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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Pemetrexed (AlimtaTM) is a multi-target antimetabolite that inhibits a number of folate-dependent enzymes. It predominantly inhibits thymidylate synthase but also DHFR and Glycinamide Ribonucleotide Formyl Transferase (GARFT) to a lesser extent. Pemetrexed has a similar molecular shape to raltitrexed, although the 2-methyl-4-oxoquinazoline and thiophene rings have been replaced with 2-amino-4-oxo-pyrrolopyrimidine and benzene rings, respectively, and a methylamine moiety at the center of the molecule has been changed to methylene.
Hormones and Behavior
Published in Paul V. Malven, Mammalian Neuroendocrinology, 2019
Peripheral or central administration of vasopressin as well as central administration of des-glycinamide9 vasopressin, which has little vasopressin bioactivity, facilitates learning of passive avoidance behavior in rodents (Koob et al., 1989). It has also been suggested that there exists in the CNS a unique subtype of vasopressin receptor that mediates these effects of exogenous vasopressinergic compounds on learning and memory (De Wied et al., 1991). However, it is not clear whether administration of vasopressin or its synthetic analogues simulates actions normally performed by endogenous vasopressin. One method to investigate the possible role of endogenous vasopressin is to use rats of the genetic strain that cannot synthesize vasopressin and therefore have diabetes insipidus (Brattleboro strain, discussed in Chapter 3). This vasopressin-deficient strain of rats learns passive avoidance behavior less efficiently than control strains (Van Wimersma Greidanus et al., 1983). However, other workers attribute the deficits in passive avoidance behavior to a reduced emotionality in Brattleboro rats and fail to observe consistent learning deficits (Lorenzini et al., 1991). To investigate the role of endogenous vasopressin in learning and/or retention of passive avoidance behavior in normal rats, endogenous vasopressin has been immuno-neutralized by intracerebral administration of anti-vasopressin antibodies. Intra-ventricular or intrahippocampal administration in rats subjected to one-trial passive avoidance impaired retention of the learned behavior (Velduis et al., 1987).
Overview of Neurotransmission: Relationship to the Action of Antiepileptic Drugs
Published in Carl L. Faingold, Gerhard H. Fromm, Drugs for Control of Epilepsy:, 2019
The effect of anticonvulsant drugs on glycine synthesis, metabolism, steady-state levels or release has apparently not been systematically investigated. However, glycine has been shown to potentiate the anticonvulsant action of diazepam and phenobarbital in kindled seizures124 and of phenobarbital, carbamazepine, and diazepam in the electroshock test in rats.125a In contrast, glycine failed to enhance the anticonvulsant action of phenytoin and valproate in the electroshock test. The mechanism by which glycine potentiates the action of anticonvulsant drugs remains unknown. There is now considerable interest in milacemide (a glycinamide derivative which elevates brain glycine) as a potential antiepileptic drug. Milacemide has been shown to have anticonvulsant effects in several experimental models of epilepsy including the audiogenic seizure.125b
A rare case of pemetrexed-induced diffuse punctal and canalicular stenosis: management by coronary balloon puncto-canaliculoplasty
Published in Orbit, 2022
Abhimanyu Sharma, Monalisa Pattnaik, Mohammad Javed Ali
Chemotherapy-induced epiphora is being increasingly recognized in patients with several malignancies. Chemotherapeutic agents known to cause epiphora include 5-fluorouracil, docetaxel, S-1, panitumumab, radioactive iodine, doxorubicin, capecitabine, imatinib, pentostatin, and mitomycin-C.1,2 The proposed mechanisms causing epiphora are ill-understood.1 Pemetrexed is a chemotherapeutic agent approved for pleural mesothelioma treatment and prolonged maintenance therapy in advanced cases of non-small cell lung carcinoma. It inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, and hence interferes with the folate metabolism.2 Ocular adverse effects of pemetrexed previously described in literature include conjunctivitis3 and eyelid edema.4 Epiphora as a new ocular adverse effect was first reported by Jung et al.2 The patient was successfully treated with three snip punctoplasty (for punctal stenosis) followed by probing (for canalicular stenosis). The present case is the second report to the best of authors’ knowledge, but the first to document dacryoendoscopy findings and report balloon puncto-canaliculoplasty as a minimally-invasive treatment modality for pemetrexed induced punctal and canalicular stenosis.
Moving beyond sodium valproate: choosing the right anti-epileptic drug in children
Published in Expert Opinion on Pharmacotherapy, 2019
Ganna Balagura, Giulia Iapadre, Alberto Verrotti, Pasquale Striano
Valnoctamide (VCD) is a constitutional isomer of valpromide with a potent antiepileptic activity, proven especially in status epilepticus, in rat and mouse models [42]. In humans VCD is currently used in psychiatric disorders [42,43]. A very similar efficacy profile was shown by sec‐Butylpropylacetamide, a homologue of VCD [44]. Both compounds are very promising agents, with potentially neuroprotective properties [45] and potentially lower liver toxicity and teratogenicity compared to valproic acid [46]. However, there are no studies on this drug as antiepileptic in humans yet [47]. Valrocemide (valproyl glycinamide) underwent a phase II trial as add-on treatment in patients with refractory epilepsy [48], however, the teratogenicity of this drug in humans is yet to be completely excluded. Other types of analogue compounds are in the pipeline, although the mechanism of action of VPA remains to be clarified; therefore, it is hard to mimic and assess efficacy in similar molecules.
Development and characterization of cationic solid lipid nanoparticles for co-delivery of pemetrexed and miR-21 antisense oligonucleotide to glioblastoma cells
Published in Drug Development and Industrial Pharmacy, 2018
Berrin Küçüktürkmen, Asuman Bozkır
The antifolate agents, such as methotrexate and 5-fluorouracil (5-FU), have been widely used for decades in the treatment of malignant tumors. Pemetrexed is a novel multi-targeted antifolate agent and has been found to be useful to central nervous system tumors for the development of low resistance. Pemetrexed shows its effect by disrupting folate-dependent metabolic processes, which are essential for cell proliferation. It inhibits key enzymes such as thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase in the purine–pyrimidine pathway [18,19]. Pemetrexed has attracted interest because of its possible use in the brain for treatment of primary brain tumors and the secondary brain tumors, such as lung cancer metastases. However, the penetration of pemetrexed into the central nervous system is limited. It has been suggested that the most important causes of low distribution of pemetrexed in the central nervous system are low permeability due to its hydrophilicity and significant excretion by active reflux pumps [19–21].