A Review of the Unique Drug Development Strategy of Indacaterol Acetate/Glycopyrronium Bromide/Mometasone Furoate: A First-in-Class, Once-Daily, Single-Inhaler, Fixed-Dose Combination Treatment for Asthma.

A novel, once-daily (o.d.), fixed-dose combination (FDC) of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF), delivered by the inhaler Breezhaler® device, is the first long-acting beta2-adrenergic agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS) therapy to be approved for maintenance treatment of asthma in adults inadequately controlled on LABA/ICS. The approval of IND/GLY/MF in the European Union (EU) also included an optional electronic sensor and smartphone (or other suitable device) application, making it the first "digital companion" that can be prescribed with an asthma medication. As a result, the European Medicines Agency included this approval as one of the "outstanding contributions to public health" (for Pneumology/Allergology) in their 2020 highlights report. Alongside IND/GLY/MF, an o.d. LABA/ICS FDC, IND/MF, was also developed and approved. This review outlines the unique strategy used in the accelerated development of IND/GLY/MF that combined various approaches: (1) selecting individual components with established efficacy/safety, (2) bridging doses to optimize efficacy/safety of IND/GLY/MF and IND/MF delivered via the Breezhaler® device, (3) developing IND/GLY/MF and IND/MF in parallel, and (4) submission for regulatory approval before formal completion of the pivotal phase III studies. IND/GLY/MF and IND/MF were combined in a single-development plan (PLATINUM program), which comprised four phase III studies: QUARTZ and PALLADIUM evaluated IND/MF while IRIDIUM and ARGON evaluated IND/GLY/MF. A unique feature was the inclusion of two LABA/ICS comparators in the pivotal IRIDIUM study-IND/MF as an internal comparator, and high-dose salmeterol xinafoate/fluticasone propionate (SAL/FLU) as a marketed comparator. In the ARGON study, IND/GLY/MF was compared against o.d. tiotropium (via Respimat®) plus twice-daily (b.i.d.) high-dose SAL/FLU (via Diskus®). As a result of this development strategy, the development and approval of IND/GLY/MF was accelerated by ca. 4 years as against what would be expected from a traditional approach, novel data were generated, and a unique optional digital companion was approved in the EU. A Video Abstract by Dr Dominic Brittain, Global Drug Development, Novartis. (MP4 228293 kb).

The amino acid metabolism is essential for evading physical plasma-induced tumour cell death.

BACKGROUND: Recent studies have emphasised the important role of amino acids in cancer metabolism. Cold physical plasma is an evolving technology employed to target tumour cells by introducing reactive oxygen species (ROS). However, limited understanding is available on the role of metabolic reprogramming in tumour cells fostering or reducing plasma-induced cancer cell death. METHODS: The utilisation and impact of major metabolic substrates of fatty acid, amino acid and TCA pathways were investigated in several tumour cell lines following plasma exposure by qPCR, immunoblotting and cell death analysis. RESULTS: Metabolic substrates were utilised in Panc-1 and HeLa but not in OVCAR3 and SK-MEL-28 cells following plasma treatment. Among the key genes governing these pathways, ASCT2 and SLC3A2 were consistently upregulated in Panc-1, Miapaca2GR, HeLa and MeWo cells. siRNA-mediated knockdown of ASCT2, glutamine depletion and pharmacological inhibition with V9302 sensitised HeLa cells to the plasma-induced cell death. Exogenous supplementation of glutamine, valine or tyrosine led to improved metabolism and viability of tumour cells following plasma treatment. CONCLUSION: These data suggest the amino acid influx driving metabolic reprogramming in tumour cells exposed to physical plasma, governing the extent of cell death. This pathway could be targeted in combination with existing anti-tumour agents.

Postresuscitation treatment with argon improves early neurological recovery in a porcine model of cardiac arrest.

INTRODUCTION: Effects of postresuscitation treatment with argon on neurologic recovery were investigated in a porcine model of cardiac arrest (CA) with an underlying acute myocardial infarction. METHODS: The left anterior descending coronary artery was occluded in 12 pigs, and CA was induced. After 8 min of untreated CA, cardiopulmonary resuscitation was performed for 5 min before defibrillation. Following resuscitation, animals were subjected to 4-h ventilation with 70% argon/30% oxygen or 70% nitrogen/30% oxygen. Myocardial function was echocardiographically assessed, and serum neuron-specific enolase was measured. Animals were observed up to 72 h for assessment of survival and neurologic recovery. RESULTS: All the animals were resuscitated and survived for 72 h, except for a control pig. Ventilation with argon did not have any detrimental effects on hemodynamics and respiratory gas exchange. All the six argon-treated animals had a fast and complete 72-h neurologic recovery, in contrast to only two of the six controls (P < 0.05). Seventy-two-hour neurologic alertness score and neurologic deficit score were, respectively, 100 and 0 in the argon group and 79 and 29 in the control one (P < 0.01 and P < 0.05). Significantly lower increases in serum neuron-specific enolase (12% vs. 234%) and minimal histological brain injury (neuronal degeneration: 0 vs. 1) were also observed in argon-treated animals, in comparison to controls. CONCLUSIONS: In this model, postresuscitation treatment with argon allowed for a faster and complete neurologic recovery, without detrimental effects on hemodynamics and respiratory gas exchanges.

Argon reduces neurohistopathological damage and preserves functional recovery after cardiac arrest in rats.

BACKGROUND: Xenon has profound neuroprotective effects after neurological injury and is currently undergoing phase 2 clinical trials in cardiac arrest patients. However, xenon is very costly, which might preclude its widespread use. We hypothesized argon, which is more available, might also protect central nervous tissues and allow better functional recovery in a rodent model of global cerebral ischaemia. METHODS: Fourteen male Sprague-Dawley rats were subjected to 7 min of cardiac arrest and 3 min of cardiopulmonary resuscitation (CPR). One hour after successful CPR, animals were randomized to either ventilation with 70% argon in oxygen (n = 7) for 1 h or 70% nitrogen (controls, n=7). A neurological deficit score (NDS) was calculated daily for the following 7 days, then the animals were killed and the brains harvested for histopathological analyses. RESULTS: All animals survived. Control rats had severe neurological dysfunction, while argon-treated animals showed significant improvements in the NDS at all time points. This was paralleled by a significant reduction in the neuronal damage index in the neocortex and the hippocampal CA 3/4 region. CONCLUSIONS: Our study demonstrates that a single 1 h application of 70% argon significantly reduced histopathological damage of the neocortex and hippocampus, associated with a marked improvement in functional neurological recovery.

Bactericidal effects of non-thermal argon plasma in vitro, in biofilms and in the animal model of infected wounds.

Non-thermal (low-temperature) physical plasma is under intensive study as an alternative approach to control superficial wound and skin infections when the effectiveness of chemical agents is weak due to natural pathogen or biofilm resistance. The purpose of this study was to test the individual susceptibility of pathogenic bacteria to non-thermal argon plasma and to measure the effectiveness of plasma treatments against bacteria in biofilms and on wound surfaces. Overall, Gram-negative bacteria were more susceptible to plasma treatment than Gram-positive bacteria. For the Gram-negative bacteria Pseudomonas aeruginosa, Burkholderia cenocepacia and Escherichia coli, there were no survivors among the initial 10(5) c.f.u. after a 5 min plasma treatment. The susceptibility of Gram-positive bacteria was species- and strain-specific. Streptococcus pyogenes was the most resistant with 17 % survival of the initial 10(5) c.f.u. after a 5 min plasma treatment. Staphylococcus aureus had a strain-dependent resistance with 0 and 10 % survival from 10(5) c.f.u. of the Sa 78 and ATCC 6538 strains, respectively. Staphylococcus epidermidis and Enterococcus faecium had medium resistance. Non-ionized argon gas was not bactericidal. Biofilms partly protected bacteria, with the efficiency of protection dependent on biofilm thickness. Bacteria in deeper biofilm layers survived better after the plasma treatment. A rat model of a superficial slash wound infected with P. aeruginosa and the plasma-sensitive Staphylococcus aureus strain Sa 78 was used to assess the efficiency of argon plasma treatment. A 10 min treatment significantly reduced bacterial loads on the wound surface. A 5-day course of daily plasma treatments eliminated P. aeruginosa from the plasma-treated animals 2 days earlier than from the control ones. A statistically significant increase in the rate of wound closure was observed in plasma-treated animals after the third day of the course. Wound healing in plasma-treated animals slowed down after the course had been completed. Overall, the results show considerable potential for non-thermal argon plasma in eliminating pathogenic bacteria from biofilms and wound surfaces.

Tratamiento conargón plasma dela membrana esofágica secundaria a síndrome de Plummer-Vinson: una nueva alternativa terapética (AU) / Argon plasma coagulation therapy of upper esophageal web in a patient with Plummer- Vinson syndrome: A new therapeutical option

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Healing of a bleeding solitary rectal ulcer with multiple sessions of argon plasma.

BACKGROUND: Solitary rectal ulcer syndrome (SRUS) is an uncommon disorder of evacuation. Management of bleeding ulcers is usually unsatisfactory with conventional treatments. Argon plasma coagulation (APC) has been reported in case reports to control bleeding; however, it has not been shown to result in ulcer healing. OBJECTIVE: To investigate the efficacy and safety of APC in controlling bleeding from SRUS and to study its efficacy in eventual healing of ulcers. DESIGN: A randomized, controlled trial of the management of 24 consecutive patients with SRUS. SETTING: The gastroenterology unit at 2 tertiary care hospitals. PATIENTS: Twenty-four patients with bleeding SRUS. MAIN OUTCOME MEASUREMENTS: Control of bleeding and endoscopic healing of SRUS. METHODS: Twenty-four patients with bleeding SRUS, whose diagnoses were based on clinical, colonoscopic, and histologic findings, were randomized to receive either standard care only (12 patients, biofeedback therapy [BT] group) or multiple sessions of APC in addition to BT (12 patients, APC group). All patients were advised to intake a high level of fluids and fibers, laxatives, biofeedback, and behavior modification therapy in addition to the treatment. Patients were followed to determine whether ulcers healed. RESULTS: Twenty-four patients with symptoms that lasted 12.6 +/- 4.8 months were included. Bleeding was controlled in all 12 patients in the APC group, but only in 5 of 12 patients in BT group. We also made the following observations about healing of the ulcers: 8 of 12 patients in the APC group had complete healing of their ulcers after 4 to 8 sessions, whereas in the BT group, ulcers healed in only 2 of 12 patients. CONCLUSIONS: APC controls the bleeding in patients with SRUS and also improves the healing of these ulcers.

Treatment of epistaxis in hereditary hemorrhagic telangiectasia patients by argon plasma coagulation with local anesthesia.

BACKGROUND: Recurrent epistaxis is the most common manifestation of hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to determine the role and efficacy of argon plasma coagulation (APC) in the management of epistaxis caused by HHT. METHODS: From 1997 to 2004, 43 patients with diagnosed HHT were treated for recurrent epistaxis with APC in our department. RESULTS: Thirty-six patients reported substantial reduction of bleeding after treatment. Of the 18 patients who previously needed blood transfusions, 13 reported substantial reduction of bleeding after treatment and no blood transfusions were necessary. CONCLUSION: APC allows a control of epistaxis in HHT patients and guarantees a long time free from blood transfusions. This treatment modality can be performed with local anesthesia, is not invasive, is well tolerated, is inexpensive, and can be used as a first step even in patients who need to undergo several blood transfusions for their epistaxis.

Tratamiento quirúrgico de la hipertrofia de los cornetes inferiores con plasma argón / Surgical treatment of the hypertrophy of the inferior turbinal bones with argon plasma

En nuestras consultas atendemos con frecuencia la obstrucción nasal crónica y la causa más frecuente es la hipertrofia de los cornetes inferiores. Cuando estos pacientes no tienen una respuesta positiva al tratamiento médico y luego de analizar los resultados del estudio de la enfermedad alérgica de estos, es que decidimos realizar la reducción quirúrgica del tamaño de los cornetes inferiores. Entre las técnicas utilizadas para este propósito se encuentra la coagulación con plasma argón, un procedimiento que utiliza corriente eléctrica de alta frecuencia y una fuente de plasma argón. La reducción efectiva de los cornetes, la posibilidad de alcanzarlo en toda la longitud de estos, la penetración limitada, el poco tiempo quirúrgico y la ausencia de complicaciones hemorrágicas entre otras ventajas, hacen de esta técnica algo excepcional. Fueron atendidos 40 pacientes diagnosticados de rinitis crónica hipertrófica, quienes fueron revisados a los 3 meses, 12 meses y 24 meses después del tratamiento. A los 24 meses, 38 pacientes (95 por ciento) refirieron una mejoría significativa de los síntomas. Se revisan y discuten las indicaciones, ventajas, complicaciones y resultados a largo plazo del uso de la coagulación con plasma argón en rinocirugía(AU)

O uso do laser de argônio no tratamento da triquíase / Argon laser in the treatment of trichiasis

OBJETIVO: Avaliar a eficácia da técnica de termoablação dos folículos pilosos dos cílios em triquíase com laser de argônio e observar a preferência dos pacientes submetidos a este tratamento, pela anestesia tópica com colírio anestésico ou pela anestesia local injetável. MÉTODOS: Estudo prospectivo de 55 pálpebras de 39 pacientes com triquíase, tratados com fotocoagulação dos folículos pilosos com Argon green laser (Alcon® - EUA). Neste estudo avaliou-se a idade e o sexo dos pacientes, o número de sessões realizadas, a evolução após as aplicações e a preferência pelo tipo de anestesia. Os parâmetros utilizados foram: (1) Mira - 150 µm; (2) Potência- 750 mW; (3) Tempo de exposição- 0,2 s. Cada cílio recebeu, no máximo, 9 disparos por sessão. RESULTADOS: Dentre os 39 participantes do estudo, 58,9 por cento eram do sexo feminino e 41 por cento do sexo masculino. A idade média foi de 71 anos. Houve cura em 69 por cento (38 pálpebras), sendo 29 por cento (16 pálpebras) com apenas uma sessão de laser. Houve preferência estatisticamente significativa pelo procedimento realizado sob anestesia local injetável. CONCLUSAO: Os resultados sugerem que a anestesia local no tratamento da triquíase com laser de argônio é a preferência da maioria dos pacientes e que a termoablação dos folículos pilosos com laser de argônio é tratamento efetivo para a triquíase.

Argon plasma coagulation is an effective treatment for refractory hemorrhagic radiation proctitis.

INTRODUCTION: Chronic radiation proctitis complicating pelvic radiotherapy can be debilitating. It commonly presents with rectal bleeding, which can be difficult to control. Medical management of hemorrhagic radiation proctitis is not very successful, although surgery carries high risks. Thus, endoscopic treatments are preferred. The aim of this study is to assess the efficacy of argon plasma coagulation applied endoscopically to treat hemorrhagic radiation proctitis that has been refractory to topical formalin therapy. METHODS: Twelve patients who had ongoing bleeding from radiation proctitis, after previously failed formalin therapy, underwent endoscopic treatment using argon plasma coagulation. The efficacy of treatment was assessed by grading the frequency and severity of bleeding (0-4, 0 being no bleeding), hemoglobin level, and transfusion requirements. RESULTS: At a median follow-up of 11 months, ten patients (83 percent) had a significant reduction in the severity and frequency of bleeding, with complete cessation in six (50 percent). The presence of coexistent radiation-induced sigmoiditis in two patients was associated with reduced but persistent bleeding, because of difficulty in targeting the bleeding sites in the sigmoid colon. The median number of treatment sessions per patient was two (range, 1-3), with the number of sessions correlated with the extent of the proctitis. All patients had an improvement in their hemoglobin level, with the mean increasing from 11.2 to 12.3 g/dl. In the six months before starting therapy, all patients had been taking iron supplements, and four had required blood transfusions (median 3 units, range, 2-6). Iron supplements were ceased four weeks after the completion of therapy in all cases, and no further transfusions were required during the study period. None of the patients experienced any significant side effects or complications. CONCLUSIONS: Argon plasma coagulation is an effective and safe treatment for hemorrhagic radiation proctitis that has been refractory to topical formalin therapy.

Argon plasma coagulation for rectal bleeding after prostate brachytherapy.

PURPOSE: To better define the efficacy and safety of argon plasma coagulation (APC), specifically for brachytherapy-related proctitis, we reviewed the clinical course of 7 patients treated for persistent rectal bleeding. Approximately 2-10% of prostate cancer patients treated with 125I or 103Pd brachytherapy will develop radiation proctitis. The optimum treatment for patients with persistent bleeding is unclear from the paucity of available data. Prior reports lack specific dosimetric information, and patients with widely divergent forms of radiation were grouped together in the analyses. METHODS AND MATERIALS: Seven patients were treated with APC at the Veterans Affairs Puget Sound Health Care System and the University of Washington from 1997 to 1999 for persistent rectal bleeding due to prostate brachytherapy-related proctitis. Four patients received supplemental external beam radiation, delivered by a four-field technique. A single gastroenterologist at the Veterans Affairs Puget Sound Health Care System treated 6 of the 7 patients. If the degree of proctitis was limited, all sites of active bleeding were coagulated in symptomatic patients. An argon plasma coagulator electrosurgical system was used to administer treatments every 4-8 weeks as needed. The argon gas flow was set at 1.6 L/min, with an electrical power setting of 40-45 W. RESULTS: The rectal V100 (the total rectal volume, including the lumen, receiving the prescription dose or greater) for the 7 patients ranged from 0.13 to 4.61 cc. Rectal bleeding was first noticed 3-18 months after implantation. APC (range 1-3 sessions) was performed 9-22 months after implantation. Five patients had complete resolution of their bleeding, usually within days of completing APC. Two patients had only partial relief from bleeding, but declined additional APC therapy. No patient developed clinically evident progressive rectal wall abnormalities after APC, (post-APC follow-up range 4-13 months). CONCLUSIONS: Most patients benefited from APC, and no cases of clinically evident progressive tissue destruction were noted. Although APC appears to be efficacious and safe in the setting of the rectal doses described here, caution is in order when contemplating APC for brachytherapy patients.

Macroaneurismas retinales adquirido: estudio retrospectivo / Acquired retinal macroaneurisms: retrospective study

Se estudian en forma retrospectiva 22 ojos de 21 pacientes con el diagnóstico de macroaneurismas retinales adquiridos, evaluados en el Servicio Oftalmología del Hospitalclínico de la U. de Chile, en la Fundación Oftalmológica Los Andes y e la práctica privada de los autores. El objetivo de este trabajo fue definir las características clínicas de los pacientes con esta con fotocoagulación con láser argón y el resultado de otro grupo no tratado. Se estudiaron 22 ojos de 21 pacientes con macroaneurisma retinales, de los cuales 13 pacientes fueron sometidos a tratamiento con láser argón y 8 fueron observados. En los resultados se encuentra que la patología se presenta de predominio en mujeres mayores de 65 años, con hipertensión arterial asociada y que consultan por baja de visión o un escotoma central. Se encuentra una agudeza visual promedio de 0,15 (Snellen) del ojo afectado v/s 0.22 (Snellen) del ojo contralateral (t test p<0.05). Al fondo de ojo el macroaneurisma predominal en el O1 en 13 casos (62 por ciento), es visible en 11 casos (50 por ciento) en el primer examen, es predominante único en 20 casos (91 por ciento) y se ubica preferentemente en la rama temporal superior en 13 casos (62 por ciento). Encontramos 2 formas clínicas de presentación del macroaneurisma: una asociada a edema macular y exudación lipídica, y la otra asociada a hemorragia prerretinal, intrarretinal, subretinal o hemorragia vítrea. La angiofluoresceinografía nos muestra el macroaneurisma en 12 casos (57 por ciento), y nos ayuda al diagnóstico en 6 casos (28 por ciento) sin diagnóstico claro inicial. existen 5 casos (22 por ciento) en que el diagnóstico se hace en forma tardía, por que se presentan con una complicación hemorrágica y luego el macroaneurisma finalmente se hace visible al desaparecer la hemorragia. Se dispone el seguimiento en 16 casos (77 por ciento), y se observa que los ojos que presentan complicaciones hemorrágicas mejoran la agudeza visual, mientras que aquellos que se asocian a edema maculary exudación lipídica mantienen igual su agudeza visual. Trece casos (62 por ciento) fueron tratados con láser argón, y estos ojos finalmente mantuvieron igual visión. En nuestro estudio el resultado visual final más bien se asocia a la presencia o no edema macular o hemorragia en el examen inicial, y no al tratamiento con láser argón. El tratamiento con láser argón se sugiere solamente en caso con edema macular

Photothrombosis of corneal neovascularization by intravenous rose bengal and argon laser irradiation.

Management of corneal neovascularization by photocoagulation has been limited and rarely successful. We evaluated the efficacy and safety of the novel technique of photothrombosis to occlude corneal neovascularization. Sixteen rabbit corneas with previous ocular surface wounds that had healed with 360 degrees extensive neovascularization (persistent for 20 months) were used. After an intravenous injection of rose bengal solution (40 mg/kg of body weight [BW]), each vessel on the upper half of the cornea was occluded with a photochemically induced thrombus within ten shots of argon laser irradiation (514.5 nm, 130 mW, 63 microns, 0.2 s); those on the lower half were used as an internal control. Throughout the four-month study period, the treated vessels remained occluded, as evidenced by corneal fluorescein angiography. Corneal clarity was improved after treatment. A single injection of rose bengal at a dose of 8 mg/kg of BW or higher was sufficient for successful photothrombotic occlusion of corneal vessels within one hour of experimentation. Transient elevations of serum urea nitrogen, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin levels and decrease of serum phosphorus level were noted on the first day after injection with 40 mg/kg of BW of rose bengal solution.