Until now, we have concentrated on the calculation of fundamental thermochemical values of molecules in the gas phase. With the next example, we aim to show that simple additivity schemes can be quite useful in a completely different area, in drug design for the study of ligand-receptor interactions. Andrews et al. [25] have analyzed binding constants and the derived binding energies for the binding of a series of 200 drug and enzyme inhibitors to their respective protein receptors. They reasoned that the individual functional groups in a molecule contributed an intrinsic value to the binding of a drug to its receptor. They came up with a simple additivity model based on contributions from atoms and groups in a molecule to estimate its average binding energy to a receptor. Thus, drugs that match their receptors exceptionally well have a measured binding energy that substantially exceeds the calculated average value - examples are biotin and estradiol. Conversely, if the observed binding energy is much less than the calculated average binding energy, then the drug matches the receptor less well than the average - examples are methotrexate and thyroxine.  [c.326]

Percutaneous Hver biopsy after each 1.5 g of total accumulated methotrexate dosage to detect hepatic fibrosis or cirrhosis not rehably predicted by semm aminotransferase tests are recommended (1,50). Concurrent use of NSAIDs may increase toxicity of methotrexate, although toxicity may be avoided if the dmgs are separated by 12 h.  [c.40]

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4].  [c.406]

Methotrexate — see Folic acid, 4-amino-4-deoxy-10-methyl-  [c.702]

For illustration of the parametrization concepts, methotrexate, the dihydrofolate reductase inhibitor, was selected as a model system. Its strucmre is shown in Figure 3a. Methotrexate itself is too large for QM calculations at a satisfactory level, requiring the use of smaller model compounds that represent the various parts of methotrexate. Examples of model compounds that could be used for the parametrization of methotrexate are included as compounds 1-3 in Figure 3a, which are, associated with the pteridine, benzene, and diacid moieties, respectively. It may be assumed that some experimental data would be available for the pteridine and diacid compounds and that information on the chemical connectivities internal to each compound could be obtained from a survey of the CSD [60]. Each of these compounds is of such a size that HF/6-31G calculations are accessible, and at least HE/3-21G calculations would be accessible to the dimers, as required to test the parameters connecting the individual model compounds. An alternative model compound would include the amino group with model 3, yielding glutamic acid however, that would require breaking the amide bond on compound 2, which would cause the loss of some of the significant chemical characteristics of methotrexate. Of note is the use of capping methyl groups on compounds 1 and 2. With 1 the methyl group will ensure that the partial atomic charges assigned to the pteridine ring accurately reflect the covalent bond to the remainder of the molecule. The same is true in the case of model compound 2, although  [c.24]

Figure 3 (a) Structure of methotrexate and the structures of three model compounds that could  [c.25]

Steroids, also used for RA treatment, generally influence the synthesis and response to IL-1. Glucocorticoids, eg, prednisone [53-03-2] (18), can affect virtually every aspect, phase, and cell type involved in immunologic and inflammatory reactions (56). Some rheumatologists are now using immunosuppressive dmgs such as methotrexate [59-05-2] (19) in eady stages of RA with significant success. Antimalarials, gold compounds, penicillamine, and sulfasala2ine are all used as antirheumatics. Traditional antirheumatic dmgs having immunological activity are Hsted in Table 2 and stmctures are given in Figure 2. Immunosuppressive dmgs that are increasingly used for treatment of severe and active RA are given in Table 3. Stmctures are shown in Figures 3 and 4.  [c.37]

Initially, the immunosuppressive agents, such as cyclophosphamide (32), a2athioprine, and methotrexate, were developed to inhibit malignant ceU proliferation. The immunosuppressant activity was discovered later and these agents were then appHed to treat autoimmune diseases, where patients did not respond to high doses of steroids (51). The potential side effects associated with these agents have encouraged the search for unique immunosuppressants having more acceptable safety and efficacy profiles (62). Future approaches need to incorporate early treatment with immunotherapy  [c.41]

Fohc acid analogues containing amino acids other than glutamate, and also folate covalendy bound to a protein for the purposes of antibody production, have been prepared (58—60). Methotrexate is an analogue of fohc acid that is widely used in cancer chemotherapy (61) (see Chemotherapeutics, anticancer). Other analogues such as trimethoprim and pyrimethamine are used in the treatment of malaria and proto2oal diseases (62). These analogues bind extremely tightly to dihydrofolate reductase.  [c.40]

Folate antagonists (eg, methotrexate and certain antiepileptics) are used ia treatment for various diseases, but their adininistration can lead to a functional folate deficiency. Folate utilization can be impaired by a depletion of ziac (see Zinc compounds). In humans, the intestinal bmsh border folate conjugase is a ziac metaHoenzyme (72). One study iadicates that the substantial consumption of alcohol, when combiaed with an iaadequate iatake of folate and methionine, may iacrease the risk of colon cancer (73). Based on this study, it is recommended to avoid excess alcohol consumption and iacrease folate iatake to lower the risk of colon cancer.  [c.42]

The classification of these dmgs as antimetaboHtes stems from the mode of action as antagonists to the natural metaboHc processes leading to either DNA, RNA, or proteiu synthesis (13) (see Nucleic acids Proteins). They either inhibit function of a key en2yme involved in protein synthesis or are recmited into the cell division process as DNA synthesis terrninators. For example, methotrexate (8) is a foHc acid [59-30-3], antagonist and  [c.435]

Gene Amplifica.tion. This mechanism of dmg resistance appears to be operative in dmgs which act on in vivo enzymatic targets. For example, in the case of resistance to methotrexate (8), overexpression of the dihydrofolate reductase (DHFR) gene has been impHcated. However, other mechanisms involving defects in dmg uptake and polyglutamation also have been proposed and studied (50). Specifically, the multifactorial nature of methotrexate resistance represents a large therapeutic challenge. It is one example of how the heterogeneity of clinical resistance may be a serious problem.  [c.445]

Elasticity. A portable infusion controUed-release device, the Baxter Infusor, utilizes energy stored in a distended, elastomeric mbber tube to dehver dmg solutions at constant rates of flow through fixed resistances (85). The pharmacist inflates the dmg reservoir with a loaded syringe inserted through a septum at the filling port, and the Hquid dmg is metered through a glass capillary. Figure 5 shows the tubular mbber reservoir fiiUy inflated and ready to deHver a dmg in Hquid form. A description of the physicochemical properties of the elastomeric component and the design of the elastomeric reservoir is available (85—87). The system provides continuous deHvery of cancer chemotherapeutic agents, for example 5-FU [51-21-8] intedeukin-2 [85898-30-2] interferon [82115-62-6] methotrexate [59-05-2] cytosine arabinoside [147-94-4] doxombicin [23214-92-8] bleomycin [11056-06-7], or cisplatin [15663-27-1] (see Chemotherapeutics, anticancer). An alternative design allows patient-controUed deHvery of analgesics such as meperidine [57-42-1] or morphine sulfate [64-31-3] (88) (see Analgesics, antipyretics, and antiinflap tory agents).  [c.144]

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605).  [c.326]

In the treatment of human neoplastic diseases methotrexate has largely supplanted aminopterin in chemotherapy, due to the better therapeutic index of the former in experimental animals, although this superiority over (325) has not been conclusively demonstrated in man.  [c.327]

Amethopterin (Methotrexate, 4-amino-4-deoxy-W -inethylpteroyl-L-glutaniic acid) [59-05-2] M 454.4, m 185-204°(dec), [a]p -t-19° (c 2, O.IN aq NaOH), pKj <0.5 (pyrimidine ), pKj 2.5 (N5-Me+), pKj 3.49 (a-COjH), PK4 4.99 (y-COjH), pKj 5.50 (pyrimidine+).  [c.511]

See pages that mention the term Methotrexate : [c.44]    [c.614]    [c.614]    [c.614]    [c.785]    [c.44]    [c.39]    [c.40]    [c.474]    [c.275]    [c.275]    [c.435]    [c.435]    [c.444]    [c.445]    [c.308]    [c.260]    [c.262]    [c.262]    [c.285]    [c.302]    [c.325]    [c.326]    [c.327]    [c.327]    [c.512]    [c.25]    [c.25]    [c.29]    [c.231]    [c.89]    [c.339]    [c.1016]    [c.149]   
See chapters in:

Pharmaceutical manufacturing encyclopedia Edition 2  -> Methotrexate

Computational biochemistry and biophysics (2001) -- [ c.24 ]

The organic chemistry of drug synthesis Vol.4 (1990) -- [ c.149 ]