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1.
Clin Exp Dermatol ; 45(5): 549-554, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32410250

RESUMO

BACKGROUND: Wet dressings combined with topical corticosteroids are beneficial for patients with generalized and refractory dermatosis; however, to our knowledge, serum levels after topical corticosteroid absorption during intensive therapy have not been reported previously. AIM: To examine serum levels of triamcinolone acetonide (TAC) after topical corticosteroid application during intensive wet-dressing therapy. METHODS: We performed a retrospective study of adult patients admitted for inpatient wet-dressing therapy from 7 November 2015 to 24 June 2016. Data were collected on sex, age, body surface area, TAC serum levels, number of wet-dressing changes after 24 and 48 h, and type of wet dressing. RESULTS: In total, 29 patients (14 men, 15 women) were assessed. Median [interquartile range (IQR)] age was 57 years (51.5-67.0 years) and involved body surface area was 1.98 m2 (1.88-2.15) m2 . Before the 24-hour blood draw, patients had received 1-3 dressing changes. Median (IQR) TAC level at 24 h was 0.33 µg/dL (0.20-0.58 µg/dL), with no significant difference noted between the number of dressing changes and TAC serum level. At 48 h, results of a serum TAC test were available for 22 patients with 2-6 dressing changes. Mean (IQR) serum level was 0.30 µg/dL (0.30-0.87 µg/dL). For each additional dressing change, there was an estimated 0.21 µg/dL increase in TAC serum level (95% CI 0.11-0.31; P < 0.001). TAC serum level was not significantly associated with sex, age, body surface area or dressing type. CONCLUSIONS: Intensive, inpatient wet-dressing therapy is associated with detectable TAC serum levels. However, we suspect that topical TAC has a primarily local therapeutic effect on the skin.


Assuntos
Bandagens , Glucocorticoides/sangue , Dermatopatias/tratamento farmacológico , Triancinolona Acetonida/sangue , Administração Tópica , Idoso , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacocinética , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Triancinolona Acetonida/administração & dosagem , Triancinolona Acetonida/farmacocinética
2.
Am J Gastroenterol ; 113(2): 216-224, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29257140

RESUMO

BACKGROUND: Functional dyspepsia (FD) is a highly prevalent functional bowel disorder. The effects of antidepressant therapy (ADTx) on gastric sensorimotor function in FD patients are poorly understood. AIMS: Determine whether FD and subtypes with abnormalities in gastric function respond differently to ADTx compared to those with normal physiology. METHODS: This multicenter, prospective trial randomized FD patients to 12 weeks of amitriptyline (AMI; 50 mg), escitalopram (ESC; 10 mg), or matching placebo. Demographics, symptoms, psychological distress, gastric emptying, and satiation were measured. Gastric accommodation (GA) using single-photon emission computed tomography imaging was performed in a subset of patients. An intent to treat analysis included all randomized subjects. The effect of treatment on gastric emptying was assessed using ANCOVA. A post hoc appraisal of the data was performed categorizing patients according to the Rome III subgrouping (PDS and EPS). RESULTS: In total, 292 subjects were randomized; mean age=44 yrs. 21% had delayed gastric emptying. Neither antidepressant altered gastric emptying, even in those with baseline delayed gastric emptying. GA increased with ADTx (P=0.02). Neither antidepressant affected the maximal-tolerated volume (MTV) of the nutrient drink test although aggregate symptom scores improved compared to placebo (P=0.04). Patients with the combined EPS-PDS subtype (48%) had a lower MTV on the nutrient drink test compared to the EPS group at baseline (P=0.02). Postprandial bloating improved with both AMI (P=0.03) and ESC (P=0.02). CONCLUSIONS: Amitriptyline (50 mg) improves FD symptoms but does not delay gastric emptying, even in patients with baseline delayed gastric emptying. GA improved with low-dose ADTx; the precise mechanism of action is unknown warranting further study.


Assuntos
Amitriptilina/uso terapêutico , Antidepressivos/uso terapêutico , Citalopram/uso terapêutico , Dispepsia/tratamento farmacológico , Esvaziamento Gástrico , Gastroparesia/tratamento farmacológico , Saciação , Adulto , Dispepsia/diagnóstico por imagem , Dispepsia/fisiopatologia , Dispepsia/psicologia , Feminino , Gastroparesia/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Estresse Psicológico/psicologia , Tomografia Computadorizada de Emissão de Fóton Único
3.
Gut ; 64(10): 1650-68, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26342014

RESUMO

The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer.


Assuntos
Gastropatias/diagnóstico , Gastropatias/metabolismo , Estômago/anatomia & histologia , Estômago/fisiologia , Mucosa Gástrica/metabolismo , Humanos
4.
Br J Dermatol ; 171(6): 1397-401, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24958433

RESUMO

BACKGROUND: Histopathological findings in biopsy specimens from patients with cutaneous small-vessel vasculitis (CSVV) secondary to solid-organ malignancy have not been previously reported. OBJECTIVES: We aimed to understand better the differences in histopathological findings between biopsy specimens from patients with CSVV associated with solid-organ malignancies and patients with CSVV secondary to other causes. METHODS: From a previously published group of patients with CSVV and solid-organ malignancy, we identified patients with available histopathology slides of biopsy specimens. We compared histopathological findings from these patients with those from 68 previously published patients with Henoch-Schönlein purpura not associated with solid-organ malignancy (60% male). RESULTS: We identified 15 patients (eight male, 53%) with available slides from biopsy specimens. The mean age of these patients with solid-organ malignancy-associated CSVV was 66·6 years, compared with 45·8 years in the Henoch-Schönlein purpura cases not associated with solid-organ malignancy (P < 0·001). Solid-organ malignancy-associated CSVV was less likely to demonstrate papillary dermal oedema (P = 0·04), papillary dermal inflammation (P < 0·001) and lymphocytes (P < 0·001), and more likely to have plasma cells (P = 0·02). Additionally, we detected nonsignificant differences in the presence of histiocytes (P = 0·05), intravascular thrombosis (P = 0·052) and microabscess formation (P = 0·06). CONCLUSIONS: CSVV associated with solid-organ malignancies tended to have deeper dermal involvement and a different cellular milieu from cases not associated with solid-organ malignancies. In addition, the patients with CSVV with solid-organ malignancies were significantly older than those without. Prospective studies with age-matched controls are needed to determine the clinical significance of the histopathological differences in solid-organ malignancy-associated CSVV.


Assuntos
Neoplasias/patologia , Dermatopatias Vasculares/patologia , Pele/patologia , Vasculite/patologia , Adulto , Idoso , Biópsia , Feminino , Humanos , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Pele/irrigação sanguínea , Adulto Jovem
5.
J Eur Acad Dermatol Venereol ; 27(11): 1360-5, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23066743

RESUMO

BACKGROUND: There is a paucity of medical literature describing the role of dermatology inpatient hospital services for patients with severe dermatologic disease. A diminishing number of US hospitals have a dedicated dermatology inpatient service run by dermatologists. OBJECTIVES: To describe the role of a dermatology-run inpatient service in treatment of severe dermatologic disease from 2000 to 2010 at our institution. METHODS: We studied demographic characteristics, indications for admission and length of stay for the adult (age, >18 years) dermatology inpatient hospital service over the most recent decade. We compared data from the first 5.5 years with the subsequent 5.5 years and with previously published data. RESULTS: A total of 1732 patients had 2216 inpatient admissions to the adult service from 2000 to 2010. The mean (SD) age was 61.3 (17.7) years (age range 18-100 years). Median duration of admission was 3 days interquartile range (IQR), 2-5 days. The most common indications for admission were dermatitis (44.2%), psoriasis (17.4%) and cutaneous T-cell lymphoma (9.2%). We compared admissions from 2000 to mid-2005 (n = 1260) to admissions from mid-2005 to 2010 (n = 956). Statistically significant changes included median length of stay (decreased from 4 days [IQR, 3-6 days] to 3 days [IQR, 2-4 days] P < 0.01), admissions for psoriasis (decreased from 20.7% to 13.0%; P < .01) and admissions for dermatitis (increased from 41.6% to 47.6%; P < .01). CONCLUSION: The number of patients admitted and the median length of stay decreased between the 2 periods. Indications for admission have changed significantly across the two time periods.


Assuntos
Dermatologia , Departamentos Hospitalares , Dermatopatias/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota , Dermatopatias/classificação , Adulto Jovem
6.
J Eur Acad Dermatol Venereol ; 25(1): 100-4, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20477930

RESUMO

BACKGROUND: Lichen planus is an autoimmune, inflammatory dermatosis of unknown cause that affects the skin and mucous membranes. OBJECTIVE: The aim of this study was to report the clinical features and response to therapy in a series of patients with ocular lichen planus. METHODS: A retrospective chart review was performed to identify patients with ocular lichen planus. Information about clinical presentation, treatment, and therapeutic response was extracted from the medical records. RESULTS: Eleven patients with ocular lichen planus were identified. The diagnosis was confirmed histologically for 10 patients. Nine patients were women. The average time from onset of ocular symptoms to diagnosis was 4.1 years. Eight patients had mucous membrane involvement at other sites. Disease was well controlled in eight patients. CONCLUSION: Lichen planus should be considered in the differential diagnosis of cicatricial conjunctivitis, especially when severe lichen planus is noted at other sites.


Assuntos
Cicatriz/complicações , Conjuntivite/patologia , Conjuntivite/terapia , Líquen Plano/patologia , Líquen Plano/terapia , Conjuntivite/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
7.
Lupus ; 19(7): 815-29, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20142296

RESUMO

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE(0)DQ2). These AE(0)DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE(0)DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE(0)DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE(0)DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE(0)DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a 'fingerprint' substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE(0)DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE(0)DQ2 mice compared with AE(0)DQ6 mice (p < 0.001). In conclusion, AE(0)DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815-829.


Assuntos
Modelos Animais de Doenças , Antígenos HLA-DQ/genética , Lúpus Eritematoso Sistêmico/genética , Animais , DNA/sangue , Feminino , Imunofluorescência , Antígenos HLA-DQ/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica
8.
Int J Obes (Lond) ; 33(3): 342-53, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19139750

RESUMO

BACKGROUND: The psychological symptoms associated with binge eating disorder (BED) have been well documented. However, the physical symptoms associated with BED have not been explored. Gastrointestinal (GI) symptoms such as heartburn and diarrhea are more prevalent in obese adults, but the associations remain unexplained. Patients with bulimia have increased gastric capacity. The objective of the study was to examine if the severity of binge eating episodes would be associated with upper and lower GI symptoms. METHODS: Population-based survey of community residents through a mailed questionnaire measuring GI symptoms, frequency of binge eating episodes and physical activity level. The association of GI symptoms with frequency of binge eating episodes was assessed using logistic regression models adjusting for age, gender, body mass index (BMI) and physical activity level. RESULTS: In 4096 subjects, BED was present in 6.1%. After adjusting for BMI, age, gender, race, diabetes mellitus, socioeconomic status and physical activity level, BED was independently associated with the following upper GI symptoms: acid regurgitation (P<0.001), heartburn (P<0.001), dysphagia (P<0.001), bloating (P<0.001) and upper abdominal pain (P<0.001). BED was also associated with the following lower GI symptoms: diarrhea (P<0.001), urgency (P<0.001), constipation (P<0.01) and feeling of anal blockage (P=0.001). CONCLUSION: BED appears to be associated with the experience of both upper and lower GI symptoms in the general population, independent of the level of obesity. The relationship between increased GI symptoms and physiological responses to increased volume and calorie loads, nutritional selections and rapidity of food ingestion in individuals with BED deserves further study.


Assuntos
Bulimia/complicações , Gastroenteropatias/etiologia , Obesidade/complicações , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Bulimia/epidemiologia , Bulimia/psicologia , Comportamento Alimentar/psicologia , Feminino , Gastroenteropatias/epidemiologia , Gastroenteropatias/psicologia , Inquéritos Epidemiológicos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/psicologia , Medição de Risco , Inquéritos e Questionários , Adulto Jovem
9.
Gut ; 57(8): 1140-55, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18397936

RESUMO

A multitude of physiological effects and putative pathophysiological roles have been proposed for the endogenous cannabinoid system in the gastrointestinal tract, liver and pancreas. These range from effects on epithelial growth and regeneration, immune function, motor function, appetite control, fibrogenesis and secretion. Cannabinoids have the potential for therapeutic application in gut and liver diseases. Two exciting therapeutic applications in the area of reversing hepatic fibrosis as well as antineoplastic effects may have a significant impact in these diseases. This review critically appraises the experimental and clinical evidence supporting the clinical application of cannabinoid receptor-based drugs in gastrointestinal, liver and pancreatic diseases. Application of modern pharmacological principles will most probably expand the selective modulation of the cannabinoid system peripherally in humans. We anticipate that, in addition to the approval in several countries of the CB(1) antagonist, rimonabant, for the treatment of obesity and associated metabolic dysfunctions, other cannabinoid modulators are likely to have an impact on human disease in the future, including hepatic fibrosis and neoplasia.


Assuntos
Moduladores de Receptores de Canabinoides/fisiologia , Gastroenteropatias/fisiopatologia , Hepatopatias/fisiopatologia , Animais , Canabinoides/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Trato Gastrointestinal/metabolismo , Humanos , Ligantes , Hepatopatias/tratamento farmacológico , Receptores de Canabinoides/metabolismo
11.
Neurogastroenterol Motil ; 20(3): 185-96, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18257768

RESUMO

The objective of this article is to review the clinical presentation and neurobiology of degeneration of the enteric nervous system with emphasis on human data where available. Constipation, incontinence and evacuation disorders are frequently encountered in the ageing population. Healthy lower gastrointestinal function is essential for successful ageing as it is critical to maintaining independence and autonomy to pursue further activity. One clinical expression of enteric neurodegeneration is constipation. However, the aetiology may be multifactorial as disturbances of epithelial, muscle or neural function may all result from neurodegeneration. There is evidence of loss of excitatory (e.g. cholinergic) enteric neurons and interstitial cells of Cajal, whereas inhibitory (including nitrergic) neurons appear unaffected. Understanding neurodegeneration in the enteric nervous system is key to developing treatments to reverse it. Neurotrophins have been shown to accelerate colonic transit and relieve constipation in the medium term; they are also implicated in maintenance programmes in adult enteric neurons through a role in antioxidant defence. However, their effects in ageing colon require further study. There is evidence that 5-HT(2) and 5-HT(4) mechanisms are involved in development, maintenance and survival of enteric neurons. Further research is needed to understand and potentially reverse enteric neurodegeneration.


Assuntos
Envelhecimento/fisiologia , Sistema Nervoso Entérico/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Idoso/fisiologia , Animais , Sistema Nervoso Entérico/patologia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/patologia , Doenças Neuromusculares/tratamento farmacológico , Doenças Neuromusculares/patologia , Doenças Neuromusculares/fisiopatologia , Neurônios/patologia , Fatores de Risco , Serotonina/fisiologia
12.
Neurogastroenterol Motil ; 20(3): 213-9, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17971028

RESUMO

Adrenergic and serotonergic mechanisms alter human gut motor functions. Genotype variation influences phenotype. Our aim was to test the hypothesis that variation in genes that control these functions is associated with gastrointestinal (GI) motor functions in humans with functional GI disorders (FGID). A database of 251 people was assembled by combining genotype data with measurements of gut transit and gastric volumes. Genetic variations evaluated were: alpha(2A) adrenergic (C-1291G), alpha(2C) (Del 332-325), 5-HT transporter (SLC6A4) and GNbeta3 (C825T). We sought associations between motor function or disease groups and genotypes, adjusting for age, gender and body mass index. Among 251 participants, 82 were healthy, 20 with irritable bowel syndrome (IBS) with mixed bowel habit, 49 with constipation-predominant IBS, 67 with diarrhoea-predominant IBS and 33 with functional dyspepsia. For all candidate genes, there was no significant association between motor function and wildtype vs non-wildtype gene status. There were significant interactions between genotype and motility phenotype, specifically GNbeta3 and alpha(2A) and gastric emptying at 4 h. Borderline associations were noted for SCL6A4 and alpha(2A) and postprandial gastric volume, and for alpha(2C) and gastric emptying at 2 h. We conclude that genotype variation may affect gastric motor functions in different FGID phenotypes. However, these candidate genes account for only a limited amount of the variance in gastric function of patients with FGID.


Assuntos
Motilidade Gastrointestinal/fisiologia , Serotonina/fisiologia , Sistema Nervoso Simpático/fisiologia , Adulto , Índice de Massa Corporal , Determinação de Ponto Final , Feminino , Trato Gastrointestinal/diagnóstico por imagem , Trânsito Gastrointestinal/fisiologia , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Receptor 5-HT1A de Serotonina/genética , Receptor 5-HT1A de Serotonina/fisiologia , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serotonina/genética , Pertecnetato Tc 99m de Sódio , Sistema Nervoso Simpático/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único
13.
Eur J Gynaecol Oncol ; 29(6): 578-82, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-19115682

RESUMO

PURPOSE: To describe chronic intestinal pseudo-obstruction (IPO) syndromes that occur after radiotherapy or chemotherapy (or both) for gynecologic cancer. METHODS: All 48 patients in the study population had a history of gynecologic cancer, treatment with radiotherapy or chemotherapy (or both), and suspected chronic IPO. The final diagnosis was based on clinical symptoms, radiographic imaging, motility studies, and surgical findings. Treatment was expectant for 27 patients and surgical for 21. RESULTS: In six of the 21 surgical patients, the final diagnosis was mechanical obstruction. In the other 15, it was IPO syndrome: six had an idiopathic dysfunction (ID) and nine had a thick fibrinous coating (FC) on the serosal surface. Intestines of these 15 patients had patent lumens but decreased motility. The ID and FC groups differed in mean age, chemotherapy administration, and mean time from radiotherapy to surgery. Symptoms improved in 67% of FC patients compared with 17% of ID patients. Among patients treated expectantly, symptoms improved in 50% of the ID patients and in 38% of the FC patients. Motility studies were useful for distinguishing ID from FC or mechanical obstruction. CONCLUSION: Clinical history and motility studies may assist in diagnosing IPO syndrome in gynecologic cancer patients treated with radiotherapy or chemotherapy (or both) and in identifying patients who might benefit from surgical intervention.


Assuntos
Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/radioterapia , Pseudo-Obstrução Intestinal/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos de Coortes , Feminino , Motilidade Gastrointestinal , Humanos , Pseudo-Obstrução Intestinal/diagnóstico , Pseudo-Obstrução Intestinal/cirurgia , Pessoa de Meia-Idade , Radioterapia Adjuvante/efeitos adversos
14.
Neurogastroenterol Motil ; 30(9): e13370, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29745439

RESUMO

BACKGROUND: Cannabinoid agents and cannabis are frequently used for relief of diverse gastrointestinal symptoms. PURPOSE: The objective of this article is to increase the awareness of gastroenterologists to the effects of cannabinoids on gastrointestinal motility, as gastroenterologists are likely to encounter patients who are taking cannabinoids, or those with dysmotility that may be associated with cannabinoid mechanisms. The non-selective cannabinoid agonist, dronabinol, retards gastric emptying and inhibits colonic tone and phasic pressure activity. In addition to the well-recognized manifestations of cannabinoid hyperemesis, cannabinoid mechanisms result in human and animal models of gastrointestinal and colonic dysmotility. Decreased enteric FAAH activity is associated with colonic inertia in slow transit constipation and, conversely, the orphan G protein-coupled receptor, GPR55, is overexpressed in streptozotocin-induced gastroparesis, suggesting it is involved in inhibition of antral motility. Experimental therapies in gastrointestinal motility and functional disorders are focused predominantly on pain relief mediated through cannabinoid 2 receptors or inhibition of DAGLα to normalize colonic transit. In summary, cannabinoid mechanisms and pharmacology are relevant to the current and future practice of clinical gastroenterology.


Assuntos
Canabinoides/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Animais , Humanos , Farmacologia Clínica
15.
Neurogastroenterol Motil ; 30(5): e13250, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29119706

RESUMO

BACKGROUND: Opioid-induced constipation (OIC) is a major side effect of opioid use. Centrally acting antagonists result in opioid withdrawal or worsening of pain and lead to use of peripherally acting mu-opioid receptor antagonists (PAMORAs). The required doses of the PAMORAs, methylnaltrexone and naloxegol, in the treatment of OIC are well established in chronic opioid users. OIC may occur after short duration of opioid treatment; the required doses of naloxone, naltrexone, and PAMORAs in opioid-naïve subjects (with no opioid use for at least 3 months) are unclear. The aim of this review was to evaluate the PAMORA dose required for opioid-naïve subjects to achieve similar beneficial effects on symptoms or valid surrogates to those observed in chronic opioid users. METHODS: A PubMed search of µ-opioid antagonists to counter µ-opioid effects included terms: naloxone, naltrexone, methylnaltrexone, alvimopan, and naloxegol, as well as OIC and colonic transit. KEY RESULTS: The approved dose of methylnaltrexone in chronic opioid users, 0.3 mg/kg subcutaneous (SQ), did not affect motility in opioid-naïve subjects. Trials investigating the required dose of alvimopan showed 0.5-1 mg dose was efficacious in treating OIC; a 10-fold higher dose (12 mg) of alvimopan is needed to block effects of codeine on small bowel and colonic transit in opioid-naïve subjects compared to chronic opioid users. Opioid-naïve users need 125 mg of naloxegol to reverse the effects of opioids on transit; this is in contrast to the 12.5 to 25 mg needed to treat OIC in chronic opioid users. CONCLUSIONS & INFERENCES: Opioid-naïve subjects require a higher dose of PAMORA than chronic opioid users to achieve µ-opioid antagonist effect.


Assuntos
Analgésicos Opioides/efeitos adversos , Constipação Intestinal/prevenção & controle , Fármacos Gastrointestinais/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Receptores Opioides mu/antagonistas & inibidores , Analgésicos Opioides/uso terapêutico , Constipação Intestinal/induzido quimicamente , Relação Dose-Resposta a Droga , Fármacos Gastrointestinais/uso terapêutico , Humanos , Morfinanos/administração & dosagem , Morfinanos/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Dor/tratamento farmacológico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Resultado do Tratamento
16.
Neurogastroenterol Motil ; 30(6): e13302, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29441683

RESUMO

BACKGROUND: Gastrointestinal sensorimotor dysfunction underlies a wide range of esophageal, gastric, and intestinal motility and functional disorders that collectively constitute nearly half of all referrals to gastroenterologists. As a result, substantial effort has been dedicated toward the development of prokinetic agents intended to augment or restore normal gastrointestinal motility. However, the use of several clinically efficacious gastroprokinetic agents, such as cisapride, domperidone, erythromycin, and tegaserod, is associated with unfavorable cardiovascular safety profiles, leading to restrictions in their use. PURPOSE: The purpose of this review is to detail the cellular and molecular mechanisms that lead commonly to drug-induced cardiac arrhythmias, specifically drug-induced long QT syndrome, torsades de pointes, and ventricular fibrillation, to examine the cardiovascular safety profiles of several classes of prokinetic agents currently in clinical use, and to explore potential strategies by which the risk of drug-induced cardiac arrhythmia associated with prokinetic agents and other QT interval prolonging medications can be mitigated successfully.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Fármacos Gastrointestinais/efeitos adversos , Motilidade Gastrointestinal/efeitos dos fármacos , Animais , Antibacterianos/efeitos adversos , Arritmias Cardíacas/diagnóstico , Fármacos Cardiovasculares/efeitos adversos , Motilidade Gastrointestinal/fisiologia , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia
18.
Int J Pharm ; 544(1): 158-164, 2018 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-29678546

RESUMO

Gastrointestinal luminal pH shows a rise from the duodenum to the terminal ileum in healthy individuals. Our objectives were to compare the pH in the proximal small intestine (SI) (first 60 min of small intestinal transit) lumen of human volunteers and patients with symptomatic constipation; to quantify contractile pressure profiles of the proximal SI, and to assess the relationship between luminally-recorded contractile pressure and small intestinal transit times (SITT) of a non-disintegrating capsule that measures pH and pressure activity (wireless motility capsule). We used previously acquired records from 39 healthy subjects and 41 patients with symptomatic constipation. Mean pH (±SD) of the proximal SI was similar in healthy subjects and patients with constipation at 6.2 (±0.6) and 6.3 (±0.4), respectively. In 13 of the healthy subjects, pH did not rise uniformly in the proximal SI though the pHmedian was 6.0 (5th, 95th percentiles 3.09, 7.06) and the pH fluctuated over a mean period of 28 min. Large inter-individual variability in frequency of pressure activity (Ct) and area under pressure curve (AUC) were observed in the proximal SI of healthy subjects and patients with constipation. Median AUC was 3996 mmHg s-1 (5th, 95th percentiles 948, 16866 mmHg s-1) in these two populations combined. Ct and AUC showed a strong direct linear correlation at r = 0.91, p < 1 × 10-6. An inverse correlation (suggesting longer SITT with lower pressure activity) was observed between Ct/AUC and SITT in both healthy subjects and patients with symptomatic constipation. The pooled results for both groups showed: AUC and SITT correlation at r = -0.49, p < 1 × 10-6. We concluded that both the frequency and amplitude of contractions in the proximal SI are important for the propagation of non-disintegrating capsules. The observed pH fluctuations in the proximal SI may impact supersaturation and precipitation of weakly basic drugs.


Assuntos
Cápsulas/administração & dosagem , Motilidade Gastrointestinal , Intestino Delgado/fisiologia , Tecnologia sem Fio , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Constipação Intestinal/fisiopatologia , Feminino , Voluntários Saudáveis , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Neurogastroenterol Motil ; 30(7): e13313, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29488276

RESUMO

BACKGROUND: Weight loss in response to the long-acting GLP-1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric-emptying (GE). The aim of this pilot study was to assess whether specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short-acting GLP-1 agonist, exenatide. METHODS: We evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T1/2 and weight from two trials that evaluated separately exenatide, 5 µg BID for 30 days, or liraglutide, 3 mg daily for 5 weeks. Data were analyzed using the dominant genetic model and intention-to-treat analysis. KEY RESULTS: There was a significant correlation between changes in weight and GE T1/2 (rs  = -.382, P = .004). GLP1R rs6923761 minor allele A (AA_AG) carriers who received either exenatide or liraglutide had greater delay in GE T1/2 relative to baseline (117.9 ± 27.5 [SEM] minutes and 128.9 ± 38.32 minutes) compared to GG genotype (95.8 ± 30.4 minutes and 61.4 ± 21.4 minutes, respectively; P = .11). There was a non-significant difference in weight loss based on GLP1R rs6923761 genotype after 5 weeks of treatment. There were no significant correlations with TCF7L2 (rs7903146) genotype. CONCLUSIONS & INFERENCES: The minor A allele of GLP1R (rs6923761) is associated with greater delay in GE T1/2 in response to liraglutide and exenatide. These studies provide data to plan pharmacogenetics testing of the hypothesis that GLP1R (rs6923761) influences weight loss in response to GLP1R agonists.


Assuntos
Exenatida/farmacologia , Esvaziamento Gástrico/genética , Variação Genética/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Liraglutida/farmacologia , Farmacogenética/métodos , Adulto , Alelos , Método Duplo-Cego , Exenatida/uso terapêutico , Feminino , Esvaziamento Gástrico/efeitos dos fármacos , Variação Genética/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/genética , Projetos Piloto , Redução de Peso/efeitos dos fármacos , Redução de Peso/fisiologia
20.
Neurogastroenterol Motil ; 30(10): e13365, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29722126

RESUMO

BACKGROUND: The reproducibility of gastric emptying (GE) measured with scintigraphy in patients is poorly understood. Our aims were to assess the intra and inter-individual reproducibility of these parameters in patients with upper gastrointestinal symptoms. METHODS: Sixty patients (21 diabetics, 39 non-diabetics) with upper gastrointestinal symptoms underwent scintigraphic-assessment of GE of a solid meal (296 kcal, 30% fat) over 4 hours on two occasions at an average interval of 15 days. The concordance correlation coefficient (CCC), intra and inter-individual coefficients of variation (COV) of GE endpoints were analyzed. RESULTS: The GE t1/2 was 134 ± 8 minutes (mean ± SEM) for the first and 128 ± 6 minutes for the second study. The mean (95% CI) CCC between the two studies was 0.79 (0.67, 0.87) for GE at 1 hour, 0.83 (0.75, 0.9) for GE at 2 hours, 0.54 (0.34, 0.7) for GE at 4 hours, and 0.79 (0.68, 0.86) for GE t1/2 . However, in 18 of 60 patients (30%), the characterization of GE as normal, delayed, or rapid differed between the first and second studies. For gastric empting t1/2 , the inter-individual coefficients of variation was 40%; the intra-individual COV was 20%, comparable in diabetics and non-diabetics, and greater in patients with rapid (28%) than delayed (18%) or normal GE (12%). CONCLUSIONS & INFERENCES: Among patients with upper gastrointestinal symptoms, GE measured with scintigraphy is relatively reproducible. In 30% of cases, the interpretation was different between the two assessments. Hence, a diagnosis of gastroparesis based on a single study may occasionally be inaccurate.


Assuntos
Gastroparesia/diagnóstico , Cintilografia/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Esvaziamento Gástrico , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
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