting, diarrhea, stomatitis, anorexiaGU: proteinuria Hematologic: leukopenia, thrombocytopenia, bleeding syndrome Hepatic: mild and reversible hepatotoxicity

Metabolic: hypokalemia, hypocalcemia, hypophosphatemia

Skin: facial flushing; rash; pain, redness, or swelling at injection site; cellulitis with extravasation

Other: fever

Interactions: Drug-drug. Other antineoplastics: increased plicamycin toxicity

Drug-diagnostic tests. Blood urea nitrogen, creatinine, hepatic enzymes: increased levels

Calcium, phosphate, potassium, platelets, white blood cells (WBCs): decreased levels

Drug-herbs. Anise, arnica, chamomile, clove, dong quai, fenugreek, garlic, ginger, ginkgo, ginseng, licorice: increased risk of bleeding,Chaparral, comfrey, eucalyptus, germander, jin bu huan, kava, pennyroyal, skullcap, valerian: increased risk of hepatotoxicity Patient monitoring:Watch closely for bleeding syndrome, which usually starts with epistaxis and progresses quickly.Monitor liver function tests, electrolyte levels, platelet and WBC counts, and prothrombin time. Notify prescriber of platelet count less than 150,000/mm3, WBC count less than 4,000/mm3, or prothrombin time greater than 4 seconds longer than control. Assess for indications of sudden drop in calcium level, such as Chvostek's sign, muscle cramps, carpopedal spasm, or tetany.Monitor I.V. site closely to avoid extravasation.

Patient teaching:

Teach patient to recognize and immediately report easy bruising, bleeding, and hypocalcemia. Inform him that nosebleed may be first sign of a bleeding problem. Instruct patient to report unusual pain, redness, swelling, or other changes at infusion site. Caution female of childbearing age to avoid pregnancy during therapy. Advise her to report suspected pregnancy right away. Instruct patient to avoid herbs, because many herbs increase the risk of liver damage. As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and herbs mentioned above.

Alkyl sulfunates:

Busulfan: Generic Names: Busulphan; Busulphane; Butanedioldimethanesulfonate; Buzulfan; Sulfabutin; Sulphabutin; Tetramethylene Dimethane Sulfonate; Tetramethylenester Kyseliny Methansulfonove; busulfan Trade Names: Busulfex; Citosulfan; Leucosulfan; Mablin; Mielevcin; Mielosan; Mielucin; Milecitan; Mileran; Misulban; Mitosan; Mitostan; Myeleukon; Myeloleukon; Myelosan; Mylecytan; Myleran; Myleran Tablets PharmGKB Accession Id: PA448691 Description: An alkylating agent having a selective immunosuppressive effect on bone marrow. It has been used in the palliative treatment of chronic myeloid leukemia (myeloid leukemia, chronic), but although symptomatic relief is provided, no permanent remission is brought about. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), busulfan is listed as a known carcinogen. Indication: For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia. ATC therapeutic category: L01AB:Alkyl sulfonates

Pharmacology,interaction,and contraindications: Mechanism of action: Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. Pharmacology:Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. Food Interaction:Drink liberally.Take without regard to meals. Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation:Mainly Hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. Protein binding: 32.4% Absorption: Completely absorbed from the gastrointestinal tract.

Toxicity: Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain;

pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness.

Chemical Properties: Isomeric smile CS(=O)(=O)OCCCCOS(=O)(=O)C

Anti-Metabolites agents:

Generic Names: -Etoposide; Etoposidum [INN-Latin]; trans-Etoposide Trade Names: Eposin; Etopophos; Lastet; Toposar; Vepesid; Vepesid J; Zuyeyidal PharmGKB Accession Id: PA449552

Description: A semisynthetic derivative of podophyllotoxin that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.

Indication: For use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer. Also used to treat other malignancies such as lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme.

ATC therapeutic category: L01CB:Podophyllotoxin derivatives Pharmacology,interaction,and contraindication Mechanism of Action: Etoposide inhibits DNA topoisomerase II, thereby inhibiting DNA synthesis at the premitotic stage of cell division. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases of cell division.

Pharmacology: Etoposide is an antineoplastic agent and an epipodophyllotoxin (a semisynthetic derivative of the podophyllotoxins). It inhibits DNA topoisomerase II, thereby inhibiting DNA synthesis. Etoposide is cell cycle dependent and phase specific, affecting mainly the S and G2 phases. Two different dose-dependent responses are seen. At high concentrations (10 µg/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 µg/mL), cells are inhibited from entering prophase. It does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be the induction of DNA strand breaks by an interaction with DNA-topoisomerase II or the formation of free radicals.

Food interaction: Grapefruit and grapefruit juice should be avoided throughout treatment as grapefruit can decrease serum levels of this product. Absorption, Distribution, Metabolism, Elimination & Toxicity Biotransformation:Primarily hepatic (through O-demethylation via the CYP450 3A4 isoenzyme pathway) with 40% excreted unchanged in the urine. Protein binding: 97% Absorption: Absorbed well, time to peak plasma concentration is 1-1.5 hrs. Mean bioavailability is 50%. Toxicity: Side effects include alopecia, constipation, diarrhea, nausea and vomiting and secondary malignancies (leukemia).

Chemical properties: isomeric smile: C[C@@H]1OC[C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H](O2)OC3c4cc5c(cc4[C@H]([C@@H]6C3COC6=O)c7cc

Trade Names: 5 Fluorouracil; Adrucil; Arumel; Carac; Carzonal; Effluderm; Efudex; Efudix; Efurix; FU; Fluoroblastin; Fluoroplex; Fluracil; Fluracilum; Fluri; Fluril; Fluro Uracil; Flurouracil; Ftoruracil; Kecimeton; Phthoruracil; Phtoruracil; Queroplex; Timazin; URF; Ulup PharmGKB Accession Id: PA128406956

Description: A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid.

Indication: For the topical treatment of multiple actinic or solar keratoses. In the 5% strength it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Fluorouracil injection is indicated in the palliative management of some types of cancer, including colon, rectum, breast, stomach and pancreas.

ATC therapeutic category: L01BC:Pyrimidine analogues

Pharmacology, Interactions, and Contraindications

Mechanism of Action: Fluorouracil inhibits thymidylate synthetase, leading to inhibition of DNA and RNA synthesis and cell death.

Pharmacology: Fluorouracil is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Fluorouracil blocks an enzyme which converts the cytosine nucleotide into the deoxy derivative. In addition, DNA synthesis is further inhibited because Fluorouracil blocks the incorporation of the thymidine nucleotide into the DNA strand.

Food interaction: Vitamin B1 needs increased with long term use.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation: Hepatic

Protein binding: 8-12%

Absorption: 28-100%

Toxicity: LD 50=230mg/kg (orally in mice)

Chemical Properties:Isomeric smile c1c(c(=O)[nH]c(=O)[nH]1)F

Thioguanine: Generic Names: 2-Amino 6MP; 2-Amino-6-mercaptopurine; 2-Amino-6-merkaptopurin; 2-Amino-6-purinethiol; 2-Aminopurin-6-thiol; 2-Aminopurine-6(1H)-thione; 2-Aminopurine-6-thiol; 6-Mercapto-2-aminopurine; 6-Mercaptoguanine; 6-Thioguanine; TG; ThG; Tioguanin; Tioguanine Trade Names: Lanvis; Tabloid; Wellcome U3B PharmGKB Accession Id: PA451663 Description: An antineoplastic compound which also has antimetabolite action. The drug is used in the therapy of acute leukemia.

Indication: For remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.

ATC therapeutic category: L01BB:Purine analogues Pharmacology, Interactions, and Contraindications Mechanism of Action: Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides.

Pharmacology: Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase). Absorption, Distribution, Metabolism, Elimination & Toxicity Biotransformation:Hepatic. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides. Absorption:Absorption of an oral dose is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%)Toxicity:Oral, mouse: LD 50 = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis.

Chemical properties:isomeric smile c1[nH]c2c(=S)[nH]c(nc2n1)N

Methotrexate: Generic Names: Amethopterin; Amethopterine; HDMTX; L-Amethopterin; MTX; Methopterin; Methotextrate; Methotrexat; Methotrexate Sodium; Methylaminopterin; Methylaminopterinum; N-Bismethylpteroylglutamic Acid Trade Names: Abitrexate; Antifolan; Arbitrexate; Emtexate; Folex; Ledertrexate; Metatrexan; Methotrate; Mexate; Rheumatrex; Trexall PharmGKB Accession Id: PA450428

Description: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.

Indication: For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis.

ATC therapeutic category: L04AX:Other immunosuppressants Pharmacology, Interactions, and Contraindications Mechanism of Action: Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.

Pharmacology: Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrexate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). Methotrexate is also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.

Food interaction: Milk appears to reduce its absorption.Take without regard to meals. Limit caffeine intake. Absorption, Distribution, Metabolism, Elimination & Toxicity Biotransformation:Hepatic.

Protein binding: 50%, primarily to albumin

Absorption: Generally well absorbed with a mean bioavailability of about 60%.

Toxicity: Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD 50=43mg/kg(orally in rat). Chemical properties:isomeric :CN(Cc1cnc2c(n1)c(nc(n2)N)N)c3ccc(cc3)C(=O)NC(CCC(=O)O)C(=O)O

Immunosuppressive drugs:

Drug description: Imuran(azathioprine)50-mg Scored Tablets100 mg (as the sodium salt) for I.V. injection,Equivalent to 100 mg azathioprine sterile lyophilized material.IMURAN (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration and 100-mg vials for intravenous injection. Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid. Each 100-mg vial contains azathioprine, as the sodium salt, equivalent to 100 mg azathioprine sterile lyophilized material and sodium hydroxide to adjust pH.

Indications:Renal Homotransplantation: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. The effect of IMURAN on these variables has not been tested in controlled trials.Rheumatoid Arthritis: IMURAN is indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms.aspiren, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with IMURAN. The combined use of IMURAN with disease modifying antirheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with these agents cannot be recommended.

Parenteral Administration: Add 10 mL of Sterile Water for Injection, and swirl until a clear solution results. This solution, equivalent to 100 mg azathioprine, is for intravenous use only; it has a pH of approximately 9.6, and it should be used within 24 hours. Further dilution into sterile saline or dextrose,is usually made for infusion; the final volume depends on time for the infusion, usually 30 to 60 minutes, but as short as 5 minutes and as long as 8 hours for the daily dose.

Side effects: hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of Therapy with IMURAN. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Macrocytic anemia and/or bleeding have been reported.

Drug interactions: Use with Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving IMURAN and allopurinol because both TPMT and XO inactivation pathways are affected.

Clinical pharmacology:Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptupurine.derived from it, which are low ( < 1 mcg/mL). Blood levels are of

little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable.

Generic Names: Ciclosporin; Cyclosporin; Cyclosporin A; cyclosporine Trade Names: Gengraf (Abbott labs); Neoral (Novartis); Restasis; Restasis (Allergan Inc); Sandimmune (Novartis); Sangcya PharmGKB Accession Id: PA449167

Description: A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed).

Indication: For treatment of transplant rejection, rheumatoid arthritis, severe psoriasis ATC Therapeutic Category Pharmacology, Interactions, and Contraindications Mechanism of Action:Cyclosporine binds to cyclophillin. The complex then inhibits calcineurin which is normally responsible for activating transcription of interleukin 2. Cyclosporine also inhibits lymphokine production and interleukin release. In ophthalmic applications, the precise mechanism of action is not known. Cyclosporine emulsion is thought to act as a partial immunomodulator in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Pharmacology:Used in immunosuppression for prophylactic treatment of organ transplants, cyclosporine exerts specific and reversible inhibition of immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T1-helper cell is the main target, although the T1-suppressor cell may also be suppressed. Sandimmune (cyclosporine) also inhibits lymphokine production and release including interleukin-2.

Food interaction: Avoid salt substitutes containing potassium.Avoid taking with grapefruit or grapefruit juice as grapefruit can significantly increase serum levels of this product.Red wine may reduce cyclosporine levels due to increased metabolism, therefore it appears prudent to avoid red wine (white wine does not appear to affect cyclosporine metabolism).Take without regard to meals. Absorption, Distribution, Metabolism, Elimination & Toxicity Biotransformatio : Hepatic, extensively metabolized.

Protein binding: Approximately 90% is bound to proteins, primarily lipoproteins.

Absorption: The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients.

Toxicity: The oral LD 50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD 50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits. Chemical Properties: Isomeric SMILES

CC[C@H]1C(=O)N(CC(=O)N([C@H](C(=O)N[C@H](C(=O)N([C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N1)[C@@H]([C@H](C)C/C=C/C)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C

Generic Names: FK-506; FK5; FK506; K506; Tacarolimus; tacrolimus; tacrolimus hydrate Trade Names: Fujimycin; LCP-Tacro; Prograf; Protopic PharmGKB Accession Id: PA451578 Description: Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It was discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Indications: For use after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It was first approved by the FDA in 1994 for use in liver transplantation, this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis. ATC Therapeutic Categories :D11AX:Other dermatologicals ;L04AA:Selective immunosuppressants Pharmacology, Interactions, and Contraindications Mechanism of Action: The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Pharmacology: Tacrolimus is a macrolide antibiotic. It acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to cyclosporine studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporine. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they think the skin dramatically there. Absorption, Distribution, Metabolism, Elimination & Toxicity Biotransformation:Hepatic, extensive, primarily by CYP3A4. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. Protein binding:75-99% Absorption: 20% bioavailability; less after eating food rich in fat Toxicity:Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD 50=134-

194 mg/kg (rat). Chemical properties:isomeric smile C[C@@H]1C[C@@H]([C@@H]2[C@H](C[C@H]([C@@](O2)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@@H]([C@@H]

Basiliximab: Pharmacologic class: Monoclonal antibody Therapeutic class: Immunosuppressant Pregnancy risk category B FDA Boxed Warning: Give under supervision of physician experienced in immunosuppressive therapy and management of organ transplant recipients, in facility with adequate diagnostic and treatment resources. Action:Blocks specific interleukin-2 (IL-2) receptor sites on activated T lymphocytes. Specific binding competitively inhibits IL-2-mediated activation and differentiation of lymphocytes responsible for cell-mediated immunity. Also impairs immunologic response to antigenic challenges. Availabilty: Powder for injection: 20 mg in single-use vials ⊘Indications and dosages :Prevention of acute organ rejection in kidney transplantation Adults and children weighing 35 kg (77 lb) or more: 20 mg I.V. 2 hours before transplantation surgery, then 20 mg I.V. 4 days after surgery. Withhold second dose if complications, hypersensitivity reaction, or graft loss occurs. Children weighing less than 35 kg (77 lb): 10 mg I.V. 2 hours before transplantation surgery, then 10 mg I.V. 4 days after surgery. Withhold second dose if complications, hypersensitivity reaction, or graft loss occurs. Contraindication: Hypersensitivity to drug; Pregnancy or breastfeeding Precautions: Use cautiously in:elderly patients;females of childbearing age. Administration: Give by central or peripheral I.V. route only. Reconstitute by adding 5 ml of sterile water for injection to vial for bolus injection, or dilute with normal saline solution or dextrose 5% in water to a volume of 50 ml and infuse over 20 to 30 minutes. Discard any remaining product after preparing each dose. Don't infuse other drugs simultaneously through same I.V. line. Know that drug should be used only as part of regimen that includes cyclosporine and corticosteroids.

Route Onset Peak Duration

I.V. 2 hr Unknown 36 days

Adverse effect: CNS: headache, insomnia, paresthesia, dizziness, drowsiness, tremor, anxiety, confusion, coma, seizures ;CV: palpitations, edema, chest pain, ECG abnormalities, hypotension, hypertension, prolonged QT interval ;EENT: blurred vision, eye irritation, tinnitus, earache, epistaxis, nasopharyngitis, sinusitis;GI: nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, oral blisters, oral candidiasis, GI hemorrhage ;GU: urinary incontinence, intermenstrual bleeding, oliguria, renal;failure ;Hematologic: anemia, disseminated intravascular coagulation, hemorrhage, neutropenia, thrombocytopenia ;Metabolic: hypokalemia, hypomagnesemia, hyperglycemia, acidosis, hypoglycemia, hyperkalemia ;Musculoskeletal: bone, back, neck, or limb pain;Respiratory: dyspnea, cough, hypoxia, tachypnea, hemoptysis, upper respiratory tract infection, pleural effusions ;Skin: bruising, pruritus, dermatitis, skin lesions, diaphoresis, night sweats, erythema, hyperpigmentation, urticaria

Interactions:Drug-drug. Immunosuppressants: additive immunosuppression Drug-diagnostic tests. Alanine aminotransferase, aspartate aminotransferase, magnesium, calcium, white blood cells: increased levels Glucose, potassium: increased or decreased levelsHemoglobin, neutrophils, platelets: decreased values

Immuno-modulating drugs:

Generic Names: Ig gamma-1 chain C region

Trade Names: Remicade (Centocor Inc)


Description: Tumor necrosis factor (TNF-alpha) binding antibody (chimeric IgG1). It is composed of human constant and murine variable regions. Infliximab is produced by a recombinant cell line cultured by continuous perfusion

Indication: For treatment of Crohn's disease, psoriasis, rheumatoid arthitis and ankylosing spondylitis

ATC Therapeutic Category : L04AA:Selective immunosuppressants Pharmacology, Interactions, and Contraindications

Mechanism of Action: Infliximab neutralizes the biological activity of TNFa by binding with high affinity to the soluble and transmembrane forms of TNFa and inhibits binding of TNFa with its receptors. Infliximab does not neutralize TNFb (lymphotoxin a), a related cytokine that utilizes the same receptors as TNFa

Pharmacology: Used in the treatment of auto-immune disorders such as Crohn's disease and rheumatoid arthritis. Infliximab binds to tumor necrosis factor alpha (TNFa) and inhibits binding of TNFa with its receptors. This reduces production of pro-inflammatory cytokines such as interleukins (IL) 1 and 6. This also limits leukocyte migration and expression of adhesion molecules by endothelial cells and leukocytes. Infliximab also limits the activation of neutrophil and eosinophil functional activity, reduces production of tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Infliximab decreases synovitis and joint erosions in collagen-induced arthritis and allows eroded joints to heal.


Biotransformation: Most likely removed by opsonization via the reticuloendothelial system when bound to T ly

Generic Names:

Leflunomidum [INN-Latin]; Lefunomide [INN-Spanish]; leflunomide

Trade Names:

Arava

PharmGKB Accession Id:

PA450192

Description: Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries (e.g., Canada, Europe) in 1999.

Indication: rheumatoid arthritis (RA). ATC Therapeutic Category L04AA:Selective immunosuppressants Pharmacology, Interactions, and Contraindications Mechanism of Action: Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Specifically Leflunomide blocks the de novo synthesis of pyrimidines, thus preventing the proliferation of activated T cells. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 which is responsible for essentially all of its activity in vivo.

Pharmacology: Leflunomide is a pyrimidine synthesis inhibitor indicated in adults for the treatment of active rheumatoid arthritis (RA). RA is an auto-immune disease characterized by high T-cell activity. T cells have two pathways to synthesize pyrimidines: the salvage pathways and the de novo synthesis. At rest, T lymphocytes meet their metabolic requirements by the salvage pathway. Activated lymphocytes need to expand their pyrimidine pool 7- to 8-fold, while the purine pool is expanded only 2- to 3-fold. To meet the need for more pyrimidines, activated T cells use the de novo pathway for pyrimidine synthesis. Therefore, activated T cells, which are dependent on de novo pyrimidine synthesis, will be more affected by leflunomide's inhibition of dihydroorotate dehydrogenase than other cell types that use the salvage pathway of pyrimidine synthesis.

Food interaction: Take without regard to meals. Absorption, Distribution, Metabolism, Elimination & Toxicity Biotransformation: Primarily hepatic. Leflunomide is converted to its active form following oral intake.

Protein binding:>99.3%

Absorpton: Well absorbed, peak plasma concentrations appear 6-12 hours after dosing

Toxicity: LD 50=100-250 mg/kg (acute oral toxicity) Chemical Properties: Isomeric SMILES Cc1c(cno1)C(=O)Nc2ccc(cc2)C(F)(F)F

Anti-inflamatory drugs:

Aspirin:

Generic Names:

2-Acetoxybenzenecarboxylic acid; 2-Acetoxybenzoic acid; 2-Carboxyphenyl acetate; A.S.A.; ASA; Acetilsalicilico; Acetilum acidulatum; Acetosalic acid; Acetoxybenzoic acid; Acetylsalicylate; Acetylsalicylic acid; Acetylsalicylsaure (GERMAN); Acetysalicylic acid; Acide acetylsalicylique (FRENCH); Acido O-acetil-benzoico; Acido acetilsalicilico; Acidum acetylsalicylicum; Kyselina 2-acetoxybenzoova; Kyselina acetylsalicylova; O-Acetylsalicylic acid; O-accetylsalicylic acid; Salicylic acid acetate; Salicylic acid, acetate; o-Acetoxybenzoic acid; o-Carboxyphenyl acetate

Trade Names:

8-hour Bayer; A.S.A. Empirin; Acenterine; Acesal; Acetal; Aceticyl; Acetisal; Acetol; Acetonyl; Acetophen; Acetosal; Acetosalin; Acetylin; Acetylsal; Acimetten; Acisal; Acylpyrin; Adiro; Asagran; Asatard; Ascoden-30; Aspalon; Aspec; Aspergum; Aspirdrops; Aspirine; Aspro; Asteric; Bayer Extra Strength Aspirin For Migraine Pain; Benaspir; Bi-prin; Bialpirina; Bialpirinia; Bufferin; Caprin; Cemirit; Claradin; Clariprin; Colfarit; Contrheuma retard; Coricidin; Crystar; Decaten; Delgesic; Dolean pH 8; Duramax; ECM; Easprin; Ecolen; Ecotrin; Empirin; Endydol; Entericin; Enterophen; Enterosarein; Enterosarine; Entrophen; Extren; Globentyl; Globoid; Helicon; Idragin; Levius; Measurin; Micristin; Neuronika; Novid; Nu-seals; Nu-seals aspirin; Persistin; Pharmacin; Pirseal; Polopiryna; Premaspin; Rheumintabletten; Rhodine; Rhonal; Salacetin; Salcetogen; Saletin; Solfrin; Solprin; Solprin acid; Solpyron; Spira-Dine; St. Joseph; St. Joseph Aspirin for Adults; Supac; Tasprin; Temperal; Triaminicin; Triple-sal; Vanquish; Xaxa; Yasta

Brand Mixtures:

Aspirin Plus Stomach Guard (Acetylsalicylic Acid + Calcium Carbonate + Magnesium Carbonate + Magnesium Oxide); Aspirin Plus Stomach Guard Ext.Stgth.Caplet (Acetylsalicylic Acid + Calcium Carbonate + Magnesium Carbonate + Magnesium Oxide); Aspirin Plus Stomach Guard Extra Strength (Acetylsalicylic Acid + Calcium Carbonate + Magnesium Carbonate + Magnesium Oxide); Aspirin Plus Stomach Guard Tab (Acetylsalicylic Acid + Calcium Carbonate + Magnesium Carbonate + Magnesium Oxide); Aspirin with Stomach Guard (Acetylsalicylic Acid + Calcium Carbonate + Magnesium Carbonate + Magnesium Oxide)

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PA448497

http://www.pharmgkb.org/do/serve?objId=PA448497

Description

The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. (From Martindale, The Extra Pharmacopoeia, 30th ed, p5)

Source: unavailable

Indication

For use in the temporary relief of various forms of pain, inflammation associated with various conditions (including rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and ankylosing spondylitis), and is also used to reduce the risk of death and/or nonfatal myocardial infarction in patients with a previous infarction or unstable angina pectoris.

Source: Drug Bank

ATC Therapeutic Categories

A01AD:Other agents for local oral treatment B01AC:Platelet aggregation inhibitors excl. heparin N02BA:Salicylic acid and derivatives


Mechanism of Action

The analgesic, antipyretic, and anti-inflammatory effects of aspirin are due to actions by both the acetyl and the salicylate portions of the intact molecule as well as by the active salicylate metabolite. Aspirin directly and irreversibly inhibits the activity of both types of cyclo-oxygenase (COX-1 and COX-2) to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid. This makes aspirin different from other NSAIDS (such as diclofenac and ibuprofen) which are reversible inhibitors. Salicylate may competitively inhibit prostaglandin formation. Aspirin's antirheumatic (nonsteroidal anti-inflammatory) actions are a result of its analgesic and anti-inflammatory mechanisms; the therapeutic effects are not due to pituitary-adrenal stimulation. The platelet aggregation–inhibiting effect of aspirin specifically involves the compound's ability to act as an acetyl donor to the platelet membrane; the nonacetylated salicylates have no clinically significant effect on platelet aggregation. Aspirin affects platelet function by inhibiting the enzyme prostaglandin cyclooxygenase in platelets, thereby preventing the formation of the aggregating agent thromboxane A2. This action is irreversible; the effects persist for the life of the platelets exposed. Aspirin may also inhibit formation of the platelet aggregation inhibitor prostacyclin (prostaglandin I2) in blood vessels; however, this action is reversible.

Pharmacology

Aspirin (acetylsalicylic acid) is an analgesic, antipyretic, antirheumatic, and anti-inflammatory agent. Aspirin's mode of action as an antiinflammatory and antirheumatic agent may be due to inhibition of synthesis and release of prostaglandins. Aspirin appears to produce analgesia by virtue of both a peripheral

and CNS effect. Peripherally, Aspirin acts by inhibiting the synthesis and release of prostaglandins. Acting centrally, it would appear to produce analgesia at a hypothalamic site in the brain, although the mode of action is not known. Aspirin also acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow. Aspirin's antipyretic activity may also be related to inhibition of synthesis and release of prostaglandins.

Food Interaction

Avoid alcohol, alcohol appears to cause a 50 to 100% increases in ASA serum levels.Avoid drastic changes in dietary habit.Consult your doctor before taking large amounts of Vitamin K (Green leafy vegetables).Take with a full glass of water.Take with food to reduce irritation.

Source: Drug Bank


Biotransformation

Aspirin is rapidly hydrolyzed primarily in the liver to salicylic acid, which is conjugated with glycine (forming salicyluric acid) and glucuronic acid and excreted largely in the urine.

Source: Drug Bank

Protein Binding

High (99.5%) to albumin. Decreases as plasma salicylate concentration increases, with reduced plasma albumin concentration or renal dysfunction, and during pregnancy.

Source: Drug Bank

Absorption

Absorption is generally rapid and complete following oral administration but may vary according to specific salicylate used, dosage form, and other factors such as tablet dissolution rate and gastric or intraluminal pH.

Source: Drug Bank

Toxicity

Oral, mouse: LD 50 = 250 mg/kg; Oral, rabbit: LD 50 = 1010 mg/kg; Oral, rat: LD 50 = 200 mg/kg. Effects of overdose include: tinnitus, abdominal pain, hypokalemia, hypoglycemia, pyrexia, hyperventilation, dysrhythmia, hypotension, hallucination, renal failure, confusion, seizure, coma, and death.

Source: Drug Bank

Chemical Properties

Isomeric SMILESCC(=O)Oc1ccccc1C(=O)O

Drugs for arthritis:

Allopurinol:

Generic Names:

Allopurinol Sodium; Allopurinolum [INN-Latin]; Alopurinol [INN-Spanish]

Trade Names:

7HP; Adenock; Ailural; Allo-Puren; Allohexal; Allopur; Allozym; Allural; Aloprim; Aloral; Alositol; Aluline; Anoprolin; Anzief; Apo-Allopurinol; Apulonga; Apurin; Apurol; Atisuril; Bleminol; Bloxanth; Caplenal; Cellidrin; Cosuric; Dabrosin; Dabroson; Dura Al; Embarin; Epidropal; Epuric; Foligan; Geapur; Gichtex; Gotax; HPP; Hamarin; Hexanuret; Ketanrift; Ketobun-A; Ledopur; Lopurin; Lysuron; Milurit; Miniplanor; Monarch; Nektrohan; Progout; Purinol; Remid; Riball; Sigapurol; Suspendol; Takanarumin; Urbol; Uricemil; Uriprim; Uripurinol; Uritas; Urobenyl; Urolit; Urosin; Urtias; Urtias 100; Xanturat; Zyloprim; Zyloric


PA448320

Description

A xanthine oxidase inhibitor that decreases uric acid production. It also acts as an antimetabolite on some simpler organisms.

Source: Drug Bank

Indication

For the treatment of hyperuricemia associated with primary or secondary gout.

Source: Drug Bank

ATC Therapeutic Category

M04AA:Preparations inhibiting uric acid production


Mechanism of Action

Allopurinol inhibits the enzyme xanthine oxidase, blocking the conversion of the oxypurines hypoxanthine and xanthine to uric acid. Elevated concentrations of oxypurine and oxypurine inhibition of xanthine oxidase through negative feedback results in a decrease in the concentrations of uric acid in the blood and urine. Allopurinol also facilitates the incorporation of hypoxanthine and xanthine into DNA and RNA, resulting in further reductions of serum uric acid concentrations.

Source: Drug Bank

Pharmacology

Allopurinol, a structural analog of the natural purine base hypoxanthine, is used to prevent gout and renal calculi due to either uric acid or calcium oxalate and to treat uric acid nephropathy, hyperuricemia, and some solid tumors.

Source: Drug Bank

Food Interaction

Avoid alcohol.Take with a full glass of water.Take with food.

Source: Drug Bank


Biotransformation

Hepatic

Source: Drug Bank

Protein Binding

Negligible

Source: Drug Bank

Absorption

Approximately 90% absorbed from the gastrointestinal tract.

Source: Drug Bank

Toxicity

LD 50=214 mg/kg (in mice)

Chemical Properties

Isomeric SMILESc1c2c([nH]n1)ncnc2O

Generic Names:

Sulfasalazin; Sulphasalazine

Trade Names:

Accucol; Alti-Sulfasalazine; Asulfidine; Azlufidine EN-Tabs; Azopyrin; Azopyrine; Azulfidine; Azulfidine EN-Tabs; Benzosulfa; Colo-Pleon; PMS-Sulfasalazine; Pms-Sulfasalazine E.C.; Reupirin; Rorasul; S.A.S. Enteric-500; Salazopiridazin; Salazopyridin; Salazopyrin; Salazopyrin EN-Tabs; Salazosulfapyridin; Salazosulfapyridine; Salicylazosulfapyridine; Salisulf; Sulcolon; W-T Sasp Oral


PA451547

Description

A drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid (see mesalamine) released in the colon. (From Martindale, The Extra Pharmacopoeia, 30th ed, p907)

Source: Drug Bank

Indication

For the treatment of Crohn's disease and rheumatoid arthritis as a second-line agent.

Source: Drug Bank

ATC Therapeutic Category

A07EC:Aminosalicylic acid and similar agents


Mechanism of Action

The mode of action of Sulfasalazine or its metabolites, 5-aminosalicylic acid (5-ASA) and sulfapyridine (SP), is still under investigation, but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of Sulfasalazine, SP and 5-ASA have indicated that the major therapeutic action may reside in the 5-ASA moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown.

Source: Drug Bank

Pharmacology

Sulfasalazine is an anti-inflammatory indicated for the treatment of ulcerative colitis and rheumatoid arthritis.

Source: Drug Bank

Food Interaction

May take Vitamin D.Take with a full glass of water No iron, zinc or fluoride within 2 hours of taking this medication.Take with food.

Source: Drug Bank

Chemical Properties

Isomeric SMILESc1ccnc(c1)NS(=O)(=O)c2ccc(cc2)N=Nc3ccc(c(c3)C(=O)O)O

Anorexiant drugs:

Pronunciation: fen-MET-rah-zeenChemical Abstracts Service Registry Number: 134-49-6Formal Names: Filon, PreludinInformal Names: SweetiesType: Stimulant (anorectic class).Uses. Immediately upon announcement of the drug’s discovery in 1954 it was utilized in Germany as an appetite suppressant. A couple years later the same medical use began in the United States with expansive claims about

http://drugsencyclopedia.net/category/stimulant/

patients obtaining substantial weight loss without having to follow a regimen of dieting, claims that became more modest as experience with the drug spread. One experiment testing the drug’s influence on appetite yielded a result relevant to drug experiments in general: The substance worked better when people knew its intended effect. If people knew they were supposed to feel less hungry, they noticed less desire for food and then ate less. Early reports praised phenmetrazine for producing more appetite loss than amphetamine and with fewer unwanted effects. Since then phenmetrazine has fallen into disfavor due to concern about addictive potential even though the drug is described as resembling caffeine more than amphetamine.

Drug interactions. An experiment found that chlorpromazine (Thorazine) interacts with phenmetrazine, hindering phenmetrazine’s normal anorectic benefit.

Cancer. In pregnant women phenmetrazine may undergo transformations suspected of promoting childhood tumors.

Pregnancy. Phenmetrazine was formerly prescribed to pregnant women seeking to lose weight. A study of over 10,000 birth and childhood records found the drug having no “severe” impact on fetal development. Other studies have found no birth defects at all, although medical literature from the early 1960s does contain a handful of reports in which the drug is suspected of harming fetuses. Those suspicions were never verified but were strong enough to suspend medical use of the drug in some countries for a while.

Combination products. Filon combines phenmetrazine theoclate (CAS RN 13931-75-4) and phenbutrazate hydrochloride and is promoted as having phenmetrazine’s weight loss characteristics while lacking hazard of addiction. Initial clinical trials showed Filon to be an effective anorectic with fewer of phenmetrazine’s unwanted qualities, but a later study found the two drugsto have the same unwanted effects. A case of Filon addiction also surfaced, but that single instance hardly proves Filon to have more addictive potential than any other drug

Benzphetamine:

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http://drugsencyclopedia.net/drugs/opium-papaver-album-papaver-somniferum-poppy/

Analeptic drugs:

Methylxanthines:

Documents

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