Mono and dual agonists of the amylin, calcitonin, and CGRP receptors and their potential in metabolic diseases.

BACKGROUND: Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for novel treatment candidates that can stimulate insulin sensitivity and increase weight loss efficacy in combination with current treatment options. Calcitonin gene-related peptide (CGRP) and amylin belong to the same peptide family and have been explored as treatments for metabolic diseases. However, their full potential remains controversial. SCOPE OF REVIEW: In this article, we introduce this rather complex peptide family and its corresponding receptors. We discuss the physiology of the peptides with a focus on metabolism and insulin sensitivity. We also thoroughly review the pharmacological potential of amylin, calcitonin, CGRP, and peptide derivatives as treatments for metabolic diseases, emphasizing their ability to increase insulin sensitivity based on preclinical and clinical studies. MAJOR CONCLUSIONS: Amylin receptor agonists and dual amylin and calcitonin receptor agonists are relevant treatment candidates, especially because they increase insulin sensitivity while also assisting weight loss, and their unique mode of action complements incretin-based therapies. However, CGRP and its derivatives seem to have only modest if any metabolic effects and are no longer of interest as therapies for metabolic diseases.

Procalcitonina y síndrome febril precoz: ¿cuándo nos ofrece mayor rentabilidad diagnóstica? / Procalcitonin and early-onset seizures: when do we offer a higher diagnostic yield?

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Capacidad del lactato y la procalcitonina para predecir bacteriemia y mortalidad en Urgencias / Power of lactate and procalcitonin to predict bacteremia and mortality in the Emergency Department

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Papel de la procalcitonina plasmática en el diagnóstico de laneumonía asociada a ventilación mecánica: revisión sistemática y metaanálisis / Role of plasma procalcitonin in the diagnosis of ventilator-associated pneumonia: Systematic review and metaanalysis

OBJETIVO: Determinar el papel de los niveles plasmáticos de procalcitonina (PCT) en el diagnóstico de neumonía asociada a ventilación mecánica. Diseño Revisión sistemática y metaanálisis de los trabajos originales que evalúan el papel de PCT en el diagnóstico de neumonía asociada a ventilación mecánica. La búsqueda de trabajos se llevó a cabo en Medline, Embase, Colaboración Cochrane y MEDION y tras revisión de las referencias de los artículos obtenidos. Se extrajeron datos que permitieron el cálculo de la sensibilidad, la especificidad, las razones de verosimilitud y la odds ratio diagnóstica. Intervención: Metarregresión para determinar si la exposición a tratamiento antibiótico previo, el tiempo de desarrollo de neumonía y el tipo de paciente crítico tienen impacto en el rendimiento diagnóstico de la procalcitonina. RESULTADOS: Se incluyeron 7 estudios (373 pacientes, 434 episodios). No encontramos sesgos de publicación ni efecto umbral. Las cifras elevadas de PCT plasmática se asocian a un mayor riesgo de padecer neumonía (OR 8,39; IC 95% 5,4-12,6). Los datos agrupados de sensibilidad, especificidad, razón de verosimilitud positiva y negativa y odds ratio diagnóstica encontrados son, respectivamente, 76% (69-82), 79% (74-84), 4,35 (2,48-7,62), 0,26 (0,15-0,46) y 17,9 (10,1-31,7). El rendimiento diagnóstico se ve modificado por la exposición previa a antibióticos (rORD0,11, 0,02-0,069), no así por el tipo de paciente crítico o el tiempo de desarrollo de neumonía. CONCLUSIONES: Nuestros resultados muestran que la PCT aporta información adicional respecto al riesgo de sufrir neumonía asociada a ventilación mecánica. Su inclusión en los algoritmos diagnósticos podría mejorar la capacidad de los mismos

OBJECTIVE: To determine the role of plasma procalcitonin (PCT) levels in diagnosing ventilator associated pneumonia. DESIGN: A systematic review of publications prospectively assessing the diagnostic role of PCT in ventilator-associated pneumonia was carried out. The search was performed using Medline, Embase, the Cochrane Collaboration and MEDION, with reviewing of the references of retrieved articles. We extracted data that allowed the calculation of sensitivity, specificity, like lihoodratios and diagnostic odds ratio. Intervention Metaregression was performed to determine whether exposure to previous antibiotic treatment, the time to occurrence of ventilator-associated pneumonia and the type of patients had an impact upon the diagnostic performance of procalcitonin. RESULTS: Seven studies were considered (373 patients, 434 episodes). We found no publication bias or threshold effect. High plasma PCT levels were associated to an increased risk of suffering ventilator-associated pneumonia (OR: 8.39; 95% CI: 5.4-12.6). The pooled data on sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio found were 76% (69-82), 79% (74-84), 4.35 (2.48-7.62), 0.26 (0.15-0.46) and 17.9 (10.1-31.7), respectively. Diagnostic yield was modified by prior exposure to antibiotics (rDOR 0.11, 0.02-0.069),but not by the type of critically ill patient or the time to occurrence of ventilator-associated pneumonia. CONCLUSIONS: Our results suggest that PCT provides additional information on the risk of VAP. Inclusion of PCT in diagnostic algorithms could improve their effectiveness

Factores predictivos de daño renal en la infección febril del tracto urinario. Utilidad de la procalcitonina / Predictive factors for kidney damage in febrile urinary tract infection. Usefulness of procalcitonin

Objetivo: Establecer la utilidad de la procalcitonina (PCT) y otros parámetros clínicos y analíticos como indicadores de daño renal agudo y permanente en niños tras una primera infección del tracto urinario (ITU) febril. Material y métodos: Estudio retrospectivo multicéntrico. Estudio estadístico: descriptivo, curvas ROC y regresión logística múltiple. Resultados: 219 pacientes, con edades entre 1 semana y 14 años (68 % menores de 1 año). Las medias de PCT fueron significativamente mayores en pacientes con pielonefritis aguda respecto a aquellos con DMSA agudo normal (4,8 frente a 1,44; p = 0,0001), sin alcanzar significación para DMSA tardío (6,5 frente a 5,05; p = 0,6). El área bajo la curva ROC de PCT fue 0,64 (IC 95 % 0,55-0,72) para daño renal agudo y 0,62 (IC 95 % 0,44-0,80) para permanente; con puntos de corte óptimos de 0,85 y 1,17 ng/ml. El análisis multivariante para daño renal agudo solo encontró correlación con PCT (odds ratio [OR] 1,2, IC 95 % 1,06-1,4; p = 0,005) y horas de fiebre (OR para < 6 h 0,4, IC 95 % 0,2-1,02; p = 0,05). En los pacientes con cicatriz, la OR para PCT fue 1,0 (IC 95 % 0,9-1,1; p = 0,6). Conclusiones: La PCT y la duración de la fiebre fueron los únicos parámetros que se asociaron de forma significativa a daño parenquimatoso agudo. No se observó relación estadísticamente significativa entre la PCT y la cicatriz renal (AU)

Objective: To establish the utility of procalcitonin (PCT) and other clinical and analytical parameters as markers of acute and permanent renal damage in children after a first febrile urinary tract infection (UTI). Methods: Retrospective multicentre study. Statistical study: descriptive, receiver operating characteristic (ROC) curves and multiple logistic regression. Results: 219 patients, aged between 1 week and 14 years (68% under 1 year). The mean PCT values were significantly higher in patients with acute pyelonephritis with respect to normal acute DMSA (4.8 vs 1.44; p=0.0001), without achieving that signification for late affected DMSA (6.5 vs 5.05; p=0.6). The area under the ROC curve for PCT was 0.64 (CI 95% 0.55-0.72) for acute renal damage, and 0.62 (CI 95% 0.44-0.80) for permanent damage, with optimum statistical cut-off values of 0.85 and 1.17ng/ml. Multivariate analysis for acute renal damage only found correlation with PCT (Odds Ratio [OR] 1.2 (CI 95% 1.06-1.4, p=0.005), and hours of fever (OR for less than 6 hours of fever 0.4 (CI 95% 0.2-1.02, p=0.05). In patients with renal scarring, PCT showed an OR 1.0 (CI 95% 0.9-1.1, p=0.6). Conclusions: PCT and the duration of fever were the only parameters statistically associated with early renal damage. PCT and renal scarring did not reach statistical significance (AU)

Utilidad de la procalcitonina para la prescripción antibiótica y la sospecha de bacteriemia en urgencias / Usefulness of procalcitonin for prescribing of antibiotics and suspicion of bacteremia in the emergency department

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Utilidad de la procalcitonina para la prescripción antibiótica y la sospecha de bacteriemia en urgencias. Respuesta de los autores / Usefulness of procalcitonin for prescribing of antibiotics and suspicion of bacteremia in theemergency department. Author’s reply

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Procalcitonin as an early predictor of acute infection in hemodialysis patients

Background and aims: Hemodialysis patients have a greater risk of infection than individuals not on dialysis. Procalcitonin has been shown to rise in bacterial from but widely studied in hemodialysis patients. The present study evaluates procalcitonin as an early predictor of infection in this population. Methods: A historical cohorts study was made of 211 prevalent hemodialysis patients (median age 73 years [range 60-80], 58% males) covering the period 2005-2012. Serum samples were thawed and patients were followed-up on for 40±25 months (0-84). Demographic and laboratory test (including inflammatory values) data were recorded at baseline. During follow-up, all infections were documented and analyzed. Results: During follow-up, 112 patients (53.3%) suffered acute infection. A positive correlation was established for procalcitonin and C-reactive protein (σ=0.482, p<0.0001). Procalcitonin was the only inflammatory marker capable of predicting infection at one month (p=0.023) in a model with all the studied inflammatory markers. C-reactive protein was the best predictor of infection over global follow-up (p=0.003), after adjusting for all the studied factors. Conclusions: Procalcitonin is an early predictor of infection in the first 30 days in hemodialysis patients. However, in relation to the long-term prognosis, C-reactive protein is the most important independent predictor of infection (AU)

Antecedentes y objetivos: Los pacientes en hemodiálisis tienen un riesgo aumentado de padecer infecciones en comparación con sujetos no en diálisis. La procalcitonina se eleva en pacientes con infecciones bacterianas. Sin embargo, no ha sido estudiada en los pacientes en diálisis. El objetivo del presente estudio es evaluar la procalcitonina como predictor precoz de infecciones en los pacientes en hemodiálisis. Métodos: Se trata de un estudio de cohortes retrospectivo con 211 pacientes prevalentes en hemodiálisis (mediana de edad: 73 años [rango 60-80], 58 % varones) entre 2005-2012. Se extrajeron muestras prediálisis y se siguió a los pacientes durante 40 ± 25 meses (0-84). Se recogieron datos basales demográficos y de laboratorio, incluyendo marcadores inflamatorios. Durante el seguimiento se documentaron y analizaron las nuevas infecciones. Resultados: Durante el seguimiento, 112 pacientes (53 %) tuvieron una infección. Se estableció una correlación entre procalcitonina y proteína C reactiva (PCR) (σ = 0,482, p < 0,0001). El único marcador estudiado capaz de predecir infecciones al primer mes fue la procalcitonina (p = 0,023) en un modelo ajustado. La PCR fue el mejor predictor de infección durante el seguimiento global (p = 0,003), en un modelo ajustado. Conclusiones: La procalcitonina es un marcador de infección precoz (a 30 días) en los pacientes en hemodiálisis. Sin embargo, la PCR resultó ser el único marcador asociado con infecciones a largo plazo (AU)

Valor de la procalcitonina al ingreso en terapia intensiva para el diagnóstico y el pronóstico de la sepsis / Usefulness of procalcitonin upon admission to intensive care in the diagnosis and prognosis of sepsis

Objetivo Evaluar la capacidad de la procalcitonina (PCT) al ingreso a la Unidad de Terapia Intensiva (UTI) para el diagnóstico y el pronóstico de la sepsis. Diseño Cohorte prospectivo observacional. Doce meses de duración. Ámbito Terapia intensiva polivalente de 11 camas. Hospital Universitario. Pacientes Se incluyeron 50 enfermos con síndrome de respuesta inflamatoria sistémica (SIRS). La edad media de los mismos fue de 51,66 años y el 68% fueron varones. Variables de interés: al ingreso se determino la PCT y proteína C reactiva (PCR). Al alta el diagnóstico definitivo y la evolución. Resultados Treinta y seis pacientes presentaron sepsis. Los valores medios ± DE de PCT fueron mayores en sepsis que en el SIRS no infeccioso (19,3±4,9 vs 0,65±0,2 ng/ml); p=0,001. La PCT tuvo mayor poder de discriminación que la PCR (AUC 0,932 vs 0,827). El valor de corte de PCT para diagnóstico de sepsis fue de 0,92ng/dl, con una sensibilidad, especificidad, valor predictivo positivo y negativo del 80,56, 85,71, 93,55 y 63,16% respectivamente. L-R positivo 5,64 y L-R negativo 0,23. La mortalidad fue mayor en los pacientes con sepsis (52,78 vs 21,43%) p=0,039. El valor medio de PCT al ingreso de los pacientes con sepsis que sobrevivieron y fallecieron fue de 18,7±6,7) y 19,5 ±7,5) ng/ml respectivamente (p=0,934).Conclusiones La PCT al ingreso a la UTI resultó útil para el diagnóstico de sepsis, superando a la PCR. No tuvo capacidad para estimar el pronóstico a corto plazo (AU)

Objective To assess the usefulness of procalcitonin (PCT) upon admission to the Intensive Care Unit (ICU) in the diagnosis and prognosis of sepsis Design A 12-month prospective observational cohort study was carried out Setting An 11-bed polyvalent ICU Belonging to a University hospital Patients Fifty patients with systemic inflammatory response syndrome (SIRS) were included. The mean age of the patients was 51.66 years, and 68% of them were males Variables of interest Upon admission, the concentration of PCT and C-reactive protein (CRP) was assessed. At discharge, the final diagnosis and outcome were reviewed Results Thirty-six patients had sepsis. Mean PCT±SD was higher in sepsis than in non-infectious SIRS (19.3±4.9 vs. 0.65±0.2) ng/ml) (P=.001). PCT had greater discriminating power than CRP (AUC 0.932 vs. 0.827). The cut-off value of PCT for the diagnosis of sepsis was 0.92ng/dl, with a sensitivity of 80.56%, specificity 85.71%, positive predictive value 93.55% and negative predictive value 63.16%, LR+ 5.64 and LR- 0.23. Mortality was higher in patients with sepsis (52.78% vs. 21.43%) (P=.039). Mean PCT± SD upon admission among survivors and deceased patients with sepsis was 18.7±6.7 and 19.5±7.5 ng/ml, respectively (P=.934).Conclusions PCT upon admission to the ICU is useful for the diagnosis of sepsis, and is more effective than PCR in this respect. However, it is of no help in estimating the short-term prognosis (AU)

Valor pronóstico de los biomarcadores procalcitonina, interleukina 6 y proteína C reactiva en la sepsis grave / Prognostic value of the biomarkers procalcitonin, interleukin-6 and C-reactive protein in severe sepsis

Objetivo: Comprobar el valor pronóstico de los biomarcadores procalcitonina, interleukina 6 y proteína C reactiva en pacientes sépticos graves Diseño: Cohorte de 81 pacientes críticos Ambito: Unidad de Críticos Hospital Dr. Peset. Valencia. Pacientes: Divididos según el grado de sepsis (sepsis, sepsis severa, shock séptico), foco de sepsis y grupo (pacientes médicos y posquirúrgicos de alto riesgo). Variables analizadas: Cuantitativas (procalcitonina, interleukina-6, proteína C reactiva, lactato, edad, Apache II y SOFA) al ingreso, 3.er y 7.o día de evolución. Cualitativas (mortalidad intra UCI, desarrollo Fallo Multiorgánico y sexo). Estadística: comparación variables cuantitativas con test U de Mann-Whitney; las cualitativas con test de χ2; análisis multivariante variables dependientes mortalidad y fallo multiorgánico e independientes las cuantitativas descritas; curvas ROC de las variables significativas en el multivariante Resultados: Pacientes con shock séptico fallecieron más y desarrollaron más fallo multiorgánico. Comparación entre vivos y fallecidos, mostró diferencias significativas Apache II, interleukina-6 y lactato (p <0,001) al ingreso, 3.er y 7.o día. Entre pacientes con fallo multiorgánico y sin él, también y los mismos días. La procalcitonina mostró diferencias solo en 3.er y 7.o día (p=0,001). Análisis multivariante con variable dependiente mortalidad la interleukina-6 mostró significación al 3.er día (O.R. 2,6). Con variable dependiente fallo multiorgánico solo SOFA tuvo significación (O.R. 2,3). Curva ROC Apache II e interleukina-6 3.er día mostró área 0,80 y 0,86 respectivamente. Conclusiones: 1) La interleukina-6 es un biomarcador inflamatorio con valor pronóstico de mortalidad; 2) Ningún biomarcador tuvo valor predictivo de fallo multiorgánico (AU)

Aim: To determine the prognostic value of the biomarkers procalcitonin, interlukin-6 and C-reactive protein in septic patients. Design: A cohort of 81 septic patients. Setting: Critical Care Unit. Dr. Peset Hospital. Valencia (Spain). Patients: Divided according to sepsis classification (sepsis, severe sepsis and septic shock), source and two different groups (medical and postsurgical). Variables analyzed: Quantitative (procalcitonin, interleukin-6, C-reactive protein, lactate, age, Apache II and SOFA scores upon admission and after 3 and 7 days). Qualitative (ICU mortality, multiorgan failure development and sex). Statistical analysis: Mann-Whitney U-test for the comparison of quantitative variables, X2 test for qualitative variables. Multivariate analysis with mortality and multiorgan failure as dependent variables and the described quantitative parameters as independent variables. ROC curves of the variables found to be significant in the multivariate analysis. Results: Septic shock patients showed greater mortality and more frequent multiorgan failure. Comparison of survivors versus deceased patients showed significant differences in Apache II score, interleukin-6 and lactate (p<0.001) upon admission and after 3 and 7 days. Similar findings applied to the comparison of patients with and without multiorgan failure, and on the same days. Procalcitonin only showed differences on days 3 and 7 (p=0.001). In the multivariate analysis with mortality as dependent variable, interleukin-6 proved significant on day 3 (OR 2.6). With multiorgan failure as dependent variable, only the SOFA score showed significance (OR 2.3). The Apache II and interleukin-6 ROC curves corresponding to day 3 showed areas of 0.80 and 0.86, respectively. Conclusions: 1) Interleukin-6 is an inflammatory biomarker with mortality prognostic value. 2) None of the biomarkers proved predictive of multiorgan failure (AU)

Cinética de la proteína C reactiva y procalcitonina en el postoperatorio de la escoliosis / Kinetics of C-reactive protein and procalcitonin after scoliosis surgery

Introducción. El síndrome de respuesta inflamatoria sistémica que se desencadena tras distintos tipos de cirugía condiciona una elevación en los niveles de proteína C reactiva (PCR) y procalcitonina (PCT) que puede limitar su valor para el diagnóstico de una infección postoperatoria. El objetivo del estudio es describir la cinética de ambas tras la cirugía de escoliosis. Métodos. Estudio prospectivo observacional desarrollado en una Unidad de Cuidados Intensivos Pediátricos de8 camas de un hospital universitario. Se incluyeron 29 niños. Se analizaron los niveles de PCR y PCT a las 0, 24, 48 y 72horas del postoperatorio de la escoliosis. Resultados. La PCT se elevó precozmente con un pico máximo a las 24 horas (media: 0,41 ng/ml; IC 95%: 0,11-0,71ng/ml) y se mantuvo por debajo de los puntos de corte para infección localizada y sepsis, establecidos en nuestra Unidad (0,79 y 1,80 ng/ml respectivamente). La proteína C reactiva se elevó más tardíamente, alcanzando su pico a las 48horas (media: 12,23 mg/dl; IC 95%: 5,61-18,86 mg/dl) y superando los puntos de corte para sepsis e infección localizada (5,7 y 6,45 mg/dl respectivamente) establecidos en nuestra unidad. Conclusiones. La PCT, debido a su elevación más precoz manteniéndose por debajo de 0,5 ng/ml, se perfila como una herramienta más fiable que la PCR para el diagnóstico de infección en el postoperatorio de la escoliosis (AU)

Introduction. Post-surgery systemic inflammatory response syndrome leads to an elevation in C reactive protein (CRP) and procalcitonin (PCT) levels which may impedet heir diagnostic value for postoperative infection. The aim of this study is to establish the kinetics of both markers after scoliosis surgery. Methods. Prospective observational study setting in an eight-bed pediatric intensive care unit of a university hospital. Twenty-nine children were included. CRP and PCT levels were determined at 0, 24, 48 y 72 h after scoliosis surgery. Results. PCT levels increased early after surgery with a maximum peak at 24 hours (mean: 0.41 ng/ml; IC 95% 0.11-0.71 ng/ml) that is below the cutoff values for local infection or sepsis diagnosis (0.79 and 1.8 ng/ml respectively)previously established in our pediatric intensive care unit. However, C reactive protein increased later, reached the higher peak at 48 hours (mean: 12.23 mg/dl IC 95% 5.61-18.86 mg/dl) that is above cutoff values for sepsis and local infection (5.7 and 6.45 mg/dl respectively) previously established in our pediatric intensive care unit Conclusion. Procalcitonin seems to be a more reliable diagnosis tool of postoperative scoliosis infection due to its earlier elevation and the maintenance of its levels below the cut-off value for infection (AU)

Phosphodiesterase 4 inhibitor rolipram potentiates the inhibitory effect of calcitonin on osteoclastogenesis.

To assess the combination effect of calcitonin and the phosphodiesterase 4 inhibitor rolipram on osteoclastogenesis, adherent cell-depleted bone marrow cells from mouse tibia and femur (ACD-BMCs), which were cultured in the presence of 25 ng/ml colony-stimulating factor 1 (CSF-1) and 100 ng/ml soluble receptor activator of NF-kappaB ligand (sRANKL), were utilized. Calcitonin inhibited formation of tartrate-resistant acid phosphatase-positive multinucleated cells, as mature osteoclasts, by 70% even at 20 pM, whereas rolipram (10 microM) scarcely affected osteoclast formation; in contrast, the combination of both agents led to significant inhibition of multinucleation and pit formation ability of osteoclasts. The combined administration of calcitonin and rolipram attenuated calcitonin receptor mRNA expression in comparison to treatment with either agent alone, whereas expression of RANK and CSF-1 receptor mRNAs was unchanged. Alone, these agents scarcely elevated intracellular cyclic AMP (cAMP) concentration; however, combination treatment with both agents significantly increased cAMP concentration in osteoclast progenitors and osteoclasts. The combination effect was abolished by H-89, an inhibitor of protein kinase A. It appears that rolipram inhibited hydrolysis of cAMP formed by calcitonin in cells and potentiated the inhibitory effect of calcitonin on osteoclastogenesis. The escape phenomenon following calcitonin treatment may also be prevented by concomitant treatment with the phosphodiesterase 4 inhibitor.

Contribution of conformationally constrained calcitonin (Ct) analogs to the understanding of the structural and conformational requirements of calcitonin bioactivity and to the design of potent agonists.

Restricting the conformational flexibility of medium-sized linear polypeptides is a valuable approach to identify and characterize the structural and conformational features that define their biological activities and to design analogs with enhanced agonistic or antagonistic properties and with potential therapeutic applications. The calcium-regulating and bone resorption-inhibiting hormone calcitonin (Ct) is a conformationally flexible polypeptide of 32 amino acid residues that has long been applied therapeutically for the treatment of osteoporosis and other bone disorder diseases. This review describes studies on the structural and conformational features of the Ct sequence that are relevant for Ct bioactivity and focuses on research work performed on rationally designed conformationally constrained Ct analogs as tools for the understanding of the molecular basis of Ct bioactivity and as potential candidates or lead structures for novel Ct-based bone disorder therapeutics.

Receptor autoradiography as mean to explore the possible functional relevance of neuropeptides: focus on new agonists and antagonists to study natriuretic peptides, neuropeptide Y and calcitonin gene-related peptides.

Over the past 20 years, receptor autoradiography has proven most useful to provide clues as to the role of various families of peptides expressed in the brain. Early on, we used this method to investigate the possible roles of various brain peptides. Natriuretic peptide (NP), neuropeptide Y (NPY) and calcitonin (CT) peptide families are widely distributed in the peripheral and central nervous system and induced multiple biological effects by activating plasma membrane receptor proteins. The NP family includes atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). The NPY family is composed of at least three peptides NPY, peptide YY (PYY) and the pancreatic polypeptides (PPs). The CT family includes CT, calcitonin gene-related peptide (CGRP), amylin (AMY), adrenomedullin (AM) and two newly isolated peptides, intermedin and calcitonin receptor-stimulating peptide (CRSP). Using quantitative receptor autoradiography as well as selective agonists and antagonists for each peptide family, in vivo and in vitro assays revealed complex pharmacological responses and radioligand binding profile. The existence of heterogeneous populations of NP, NPY and CT/CGRP receptors has been confirmed by cloning. Three NP receptors have been cloned. One is a single-transmembrane clearance receptor (NPR-C) while the other two known as CG-A (or NPR-A) and CG-B (or NPR-B) are coupled to guanylate cyclase. Five NPY receptors have been cloned designated as Y(1), Y(2), Y(4), Y(5) and y(6). All NPY receptors belong to the seven-transmembrane G-protein coupled receptors family (GPCRs; subfamily type I). CGRP, AMY and AM receptors are complexes which include a GPCR (the CT receptor or CTR and calcitonin receptor-like receptor or CRLR) and a single-transmembrane domain protein known as receptor-activity-modifying-proteins (RAMPs) as well as an intracellular protein named receptor-component-protein (RCP). We review here tools that are currently available in order to target each NP, NPY and CT/CGRP receptor subtype and establish their respective pathophysiological relevance.