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Anticonvulsant Drugs during Pregnancy
Published in “Bert” Bertis Britt Little, Drugs and Pregnancy, 2022
In general, women with epilepsy should be given preconception counseling, and a management plan developed (Box 9.5). If a pregnant woman presents on anticonvulsant therapy, she should be given counseling regarding the two- to threefold increased risk of malformations. She should also be offered high-resolution ultrasound and alpha-fetoprotein screening at appropriate gestational intervals. It should be emphasized that these techniques, although helpful, may not rule out anticonvulsant embryopathy. Anticonvulsant therapy should be continued if necessary. It may be possible to discontinue medications in certain patients who have been seizure-free for protracted periods, especially in patients who have had petit mal seizures. Trimethadione and paramethadione are generally contraindicated during pregnancy, and valproic acid should be avoided if possible. One of the succinimides, ethosuximide, would appear to be a better choice for petit mal seizures in the rare pregnant patient where it is indicated. Monitoring of serum levels of anticonvulsants may be indicated in some pregnant women, especially those with increased seizure activity. A suggested management protocol for pregnant patients with epilepsy is summarized in Box 9.15.
Methsuximide
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Methsuximide (MSM) was introduced in 1957 for the treatment of refractory absence seizures. It belongs to the succinimide family [ethosuximide (ESM) and phensuximide (PSM)], which shares a common heterocyclic (succinimide) ring. The differing effects of these drugs on a variety of experimental and clinical seizure types is probably related to the substitution of different chemical groups on the succinimide ring (see structure).
Racemization and Isomerization of Aspartyl Residues in Amyloid Peptides Involved in the Development of Alzheimer’s Disease
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Koichi Inoue, Toshimasa Toyo’oka
Asp racemization/isomerization is a natural process that occurs under physiological conditions. Recent reports suggest that the water molecules or radical reaction with ions would effect the succinimide formation of the Asp residues (Takahashi et al. 2014, Tambo et al. 2013). Moreover, the technical practicability is comparable to that of age estimation based on AAR in dentin (Matzenauer et al. 2014). Based on the relationship between age and the racemization/isomerization of Asp, a variety of human tissues containing metabolically stable proteins were investigated (Zapico and Ubelaker 2013). If this reaction can take place in any metabolically-activated protein, these proteins would have altered conformations which produce changes in their biological activities and/or chemical properties. The physicochemical properties of the affected proteins may contribute to the progressive changes associated with the aging process related to the homeostatic mechanism. Thus, there is the possibility that some of this Asp racemization/isomerization in the Aβ peptides might serve as useful diagnostic markers for the AD progress. Actually, an interesting study suggested that antibodies recognized either oligomeric or post-translationally modified Aβ peptides in the plasma and CSF that might be a relevant target for passive or active immunotherapy (Britschgi et al. 2009). In addition, Aβ peptides can be easily excreted from the normal brain into the blood (Ueno et al. 2014). The research of the mechanisms that control the Aβ folding/aggregation and the balance between the Aβ production and clearance is a central step in the comprehension of the AD pathology. However, the mechanism for the onset of AD is unknown, thus to capture the conversion from normal aging to dementia and the most appropriate biomarkers for the AD progress will be a significant challenge in future studies. Although the role of the Asp racemization/isomerization of the Aβ peptides in AD pathology is still unclear, evidence has demonstrated that the Aβ peptides isolated from AD brain tissues contain high levels of Asp that have undergone racemization/isomerization. On the other hand, the accumulation of the Asp racemization/isomerization in stable proteins is linked to aging. Roher et al. suggested that these alterations may contribute to the production and stability of the Aβ peptide deposits in the AD brain of dementia patients (Roher et al. 1993). These data were considered indicative of the different times of formation of the two kinds of Aβ deposits: plaque deposition seems to be older and consequently an earlier pathological event that precedes the formation of vascular deposits in the AD pathology (Roher et al. 1993). This may be a preliminary screening of the Asp racemization/isomerization in biological samples of AD patients and these modifications can be considered as novel AD biomarkers between aging and pathology.
Development of ezetimibe eutectic with improved biopharmaceutical and mechanical properties to design an optimized oral solid dosage formulation
Published in Pharmaceutical Development and Technology, 2022
Parag Roy, Nimmy Kumari, Noopur Pandey, Abhishek Gour, Amit Raj, B. Srividya, Utpal Nandi, Animesh Ghosh
Succinimide, a coformer with a high aqueous solubility of ∼330 mg/mL, was selected to develop a eutectic on the basis of thermal screening by DSC. Moreover, SUC has antiurolithic properties, with oral LD50 of 14 g/kg observed in rodents (Melon et al. 1971); furthermore, the derivatives of succinimide are used as pharmaceuticals (Chen et al. 1951; Hudkins et al. 1997). To optimize the ideal ratio of eutectic, ETZ and SUC were screened mechanochemically (Rajbongshi et al. 2021) in different stoichiometric ratios at a total weight of 500 mg in a grinding jar of a planetary ball mill (Fritsch, Idar-Oberstein, Germany) with 10 stainless steel balls (5 mm). Neat grinding was performed by milling the mixtures at 500 rpm for 30 min and instantly analyzed by DSC. A lower endothermic peak was observed in samples with an equimolar ratio, which was distinct from ETZ and SUC. Further, liquid-assisted grinding (LAG) was employed in all the drug-coformer mixtures by taking methanol (300 µL) to monitor changes in the samples. Correspondingly, LAG also showed a similar endothermic peak of ETZ-SUC in DSC, as observed in neat grinding in the resultant sample. Thus, resulting samples obtained through neat grinding were utilized for further characterization and property evaluation.
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
At least 13 categories of CNS drugs can be differentiated: (i) general anesthetics; (ii) analgesics and antipyretics (nonsteroidal anti–inflammatory agents, opiate agonists, opiate partial agonists); (iii) opiate antagonists; (iv) anticonvulsants (barbiturates, benzodiazepines, hydantoins, succinimides); (v) psychotherapeutic agents (antidepressants: monoamine oxidase inhibitors, selective serotonin and norepinephrine-reuptake inhibitors, selective serotonin-reuptake inhibitors, serotonin modulators, tricyclics and other norepinephrine-reuptake inhibitors; antipsychotics: atypical antipsychotics, butyrophenones, phenothiazines, thioxanthenes); (vi) anorexigenic agents and respiratory and cerebral stimulants (amphetamines); (vii) anxiolytics, sedatives, and hypnotics (barbiturates, benzodiazepines, and miscellaneous anxiolytic, hypnotic and sedative agents); (viii) antimanic agents; (ix) antimigraine agents (selective serotonin agonists); (x) antiparkinsonian agents (adamantanes, anticholinergic agents, catechol-O-methyltransferase (COMT) inhibitors, dopamine precursors, dopamine receptor agonists, monoamine oxidase B inhibitors); (xi) anti-dementia agents (cholinesterase inhibitors, nootropics, neuroprotective agents, vasoactive agents, immunotrophins, anti-atherogenic compounds, other anti-dementia drugs); (xii) fibromyalgia agents; and (xiii) miscellaneous CNS agents [8, 9].
Charge variant native mass spectrometry benefits mass precision and dynamic range of monoclonal antibody intact mass analysis
Published in mAbs, 2018
Aaron O. Bailey, Guanghui Han, Wilson Phung, Paul Gazis, Jennifer Sutton, Jonathan L. Josephs, Wendy Sandoval
Succinimide formation is an intermediate step in deamidation/isomerization pathways.20 Succinimide conversion from aspartic acid will impart an increase in pI, and should therefore result in an increased RT in cation exchange separations. We identified aspartic acid-derived succinimide isoforms that eluted as relatively basic species and, as expected, modified in combination with the top three glycoforms (Figure 5a,c). We estimated a relative abundance of 3.41% aspartic acid conversion to succinimide.