Exploring the influence of hydrogen bond donor groups on the microstructure and intermolecular interactions of amorphous solid dispersions containing diflunisal structural analogues.

Drug-polymer intermolecular interactions, and H-bonds specifically, play an important role in the stabilization process of a compound in an amorphous solid dispersion (ASD). However, it is still difficult to predict whether or not interactions will form and what the strength of those interactions would be, based on the structure of drug and polymer. Therefore, in this study, structural analogues of diflunisal (DIF) were synthesized and incorporated in ASDs with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) as a stabilizing polymer. The respective DIF derivatives contained different types and numbers of H-bond donor groups, which allowed to assess the influence of these structural differences on the phase behavior and the actual interactions formed in the ASDs. The highest possible drug loading of these derivatives in PVPVA were evaluated through film casting. Subsequently, a lower drug loading of each compound was spray dried. These spray dried ASDs were subjected to an in-depth solid-state nuclear magnetic resonance (ssNMR) study, including 1D spectroscopy and relaxometry, as well as 2D dipolar HETCOR experiments. The drug loading study revealed the highest possible loading of 50 wt% for the native DIF in PVPVA. The methoxy DIF derivative reached the second highest drug loading of 35 wt%, while methylation of the carboxyl group of DIF led to a sharp decrease in the maximum loading, to around 10 wt% only. Unexpectedly, the maximum loading increased again when both the COOH and OH groups of diflunisal were methylated in the dimethyl DIF derivative, to around 30 wt%. The ssNMR study on the spray dried ASD samples confirmed intermolecular H-bonding with PVPVA for native DIF and methoxy DIF. Studies of the proton relaxation decay times and 2D 1H-13C dipolar HETCOR experiments indicated that the ASDs with native DIF and methoxy DIF were homogenously mixed, while the ASDs containing DIF methyl ester and dimethyl DIF were phase separated at the nm level. It was established that, for these systems, the availability of the carboxyl group was imperative in the formation of intermolecular H-bonds with PVPVA and in the generation of homogenously mixed ASDs.

Role for Carboxylic Acid Moiety in NSAIDs: Favoring the Binding at Site II of Bovine Serum Albumin.

The molecular structures of nonsteroidal anti-inflammatory drugs (NSAIDs) vary, but most contain a carboxylic acid functional group (RCOOH). This functional group is known to be related to the mechanism of cyclooxygenase inhibition and also causes side effects, such as gastrointestinal bleeding. This study proposes a new role for RCOOH in NSAIDs: facilitating the interaction at the binding site II of serum albumins. We used bovine serum albumin (BSA) as a model to investigate the interactions with ligands at site II. Using dansyl-proline (DP) as a fluorescent site II marker, we demonstrated that only negatively charged NSAIDs such as ibuprofen (IBP), naproxen (NPX), diflunisal (DFS), and ketoprofen (KTP) can efficiently displace DP from the albumin binding site. We confirmed the importance of RCOO by neutralizing IBP and NPX through esterification, which reduced the displacement of DP. The competition was also monitored by stopped-flow experiments. While IBP and NPX displaced DP in less than 1 s, the ester derivatives were ineffective. We also observed a higher affinity of negatively charged NSAIDs using DFS as a probe and ultrafiltration experiments. Molecular docking simulations showed an essential salt bridge between the positively charged residues Arg409 and Lys413 with RCOO-, consistent with the experimental findings. We performed a ligand dissociation pathway and corresponding energy analysis by applying molecular dynamics. The dissociation of NPX showed a higher free energy barrier than its ester. Apart from BSA, we conducted some experimental studies with human serum albumin, and similar results were obtained, suggesting a general effect for other mammalian serum albumins. Our findings support that the RCOOH moiety affects not only the mechanism of action and side effects but also the pharmacokinetics of NSAIDs.

Hereditary Transthyretin Amyloidosis and the Impact of Classic and New Treatments on Kidney Function: A Review.

Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive, and life-threatening disease caused by misfolded transthyretin (TTR) proteins that aggregate as abnormal amyloid fibrils and accumulate throughout the body. The kidney is one of the main organs affected in amyloid light chain (AL) amyloidosis and ATTRv amyloidosis. The most common clinical presentation is proteinuria, which consists mainly of albumin; this is the first step in the natural history of ATTRv nephropathy. Not all TTR mutations are equal in terms of ATTRv kidney involvement. Kidney involvement in ATTRv itself is difficult to define, given the numerous associated confounding factors. There are several treatments available to treat ATTRv, including orthotopic liver transplant (OLT), which is the classic treatment for ATTRv. However, we should be careful regarding the use of calcineurin inhibitors in the setting of OLT because these can be nephrotoxic. New treatments for amyloidosis may have an impact on kidney function, including drugs that target specific pathways involved in the disease. Tafamidis and diflunisal, which are TTR stabilizers, patisiran (RNA interference agent), and inotersen (antisense oligonucleotide inhibitor) have been shown to reduce TTR amyloid. Tafamidis and patisiran are medications that have reduced the progression of kidney disease in amyloidosis, but inotersen and diflunisal may damage kidney function.

Synthesis and PET Imaging Biodistribution Studies of Radiolabeled Iododiflunisal, a Transthyretin Tetramer Stabilizer, Candidate Drug for Alzheimer's Disease.

The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer's Disease (AD)-like pathology in mice, although the mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report an isotopic exchange reaction to obtain IDIF radiolabeled with 18F. [19F/18F]exchange reaction over IDIF in dimethyl sulfoxide at 160 °C resulted in the formation of [18F]IDIF in 7 ± 3% radiochemical yield in a 20 min reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [18F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t > 10 min post administration), rapid accumulation in the liver, long circulation time, and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects.

Difunisal vrs aspirina en el dolor post-episotomía: estudio comparativo / Diflunisal vs. aspirin for post-episotomy pain: a comparative study

Todo el estudio rellacionado con síntomas y en especial el dolor, presenta la dificultad de la medición, adecuada de los parámetros de comparación, los cuales sosn altamente subjetivos. En este estudio hemos tratado de aminorrar la subjetividad haciendo el grupo lo más homogéneo posible, así: 1. Todas las pacientes tenían estatus socio-económico semejante, perteneciendo a la clase obrera. 2. Edades que oscilaban entre los 18 a los 25 años. 3. Primer o segundo embarazo con parto eutócico. 4. Atención del parto por residentes de 1er. año de Ginecología y Obstetricia. 5. Epsiotomía Medio Lateral Izquierda. En base a los datos presentados este trabajo, es evidente que el Diflunisal provee mejor alivio del dolor, con mauor tolerancia y sin efectos secundarios indeseables. Más del 80% de mujeres en el postparto inmediato experimentan dolor de leve a moderado, el cual clasifican como periódico o transitorio y que puede ser aliviado eficientemente con cualquiera de los analgésicos actualmente disponibles. Debido a su mayor potencia y eficacia el diflunisal podía ser el analgseico de escoger ene l grupo formado por ese 20% de puérpereas que experimentan dolor más intenso y duradero, para que en ellas tamvbién el puerperio inmediato se convierta en una etapa feliz y libre de malestares

Estudo comparativo entre flurbiprofen e diflunisal no tratamento de entorses ou distensöes agudas envolvendo o tornozelo / A comparative study between flurbiprofen and diflunisal in the treatment of acute sprain and strain ankle injuries

Este foi um estudo duplo-cego, randomizado, com grupos paralelos, comparando o flurbiprofen com o diflunisal; no tratamento de entorses ou distensöes agudas do tornozelo. Num período de seis a nove meses, foram avaliados 50 pacientes com lesöes traumáticas agudas do tornozelo, sendo que 23 pacientes receberam flurbiprofen 100 mg duas vezes ao dia, e 27 pacientes foram tratados com diflunisal 500 mg duas vezes ao dia. Todos os pacientes deveriam ser avaliados no dia da inclusäo no estudo e após sete, 14, 21, e 28 dias de tratamento, tendo sido dada ênfase ao alívio dos sintomas e o retorno às atividades normais. Ocorreram algumas diferenças favoráveis ao grupo tratado com o flurbiprofen, relativas à segurança e eficácia do tratamento. Apenas um paciente, medicado com o diflunisal apresentou efeito colateral, representado por sensaçäo de peso no estômago, que näo impediu o prosseguimento do estudo. Nenhum paciente necessitou ultrapassar o 21§ dia de tratamento

Analgesia con pirprofén en el posoperatorio de cirugía general / Postoperative analgesia with pirprofen in the postoperative period of general surgery

Se valoró, por medio de método doble ciego, el efecto analgésico de la administración en dosis única de pirprofén, diflunisal y zomepirac en el posoperatorio de cirugía general de 90 pacientes distribuidos en tres grupos. Las valoraciones se realizaron mediante una escala visual análoga al momento de tomar el medicamento, a los 15 y 30 minutos, y a la una, dos, tres y cuatro horas después. El efecto analgésico inmediato de pirprofén fue satisfactorio y estadísticamente superior a diflunisal y zomepirac (p=<0.01). Al final del estudio los tres medicamentos tuvieron resultados semejantes entre sí. En cuanto a la tolerancia, fue satisfactoria para los tres medicamentos

Pirprofén en cirugía bucal / Pirprofen in oral surgery

Se valoró, mediante estudio doble ciego, el efecto analgésico de pirprofén, diflunisal y zomepirac, comparando los efectos de la administración en dosis única en 60 pacientes adultos sometidos a cirugía bucal. Los resultados demuestran que pirprofén tuvo acción más rápida que diflunisal, con efecto similar casi al final del estudio, y que tanto pirprofén como diflunisal resultaron más eficaces que zomepirac

Diflunisal comparado con dimetilpirazolona en dolor posoperatorio ortopedico. / Diflunisal compared with dimethylpyrazolone postoperative orthopedic pain

Treinta pacientes, todos ellos mayores de 17 anos, con dolor posquirurgico de cirugia ortopedica, moderado o severo, fueron seleccionados al azar para recibir 500 mg de diflunisal dos veces al dia o dimetilpirazolona 1 g tres veces al dia, por via oral durante cinco dias. Diflunisal fue analgesicamente mas efectivo desde el primero al ultimo dia del tratamiento, que la dimetilpirazolona. La evaluacion de la efectividad fue la misma tanto por el paciente como por el investigador.No se observaron efectos colaterales en ninguno de los dos grupos