RESUMO
The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2-ERIC-PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.
Assuntos
Isquemia Encefálica , COVID-19 , Precondicionamento Isquêmico Miocárdico , Acidente Vascular Cerebral , Animais , Educação , Isquemia , Resultado do TratamentoRESUMO
In the 25 years since the hypothesis was first described, therapeutic use of inhibitors of dipeptidyl peptidase-4 (DPP-4i) as a novel approach to the treatment of type 2 diabetes has become established widely, with several compounds now available to exemplify the class. Although the clinical profiles of members of the DPP-4i class have been reviewed extensively, the underlying pragmatic small molecular design and pharmaceutical properties of these agents have seldom been addressed in the context of establishment of the class as treatments for type 2 diabetes. Among the reasons contributing to the wide acceptance of DPP-4i as oral anti-hyperglycaemic therapy are: (i) the endocrine basis of their pharmacology; (ii) their chemical 'simplicity' and low molecular mass; (iii) their pharmacological selectivity for their target mechanism of action; (iv) the nature of physiologically relevant substrates for the enzyme; (v) their relative ease of formulation into tablets; (vi) their efficacy as glucose-lowering agents; (vii) their absorption, distribution, metabolism and elimination profiles; and (viii) their limited tolerability issues.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , HumanosRESUMO
In the 30 years since the original description of ischaemic preconditioning, understanding of the pathophysiology of ischaemia/reperfusion injury and concepts of cardioprotection have been revolutionised. In the same period of time, management of patients with coronary artery disease has also been transformed: coronary artery and valve surgery are now deemed routine with generally excellent outcomes, and the management of acute coronary syndromes has seen decade on decade reductions in cardiovascular mortality. Nonetheless, despite these improvements, cardiovascular disease and ischaemic heart disease in particular, remain the leading cause of death and a significant cause of long-term morbidity (with a concomitant increase in the incidence of heart failure) worldwide. The need for effective cardioprotective strategies has never been so pressing. However, despite unequivocal evidence of the existence of ischaemia/reperfusion in animal models providing a robust rationale for study in man, recent phase 3 clinical trials studying a variety of cardioprotective strategies in cardiac surgery and acute ST-elevation myocardial infarction have provided mixed results. The investigators meeting at the Hatter Cardiovascular Institute workshop describe the challenge of translating strong pre-clinical data into effective clinical intervention strategies in patients in whom effective medical therapy is already altering the pathophysiology of ischaemia/reperfusion injury-and lay out a clearly defined framework for future basic and clinical research to improve the chances of successful translation of strong pre-clinical interventions in man.
Assuntos
Traumatismo por Reperfusão Miocárdica , Pesquisa Translacional Biomédica , Animais , Humanos , Precondicionamento Isquêmico Miocárdico/métodos , Precondicionamento Isquêmico Miocárdico/tendênciasRESUMO
The dipeptidyl peptidase-4 (DPP-4) inhibitor concept is an example of prospective drug design and development based upon a distinct endocrine hypothesis. The design of enzyme inhibitors is a pragmatic approach to drug design; being compatible with the identification and optimization of small molecules that have properties commensurate with oral administration, as well as acceptable drug metabolism, distribution and elimination characteristics. Glucagon-like peptide 1 (GLP-1), a hormone with a spectrum of favourable metabolic actions, including glucose-dependent stimulation of insulin and inhibition of glucagon secretion, provided the endocrine basis from which the idea of using DPP-4 inhibitors as anti-diabetic agents was developed. The origin of the DPP-4 inhibitor concept was inspired by the angiotensin-converting enzyme inhibitor approach, which succeeded in establishing a class of extensively used therapeutic agents for the treatment of cardiovascular disorders.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Descoberta de Drogas/tendências , Difusão de Inovações , Previsões , Peptídeo 1 Semelhante ao Glucagon/antagonistas & inibidores , Humanos , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
AIM: Recent studies suggest that the incretin concept is not restricted to glucose ingestion but relevant also after non-glucose macronutrient administration. We therefore hypothesized that raising incretin hormones reduces circulating glucose after both glucose and non-glucose macronutrient ingestion in healthy subjects. METHODS: Twelve healthy subjects received the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg) or placebo before ingestion of glucose, fat (olive oil) or protein mix in equicaloric amounts (8 kcal/kg) plus paracetamol (1.5 g). The 120-min areas under curve (AUC) of intact glucagon-like peptide-1 (GLP-1), glucose, insulin, C-peptide, glucagon and paracetamol, and model-derived insulin secretion rate (ISR), insulin sensitivity, insulin clearance and glucose absorption were measured. RESULTS: The increased plasma intact GLP-1 levels after each macronutrient was augmented by sitagliptin. This was associated with a robust lowering of glucose: glucose excursion after oral glucose was diminished, and glucose fell below baseline after oral fat and protein. In spite of lower glucose, AUCC -peptide and ISR did not differ significantly between sitagliptin and placebo after any macronutrient. AUCglucagon , insulin sensitivity and insulin clearance were also not different between sitagliptin and placebo. Glucose absorption after oral glucose was reduced by sitagliptin, whereas AUCparacetamol was not statistically different between sitagliptin and placebo. CONCLUSIONS: Physiological elevation of intact GLP-1 levels after ingestion of glucose and non-glucose macronutrients is robustly glucose-lowering in healthy subjects. Hence, the incretin concept is not restricted to glucose ingestion in normal physiology. The glucose-lowering action of sitagliptin at these low glucose levels in healthy subjects may have complex mechanisms, involving both islet-dependent and islet-independent mechanisms.
Assuntos
Glicemia/efeitos dos fármacos , Gorduras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Insulina/metabolismo , Pirazinas/administração & dosagem , Triazóis/administração & dosagem , Adulto , Glicemia/metabolismo , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina/fisiologia , Secreção de Insulina , Células Secretoras de Insulina , Masculino , Micronutrientes/administração & dosagem , Fosfato de Sitagliptina , Resultado do TratamentoRESUMO
Protein elicits a stronger early (30 min) glucose-dependent insulinotropic polypeptide (GIP) response than fat ingestion in lean individuals, with no difference in glucagon-like peptide-1 (GLP-1). We assessed the incretin hormone response to protein versus fat ingestion in obesity. Equicaloric (8 kcal/kg) fat (olive oil) or protein (whey protein) was ingested by non-diabetic obese male volunteers [body mass index (BMI) >30 kg/m(2) ; n = 12] and plasma GIP and GLP-1 were determined. We found no difference in the early GIP or GLP-1 responses to fat versus protein. However, the total 300-min GIP response was greater after fat than after protein ingestion (20.3 ± 3.9 vs. 10.0 ± 2.8 nmol/l × min; p = 0.026), whereas the 300-min GLP-1 responses were the same. Thus, in obesity, protein and fat ingestion elicit similar early (30 min) incretin hormone responses, whereas 300-min GIP secretion is more pronounced after fat than protein ingestion.
Assuntos
Gorduras na Dieta/metabolismo , Proteínas Alimentares/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/biossíntese , Incretinas/metabolismo , Obesidade/metabolismo , Adulto , Humanos , MasculinoRESUMO
AIM: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that induces glucose-dependent insulin secretion and may have neurotrophic properties. Our aim was to identify the presence and activity of GLP-1 receptors (GLP-1Rs) in peripheral nerve and to assess the impact of GLP-1R agonists on diabetes-induced nerve disorders. METHODS: Tissues were collected from streptozotocin-diabetic rats. GLP-1R function was assessed by incubating tissues from normal and diabetic rats with GLP-1R agonists and antagonists and measuring induction of ERK1/2 phosphorylation by Western blot. Streptozotocin-diabetic mice were also treated with the GLP-1R agonist exenatide for 8 weeks to assess the impact of GLP-1R signalling on peripheral nerve function and structure. RESULTS: GLP-1R protein was detected in rat dorsal root ganglia and the neurons and Schwann cells of the sciatic nerve. Protein levels were not affected by streptozotocin-induced diabetes. GLP-1R agonists did not signal via ERK1/2 in sciatic nerve of normal rats. However, GLP-1R agonists significantly increased pERK1/2 levels in sciatic nerves from diabetic rats, indicating that GLP-1Rs are functional in this tissue. Exenatide treatment did not affect blood sugar, insulin levels or paw thermal response latencies in either control or diabetic mice. However, the reductions of motor nerve conduction velocity and paw intraepidermal fibre density seen in diabetic mice were attenuated by exenatide treatment. CONCLUSIONS: These data show that the peripheral nerve of diabetic rodents exhibits functional GLP-1R and suggest that GLP-1R-mediated ERK-signalling in sciatic nerve of diabetic rodents may protect large motor fibre function and small C fibre structure by a mechanism independent of glycaemic control.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/farmacologia , Condução Nervosa/efeitos dos fármacos , Nervo Isquiático/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Ratos , Receptores de Glucagon/metabolismo , Nervo Isquiático/metabolismo , Nervo Isquiático/fisiopatologia , Transdução de SinaisAssuntos
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Nitrilas/administração & dosagem , Nitrilas/farmacologia , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacologia , HumanosRESUMO
The action of repaglinide, a novel insulin secretagogue, was compared with the sulfonylurea glibenclamide with regard to the hypoglycemic action in vivo, binding to betaTC-3 cells, insulin secretion from perifused mouse islets, and capacity to stimulate exocytosis by direct interaction with the secretory machinery in single voltage-clamped mouse beta-cells. Two binding sites were identified: a high-affinity repaglinide (KD = 3.6 nmol/l) site having lower affinity for glibenclamide (14.4 nmol/l) and one high-affinity glibenclamide (25 nmol/l) site having lower affinity for repaglinide (550 nmol/l). In contrast to glibenclamide, repaglinide (in concentrations as high as 5 micromol/l) lacked the ability to enhance exocytosis in voltage-clamped beta-cells. Repaglinide was more potent than glibenclamide in stimulating insulin release from perifused mouse islets (EC50 29 vs. 80 nmol/l). The greater potency of repaglinide in vitro was paralleled by similar actions in vivo. The ED50 values for the hypoglycemic action were determined to be 10.4 and 15.6 microg/kg after intravenous and oral administration, respectively. The corresponding values for glibenclamide were 70.3 microg/kg (intravenous) and 203.2 microg/kg (oral). Further, repaglinide (1 mg/kg p.o.) was effective (P < 0.001) as an insulin-releasing agent in a rat model (low-dose streptozotocin) of type 2 diabetes. These observations suggest that the insulinotropic actions of repaglinide and glibenclamide in vitro and in vivo are secondary to their binding to the high-affinity repaglinide site and that the insulinotropic action of repaglinide involves both distinct and common cellular mechanisms.
Assuntos
Glicemia/análise , Carbamatos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glibureto/farmacologia , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Sítios de Ligação , Ligação Competitiva , Glicemia/efeitos dos fármacos , Carbamatos/análise , Carbamatos/metabolismo , Estudos de Coortes , Técnicas de Cultura , Relação Dose-Resposta a Droga , Potenciais Evocados/efeitos dos fármacos , Potenciais Evocados/fisiologia , Glucose/farmacologia , Glibureto/análise , Glibureto/metabolismo , Hipoglicemiantes/análise , Hipoglicemiantes/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Concentração Osmolar , Técnicas de Patch-Clamp , Perfusão , Piperidinas/análise , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , TrítioRESUMO
OBJECTIVE: The present study investigated the antagonism of the amino-terminal heptapeptide fragment of angiotensin II ([des-Phe8]-angiotensin II; Ang(1-7)) to angiotensin II (Ang II) both in vitro in rabbit aortae and in vivo in rats. METHODS AND RESULTS: In rabbit isolated endothelium intact aortic rings Ang(1-7) caused a concentration-related rightward displacement of the Ang II curve and depressed the maximum response to Ang II. By applying the data to a Schild plot an apparent pA2 of 5.5 was calculated. This depression of maximum response could be reversed by co-incubation of Ang(1-7) with the competitive angiotensin antagonist losartan. Ang(1-7) had no effect on the contractile responses of several other agonists. Intravenous infusion of 10 or 100 micrograms/kg per min Ang(1-7) had no effect on the resting blood pressure in the anaesthetized rat but inhibited Ang II-induced pressor responses. CONCLUSION: The present results show that Ang(1-7) is a specific non-competitive antagonist of Ang II at type 1 angiotensin II receptors.
Assuntos
Angiotensina II/antagonistas & inibidores , Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina , Fragmentos de Peptídeos/farmacologia , Angiotensina I , Animais , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Imidazóis/farmacologia , Técnicas In Vitro , Losartan , Masculino , Coelhos , Ratos , Ratos Sprague-Dawley , Tetrazóis/farmacologiaRESUMO
The first non-peptide competitive human glucagon receptor antagonist, 2-(benzimidazol-2-ylthio)-1-(3,4-dihydroxyphenyl)-1-ethan one, NNC 92-1687 (2), is described. This antagonist has a binding affinity of 20 microM (IC50) and a functional Ki = 9.1 microM at the human glucagon receptor. A structure-activity relationship (SAR) was obtained on this compound, and the results show that only the benzimidazole part can be changed without complete loss of affinity. Analogues with tert-butyl or benzyloxy groups in the 5-position of the benzimidazole moiety were found to be equipotent or slightly more potent, all displaying binding affinities around 5-20 microM. Most of the changes to the catechol and the linker gave compounds without any affinity toward the human glucagon receptor. The 3-hydroxy group could, however, in the presence of a 4-hydroxy group be changed to a methoxy or a chloro group while retaining affinity.
Assuntos
Benzimidazóis/síntese química , Receptores de Glucagon/antagonistas & inibidores , Animais , Benzimidazóis/química , Benzimidazóis/metabolismo , Linhagem Celular , Cricetinae , Humanos , Relação Estrutura-AtividadeRESUMO
Intravenous infusion of L-NG-nitro-arginine, an inhibitor of endothelial nitric oxide (NO) synthesis, produced vasoconstriction in the coronary, cerebral, renal and duodenal vascular beds of the conscious rabbit. In this study, using radiolabelled microspheres, we provide in vivo evidence for a basal NO-dependent vasodilator tone in the coronary vascular bed.
Assuntos
Arginina/análogos & derivados , Vasos Coronários/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Animais , Arginina/farmacologia , Vasos Coronários/fisiologia , Infusões Intravenosas , Masculino , Óxido Nítrico/fisiologia , Nitroarginina , Coelhos , Resistência Vascular/efeitos dos fármacosRESUMO
1. FPL 63547, in its active diacid form, was a potent inhibitor of rabbit lung angiotension converting enzyme (ACE) in vitro (IC50 0.51 nM). 2. In conscious normotensive dogs, FPL 63547 (10-300 micrograms kg-1 i.v.) produced prolonged, dose-related inhibition of plasma ACE activity and angiotensin I pressor responses, without affecting basal blood pressure, heart rate or pressor responses to angiotensin II. 3. In anaesthetized dogs, FPL 63547 diacid (3-300 micrograms kg-1 i.v. cumulatively) produced dose-related increases in cardiac output accompanied by falls in total peripheral resistance indicative of vasodilatation. Mild stimulation of cardiac rate and contractility was also observed. Enalapril diacid had a similar profile. 4. FPL 63547 was a highly effective antihypertensive agent after oral administration to spontaneously hypertensive rats (SHR) pretreated with a diuretic. It lowered systolic blood pressure (SBP) on acute administration over the range 3 X 10(-7)-10(-5) mol kg-1 p.o. (congruent to 0.13-4.5 mg kg-1 p.o.). FPL 63547 was more potent than other ACE inhibitors tested, threshold active doses for lisinopril, enalapril and captopril being 10(-6), 10(-6) and 3 X 10(-5) mol kg-1 p.o., respectively. The antihypertensive effects of FPL 63547, unlike those of enalapril and captopril, were of long duration. 5. The antihypertensive efficacy of FPL 63547 was also observed following chronic oral administration. A dose of 0.5 mg kg-1 day-1 once daily for 23 days produced a sustained reduction of SBP. By the end of the treatment period, SBP was significantly lowered both pre- and post-dose, i.e. effective 24 h control had been achieved. 6. The profile of FPL 63547 is consistent with it being a potent, selective and long-acting ACE inhibitor. As an antihypertensive agent in SHR it compared favourably with other members of this class with respect to potency and duration of action.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Tiadiazóis/farmacologia , Angiotensina I/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Masculino , Peptidil Dipeptidase A/sangue , Coelhos , Ratos , Ratos Endogâmicos SHR , Vasodilatação/efeitos dos fármacosRESUMO
1. The route of elimination of FPL 63547, a novel inhibitor of angiotensin-converting enzyme (ACE), has been investigated in the anaesthetized rat. Comparisons have been made with other ACE inhibitors. 2. Bile and urine samples were collected over a 5 hour period following a single i.v. dose of ACE inhibitor (2 mumol kg-1). Samples were bioassayed for ACE inhibitory activity using affinity-purified rabbit lung ACE and the amounts of the active form of inhibitor present in each sample were calculated by comparison with a standard curve. 3. FPL 63547 was rapidly and extensively excreted as the diacid in the bile but appeared in the urine in negligible amounts. The bile:urine ratio was 21.4:1 indicating a marked preference for the biliary route. A similar elimination profile was observed when the compound was dosed in its active form (FPL 63547 diacid), 87.9% of which was found in the bile over the 5 h collection period, with a bile: urine ratio of 14.6:1. 4. The marked preference of FPL 63547 for biliary elimination was not shared by the other ACE inhibitors tested in this study. Lisinopril demonstrated the opposite pattern, being excreted almost exclusively by the kidney (bile:urine ratio 0.06:1). Enalapril was eliminated in approximately equal amounts in bile and urine (ratio 0.7:1) while spirapril diacid showed a slight preference for the bile (ratio 2.6:1). 5. The physical chemical properties of FPL 63547 diacid may be responsible for its unusual preference for biliary elimination. In particular, the amphipathic character and strong acid functionality of the compound are thought to favour transport into the bile. 6. Elimination by the biliary route will be preferred in patients whose renal function is impaired as a result of disease or age. In such patients the elimination of renally-excreted ACE inhibitors is known to be compromised, resulting in compound accumulation and the need for closer monitoring. Therefore, the elimination profile of FPL 63547, if confirmed in man, may prove to be clinically advantageous.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Bile/metabolismo , Tiadiazóis/farmacocinética , Anestesia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/urina , Animais , Biotransformação , Enalapril/análogos & derivados , Enalapril/farmacocinética , Enalapril/urina , Lisinopril , Pulmão/enzimologia , Masculino , Coelhos , Ratos , Ratos Endogâmicos , Tiadiazóis/metabolismo , Tiadiazóis/urinaRESUMO
The angiotensin II receptor antagonist, DUP 753 (Losartan), was compared with diazepam for antianxiety properties in the rat using the elevated plus-maze. Oral diazepam (5 mg kg-1) resulted in a significantly greater number of entries of rats into the open arms of the maze, an increase in time spent in the open arms and a decreased time spent in the closed arms. Oral doses of DUP 753 likewise resulted in significantly greater numbers of entries into the open arms (active at 0.0001, 0.001, 0.01 and 0.1 mg kg-1), increased time spent on the open arms (active at 0.0001-0.01 mg kg-1) and a decreased time spent in the closed arms (active at 0.0001, 0.01 and 0.1 mg kg-1). Larger (1.0 mg kg-1) or smaller (0.00001 mg kg-1) doses of DUP 753 were not active.
Assuntos
Angiotensina II/antagonistas & inibidores , Ansiolíticos/farmacologia , Compostos de Bifenilo/farmacologia , Imidazóis/farmacologia , Tetrazóis/farmacologia , Animais , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Diazepam/farmacologia , Losartan , Masculino , Ratos , Ratos Sprague-DawleyAssuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/metabolismo , Regulação para Baixo , Inibidores Enzimáticos/administração & dosagem , Neprilisina/metabolismo , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV , Modelos Animais de Doenças , Hemoglobinas Glicadas/metabolismo , Humanos , Indanos/administração & dosagem , Masculino , Neprilisina/antagonistas & inibidores , Propionatos/administração & dosagem , Distribuição Aleatória , Ratos , Xantinas/administração & dosagemRESUMO
Five cases of progressive cribriform and zosteriform hyperpigmentation are described. The following criteria were fulfilled: (1) uniformly tan cribriform macular pigmentation in a zosteriform distribution; (2) a histologic pattern that consisted of a mild increase in melanin pigment in the basal cell layer and complete absence of nevus cells; (3) no history of rash, injury, or inflammation to suggest postinflammatory hyperpigmentation; (4) onset well after birth with gradual extension; and (5) lack of other associated cutaneous or internal abnormalities. This appears to be a newly described entity, although it resembles a Becker's nevus without hypertrichosis or an typical café au lait spot. We believe that such progressive cribriform and zosteriform pigmentation is not uncommon.
Assuntos
Transtornos da Pigmentação/diagnóstico , Adolescente , Adulto , Feminino , Humanos , MasculinoRESUMO
The pig is useful as a model for human physiology and pathophysiology and could be an important supplement to the many available rodent models of diabetes mellitus. Due to their small size, Göttingen minipigs are especially suitable for long-term studies. The aim of the study reported here was to establish reference values for a range of glucose and lipid homeostasis parameters of interest that could be used to identify possible diabetes-prone male Göttingen minipig individuals, families, or age groups. Plasma samples from nonfed animals were analyzed for glucose, leptin, fructosamine, insulin, C-peptide, triglyceride, free fatty acids, and total cholesterol values. Breeding family had significant effects only on plasma triglyceride concentrations (P < 0.001). Plasma concentrations of glucose (P = 0.012), fructosamine (P < 0.001) and triglycerides (P < 0.001) increased significantly with age, whereas total cholesterol concentration decreased significantly (P = 0.001) with age. Age did not influence other parameters. In conclusion, glycemia and insulinemia increased with age and body weight, possibly indicating a small deterioration in insulin sensitivity with age. It is, therefore, hypothesized that older, compared to younger animals may be more useful in the development of a model of type-2 diabetes mellitus. Furthermore, on the basis of decrease in cholesterol concentration with age, animals fed ad libitum with possibly a high calorie diet might be even more useful in the development of a type-2 diabetes mellitus model.
Assuntos
Glicemia/metabolismo , Lipídeos/sangue , Porco Miniatura/sangue , Envelhecimento/sangue , Animais , Peso Corporal , Cruzamento , Peptídeo C/sangue , Diabetes Mellitus Tipo 2/etiologia , Modelos Animais de Doenças , Frutosamina/sangue , Homeostase , Humanos , Insulina/sangue , Masculino , Valores de Referência , Suínos , Porco Miniatura/anatomia & histologia , Triglicerídeos/sangueRESUMO
A novel technique is described in which the effect of the beta-adrenoceptor antagonists timolol and carteolol, and the vasodilators sodium nitroprusside (SNP) and verapamil on intraocular pressure (IOP) and the distribution of ocular flow in the bovine arterially perfused eye is investigated using radiolabelled microspheres. At maximum IOP-reducing dose timolol was found to significantly reduce perfusion in the choroid and, at higher dose, it was found to significantly reduce perfusion in the iris. By contrast, a maximal IOP-reducing dose of carteolol markedly reduced perfusion in the iris, ciliary body and choroid. Vasoconstriction induced by carteolol was not inhibited by the alpha-antagonist phentolamine. Against a background of vascular tone induced by noradrenaline, SNP and verapamil were found to significantly increase perfusion in the iris, ciliary body and choroid. The effects of these drugs upon the vasculature of the bovine perfused eye are varied and complex and may not bear a direct relationship to their ocular hypotensive effect.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Olho/irrigação sanguínea , Pressão Intraocular/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Carteolol/farmacologia , Bovinos , Radioisótopos de Cério , Corioide/irrigação sanguínea , Corpo Ciliar/irrigação sanguínea , Iris/irrigação sanguínea , Microesferas , Nitroprussiato/farmacologia , Perfusão , Fluxo Sanguíneo Regional/efeitos dos fármacos , Timolol/farmacologia , Verapamil/farmacologiaRESUMO
The pharmacokinetic properties of glucagon-like peptide-1(7-36)amide (GLP-1(7-37) were compared. Four beagle dogs received on 4 separate occasions s.c. bolus doses of 50 micrograms/kg, and 2 min i.v. infusions of 50 micrograms/kg of each peptide. The plasma immunoreactivity of GLP-1 (P-GLP-1-IR) was measured by a sandwich enzyme-linked immunosorbent assay (ELISA). After i.v. infusion, the plasma half-life in the first-phase was 2.1 +/- 0.1 and 2.4 +/- 0.3 min, in the final-phase 68 +/- 6 and 81 +/- 3 min, the total plasma clearance 25 +/- 3 and 22 +/- 4 ml/kg.min, the volume of distribution at steady state 0.16 +/- 0.02 and 0.84 +/- 0.24 l/kg, and the mean residence time 6.2 +/- 0.3 and 36 +/- 5 min for GLP-1(7-36)amide and GLP-1(7-37), respectively. After s.c. administration, the maximum plasma concentration was reached after 15 +/- 5 and 19 +/- 4 min and the absolute bioavailability was 48 +/- 7 and 49 +/- 13% for GLP-1(7-36)amide and GLP-1(7-37), respectively. P-GLP-1-IR, measured by a radioimmunoassay (RIA), was considerably higher than when measured by ELISA. This discrepancy was due to cross-reactivity with metabolites of the parent peptide. The plasma degradation was studied in vitro in dog plasma at 37 degrees C, and the half-lives were found to be 61 +/- 9 and 132 +/- 16 min for GLP-1(7-36)amide and GLP-1(7-37), respectively (n = 6). Bacitracin inhibited the degradation of both peptides.