Acquired Demyelinating Syndromes of the Central Nervous System in Children: The Importance of Regular Follow-up in the First Year After Onset.

AIM: We reviewed the clinical features of a sample of pediatric acquired demyelinating syndromes with the purpose of determining the appropriate protocol for follow-up after the first episode. METHODS: A multicenter retrospective observational study was conducted on a cohort of 40 children diagnosed with a first episode of acquired demyelinating syndrome over the period 2012-2021. Patients were evaluated with clinical and neuroradiologic assessment after 3, 6, and 12 months, with a median follow-up of 4.0 years. RESULTS: At the first acquired demyelinating syndrome episode, 18 patients (45%) were diagnosed with acute disseminated encephalomyelitis, 18 (45%) with clinical isolated syndrome, and 4 (10%) with multiple sclerosis. By month 12, 12 patients (30%) had progressed from an initial diagnosis of acute disseminated encephalomyelitis (2) or clinical isolated syndrome (10) to multiple sclerosis. Of these, 6 had clinical relapse and 6 radiologic relapse only. The first relapse occurred after a median of 3 months. Among the patients who had evolved toward multiple sclerosis, there was a prevalence of females (P = .014), higher oligoclonal bands positivity (P = .009), and older median age (P < .001) as compared with those who had remained stable. INTERPRETATION: Both clinical and radiologic follow-up of children with acquired demyelinating syndromes is crucial, especially during the first year after acute onset, for early identification of multiple sclerosis and prompt initiation of disease-modifying treatment to delay axonal damage and to limit disability.

Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action.

Several aromatic/heterocyclic sulfonamide scaffolds have been used to synthesize compounds incorporating NO-donating moieties of the nitrate ester type, which have been investigated for the inhibition of five physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms: hCA I (offtarget), II, IV and XII (antiglaucoma targets) and IX (antitumor target). Some of the new compounds showed effective in vitro inhibition of the target isoforms involved in glaucoma, and the X-ray crystal structure of one of them revealed factors associated with the marked inhibitory activity. In an animal model of ocular hypertension, one of the new compounds was twice more effective than dorzolamide in reducing elevated intraocular pressure characteristic of this disease, anticipating their potential for the treatment of glaucoma.

Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma.

Novel bi-functional compounds with a nitric oxide (NO)-releasing moiety bound to a dorzolamide scaffold were investigated. Several compounds were synthesized and their activity as selective carbonic anhydrase inhibitors (CAI) evaluated in vitro on recombinant hCA type I, II and IV enzyme isoforms where they showed different degrees of potency and selectivity to hCA II. A high resolution X-ray crystal structure for the CA II adduct with 8 confirmed the high affinity of this class of compounds for the enzyme. Compounds 4, 6, and 8 showed highly potent and efficacious NO-mediated properties as assessed by their vascular relaxant effect on methoxamine-precontracted rabbit aortic rings. Finally, compounds 4 and 6 exerted potent intraocular pressure (IOP) lowering effects in vivo in normotensive rabbits thereby anticipating their potential for the treatment of hypertensive glaucoma.

Therapeutic potential of nitrate esters of commonly used drugs.

Organic nitrates, such as nitroglycerin, have been used in clinical practice for more than one century for the treatment of angina, even before the identification of Nitric Oxide (NO) as the so-called Endothelium Derived Relaxing Factor (EDRF). Recently, multiple functions of this molecule in biology and pathophysiology have been discovered and alterations in the NO signalling pathway have often been associated with disease progression in mammals, providing a strong rationale for the use of NO as a potential drug. To have a therapeutic benefit from NO properties, an elegant approach has been designed coupling well-known existing drugs with moieties able to slowly release NO following enzymatic metabolism. "Hybrid nitrates", in which activities of both the native drug and NO are present, have been obtained with the aim of originating safer and more active drugs. The technology consists in the choice of the appropriate chemical spacer arm carrying the nitric ester in order to obtain the best pharmacodynamic and pharmacokinetic profile. The connecting linkers already explored are of different chemical structure, ranging from aliphatic chains to heteroaromatic rings. The molecules so far obtained have already demonstrated their potential therapeutic interest in both pharmacological tests and clinical trials. In this review, we describe the approach and the possibility of generating new chemical entities, combining well-known drugs with an NO-donating moiety in order to increase activity and safety, along with examples of their activity and potential therapeutic application in different pathologies. A few significant examples of molecules in the early preclinical stage, as well as in advanced clinical development will be described.

Positional isomerism markedly affects the growth inhibition of colon cancer cells by nitric oxide-donating aspirin in vitro and in vivo.

NO-donating aspirin (NO-ASA), a novel pharmacological agent currently undergoing clinical testing, consists of ASA to which a nitrate group is covalently linked via a spacer molecule. We synthesized the three positional isomers of NO-ASA with respect to the -CH(2)ONO(2) group (ortho, meta, and para) and examined whether this isomerism affects the biological activity of NO-ASA on HT-29 human colon cancer cells. The ortho- and para-isomers showed similar IC(50) values (1-5 microM) for cell growth inhibition over 72 h, whereas the IC(50) of the meta-isomer was 200 to 500 microM. The ortho- and para-isomers inhibited cell proliferation more potently than the meta-isomer. All three induced apoptosis but the ortho- and para-isomers also induced atypical cells (they maintain their shape but have diminished or absent nuclear material). Treatment for 3 weeks of Min (Apc(min)(/+)) mice, a model of intestinal cancer, with equimolar amounts of meta- and para-NO-ASA decreased the number of tumors in the small intestine by 36 and 59% (P < 0.01), respectively, compared with vehicle-treated controls, thus confirming their in vitro differences in potency. A structure-activity study of the three isomers revealed that substituting an aliphatic for the aromatic spacer or removing the -ONO(2) group profoundly diminished NO-ASA's ability to inhibit cell growth, whereas removal of the acetyl group on the ASA moiety did not affect cell growth inhibition. Thus, positional isomerism is critical for the pharmacological properties of NO-ASA against colon cancer and it should be taken into consideration in rational drug design.

Synthesis of nitro esters of prednisolone, new compounds combining pharmacological properties of both glucocorticoids and nitric oxide.

Glucocorticoids (GC) are widely used in therapy for their many pharmacological properties including antiinflammatory and immunosuppressive actions. However, their use over long periods is hampered by a number of severe side effects. Given the biological properties of nitric oxide (NO) and previous experience with nonsteroidal antiinflammatory agents, we synthesized new chemical entities combining both NO and GC properties. Here we report the synthesis of nitro esters of prednisolone obtained through the esterification, with different linkers, on the hydroxy group at C-21 position of the corticosteroid structure. The alkyl chain, as of the nitrooxy derivative (2), or aromatic linkers, as of o-, m-, and p-nitrooxymethylbenzoate derivatives (3-5), respectively, furnish stable compounds that release NO and inhibit the GC receptors in biological assays. To improve solubility we introduced a more water-soluble linker such as the nitrooxyalkylpiperidine or -piperazine group (6-9). Also these compounds retained properties of both NO and prednisolone. Compound 5 (NCX 1015) was selected for its better profile: enhanced antiinflammatory properties and reduced side effects compared with prednisolone. NCX 1015 is currently under preclinical development.

Nitric oxide-donating non-steroidal anti-inflammatory drugs: the case of nitroderivatives of aspirin.

Nitric oxide (NO) acts as a key signalling mechanism in a number of cells and tissues in the mammalian organism. Modulation of the biosynthesis of NO has emerged to be relevant to the treatment of a variety of human diseases. In the attempt to reduce the serious side effects of non-steroidal anti-inflammatory drugs (NSAIDs), especially in the gastrointestinal tract, a NO-releasing moiety has been linked to conventional NSAIDs. A prototypical example is that of NO-releasing derivatives of aspirin. Thanks to the cytoprotective action of NO such compounds do not produce gastric damage and are emerging as an interesting novel group of drugs for their unique pharmacological properties.