Cytotoxic drugs

The primary objective of a Phase I trial is to assess the safety of the drug in humans. Studies are normally conducted in healthy male volunteers, although specific categories of subject may be used in certain cases. For example, to avoid the risk of low blood pressure, subjects with mild hypertension would be more appropriate for the evaluation of antihypertensive drugs, while patients are likely to be used in the case of drugs that are expected to produce significant toxic effects (e.g. anti-cancer cytotoxic drugs). Remuneration may be offered for participation in the study. The number of subjects is normally between 10 and 100 people. 

Two main apoptotic pathways have been identified in mammalian cells the extrinsic pathway that is activated by the binding of ligands to cell-surface death receptors, and the intrinsic pathway that involves the mitochondrial release of cytochrome cP The activation of extrinsic and intrinsic apoptotic pathways promotes the cleavage into the active form of the pro-caspase-8 and pro-caspase-9, respectively, that mainly determine the activation of effector caspase-3. ° The intrinsic pathway is the main apoptotic pathway activated by chemotherapeutic drugs, while the cytotoxic drug-induced activation of the extrinsic pathway is a more controversial issue. ... 

To translate this approach into clinical scenarios, the risk-benefit assessment of chemotherapy administration in already immunocompromised patients would favor situations in which cytotoxic drugs are indicated anyhow, such as in AIDS-related lymphomas, where alkylating agents are part of the standard regimens. 

Changing the distribution of a drug can lead to toxic effects not described before. It is possible that after liposomal delivery high concentrations of drugs (e.g., cytotoxic drugs) inside macrophages affect these cells detrimentally (Poste and Kirsch, 1983). This results in toxic effects in liver, spleen, and bone marrow which were not previously associated with the use of these drugs. 

MS21 Precautions for the safe handling of cytotoxic drugs. 

In oncology, to study the relationship between the normal and the tumour cell, to detect tumour-associated antigens (CEA, carcino-embryonic antigen, and AFP, a-fetoprotein) and subsequently to enable cancer therapy to be monitored, to locate tumour metastases, and to deliver cytotoxic drugs, toxins, radionuclides, or liposomes to tumour cells. 

Cushing s syndrome Cytotoxic drugs (e.g., methotrexate, cisplatin)... 

Cytotoxic drugs that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil,... 

The surface epithelial cells of the small intestine are renewed rapidly and regularly. It takes about two days for the cells of the duodenum to be renewed completely. As a result of its rapid renewal rate, the intestinal epithelium is susceptible to various factors that may influence proliferation. Exposure of the intestine to ionizing radiation and cytotoxic drugs (such as folic acid antagonists and colchicine) reduces the cell renewal rate. 

The advantageous effects of liposomal carrier systems include protection of compounds from metabolism or degradation, as well as enhanced cellular uptake. Liposome-mediated delivery of cytotoxic drugs to cells in culture has resulted in improved potency [58,59]. Prolonged release of encapsulated cargo has also been demonstrated [60,61]. More recently, liposomes with extended circulation half-lives and dose-independent pharmacokinetics (Stealth liposomes) [62] have shown promise in delivery of drugs that are normally very rapidly degraded. 

Since the late 1940s, when Farber treated leukemia with methotrexate, cancer therapy with cytotoxic drugs made enormous progress. Chemotherapy is usually integrated with other treatments such as surgery, radiotherapy, and immunotherapy, and it is clear that postsurgery, it is effective with solid tumors. This is due to the fact that only systemic therapy can attack micrometastases. 

MDR ratio = IC50(cytotoxic drug alone)/IC5o(cytotoxic drug + modulator) (16)... 

Penicillamine Gold therapy, antimalarial or cytotoxic drugs, oxyphenbutazone or phenylbutazone A Do not use these drugs in patients who are concurrently receiving penicillamine. These drugs are associated with similar serious hematologic and renal reactions. 

The hydration equilibria and phase transformations associated with a cytotoxic drug, BBR3576, have been studied [72]. The initially hydrated form could be made to undergo a phase transition where it lost approximately half of its water content, but the hemidesolvated product could be easily rehydrated to regenerate the starting material. If however, the original sample was completely dehydrated, the substance first formed a metastable anhydrate phase that underwent an irreversible exothermic transition to a new anhydrate crystal form. The hydration of this latter anhydrate form yielded a new hydrate phase whose structure was different from that of the initial material. 

Smith AJ, van Helvoort A, van Meer G, Szabo K, Welker E, Szakacs G et al. MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem 2000 275(31) 23530—23539. 

Sela, M., and Hurwitz, E. (1987) Conjugates of antibodies with cytotoxic drugs. In Immunoconjugates Antibody Conjugates in Radioimaging and Therapy of Cancer (C.-W. Vogel, ed.), p. 189. Oxford University Press, New York. 

The answer is c. (Hardman, pp 649—650.) Acute hyperuricemia, which often occurs in patients who are treated with cytotoxic drugs for neoplasic disorders, can lead to the deposition of urate crystals in the kidneys and their collecting ducts. This can produce partial or complete obstruction of the collecting ducts, renal pelvis, or ureter. Allopurinol and its primary metabolite, alloxanthine, are inhibitors of xanthine oxidase, an enzyme that catalyzes the oxidation of hypo xanthine and xanthine to uric acid. The use of allopurinol in patients at risk can markedly reduce the likelihood that they will develop acute uric acid nephropathy. 

Uric acid may also be overproduced as a consequence of increased breakdown of tissue nucleic acids, as with myeloproliferative and lympho-proliferative disorders. Cytotoxic drugs used to treat these disorders can... 

Drugs that decrease renal clearance of uric acid through modification of filtered load or one of the tubular transport processes include diuretics, nicotinic acid, salicylates (less than 2 g/day), ethanol, pyrazinamide, levodopa, ethambutol, cyclosporine, and cytotoxic drugs. 

The combination of tyrphostins with cytotoxic drugs can be followed by immunotherapy in order to eliminate residual disease. Though such combinations have not yet been examined, the combination of AG 490 and IL-12 against IL-6 dependent multiple myeloma recently showed impressive tumor suppressive effects [54], suggesting that the general idea may indeed be correct. 

Vries et al. [3.59] described the development of a stable parenteral dosage form of the cytotoxic drug E 09. E 09 dissolves poorly in water and its solution is unstable. With the addition of 200 mg of lactose per vial containing 8 mg of E 09, an optimum formulation was developed with respect to solubility, dosage of E 09 and length of the freeze drying cycle. DSC studies have been used to select the most effective parameters. The freeze dried product remains stable for 1 year when stored at 4 °C in a dark environment. 

An important advance in this field has been made by the discovery of selective serotonin (5-HT3) receptor antagonists that are effective inhibitors of cytotoxic drug-induced emesis in laboratory animals. The new agents have been found to be free of the undesirable side-effects associated with dopaminergic blockade and have shown significant protection from emesis in early clinical trials. 

In the development of cytotoxic drugs in oncology, dose-finding usually means establishing a maximum tolerated dose (MTD). This is the dose associated with serious but reversible side effects in a sizable proportion of patients and the one that... 

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