Atovaquone–Proguanil
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Atovaquone is a selective and potent inhibitor of the mitochondrial election transport chain in plasmodia. Inhibition of cytochrome c and individual respiratory chain complexes has demonstrated that the prime site of action for atovaquone is the cytochrome bc1 complex (Fry et al., 1992). It was further elucidated that atovaquone mimics endogenous ubiquinone and inhibits electron transfer by binding to cytochrome b (Fry et al., 1992). It also inhibits dihydroorotate dehydrogenase (DHOD) an enzyme that catalyzes the metabolism of dihydroorotate to orotate, resulting in inhibition of pyrimidine synthesis (Ittarat et al., 1994) (see Chapter 182 for a complete description of atovaquone’s mechanism of action). The activity of proguanil as a single agent is via its metabolite cycloguanil, which inhibits DHFR (Hyde, 1990). DHFR is required for de novo synthesis of folate, which enables salvage of exogenous folate derivatives for use in the folate pool (Nzila, 2006) (see Chapter 183 for complete description of proguanil’s mechanism of action).
Progressive multifocal leukoencephalopathy
Avindra Nath, Joseph R. Berger in Clinical Neurovirology, 2020
A number of therapies utilized in other diseases have been investigated in PML. Nucleoside analogs that impede the synthesis of DNA have been used with varying results [290]. The majority of data here comes from treatment of PML in AIDS patients and there was a trial by the AIDS Clinical Trial Group using this strategy [276], but most of the experience with viral replication inhibition in PML comes from anecdotal evidence. Agents that have been tried include acyclovir, cidofovir or brincidofovir (a lipid-ester derivative of cidofovir), cytarabine, ganciclovir, leflunomide (a drug similar to teriflunomide used in MS which inhibits DNA and RNA synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase involved in pyrimidine synthesis), topotecan, vidarabine, and zidovudine. Case reports claiming benefit of ganciclovir or leflunomide have been cited [283,291], as have inconclusive studies with topetecan [292]. The antineoplastic drug camptothecin, a DNA topoisomerase I inhibitor, has been demonstrated to block JC virus replication in vitro when administered in pulsed doses in amounts non-toxic to cells [293], but its therapeutic usefulness in PML has been anecdotal [294,295]. Some of these antineoplastic drugs may inhibit JC virus replication, but they can carry significant systemic toxicity and their value in the treatment of PML remains open to question.
Systemic Lupus Erythematosus
Vincenzo Berghella in Maternal-Fetal Evidence Based Guidelines, 2022
Antimetabolite, blocks pyrimidine synthesis by inhibiting the dihydroorotate dehydrogenase. Avoid as no data available and long half-life of its metabolite, teriflunomide, is of concern. Wait 2 years after discontinuation of therapy to attempt conception. Cholestyramine washout is recommended if detectable levels prior to a planned pregnancy or once pregnant to accelerate clearance. This is achieved with a level of <0.02 mg/L documented in 2 occasions 14 days apart. The risk of congenital anomalies does not appear increased in those pregnancies exposed to leflunomide following cholestyramine washout [67].
Knowing when to use steroids, immunosuppressants or biologics for the treatment of sarcoidosis
Published in Expert Review of Respiratory Medicine, 2020
Aman Pande, Daniel A. Culver
Leflunomide (LEF) is widely used as a DMARD in rheumatoid arthritis. It inhibits dihydroorotate dehydrogenase, an enzyme in the pyrimidine synthesis pathway. It preferentially blocks clonal expansion and terminal differentiation of activated T lymphocytes without affecting memory T lymphocytes. In doing so, it would appear to precisely target the initial phase of sarcoid granuloma formation. A systematic review of its use in 1432 rheumatoid arthritis patients showed it to be as effective as the older agents, methotrexate and sulfasalazine [69]. Meta-analysis of safety data in this paper showed a higher risk of alopecia, transaminitis, diarrhea, and allergic reactions. The first case series of LEF being used for sarcoidosis was published in 2004 [70]. This was in a small cohort of 32 patients with pulmonary and ocular sarcoidosis. Seventeen of these received LEF alone, with 12 exhibiting a complete or partial response. The drug was effective for both pulmonary (75% patients improved) as well as ocular disease (82% improved). Three patients discontinued the medication because of nausea.
Newly approved agents for relapsing remitting multiple sclerosis: how real-world evidence compares with randomized clinical trials?
Published in Expert Review of Neurotherapeutics, 2021
Giancarlo Comi, Gloria Dalla Costa, Lucia Moiola
Teriflunomide is an oral immunomodulatory drug approved for the treatment of RRMS by the FDA in 2012 and by EMA in 2013 [62,63]. The drug acts by selectively and reversibly blocking the enzyme dihydroorotate dehydrogenase which ultimately lead to the inhibition of pyrimidine de novo synthesis. Therefore TFL blocks the proliferation of rapidly dividing cells, including activated T and B cells which are though to drive the inflammatory processes in MS [64]. The effects of TFL appear to be cytostatic, not cytotoxic because the cell viability is not affected [65]. Moreover a recent study suggested that TFL also corrects metabolic disturbances in T cells, and may promote recovery of an altered T cell receptor repertoire in autoimmunity [66]. It is administered once-daily, available in 14 mg doses globally and additionally 7 mg doses in the US.
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
The process of tumorigenesis is characterized by abnormal, uncontrolled cell division at a rate that outpaces cell death. Thus, the principal goal of systemic chemotherapy for decades has been to slow down cell division and trigger cell death in actively dividing malignant cells. These therapies may be targeted to specific mutated proteins, such as using tyrosine kinase inhibitors for FLT3-mutated AML. Alternatively, they may be comparatively less specific, causing direct DNA damage primarily in actively dividing cells, a mechanism employed by conventional chemotherapies such as alkylating and intercalating agents. Whether by inhibiting oncoproteins or inducing DNA damage, such therapies typically cause cell death by apoptosis [19,122]. An alternative mechanism for slowing cell division is by depriving cells of necessary building blocks for cell division. This class of anti-metabolite therapies includes agents such as 5-fluorouracil, which reduces cell division by inhibiting thymidylate synthase and reducing cellular stores of deoxythymidine monophosphate (dTMP), a pyrimidine nucleotide necessary for DNA synthesis [123]. It is in the context of targeting AML using anti-metabolites that dihydroorotate dehydrogenase (DHODH) inhibitors were re-introduced into the field of cancer therapeutics.
Related Knowledge Centers
- Catalysis
- Coenzyme Q10
- De Novo Synthesis
- Enzyme
- Inner Mitochondrial Membrane
- Orotic Acid
- Mitochondrion
- Redox
- 4,5-Dihydroorotic Acid
- Pyrimidine Metabolism