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Experimental Hematology Mar 2001Acute graft-vs-host disease (GVHD) is a major obstacle to safe allogeneic hematopoietic stem cell transplantation (HSCT), leading to a significant morbidity and... (Review)
Review
Acute graft-vs-host disease (GVHD) is a major obstacle to safe allogeneic hematopoietic stem cell transplantation (HSCT), leading to a significant morbidity and mortality. GVHD occurs when transplanted donor T lymphocytes react to foreign host cells. It causes a wide variety of host tissue injuries. This review focuses on the pathobiological basis, clinical aspects, and current management strategies of acute GVHD. Afferent phase of acute GVHD starts with myeloablative conditioning, i.e., before the infusion of the graft. Total-body irradiation (TBI) or high-dose chemotherapy regimens cause extensive damage and activation in host tissues, which release inflammatory cytokines and enhance recipient major histocompatibility complex (MHC) antigens. Recognition of the foreign host antigens by donor T cells and activation, stimulation, and proliferation of T cells is crucial in the afferent phase. Effector phase of acute GVHD results in direct and indirect damage to host cells. The skin, gastrointestinal tract, and liver are major target organs of acute GVHD. Combination drug prophylaxis in GVHD is essential in all patients undergoing allogeneic HSCT. Steroids have remained the standard for the treatment of acute GVHD. Several clinical trials have evaluated monoclonal antibodies or receptor antagonist therapy for steroid-resistant acute GVHD, with different successes in a variety of settings. There are some newer promising agents like mycophenolate mofetil, glutamic acid-lysine-alanine-tyrosine (GLAT), rapamycin, and trimetrexate currently entering in the clinical studies, and other agents are in development. Future experimental and clinical studies on GVHD will shed further light on the better understanding of the disease pathobiology and generate the tools to treat malignant disorders with allogeneic HSCT with specific graft-vs-tumor effects devoid of GVHD.
Topics: Acute Disease; Animals; Antibodies, Monoclonal; Antigen Presentation; Antineoplastic Agents; Bone Marrow; Digestive System; Dogs; Drug Design; Drug Therapy, Combination; Forecasting; Graft vs Host Disease; HLA Antigens; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Liver; Lymphocyte Depletion; Lymphokines; Mice; Models, Biological; Premedication; Radiation Chimera; Radiation Injuries; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; Risk Factors; Severity of Illness Index; Skin; T-Lymphocytes, Cytotoxic; Transplantation Conditioning; Transplantation, Homologous; Whole-Body Irradiation
PubMed: 11274753
DOI: 10.1016/s0301-472x(00)00677-9 -
Oncology (Williston Park, N.Y.) Jul 1995Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include... (Review)
Review
Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include decreased drug transport into cells; decreased polyglutamation, leading to increased drug efflux from cells; decreased drug affinity for folate-dependent enzymes; mutations of dihydrofolate reductase (DHFR), a key enzyme required for the maintenance of adequate intracellular reduced folate levels that is inhibited by methotrexate; and increased expression of the DHFR protein. Promising antifolate compounds undergoing clinical testing as anticancer agents include trimetrexate (which was recently approved by the FDA for the treatment of Pneumocystis carinii pneumonia), edatrexate, piritrexim, Tomudex, and lometrexol. The mechanisms of action, dosage, pharmacokinetics, clinical toxicity, and antitumor activity of these drugs are profiled.
Topics: Aminopterin; Antimetabolites, Antineoplastic; Antineoplastic Agents; Drugs, Investigational; Folic Acid Antagonists; Humans; Neoplasms; Pyrimidines; Quinazolines; Thiophenes; Trimetrexate
PubMed: 8924375
DOI: No ID Found -
Public Health Reports (Washington, D.C.... 1988The Food and Drug Administration has instituted several pro-active measures to expedite the review of treatments, diagnostics, and vaccines for AIDS and related...
The Food and Drug Administration has instituted several pro-active measures to expedite the review of treatments, diagnostics, and vaccines for AIDS and related conditions. In particular, the agency has established a special designation--1-AA--for a potential AIDS product which gives top priority to its review. This special expedited review process for AIDS products has provided for greater cooperation between their sponsors and FDA's reviewers. AIDS products also receive prompt consideration for orphan product status--a status providing financial incentives to the developers of treatments for certain rare and complex diseases. FDA's special procedures for AIDS drugs have resulted in several major advances in available AIDS treatments. Foremost among these was the FDA's review and approval of zidovudine (commonly known as AZT) as the first effective palliative for AIDS within 107 days--an agency record. Similarly, the agency quickly evaluated and approved ELISA and Western blot diagnostic kits for detecting the presence of HIV antibody. These test kits have made an important contribution to safeguarding the nation's blood supply. The agency has also instituted new "treatment" investigational new drug regulations to allow earlier pre-approval distribution of promising experimental treatments to patients with immediately life-threatening conditions, including persons with AIDS. Under this system and its earlier prototype, eligible AIDS patients were able to receive pre-approval treatment with zidovudine and trimetrexate (an experimental drug for the treatment of AIDS patients with Pneumocystis carinii pneumonia who have experienced severe adverse reactions using standard approved therapies). The agency has made institutional reforms to effectively streamline the review of candidate AIDS treatments and vaccines. Two new centers within the agency have been established for the processing of drug and biologics. In addition,reviewing divisions have been created within these centers to give specialized attention to drugs and biologics designed to treat AIDS or related conditions.These efforts and the other aforementioned reforms, in part, have lead to the initiation of more than 100 ongoing clinical studies of potential drugs for AIDS and related conditions, as well as the clinical testing of two candidate vaccines against HIV. In other areas, FDA has increased inspections of the manufacturing and processing of condoms and begun a surveillance and sampling program to insure the quality of latex surgical gloves. The agency has worked with other authorities to move against quack AIDS products and to educate the public concerning this health fraud.FDA hopes that through all these efforts it can help researchers in government, academia, and industry advance the development, testing, and review of safe and effective therapies, preventatives,and diagnostics for AIDS and related conditions.
Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Drug Evaluation; Humans; Research; United States; United States Food and Drug Administration; Viral Vaccines
PubMed: 3131814
DOI: No ID Found -
International Journal of Molecular... Jun 2020Chagas disease, caused by (), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and...
Chagas disease, caused by (), affects nearly eight million people worldwide. There are currently only limited treatment options, which cause several side effects and have drug resistance. Thus, there is a great need for a novel, improved Chagas treatment. Bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS) has emerged as a promising pharmacological target. Moreover, some human dihydrofolate reductase (DHFR) inhibitors such as trimetrexate also inhibit DHFR-TS (DHFR-TS). These compounds serve as a starting point and a reference in a screening campaign to search for new DHFR-TS inhibitors. In this paper, a novel virtual screening approach was developed that combines classical docking with protein-ligand interaction profiling to identify drug repositioning opportunities against infection. In this approach, some food and drug administration (FDA)-approved drugs that were predicted to bind with high affinity to DHFR-TS and whose predicted molecular interactions are conserved among known inhibitors were selected. Overall, ten putative DHFR-TS inhibitors were identified. These exhibited a similar interaction profile and a higher computed binding affinity, compared to trimetrexate. Nilotinib, glipizide, glyburide and gliquidone were tested on epimastigotes and showed growth inhibitory activity in the micromolar range. Therefore, these compounds could lead to the development of new treatment options for Chagas disease.
Topics: Chagas Disease; Computer Simulation; Drug Repositioning; Folic Acid Antagonists; Glipizide; Glyburide; Humans; Ligands; Molecular Docking Simulation; Molecular Structure; Pyrimidines; Structure-Activity Relationship; Sulfonylurea Compounds; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 32560043
DOI: 10.3390/ijms21124270 -
Cancer Biology & Therapy Jul 2013Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by...
Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chordoma; Drug Screening Assays, Antitumor; Humans; Small Molecule Libraries
PubMed: 23792643
DOI: 10.4161/cbt.24596 -
Antimicrobial Agents and Chemotherapy Oct 1989Three sulfonamides and four dihydrofolate reductase inhibitors were tested alone and in combination to determine their in vitro effects on two strains of Toxoplasma...
Three sulfonamides and four dihydrofolate reductase inhibitors were tested alone and in combination to determine their in vitro effects on two strains of Toxoplasma gondii grown in MRC5 fibroblast tissue culture. Toxoplasma growth was quantitated by an enzyme immunoassay performed directly on the fixed cultures, and linear regression models were used to quantify the relationship between the optical density values generated by the enzyme-linked immunosorbent assay and the concentrations of the antimicrobial agents in the culture medium. The cytopathic effects of antimicrobial agents on T. gondii were examined in Giemsa-stained cultures. Sulfonamides and dihydrofolate reductase inhibitors exhibited similar patterns of inhibition, consisting of an important increase of the inhibitory effect within a narrow range of concentrations. Sulfadiazine, sulfamethoxazole, and sulfisoxazole were all found to have important inhibitory effects on T. gondii; the 50% inhibitory concentrations estimated from the regression models were 2.5 micrograms/ml for sulfadiazine, 1.1 micrograms/ml for sulfamethoxazole, and 6.4 micrograms/ml for sulfisoxazole. This inhibition of growth was associated with a reduction of the number of parasitized cells and intracellular parasites that were morphologically normal. With dihydrofolate reductase inhibitors, including pyrimethamine, trimethoprim, trimetrexate-glycuronate, and piritrexim, a strong inhibition of Toxoplasma growth was observed, which was associated with striking morphological changes of the parasites. The 50% inhibitory concentrations were 0.04 microgram/ml for pyrimethamine, 2.3 micrograms/ml for trimethoprim, 0.16 ng/ml for trimetrexate-glycuronate, and 6.9 ng/ml for piritrexim. When sulfonamides and dihydrofolate reductase inhibitors were used in combination, a synergistic effect was observed with sulfadiazine combined with pyrimethamine, trimetrexate-glycuronate, and piritrexim; sulfisoxazole combined with pyrimethamine; and trimethoprim combined with sulfamethoxazole. These results were analyzed in comparison with human pharmacokinetics data.
Topics: Animals; Enzyme-Linked Immunosorbent Assay; Folic Acid Antagonists; Microbial Sensitivity Tests; Pyrimethamine; Pyrimidines; Quinazolines; Sulfamethoxazole; Sulfisoxazole; Toxoplasma; Trimethoprim; Trimetrexate
PubMed: 2531568
DOI: 10.1128/AAC.33.10.1753 -
Drugs Oct 1991Pneumocystis carinii pneumonia (PCP) is seen in people with a defect in cell-mediated immunity. Today the most common cause for this is the Acquired Immunodeficiency... (Review)
Review
Pneumocystis carinii pneumonia (PCP) is seen in people with a defect in cell-mediated immunity. Today the most common cause for this is the Acquired Immunodeficiency Syndrome (AIDS). There have been some remarkable advances recently in the development of new drug regimens to combat this otherwise fatal infection. Although cotrimoxazole (trimethoprim-sulfamethoxazole) is still the drug of first choice it cannot be tolerated by a significant proportion of patients, and therapies such as pentamidine (pentamidine-isethionate) [intravenous or nebulised], dapsone-trimethoprim, eflornithine (DFMO; difluoromethylornithine), trimetrexate, and clindamycin-primaquine are finding therapeutic niches. The major advantage in these other agents is not improved efficacy but different toxicity profiles, enabling therapy to be most appropriately tailored to individual patients' conditions. Although the majority of patients should now survive an attack of PCP, relapses will occur if prophylaxis is not used. There is also the capacity to predict accurately which patients are at risk for this pneumonia and prevent it through the use of chemoprophylaxis. These advances in the treatment and prevention of PCP, together with anti-retroviral therapy, mean that this is an area of AIDS management that has resulted in improved long term survival.
Topics: Acquired Immunodeficiency Syndrome; Humans; Pneumonia, Pneumocystis
PubMed: 1723365
DOI: 10.2165/00003495-199142040-00006 -
Annals of Oncology : Official Journal... Jan 2002
Topics: Antimetabolites, Antineoplastic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Synergism; Fluorouracil; Humans; Leucovorin; Placebos; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome; Trimetrexate; United States; United States Food and Drug Administration
PubMed: 11863088
DOI: 10.1093/annonc/mdf086 -
Trends in Parasitology Mar 2010The emergence of artemisinin resistance could adversely impact the current strategy for malaria treatment; thus, new drugs are urgently needed. A possible approach to...
The emergence of artemisinin resistance could adversely impact the current strategy for malaria treatment; thus, new drugs are urgently needed. A possible approach to developing new antimalarials is to find new uses for old drugs. Some anticancer agents such as methotrexate and trimetrexate are active against malaria. However, they are commonly perceived to be toxic and thus not suitable for malaria treatment. In this opinion article, we examine how the toxicity of anticancer agents is just a matter of dose or 'only dose makes the poison', as coined in Paracelsus' law. Thus, the opportunity exists to discover new antimalarials using the anticancer pharmacopoeia.
Topics: Antimalarials; Antineoplastic Agents; Humans; Malaria; Methotrexate; Trimetrexate
PubMed: 20056487
DOI: 10.1016/j.pt.2009.12.002