RESUMEN
PURPOSE: We evaluated the efficacy of megestrol in improving chemotherapy-related anorexia by analyzing the related scales of taste alteration. METHODS: We conducted the current study on a group of advanced patients with cancer with two or more chemotherapy cycles. The chemotherapy-induced taste alteration scale (CiTAs) scale helped assess the megestrol effects on basic taste perception, aversive taste changes, unpleasant symptoms, and associated concerns. Furthermore, the Short Nutritional Assessment Questionnaire scale (SNAQ) helped measure the impact of megestrol on malnutrition likelihood in patients experiencing chemotherapy-induced anorexia. The World Health Organization Quality of Life (WHOQOL)-BREF Scale was used to evaluate the quality of life of participants, producing scores related to physical health, psychological well-being, environmental factors, and social relationships. RESULTS: The CiTAs scale assessment indicated that administering megestrol significantly enhanced taste perception among advanced patients with cancer undergoing chemotherapy. Notably, the megestrol group patients showed significantly higher Short Nutritional Assessment Questionnaire (SNAQ) scores than the control group. The megestrol group patients also exhibited higher physiological (PHYS) scores than their control group counterparts. However, this distinction was not statistically significant. The study findings indicate that patients who received megestrol demonstrated significantly higher scores in psychological (PSYCH) and environmental(ENVIR) domains than the control group. Furthermore, megestrol administration was associated with significantly elevated SOCIL and ENVIR levels in patients. CONCLUSION: The proficient efficacy evaluation of megestrol in enhancing appetite, mitigating malnutrition likelihood, and improving the quality of life of chemotherapy-induced anorexic patients can be achieved through taste-related scales.
Asunto(s)
Anorexia , Antineoplásicos , Neoplasias , Calidad de Vida , Humanos , Anorexia/inducido químicamente , Masculino , Femenino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Encuestas y Cuestionarios , Antineoplásicos/efectos adversos , Anciano , Adulto , Acetato de Megestrol/efectos adversos , Acetato de Megestrol/uso terapéutico , Acetato de Megestrol/administración & dosificación , Evaluación Nutricional , Estimulantes del Apetito/uso terapéutico , Estimulantes del Apetito/administración & dosificación , Estimulantes del Apetito/efectos adversos , Gusto/efectos de los fármacosRESUMEN
OBJECTIVE: Cancer-related anorexia-cachexia comprises one of the most common syndromes of advanced cancer patients. The management of cancer-related anorexia-cachexia is a great challenge in clinical practice. There are no definite practice guidelines yet for the prevention and treatment of cancer-related anorexia-cachexia. This study is considered to find out whether there is any role of mirtazapine in the improvement of anorexia in cancer patients. METHODS: A total of 80 cancer-anorexia patients were enrolled. Patients in the trial arm received the standard chemotherapy medication plus one tablet of mirtazapine 15 mg daily at night orally for 8 weeks starting from the day of an initial assessment. The control arm received the standard chemotherapy medication plus one tablet of megestrol acetate 160 mg daily orally for 8 weeks starting from the day of an initial assessment. Each patient was assessed by validated versions of Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale v 4 questionnaires. RESULTS: After 4 and 8 weeks each patient was evaluated again using the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale tool. The quality of life of each patient was assessed by European Organization for Research and Treatment QLQ-C30 v 3.0. After 4 to 8 weeks of treatment, the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale score in cancer anorexia patients in the mirtazapine improved anorexia significantly. However, the improvement after 4 to 8 weeks was not statistically significant when it was compared with the megestrol acetate (P > 0.05). CONCLUSIONS: Therefore, the findings of this study reveal that mirtazapine might be a potential alternative to megestrol acetate, as it has shown potential efficacy as like as megestrol acetate.
Asunto(s)
Anorexia , Caquexia , Acetato de Megestrol , Mirtazapina , Neoplasias , Calidad de Vida , Humanos , Mirtazapina/uso terapéutico , Mirtazapina/administración & dosificación , Anorexia/tratamiento farmacológico , Anorexia/etiología , Acetato de Megestrol/uso terapéutico , Acetato de Megestrol/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Femenino , Caquexia/tratamiento farmacológico , Caquexia/etiología , Método Doble Ciego , Anciano , Adulto , Mianserina/análogos & derivados , Mianserina/uso terapéutico , Mianserina/administración & dosificación , Estimulantes del Apetito/uso terapéutico , Estimulantes del Apetito/administración & dosificaciónRESUMEN
Nonhuman primates used in biomedical research may experience clinically significant weight loss for a variety of reasons. Episodes of anorexia (complete loss of appetite) or hyporexia (decreased appetite) can result in significant weight loss, potentially altering animal welfare and scientific studies. The FDA has approved several appetite stimulants for use in domestic species, but currently none are approved for use in NHP. Treatment of inappetence and weight loss in NHP often relies on the extralabel use of these compounds. Capromorelin is a ghrelin receptor agonist. As a growth hormone secretagogue, capromorelin increases appetite, leading to weight gain. Studies in several species have shown a positive correlation between capromorelin administration and weight gain; in 2017, an oral solution of capromorelin received FDA approval for use in dogs. We tested this solution in healthy adult rhesus macaques (n = 3 males and 3 females) for its effects on body weight and insulin like growth factor-1 (IGF-1). A control group (n = 2 males and 2 females) was used for comparison. Treated macaques received a 3mg/kg oral dose daily for 7 d. Clinical signs were observed daily. Weights were collected before, during and at the end of treatment. Blood was drawn before, during and after treatment for measurement of IGF-1 levels and standard hematology and biochemistry parameters. Baseline-adjusted mean body weights and IGF-1 levels were significantly higher in treated as compared with control monkeys after 7 d of beginning treatment (body weight of 10.5±0.1kg (mean ± SEM) and 10.1±0.1kg, respectively; IGF-1 of 758±43ng/mL and 639±22ng/mL, respectively). Capromorelin administration was not associated with appreciable changes in hematologic and biochemical values in treated macaques. These findings suggest that capromorelin may be useful for treating inappetence and weight loss in NHP, and based on blood analysis, a 7-d course of treatment does not appear to cause acute toxicity.
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Macaca mulatta , Animales , Masculino , Femenino , Factor I del Crecimiento Similar a la Insulina/análisis , Estimulantes del Apetito/uso terapéutico , Estimulantes del Apetito/administración & dosificación , Estimulantes del Apetito/farmacología , Peso Corporal/efectos de los fármacos , Aumento de Peso/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos , Receptores de Ghrelina/agonistas , Piperidinas , PirazolesRESUMEN
BACKGROUND: Hyporexia and weight loss are important indicators of physical and psychological well-being in macaque colonies. An FDA-approved transdermal formulated Mirtazapine (MTZ) shows effectiveness in managing feline hyporexia. This study sought to determine its effectiveness as an appetite stimulant in macaques. METHODS: Fourteen macaques with idiopathic hyporexia, intractable to conventional management were treated with transdermal MTZ (0.5 mg/kg) topically administered to aural pinnae once daily for 14 days. Qualitative food consumption was monitored daily for 6 months. Body weights were collected prior to treatment, every 2 weeks for the first 6 weeks, 10 weeks, and 6 months post-treatment. RESULTS: Transdermal MTZ significantly reduced the frequency of hyporexia during treatment and monthly for 6 months. No significant increase in weight noted until approximately 6 months post-treatment. CONCLUSIONS: Results from this study indicate that a short course of transdermal MTZ is an effective way to increase food consumption in macaques chronically.
Asunto(s)
Anorexia/tratamiento farmacológico , Estimulantes del Apetito/administración & dosificación , Macaca fascicularis , Macaca mulatta , Mirtazapina/administración & dosificación , Enfermedades de los Monos/tratamiento farmacológico , Administración Cutánea , Animales , Femenino , MasculinoRESUMEN
This multi-site, double blind, parallel arm, fixed dose, randomised placebo controlled phase III study compared megestrol acetate 480 mg/day with dexamethasone 4 mg/day for their net effects on appetite in people with cancer anorexia. Patients with advanced cancer and anorexia for ≥ 2 weeks with a score ≤ 4 (0-10 numeric rating scale (NRS) 0 = no appetite, 10 = best possible appetite) were recruited. Participants received megestrol 480 mg or dexamethasone 4 mg or placebo daily for up to 4 weeks. Primary outcomes were at day 7. Responders were defined as having a ≥ 25% improvement in NRS over baseline. There were 190 people randomised (megestrol acetate n = 61; dexamethasone n = 67, placebo n = 62). At week 1 (primary endpoint), 79·3% in the megestrol group, 65·5% in the dexamethasone group and 58·5% in the placebo group (p = 0.067) were responders. No differences in performance status or quality of life were reported. Treatment emergent adverse events were frequent (90·4% of participants), and included altered mood and insomnia. Hyperglycemia and deep vein thromboses were more frequent when on dexamethasone than the other two arms. There was no difference in groups between the three arms, with no benefit seen over placebo with anorexia improving in all arms.Trail registration: The trial was registered on 19/08/2008 with the Australian New Zealand Clinical Trials Registry (ACTRN12608000405314).
Asunto(s)
Anorexia/tratamiento farmacológico , Estimulantes del Apetito/uso terapéutico , Dexametasona/uso terapéutico , Acetato de Megestrol/uso terapéutico , Neoplasias/complicaciones , Anciano , Anciano de 80 o más Años , Anorexia/diagnóstico , Anorexia/etiología , Apetito , Estimulantes del Apetito/administración & dosificación , Australia , Dexametasona/administración & dosificación , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Acetato de Megestrol/administración & dosificación , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias/diagnóstico , Neoplasias/terapia , Calidad de Vida , Resultado del TratamientoRESUMEN
AIMS: Randomised controlled trials (RCTs) demonstrated benefits of pharmacological interventions for cachexia in improving weight and appetite. However, comparative efficacy and safety are not available. We conducted a systematic review and network meta-analysis (NMA) to evaluate the relative efficacy and safety of pharmacological interventions for cachexia. METHODS: PubMed, EmBase, Cochrane, and ClinicalTrials.gov were searched for RCTs until October 2019. Key outcomes were total body weight (TBW) improvement, appetite (APP) score and serious adverse events. Two reviewers independently extracted data and assessed risk of bias. NMA was performed to estimate weight gain and APP score increase at 8 weeks, presented as mean difference (MD) or standardised MD with 95% CI. RESULTS: 80 RCTs (10 579 patients) with 12 treatments were included. Majority is patients with cancer (7220). Compared with placebo, corticosteroids, high-dose megestrol acetate combination (Megace_H_Com) (≥400 mg/day), medroxyprogesterone, high-dose megestrol acetate (Megace_H) (≥400 mg/day), ghrelin mimetic and androgen analogues (Androgen) were significantly associated with MD of TBW of 6.45 (95% CI 2.45 to 10.45), 4.29 (95% CI 2.23 to 6.35), 3.18 (95% CI 0.94 to 5.41), 2.66 (95% CI 1.47 to 3.85), 1.73 (95% CI 0.27 to 3.20) and 1.50 (95% CI 0.56 to 2.44) kg. For appetite improvement, Megace_H_Com, Megace_H and Androgen significantly improved standardised APP score, compared with placebo. There is no significant difference in serious adverse events from all interventions compared with placebo. CONCLUSIONS: Our findings suggest that several pharmacological interventions have potential to offer benefits in treatment of cachexia especially Megace_H and short-term use corticosteroids. Nonetheless, high-quality comparative studies to compare safety and efficacy are warranted for better management of cachexia.
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Corticoesteroides/administración & dosificación , Estimulantes del Apetito/administración & dosificación , Caquexia/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Acetato de Megestrol/administración & dosificación , Andrógenos/administración & dosificación , Apetito/efectos de los fármacos , Caquexia/etiología , Investigación sobre la Eficacia Comparativa , Quimioterapia Combinada , Ghrelina/administración & dosificación , Humanos , Medroxiprogesterona/administración & dosificación , Diferencia Mínima Clínicamente Importante , Neoplasias/complicaciones , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Cuidado Terminal/métodos , Aumento de Peso/efectos de los fármacosRESUMEN
OBJECTIVES: The aim of this study was to assess the appetite stimulation properties of compounded transdermal mirtazapine (CTM) in cats with chronic kidney disease (CKD). METHODS: Two sequential double-blind placebo-controlled crossover prospective studies were performed in client-owned cats with stable stage 2 or 3 CKD and a history of decreased appetite. In the first study nine CKD cats were randomized to receive 3.75 mg/0.1 ml CTM gel or placebo on the inner pinna every other day for 3 weeks, then, after a 4 day washout period, the cats were crossed over to the alternate 3 week treatment. In a second study, 10 CKD cats were randomized to receive 1.88 mg/0.1 ml CTM or placebo on the same schedule. Physical examination and serum biochemistry were performed before and after each treatment period, and owners kept daily logs of appetite, activity and eating behaviors. Mirtazapine concentrations in CTM gels and steady-state mirtazapine serum concentrations were measured using liquid chromatography/tandem mass spectrometry. RESULTS: Administration of both 3.75 mg and 1.88 mg CTM resulted in a statistically significant increase in weight (P = 0.002 for both), increase in appetite (P = 0.01 and P = 0.005, respectively), and increase in rate of food consumption (P = 0.03 and P = 0.008, respectively). No significant difference in activity or vocalization was seen at either dose; however, individual cats experienced excessive meowing. Median weight increase for the 3.75 mg arm was 0.22 kg (range 0.04-0.44 kg), while median weight increase for the 1.88 mg arm was 0.26 kg (range -0.25 to 0.5 kg). Improvement in body condition score was seen in 5/9 cats in the 3.75 mg arm (P = 0.04) and 6/10 cats in the 1.88 mg arm (P = 0.004). CONCLUSIONS AND RELEVANCE: CTM increased appetite and resulted in weight gain in CKD cats despite significant inconsistencies in compounding, and may benefit cats in countries where an approved product is not available.
Asunto(s)
Estimulantes del Apetito , Enfermedades de los Gatos/tratamiento farmacológico , Mirtazapina , Insuficiencia Renal Crónica , Administración Cutánea , Animales , Estimulantes del Apetito/administración & dosificación , Estimulantes del Apetito/uso terapéutico , Gatos , Método Doble Ciego , Mirtazapina/administración & dosificación , Mirtazapina/uso terapéutico , Estudios Prospectivos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/veterinariaRESUMEN
1. The aim of the current study was to determine the effects of the central dopaminergic system on N/OFQ-induced feed intake in 3-h feed-deprived neonatal broilers. 2. In experiment 1, chicken received intracerebroventricular (ICV) injections of a control solution, SCH 23 390 (D1 receptors antagonist, 5 nmol), N/OFQ (16 nmol) or their combination (SCH23 390 + N/OFQ). In experiment 2, a control solution, AMI-193 (D2 receptors antagonist, 5 nmol), N/OFQ (16 nmol) or their combination (AMI-193 + N/OFQ) were ICV injected into chickens. In experiment 3, birds received ICV injections of a control solution, NGB2904 (D3 receptors antagonist, 6.4 nmol), N/OFQ (16 nmol) and co-injection of NGB2904 + N/OFQ. In experiment 4, ICV injections of the control solution, L-741,742 (D4 receptors antagonist, 6 nmol), N/OFQ (16 nmol) or their combination (L-741,742 + N/OFQ) were applied to broilers. In experiment 5, birds were ICV injected with control solution, L-DOPA (dopamine precursor, 125 nmol), N/OFQ (16 nmol) and L-DOPA + N/OFQ. Cumulative feed intake was recorded until 120 min after injection. 3. According to the results, ICV injection of N/OFQ significantly increased feed intake (P < 0.05). Co-injection of N/OFQ and D1 receptor antagonist (SCH 23390) amplified hyperphagic effect of N/OFQ (P < 0.05). The N/OFQ-induced feed intake was increased by the D2 receptor antagonist (P < 0.05). The hyperphagic effect of N/PFQ was weakened by co-injection of L-DOPA + N/OFQ (P < 0.05). 4. These results suggested that an interaction exists between dopamine and N/OFQ via D1 and D2 receptors on central feed intake in neonatal broiler chickens.
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Estimulantes del Apetito/farmacología , Pollos/fisiología , Conducta Alimentaria/efectos de los fármacos , Péptidos Opioides/farmacología , Alimentación Animal , Animales , Animales Recién Nacidos/fisiología , Estimulantes del Apetito/administración & dosificación , Benzazepinas/administración & dosificación , Inyecciones Intraventriculares/veterinaria , Péptidos Opioides/administración & dosificación , NociceptinaRESUMEN
Mirtazapine is classified as a weight gain drug in cats, and the purpose of this study was to evaluate its efficacy in cats experiencing unintended weight loss. This was a multi-center, double-blind, placebo-controlled, randomized clinical study in client-owned cats ≥1 year of age, weighing ≥2 kg, with a documented loss (≥5%) in body weight. Cats were treated once daily with either 2 mg/cat mirtazapine transdermal ointment (n = 83) or placebo (n = 94) (Per Protocol population) applied to the inner surface of the pinna for 14 ± 3 days. Physical examination, body weight, complete blood count, serum chemistry, and urinalysis were performed prior to treatment and on Day 14. Changes in body weight between the mirtazapine and placebo groups were evaluated from Day 1 to Day 14 and compared using a two-sample t test. The mean percent change in body weight was +3.9% (standard deviation ±5.4%) in the mirtazapine group and +0.4% (±3.3%) in the placebo group (p < 0.0001). The most common adverse event was mild erythema at the application site in 17.4% of placebo and 10.4% of mirtazapine-treated cats. Application of mirtazapine transdermal ointment was well tolerated both topically and systemically and resulted in significant weight gain in cats experiencing unintended weight loss associated with various underlying diseases.
Asunto(s)
Estimulantes del Apetito/uso terapéutico , Enfermedades de los Gatos/tratamiento farmacológico , Mirtazapina/uso terapéutico , Pérdida de Peso/efectos de los fármacos , Administración Cutánea , Animales , Estimulantes del Apetito/administración & dosificación , Gatos , Método Doble Ciego , Femenino , Masculino , Mirtazapina/administración & dosificación , Pomadas , Distribución Aleatoria , Aumento de Peso/efectos de los fármacosRESUMEN
BACKGROUND: Hospitalized patients are subject to acute illness and stress which may impact appetite or weight. Loss of appetite may lead to increased morbidity or mortality. Medications such as dronabinol, megestrol, and mirtazapine are used for weight gain in the outpatient setting; however, there is limited information about safety or effectiveness when initiated inpatient. OBJECTIVES: To analyze the effectiveness and safety of appetite-stimulating medications in hospitalized patients. METHODS: This was a retrospective cohort study of hospitalized patients initiated on dronabinol, megestrol, or mirtazapine for appetite. The primary outcome was change in meal intake between drug initiation and discontinuation. Secondary outcomes included documented improvement in appetite, change in weight and various laboratory parameters, and incidence of adverse effects. RESULTS: A total of 38 patients met inclusion criteria, and mirtazapine was most commonly used (42%). There was no significant difference between groups of appetite-stimulating medications with regard to mean change in meal intake, weight, albumin, or documented improvement in diet. Within groups, each agent showed numerical improvement in percentage meal intake, with a mean change from initiation to discontinuation of 17.12%. Almost half (48%) of the patients experienced improvement in diet after the start of medications. No serious adverse effects were observed. Conclusion and Relevance: In inpatients, there was no difference in change in meal intake or weight between dronabinol, megestrol, or mirtazapine, but they may show numerical improvements in meal intake. To our knowledge, this is the first study to evaluate the use of dronabinol, megestrol, and mirtazapine initiated in the inpatient setting.
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Regulación del Apetito/efectos de los fármacos , Estimulantes del Apetito/uso terapéutico , Apetito/efectos de los fármacos , Aumento de Peso/efectos de los fármacos , Adulto , Estimulantes del Apetito/administración & dosificación , Dronabinol/administración & dosificación , Dronabinol/uso terapéutico , Ingestión de Alimentos/efectos de los fármacos , Femenino , Humanos , Pacientes Internos , Masculino , Megestrol/administración & dosificación , Megestrol/uso terapéutico , Persona de Mediana Edad , Mirtazapina/administración & dosificación , Mirtazapina/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: The effects of the glucocorticoid and progesterone receptor agonist megestrol on declarative memory, and the ability of phenytoin to block these effects, were assessed. METHODS: Healthy volunteers received each medication combination (placebo and megestrol, phenytoin and megestrol, and placebo and placebo) using a randomized, crossover design. The Rey Auditory Verbal Learning Test assessed declarative memory. RESULTS: Megestrol was associated with a significant reduction in declarative memory (p = 0.0008), which was attenuated by phenytoin, and was associated with significant cortisol suppression compared to placebo (p < 0.001). CONCLUSION: Changes in memory and cortisol suppression were found in healthy volunteers given megestrol.
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Hidrocortisona/sangre , Acetato de Megestrol , Memoria/efectos de los fármacos , Adulto , Estimulantes del Apetito/administración & dosificación , Estimulantes del Apetito/efectos adversos , Cognición/efectos de los fármacos , Estudios Cruzados , Monitoreo de Drogas , Femenino , Voluntarios Sanos , Humanos , Masculino , Acetato de Megestrol/administración & dosificación , Acetato de Megestrol/efectos adversos , Fenitoína/administración & dosificación , Fenitoína/efectos adversos , Receptores de Progesterona/agonistas , Resultado del TratamientoRESUMEN
Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross-over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean Tmax = 15.9 hr, Cmax = 21.5 ng/mL, AUC0-24 = 100 ng*hr/mL, AUC0-∞ = 260 ng*hr/mL and calculated half-life = 26.8 hr. Single oral administration of mirtazapine resulted in mean Tmax = 1.1 hr, Cmax = 83.1 ng/mL, AUC0-24 = 377 ng*hr/mL, AUC0-∞ = 434 ng*hr/mL and calculated half-life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean Tmax = 2.1 hr, Cmax = 39.6 ng/mL, AUC0-24 = 400 ng*hr/mL, AUC0-∞ = 647 ng*hr/mL and calculated half-life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.
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Estimulantes del Apetito/farmacocinética , Mirtazapina/farmacocinética , Administración Cutánea , Animales , Estimulantes del Apetito/administración & dosificación , Estimulantes del Apetito/sangre , Gatos , Estudios Cruzados , Oído Externo , Femenino , Masculino , Mirtazapina/administración & dosificación , Mirtazapina/sangre , Pomadas , Distribución AleatoriaRESUMEN
Megestrol acetate (MGA) is used as a progestagen to treat advanced cancers in the breast or uterus and anorexia-cachexia syndrome in cancer patients. Due to its low solubility (BCS class II), MGA bioavailability needs to be enhanced for efficacy and safety. We developed MGA-encapsulated Eudragit® L100 (EUD) nanoparticles (MGA-EUD (1:1) and MGA-EUD (2:1)) using an ultrasonic nebulization method. MGA-EUD (1:1) and MGA-EUD (2:1) consisted of MGA and EUD at the mass ratios of 1:1 and 2:1. Their physicochemical properties, i.e. particle size, loading efficiency, morphology, and crystallinity were determined. Dissolution tests were performed using USP method II. For pharmacokinetics, they were orally administered at 50 mg/kg to mice. Microcrystalline MGA suspension (MGA-MC, Megace®, BMS) was used as control. MGA-EUD (1:1) and MGA-EUD (2:1) had a smooth and spherical shape of 0.70 and 1.05 µm in diameter with loading efficiencies of 93 and 95% showing amorphous states of MGA. They significantly enhanced the dissolution potential of MGA. Oral bioavailability of MGA-EUD (1:1) and MGA-EUD (2:1) increased 2.0- and 1.7-fold compared to that of MGA-MC. It suggests that ultrasonic nebulization method for the fabrication of polymeric nanoparticles is a promising approach to improve the bioavailability of poorly soluble drugs.
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Antineoplásicos Hormonales/administración & dosificación , Estimulantes del Apetito/administración & dosificación , Acetato de Megestrol/administración & dosificación , Nanopartículas/química , Ácidos Polimetacrílicos/química , Administración Oral , Animales , Antineoplásicos Hormonales/química , Antineoplásicos Hormonales/farmacocinética , Estimulantes del Apetito/química , Estimulantes del Apetito/farmacocinética , Disponibilidad Biológica , Masculino , Acetato de Megestrol/química , Acetato de Megestrol/farmacocinética , Ratones , Ratones Endogámicos BALB C , Tamaño de la Partícula , Transición de Fase , Solubilidad , Sonicación , Suspensiones , UltrasonidoRESUMEN
The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia.
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Estimulantes del Apetito/uso terapéutico , Caquexia/tratamiento farmacológico , Neoplasias del Colon/complicaciones , Receptores de Ghrelina/agonistas , Tejido Adiposo/efectos de los fármacos , Administración Oral , Animales , Estimulantes del Apetito/administración & dosificación , Peso Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Caquexia/etiología , Línea Celular , Citocinas/genética , Citocinas/metabolismo , Factor 15 de Diferenciación de Crecimiento/genética , Factor 15 de Diferenciación de Crecimiento/metabolismo , Hipotálamo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismoRESUMEN
Corticosterone plays an important role in feeding behavior. However, its mechanism remains unclear. Therefore, the present study aimed to investigate the effect of corticosterone on feeding behavior. In this study, cumulative food intake was increased by acute corticosterone administration in a dose-dependent manner. Administration of the 5-HT2c receptor agonist m-chlorophenylpiperazin (mCPP) reversed the effect of corticosterone on food intake. The anorectic effects of mCPP were also blocked by the 5-HT2c receptor antagonist RS102221 in corticosterone-treated mice. Both corticosterone and mCPP increased c-Fos expression in hypothalamic nuclei, but not the nucleus of the solitary tract. RS102221 inhibited c-Fos expression induced by mCPP, but not corticosterone. In addition, mCPP had little effect on TH and POMC levels in the hypothalamus. Furthermore, mCPP antagonized decreasing effect of the leptin produced by corticosterone. Taken together, our findings suggest that 5-HT2c receptors and leptin may be involved in the effects of corticosterone-induced hyperphagia.
Asunto(s)
Regulación del Apetito/efectos de los fármacos , Corticosterona/farmacología , Hipotálamo/efectos de los fármacos , Leptina/agonistas , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Depresores del Apetito/química , Depresores del Apetito/farmacología , Estimulantes del Apetito/administración & dosificación , Estimulantes del Apetito/agonistas , Estimulantes del Apetito/antagonistas & inhibidores , Estimulantes del Apetito/farmacología , Conducta Animal/efectos de los fármacos , Corticosterona/administración & dosificación , Corticosterona/agonistas , Corticosterona/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Ingestión de Energía/efectos de los fármacos , Hiperfagia/sangre , Hiperfagia/inducido químicamente , Hiperfagia/metabolismo , Hiperfagia/patología , Hipotálamo/metabolismo , Hipotálamo/patología , Leptina/antagonistas & inhibidores , Leptina/sangre , Leptina/metabolismo , Ratones Endogámicos ICR , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Neuronas/patología , Especificidad de Órganos , Piperazinas/antagonistas & inhibidores , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-fos/agonistas , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptor de Serotonina 5-HT2C/química , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Compuestos de Espiro/farmacología , Sulfonamidas/farmacología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Nonpsychoactive phytocannabinoids (pCBs) from Cannabis sativa may represent novel therapeutic options for cachexia because of their pleiotropic pharmacological activities, including appetite stimulation. We have recently shown that purified cannabigerol (CBG) is a novel appetite stimulant in rats. As standardized extracts from Cannabis chemotypes dominant in one pCB [botanical drug substances (BDSs)] often show greater efficacy and/or potency than purified pCBs, we investigated the effects of a CBG-rich BDS, devoid of psychoactive [INCREMENT]-tetrahydrocannabinol, on feeding behaviour. Following a 2 h prefeed satiation procedure, 16 male Lister-hooded rats were administered CBG-BDS (at 30-240 mg/kg) or vehicle. Food intake, meal pattern microstructure and locomotor activity were recorded over 2 h. The total food intake was increased by 120 and 240 mg/kg CBG-BDS (1.53 and 1.36 g, respectively, vs. 0.56 g in vehicle-treated animals). Latency to feeding onset was dose dependently decreased at all doses, and 120 and 240 mg/kg doses increased both the number of meals consumed and the cumulative size of the first two meals. No significant effect was observed on ambulatory activity or rearing behaviour. CBG-BDS is a novel appetite stimulant, which may have greater potency than purified CBG, despite the absence of [INCREMENT]-tetrahydrocannabinol in the extract.
Asunto(s)
Cannabinoides/farmacología , Cannabis/química , Hiperfagia/inducido químicamente , Extractos Vegetales/farmacología , Animales , Estimulantes del Apetito/administración & dosificación , Estimulantes del Apetito/farmacología , Caquexia/tratamiento farmacológico , Cannabinoides/administración & dosificación , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Locomoción , Masculino , Extractos Vegetales/administración & dosificación , RatasRESUMEN
BACKGROUND: Dogs can suffer from inappetence caused by a variety of medical conditions. This may present as anorexia (complete loss of appetite), hyporexia (decreased appetite) or dysrexia (change in food preferences). A drug with a new mechanism of action, capromorelin, has potential to stimulate appetite in dogs. Capromorelin is a ghrelin receptor agonist, which mimics the action of endogenous ghrelin. It is a member of the growth hormone secretagogue (GHS) class of drugs. Capromorelin oral solution (ENTYCE®) was tested in healthy adult male and female Beagle dogs (n = 6 males and 6 females per group) for its effect on food consumption and body weight. A randomized, masked, placebo controlled study was conducted to measure the effects of a daily 3 mg/kg oral dose given over 4 days. Dogs were observed for clinical signs, physical examinations were completed prior to and at the end of treatment, and blood was drawn before and after treatment for evaluation of serum chemistry and hematology parameters. RESULTS: Capromorelin was well-tolerated, with no abnormalities seen on physical examination or clinical pathology. Some dogs showed increased salivation. Capromorelin treated dogs had increased mean (±SD) food consumption compared to placebo treated dogs (60.55 ± 39.87% versus -11.15 ± 14.23% respectively, P < 0.001). Treated dogs also had increased mean body weights compared to placebo treated dogs (5.96 ± 1.76% versus 0.053 ± 1.14% respectively, P < 0.001). CONCLUSIONS: This study supports the effectiveness of capromorelin oral solution as an appetite stimulant in dogs. Treatment with the oral solution resulted in dramatic increases in appetite, as measured by food consumption, of over 60% compared to placebo. The drug was well tolerated. Capromorelin is the first ghrelin receptor agonist developed for appetite stimulation in any species, and represents a novel mechanism of action for this clinical use.
Asunto(s)
Estimulantes del Apetito/farmacología , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Animales , Estimulantes del Apetito/administración & dosificación , Estudios Cruzados , Perros , Femenino , MasculinoRESUMEN
Megestrol acetate, an appetite stimulant with low bioavailability, shows increased bioavailability when taken together with food. However, the pharmacokinetic characteristics of megestrol acetate and its relation with food are not well understood. This study aimed to investigate the food effect on the pharmacokinetics (PK) of the recently developed nano-crystallized megestrol acetate (NCMA), using a model-based approach. Data were obtained from an NCMA PK study consisting of a single dose in fasting (39 individuals) and fed conditions (40 individuals). Plasma concentrations were measured up to 120 hr after dosing. With the incorporation of body-weight via allometry, NONMEM 7.3 was used to develop a PK model, which was then used to simulate an optimal fasting dose yielding an area under concentration (AUC) and maximum concentration (Cmax ) of NCMA close to those obtained with the fed dose. NCMA concentrations were best characterized by a two-compartment model with first-order absorption linked to a recycling compartment to account for the multiple concentration peaks observed. Food increased bioavailability 2.2 times and decreased the absorption rate constant 0.58 times. Recycling event times were estimated to be 3.56, 7.99 and 24.0 hr. The optimal fast dose was 2.0 times higher than the fed dose, and the resulting difference in drug exposure between the fasting and fed dose was 7.5%. This work suggests that the PK model developed can be applied to an optimal dosage regimen design for NCMA treatment.
Asunto(s)
Estimulantes del Apetito/administración & dosificación , Estimulantes del Apetito/farmacocinética , Interacciones Alimento-Droga , Acetato de Megestrol/administración & dosificación , Acetato de Megestrol/farmacocinética , Modelos Biológicos , Administración Oral , Adulto , Estimulantes del Apetito/uso terapéutico , Disponibilidad Biológica , Caquexia/tratamiento farmacológico , Estudios Cruzados , Sistemas de Liberación de Medicamentos/métodos , Cálculo de Dosificación de Drogas , Ingestión de Alimentos , Ayuno , Voluntarios Sanos , Humanos , Masculino , Acetato de Megestrol/uso terapéutico , Nanopartículas , República de Corea , Adulto JovenRESUMEN
The objective of the study was to evaluate the safety of capromorelin, a ghrelin agonist that stimulates appetite and causes increased body weight and the release of growth hormone (GH). Beagle dogs (n = 32) received either oral placebo or 0.3, 7, or 40 mg/kg capromorelin once daily for 12 consecutive months. Safety was evaluated by physical examinations, including ECG and ophthalmic examinations, and comprehensive clinical pathology. Serum levels of capromorelin, GH, and insulin-like growth factor 1 (IGF-1) were measured periodically. Necropsies and histopathological evaluations were performed at study termination. As expected, GH and IGF-1 levels were mildly increased in capromorelin-treated dogs. Adverse events were limited to mild emesis and loose stools in all groups and excess salivation among some dogs receiving higher capromorelin doses. Clinical pathology testing was generally normal, although blood lipids and alkaline phosphatase levels were moderately increased among dogs receiving capromorelin. Treated dogs had slightly longer post-treatment PR intervals seen on ECG, but with no changes in cardiac histopathology. Postmortem findings were normal. Drug-related increases in liver weight were linked to overall increases in body weight. Capromorelin was well tolerated in dogs at daily doses up to 40 mg/kg for 12 months, demonstrating a wide safety margin.