RESUMO
CD-NP is a novel chimeric natriuretic peptide (NP) consisting of the 22-amino-acid (AA) human C-type natriuretic peptide (CNP), a venodilating peptide with limited renal actions and minimal effects on blood pressure, and the 15-AA C-terminus of Dendroaspis NP (DNP). The rationale for the design of CD-NP was to enhance the renal actions of CNP, the ligand for natriuretic peptide receptor-B, but without inducing excessive hypotension. Here we report the first-in-human studies for CD-NP, which represent the first successful clinical testing of a chimeric NP demonstrating in normal human volunteers that CD-NP possesses cyclic guanosine monophosphate-activating, natriuretic, and aldosterone-suppressing properties without inducing excessive hypotension, laying the foundation for additional studies on this first-in-class new cardiovascular therapeutic in human heart failure, which are now underway worldwide.
Assuntos
Fármacos Cardiovasculares/farmacologia , Venenos Elapídicos/farmacologia , Peptídeo Natriurético Tipo C/farmacologia , Adulto , Pressão Sanguínea/efeitos dos fármacos , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/efeitos adversos , GMP Cíclico/sangue , GMP Cíclico/urina , Desenho de Fármacos , Venenos Elapídicos/administração & dosagem , Venenos Elapídicos/efeitos adversos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Tipo C/administração & dosagem , Peptídeo Natriurético Tipo C/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/farmacologia , Sódio/urinaRESUMO
Designer natriuretic peptides (NPs) are novel hybrid peptides that are engineered from the native NPs through addition, deletion, or substitution of amino acid(s) with a goal toward optimization of pharmacological actions while minimizing undesirable effects. In this article, selected peptides that were designed in our laboratory are reviewed, and future directions for research and development of designer NPs are discussed.
Assuntos
Desenho de Fármacos , Peptídeos Natriuréticos , HumanosRESUMO
Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , AMP Cíclico/sangue , Insuficiência Cardíaca/tratamento farmacológico , Peptídeos Natriuréticos/uso terapêutico , Venenos de Serpentes/uso terapêutico , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Fármacos Cardiovasculares/efeitos adversos , Doença Crônica , AMP Cíclico/urina , Método Duplo-Cego , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/urina , Humanos , Infusões Intravenosas , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Minnesota , Peptídeos Natriuréticos/efeitos adversos , Estudos Prospectivos , Eliminação Renal , Venenos de Serpentes/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: High-density lipoproteins (HDL) favorably affect endothelial progenitor cells (EPC). Circulating progenitor cell level and function are impaired in patients with acute coronary syndrome (ACS). This study investigates the short-term effects of reconstituted HDL (rHDL) on circulating progenitor cells in patients with ACS. METHODS AND FINDINGS: The study population consisted of 33 patients with recent ACS: 20 patients from the ERASE trial (randomized to receive 4 weekly intravenous infusions of CSL-111 40 mg/kg or placebo) and 13 additional patients recruited as controls using the same enrolment criteria. Blood was collected from 16 rHDL (CSL-111)-treated patients and 17 controls at baseline and at 6-7 weeks (i.e. 2-3 weeks after the fourth infusion of CSL-111 in ERASE). CD34+ and CD34+/kinase insert domain receptor (KDR+) progenitor cell counts were analyzed by flow cytometry. We found preserved CD34+ cell counts in CSL-111-treated subjects at follow-up (change of 1.6%), while the number of CD34+ cells was reduced (-32.9%) in controls (p = 0.017 between groups). The level of circulating SDF-1 (stromal cell-derived factor-1), a chemokine involved in progenitor cell recruitment, increased significantly (change of 21.5%) in controls, while it remained unchanged in CSL-111-treated patients (p = 0.031 between groups). In vitro exposure to CSL-111 of early EPC isolated from healthy volunteers significantly increased CD34+ cells, reduced early EPC apoptosis and enhanced their migration capacity towards SDF-1. CONCLUSIONS: The relative increase in circulating CD34+ cells and the low SDF-1 levels observed following rHDL infusions in ACS patients point towards a role of rHDL in cardiovascular repair mechanisms.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , HDL-Colesterol/uso terapêutico , Células Progenitoras Endoteliais/efeitos dos fármacos , Fosfatidilcolinas/uso terapêutico , Antígenos CD34 , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
AIMS: Cenderitide is a novel dual natriuretic peptide (NP) receptor chimeric peptide activator, which targets the particulate guanylyl cyclase B (pGC-B) receptor and pGC-A unlike native NPs. Cenderitide was engineered to retain the anti-fibrotic properties of C-type natriuretic peptide (CNP)/pGC-B with renal-enhancing actions facilitated by fusion to the carboxyl terminus of Dendroaspis NP (DNP), a pGC-A agonist, to CNP. Here, we address significance of the DNP carboxyl terminus in dual pGC receptor activation and actions of cenderitide compared with CNP on renal function and cyclic guanosine monophosphate (cGMP) in vivo and ex vivo in normal canines. METHODS AND RESULTS: In vitro, only cenderitide and not CNP or three CNP-based variants was a potent dual pGC-A/pGC-B activator of cGMP production (from 5 to 237 pmol/mL) in human embryonic kidney (HEK) 293 cells overexpressing human pGC-A while in pGC-B overexpressing cells cenderitide increased cGMP production (from 4 to 321 pmol/mL) while the three CNP-based variants were weak agonists. Based upon our finding that the DNP carboxyl terminus is a key structural requirement for dual pGC-A/pGC-B activation, we defined in vivo the renal-enhancing actions of cenderitide compared with CNP. Cenderitide increased urinary cGMP excretion (from 989 to 5977 pmol/mL), net generation of renal cGMP (821-4124 pmol/min), natriuresis (12-242 µEq/min), and glomerular filtration rate (GFR) (37-51 mL/min) while CNP did not. We then demonstrated the transformation of CNP ex vivo into a renal cGMP-activating peptide which increased cGMP in freshly isolated glomeruli eight-fold greater than CNP. CONCLUSION: The current study establishes that dual pGC-A and pGC-B activation with CNP requires the specific carboxyl terminus of DNP. In normal canines in vivo and in glomeruli ex vivo, the carboxyl terminus of DNP transforms CNP into a natriuretic and GFR-enhancing peptide. Future studies of cenderitide are warranted in cardiorenal disease states to explore its efficacy in overall cardiorenal homeostasis.
Assuntos
Natriuréticos/farmacologia , Peptídeos Natriuréticos/farmacologia , Receptores do Fator Natriurético Atrial/agonistas , Fármacos Renais/farmacologia , Venenos de Serpentes/farmacologia , Animais , GMP Cíclico/urina , Dendroaspis , Cães , Desenho de Fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Células HEK293 , Humanos , Testes de Função Renal , Masculino , Natriuréticos/química , Peptídeo Natriurético Tipo C/química , Peptídeo Natriurético Tipo C/farmacologia , Peptídeos Natriuréticos/química , Venenos de Serpentes/química , Relação Estrutura-AtividadeRESUMO
We present a case of digoxin toxicity in the context of dehydration, renal dysfunction and concomitant use of the macrolide antibiotic, clarithromycin, which is known to inhibit P-glycoprotein-mediated efflux mechanisms of digoxin. A focused review of the literature is presented. Health care providers need to be vigilant of this mechanism of drug-drug interaction, which is also relevant to other commonly used cardiovascular drugs.
Assuntos
Antiarrítmicos/efeitos adversos , Claritromicina/uso terapêutico , Digoxina/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Nefropatias/induzido quimicamente , Pneumonia/tratamento farmacológico , Idoso de 80 Anos ou mais , Antiarrítmicos/uso terapêutico , Antibacterianos/uso terapêutico , Digoxina/uso terapêutico , Interações Medicamentosas , Seguimentos , Insuficiência Cardíaca/complicações , Humanos , Nefropatias/diagnóstico , Masculino , Pneumonia/complicaçõesRESUMO
BACKGROUND: There is a dearth of information on paternal drug exposure at the time of conception. The Motherisk Program, established in 1985, is a teratology information and clinical consultation service on drug safety during pregnancy and lactation, as well as paternal exposure (PEx). Here, we reviewed for the first time our experience with PEx. METHODS: This was an observational retrospective cohort study using a prospectively collected database. Telephone counselling records from January 2002 to December 2007, inclusive, were screened to identify cases concerning PEx. RESULTS: Of a total of 188,188 counselling requests over these 6 years, 301 (0.16%) pertained to PEx. Counselling was most frequently sought on methotrexate, finasteride, prednisone and azathioprine. For many drugs, limited or no information was available on PEx. CONCLUSIONS: Paternal exposure represents a small fraction of counselling requests to Motherisk. Our findings suggest that there is an ongoing need for information on paternal drug exposure.
Assuntos
Exposição Paterna/efeitos adversos , Preparações Farmacêuticas , Teratologia/estatística & dados numéricos , Azatioprina/uso terapêutico , Aleitamento Materno/estatística & dados numéricos , Estudos de Coortes , Aconselhamento/estatística & dados numéricos , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Lactação/efeitos dos fármacos , Masculino , Metotrexato/uso terapêutico , Preparações Farmacêuticas/classificação , Projetos Piloto , Gravidez , Estudos Retrospectivos , TelefoneRESUMO
A case of unusual reactions consisting of involuntary abnormal facial movements in a child following exposure to the 5-HT3 receptor antagonists for prophylaxis against chemotherapy-induced vomiting is presented. Potential mechanisms for these reactions are discussed.
Assuntos
Músculos Faciais/efeitos dos fármacos , Ondansetron/efeitos adversos , Antagonistas da Serotonina/efeitos adversos , Antieméticos/efeitos adversos , Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Criança , Músculos Faciais/fisiopatologia , Humanos , Masculino , Ondansetron/uso terapêutico , Rabdomiossarcoma/tratamento farmacológico , Antagonistas do Receptor 5-HT3 de Serotonina , Antagonistas da Serotonina/uso terapêutico , Vômito/induzido quimicamente , Vômito/prevenção & controleRESUMO
Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.