Onasemnogene Abeparvovec Administration via Peripherally Inserted Central Catheter: A Case Report.

Onasemnogene abeparvovec (OA) is the approved intravenous gene therapy for the treatment of spinal muscular atrophy (SMA). A functional copy of the human SMN1 gene was inserted into the target motor neuron cells via a viral vector, AAV9. In clinical trials, OA was infused through a peripheral venous catheter, and no data are available on central catheter use. Recently, we had a case where OA was administered directly into the right atrium via a peripherally inserted central catheter (PICC) instead of a peripheral line, as recommended. The patient was a female child aged 4 months, diagnosed as SMA type I. For practical reasons, a dose of OA according to the weight of the patient (1.1 × 1014 vectorial genomes/kg) was administered via PICC in 1 h, as the product information recommends. The drug was well tolerated, with no hypersensitivity reactions or initial elevation of transaminases or other adverse effects. To our knowledge, this is the first case reported where OA was administered via a central line. This type of administration is not contraindicated, but it is not specifically contemplated or recommended. It is unknown whether central line administration could have any implications for transduction efficiency and immunogenicity. Future studies should clarify these aspects, as each gene therapy has a specific optimal dose recorded that depends on the site and route of administration of the drug, the AAV variant and the transgene.

Synthesis of charged bis-heteroaryl donor-acceptor (D-A+) NLO-phores coupling (π-deficient-π-excessive) heteroaromatic rings.

Charged chromophores based on heteroaromatic cations were prepared by reaction of alkylazinium salts with N-heteroarylstannanes under Stille conditions. This approach provides easy access to potential single donor D-A(+) chromophores in which the acceptor moiety A(+) is the pyridinium cation and the donors are different π-excessive N-heterocycles. The ß hyperpolarizabilities were measured in hyper-Rayleigh scattering experiments and the experimental data are supported by a theoretical analysis that combines a variety of computational procedures, including density functional theory and correlated Hartree-Fock-based methods. In some chromophores, the absence of a bridge between donor and acceptor fragments increases the NLO properties.

Donor-(π-bridge)-azinium as D-π-A+ one-dimensional and D-π-A(+)-π-D multidimensional V-shaped chromophores.

Heteroaromatic cations reacted with N-heteroarylacetylenes under Sonogashira conditions to allow easy access to potential single donor D-π-A(+) and V-shaped D-π-A(+)-π-D chromophores, where the acceptor moiety A is the π-deficient pyridinium cation and the donor moiety is represented by different π-excessive N-heterocycles. The ß hyperpolarizabilities were measured using hyper-Rayleigh scattering experiments and the experimental data are supported by a theoretical analysis that combines a variety of computational procedures, including Density Functional Theory (DFT) and correlated Hartree-Fock-based methods (RCIS(D)).

Mechanistic Versatility at Ir(PSiP) Pincer Catalysts: Triflate Proton Shuttling from 2-Butyne to Diene and [3]Dendralene Motifs.

The five-coordinate hydrido complex [IrH(OTf)(PSiP)] (1) catalytically transforms 2-butyne into a mixture of its isomer 1,3-butadiene, and [3]dendralene and linear hexatriene dimerization products: (E)-4-methyl-3-methylene-1,4-hexadiene and (3Z)-3,4-dimethyl-1,3,5-hexatriene, respectively. Under the conditions of the catalytic reaction, benzene, and 363 K, the hexatriene further undergoes thermal electrocyclization into 2,3-dimethyl-1,3-cyclohexadiene. The reactions between 1 and the alkyne substrate allow isolation or nuclear magnetic resonance (NMR) observation of catalyst resting states and possible reaction intermediates, including complexes with the former PSiP pincer ligands disassembled into PSi and PC chelates, and species coordinating allyl or carbene fragments en route to products. The density functional theory (DFT) calculations guided by these experimental observations disclose competing mechanisms for C-H bond elaboration that move H atoms either classically, as hydrides, or as protons transported by the triflate. This latter role of triflate, previously recognized only for more basic anions such as carboxylates, is discussed to result from combining the unfavorable charge separation in the nonpolar solvent and the low electronic demand from the metal to the anion at coordination positions trans to silicon. Triflate deprotonation of methyl groups is key to release highly coordinating diene products from stable allyl intermediates, thus enabling catalytic cycling.

Iridium compounds with kappa-P,P,Si (biPSi) pincer ligands: favoring reactive structures in unsaturated complexes.

The structure, coordination properties, insertion processes, and dynamic behavior in solution of the five-coordinate complexes [IrXH(biPSi)] (biPSi = kappa-P,P,Si-Si(Me){(CH(2))(3)PPh(2)}(2); X = Cl (1), Br (2), or I (3)) have been investigated. The compounds are formed as mixtures of two isomers, anti and syn, in slow equilibrium in solution. The equilibrium position depends on the halogen and the solvent. Both isomers display distorted square-based pyramidal structures in which the vacant position sits trans to silicon. The equatorial plane of the syn isomer is closer to the T structure due to distortions of steric origin. The small structural differences between the isomers trigger remarkable differences in reactivity. The syn isomers form six-coordinate adducts with chlorinated solvents, CO, P(OMe)(3), or NCMe, always after ligand coordination trans to silicon. The anti isomers do not form detectable adducts with chlorinated solvents and coordinate CO or P(OMe)(3) either trans to silicon (kinetic) or trans to hydride (thermodynamic). NCMe coordinates the anti isomers exclusively at the position trans to hydride. Qualitative and quantitative details (equilibrium constants, enthalpies, entropies, etc.) on these coordination processes are given and discussed. As a result of the different coordination properties, insertion reagents such as acetylene, diphenylacetylene, or the alkylidene resulting from the decomposition of ethyl diazoacetate selectively insert into the Ir-H bond of 1-syn, not into that of 1-anti. These reactions give five-coordinate syn alkenyl or alkyl compounds in which the vacancy also sits trans to silicon. Acetylene is polymerized in the coordination sphere of 1. The nonreactive isomer 1-anti also evolves into the syn insertion products via anti<-->syn isomerizations, the rates of which are notably dependent on the nature of the insertion reactants. H(2) renders anti<-->syn isomerization rates of the same order as the NMR time scale. The reactions are second order (k(obs) = k(anti<-->syn)[H(2)]) and do not involve H(2)/IrH hydrogen atom scrambling. A possible isomerization mechanism, supported by MP2 calculations and compatible with the various experimental observations, is described. It involves Ir(V) intermediates and a key sigma Ir-(eta(2)-SiH) agostic transition state. A similar transition state could also explain the anti<-->syn isomerizations in the absence of oxidative addition reactants, although at the expense of high kinetic barriers strongly dependent on the presence of potential ligands and their nature.

Serum Adalimumab Levels Predict Successful Remission and Safe Deintensification in Inflammatory Bowel Disease Patients in Clinical Practice.

BACKGROUND: Little is known about the association between the pharmacokinetic features of adalimumab (ADL) and disease outcome in patients with inflammatory bowel disease (IBD). AIMS: To assess the association between random serum ADL levels and clinical or biochemical remission with clinical decision making in daily practice according to these levels; and to determine the cutoff value for successful dose reduction in patients with IBD treated with ADL. METHODS: We conducted a prospective observational study of patients with IBD who received long-term maintenance therapy with ADL. RESULTS: Data were available for 157 serum samples from 87 patients. Serum ADL levels were associated with clinical remission: median 9.2 versus 6.0 µg/mL for patients with Crohn's disease with active disease (P = 0.009) and 14.4 versus 5.2 µg/mL in patients with ulcerative colitis with active disease (P = 0.002). Serum ADL levels were 9.2 µg/mL for patients with a normal C-reactive protein value (<5 mg/L) and 5.2 µg/mL for patients with a high C-reactive protein value (P = 0.002). ADL levels were significantly associated with normal fecal calprotectin value (<80 ng/g) (10.8 versus 7.6 µg/mL, respectively, P = 0.038). Serum ADL levels were significantly associated with successful deintensification, over a 6-month period of clinical follow-up, compared with the group in which doses remained unchanged (area under the curve 0.88; 95% confidence interval, 0.81-0.95; P < 0.001), with a cutoff value for successful deintensification of 12.2 µg/mL. CONCLUSIONS: Higher ADA levels were significantly associated with clinical and biochemical remission. Our results, which were obtained under conditions of daily clinical practice, suggest that an ADL cutoff of 12.2 µg/mL could be appropriate for successful dose reduction in patients with IBD treated with ADL.

Pyrrolodiazines. 2. Structure and Chemistry of Pyrrolo[1,2-a]pyrazine and 1,3-Dipolar Cycloaddition of Its Azomethine Ylides.

A new synthesis of the pyrrolo[1,2-a]pyrazine system from pyrrole is described. In light of the ab initio calculations carried out on this heterocyclic system some of its basic chemistry was investigated and included electrophilic substitution, addition of organolithium reagents, metalation with lithium diisopropylamide and subsequent reaction with electrophiles, and formation of salts by quaternization of the nonbridgehead nitrogen. N-ylides obtained from these salts undergo 1,3-dipolar cycloaddition with suitable dipolarophiles to give dipyrrolo[1,2-a]pyrazines, pyrazolo[1,5-a]-pyrrolo[2,1-c]pyrazines, and heterobetaines. Examples of intramolecular 1,3-dipolar cycloadditions are also reported.

Mechanistic investigations of imine hydrogenation catalyzed by cationic iridium complexes.

Complexes [IrH2(eta6-C6H6)(PiPr3)]BF4 (1) and [IrH2(NCMe)3(PiPr3)]BF4 (2) are catalyst precursors for homogeneous hydrogenation of N-benzylideneaniline under mild conditions. Precursor 1 generates the resting state [IrH2{eta5-(C6H5)NHCH2Ph}(PiPr3)]BF4 (3), while 2 gives rise to a mixture of [IrH{PhN=CH(C6H4)-kappaN,C}(NCMe)2(PiPr3)]BF4 (4) and [IrH{PhN=CH(C6H4)-kappaN,C}(NCMe)(NH2Ph)(PiPr3)]BF4 (5), in which the aniline ligand is derived from hydrolysis of the imine. The less hindered benzophenone imine forms the catalytically inactive, doubly cyclometalated compound [Ir{HN=CPh(C6H4)-kappaN,C}2(NH2CHPh2)(PiPr3)]BF4 (6). Hydrogenations with precursor 1 are fast and their reaction profiles are strongly dependent on solvent, concentrations, and temperature. Significant induction periods, minimized by addition of the amine hydrogenation product, are commonly observed. The catalytic rate law (THF) is rate = k[1][PhN=CHPh]p(H2). The results of selected stoichiometric reactions of potential catalytic intermediates exclude participation of the cyclometalated compounds [IrH{PhN=CH(C6H4)-kappaN,C}(S)2(PiPr3)]BF4 [S = acetonitrile (4), [D6]acetone (7), [D4]methanol (8)] in catalysis. Reactions between resting state 3 and D2 reveal a selective sequence of deuterium incorporation into the complex which is accelerated by the amine product. Hydrogen bonding among the components of the catalytic reaction was examined by MP2 calculations on model compounds. The calculations allow formulation of an ionic, outer-sphere, bifunctional hydrogenation mechanism comprising 1) amine-assisted oxidative addition of H2 to 3, the result of which is equivalent to heterolytic splitting of dihydrogen, 2) replacement of a hydrogen-bonded amine by imine, and 3) simultaneous H delta+/H delta- transfer to the imine substrate from the NH moiety of an arene-coordinated amine ligand and the metal, respectively.

Fetal exposure to 3,4-diaminopyridine in a pregnant woman with congenital myasthenia syndrome.

OBJECTIVE: To report a case of fetal exposure to pyridostigmine and 3,4-diaminopyridine (3,4-DAP) in a pregnant woman with congenital myasthenia syndrome (CMS). CASE SUMMARY: A 31-year-old woman with postsynaptic CMS, not genetically characterized, was being treated with pyridostigmine and 3,4-DAP. She decided to become pregnant, despite having been informed about the paucity of available information on the possible risks of these drugs for the fetus. The dose of pyridostigmine remained stable throughout the pregnancy (60 mg every 8 h), and the 3,4-DAP dose was adjusted according to the patient's level of fatigue (20 mg/day, with occasional additional doses of 5 mg). At 25 weeks' gestation, ultrasonography confirmed the presence of only one umbilical artery. The results of other tests were normal. At 38 weeks' gestation, a healthy male neonate was born. His APGAR scores were 9 and 10 at 1 and 5 minutes, respectively. Five months later, the infant was healthy and his pediatric progress had been uneventful. DISCUSSION: It was difficult to find information about the possible congenital defects related to the use of 3,4-DAP because it is a rarely used drug. This case attracted our interest because it is an uncommon disease, and we found no reports on the use of 3,4-DAP during pregnancy. To our knowledge, as of this writing, this is the first published report of the use of 3,4-DAP during pregnancy. CONCLUSIONS: A successful pregnancy with a healthy infant was achieved after fetal exposure to 3,4-DAP and pyridostigmine.