Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice.

BACKGROUND/OBJECTIVE: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer's disease (AD) mice. METHODS: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration. RESULTS: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice. CONCLUSIONS: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality.

Safety and Pharmacokinetics of Bendamustine Rapid-Infusion Formulation.

Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution. Both formulations are administered as a 500 mL admixture with a recommended infusion time of 30 or 60 minutes for chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma, respectively. A newer liquid BDM formulation (rapid BDM) is a ready-to-dilute solution not requiring reconstitution that dilutes into an admixture of only 50 mL and can be safely administered in a shorter infusion time (10 minutes). Rapid BDM admixture also has longer stability at room temperature than both lyophilized and liquid BDM formulations (6 vs 2 to 3 hours). This phase 1, open-label, randomized, crossover (3-period, partially replicated) study, conducted in "end-of-life" cancer patients at 10 oncology centers in the United States, demonstrates that rapid BDM is bioequivalent to original BDM as determined by area under the curve. Expected differences in maximum plasma concentration and time to maximum plasma concentration were observed between study treatments, given the substantially shorter infusion time of rapid BDM. No clinically relevant differences in other evaluated pharmacokinetic parameters were found. Rapid BDM infusions were safe and tolerable for cancer patients in this study. The overall safety profiles of the 2 BDM formulations were comparable, with no new safety signals identified and no differences in infusion-related adverse events.

Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study.

OBJECTIVE: To evaluate dextromethorphan coadministered with quinidine as treatment of diabetic peripheral neuropathic pain. DESIGN: In a 13-week, phase 3, randomized controlled trial, 379 adults with daily symmetric diabetic peripheral neuropathy (DPN) leg pain for ≥3 months received double-blind placebo, dextromethorphan/quinidine (DMQ) 45/30 mg, or DMQ 30/30 mg, administered once daily for 7 days and twice daily thereafter. Efficacy measures included four pain rating scales applied daily using patient diaries, and another two applied at five clinic visits. RESULTS: On all six scales, DMQ 45/30 mg was significantly superior to placebo, including the primary efficacy analysis, which utilized mixed-effects modeling to test all scores on an 11-point numerical Pain Rating Scale (P < 0.0001). Sensitivity analyses gave consistent results. Efficacy vs placebo was also seen for diary ratings of present pain intensity, and pain interference with sleep and with activities (all P < 0.0001). Among clinic visit assessments, DMQ 45/30 mg demonstrated greater leg pain relief (P = 0.0002) and greater reduction of leg pain intensity (P = 0.0286) vs placebo. The efficacy of DMQ 30/30 mg was numerically less than for 45/30 mg but for most outcomes remained significantly greater vs placebo. Adverse events were mostly mild or moderate and of expected types. Discontinuation for adverse events in the DMQ groups was at least twice as common as placebo. CONCLUSIONS: Throughout a 13-week trial, DMQ was effective, with an acceptable safety profile, for treatment of DPN pain. Other fixed-dose combinations of DMQ should be studied to improve overall tolerability while maintaining significant efficacy.

Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect.

OBJECTIVE: To evaluate dextromethorphan combined with ultra low-dose quinidine (DMq) for treating pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). METHODS: In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score ≥13 on the Center for Neurologic Studies-Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20). RESULTS: In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo and 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis. Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p= 0.0002 and p= 0.0113, respectively). Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days and, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated. INTERPRETATION: DMq markedly reduced PBA frequency and severity, decreasing the condition's detrimental impact on a patient's life, with satisfactory safety and high tolerability. The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA.

La involución cerebral como problema clave de la medicina interna: consideraciones sobre las demencias / The cerebral involution as key problem of the internal medicine: considerations on the dementias

El envejecimiento es una problemática que incumbe básicamente a la medicina interna. Debe ser afrontada agregando a los recursos clínicos convencionales, las nuevas perspectivas que nos ofrece el avance de las ciencias biológicas. Juega un rol fundamental la medicina molecular, a través del desarrollo de la genética, la neuroendocrinología y la psiquiatría biológica. La manipulación genética inducida por la biotecnología del ADN recombinante, se apoya, en los últimos años, en poderosos instrumentos como las enzimas de restricción, las sondas moleculares radiactivas y la reacción en cadena de la polimerasa [PCR], que permiten describir el material genético, proporcionan evidencias crecientes del nexo entre alteración del proceso genético y envejecimiento. Las mutaciones sucesivas en el ADN, en el nuclear en menos medida y en el mitocondrial de forma más notoria, generarían efectos en la fosforilación oxidativa, y por ende, disminuirían las fuentes de energía en casi todos los órganos. Al mismo tiempo, los trastornos en la expresión de genes que codifican para determinadas moléculas contribuirían al detrimento de la respuesta fisiológica de la senescencia. Permite también que se hayan individualizado algunos marcadores relacionables con la demencia en la enfermedad de Alzheimer. La degeneración neuronal, en este caso, se la vincula con una acentuada pérdida en el repertorio de procesos reparadores del ADN, y será relacionado con alteraciones en secuencias de nucleótidos que favorecerían el depósito aberrante de fracciones proteícas. Las conexiones estructurales y funcionales ente el Sistema Nervioso Central y el Sistema Endócrino, desarrollan complejísimas interacciones que conducen a modelos de interpretación que, inevitablemente deberán ser integrativos cuando se trata de descifrar hechos clínicos. Paradigmáticamente, el modelo de stress, cuyo correcto funcionamiento es imprescindible para mantener la homeostasis, es el resultado de una respuesta efectuada desde múltiples tejidos, y ajustada por una extensa red de secreciones coordinadas. La senectud conspiraría contra esta coordinación a través de modificaciones en los sistemas de neurotrasmisores y en los circuitos de retroalimentación... (TRUNCADO)

La involución cerebral como problema clave de la medicina interna: consideraciones sobre las demencias / The cerebral involution as key problem of the internal medicine: considerations on the dementias

El envejecimiento es una problemática que incumbe básicamente a la medicina interna. Debe ser afrontada agregando a los recursos clínicos convencionales, las nuevas perspectivas que nos ofrece el avance de las ciencias biológicas. Juega un rol fundamental la medicina molecular, a través del desarrollo de la genética, la neuroendocrinología y la psiquiatría biológica. La manipulación genética inducida por la biotecnología del ADN recombinante, se apoya, en los últimos años, en poderosos instrumentos como las enzimas de restricción, las sondas moleculares radiactivas y la reacción en cadena de la polimerasa [PCR], que permiten describir el material genético, proporcionan evidencias crecientes del nexo entre alteración del proceso genético y envejecimiento. Las mutaciones sucesivas en el ADN, en el nuclear en menos medida y en el mitocondrial de forma más notoria, generarían efectos en la fosforilación oxidativa, y por ende, disminuirían las fuentes de energía en casi todos los órganos. Al mismo tiempo, los trastornos en la expresión de genes que codifican para determinadas moléculas contribuirían al detrimento de la respuesta fisiológica de la senescencia. Permite también que se hayan individualizado algunos marcadores relacionables con la demencia en la enfermedad de Alzheimer. La degeneración neuronal, en este caso, se la vincula con una acentuada pérdida en el repertorio de procesos reparadores del ADN, y será relacionado con alteraciones en secuencias de nucleótidos que favorecerían el depósito aberrante de fracciones proteícas. Las conexiones estructurales y funcionales ente el Sistema Nervioso Central y el Sistema Endócrino, desarrollan complejísimas interacciones que conducen a modelos de interpretación que, inevitablemente deberán ser integrativos cuando se trata de descifrar hechos clínicos. Paradigmáticamente, el modelo de stress, cuyo correcto funcionamiento es imprescindible para mantener la homeostasis, es el resultado de una respuesta efectuada desde múltiples tejidos, y ajustada por una extensa red de secreciones coordinadas. La senectud conspiraría contra esta coordinación a través de modificaciones en los sistemas de neurotrasmisores y en los circuitos de retroalimentación... (TRUNCADO)(AU)