Vascular effects of serelaxin in patients with stable coronary artery disease: a randomized placebo-controlled trial.

AIMS: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. CONCLUSION: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

Administration study of recombinant human relaxin-2 in horse for doping control purpose.

The insulin-like peptide relaxin (RLX), an endogenous peptide hormone produced in human for pregnancy and reproduction, is also known to exert a range of physiological and pathological effects. Its use is banned in human sports, horseracing, and equestrian competitions due to its potential performance enhancing effect through vasodilation resulting in the increase of blood and oxygen supplies to muscles. Little is known about the biotransformation and elimination of RLX in horses. This paper describes an administration study of rhRLX-2 and its elimination in horses, and the development of sensitive methods for the detection and confirmation of rhRLX-2 in both horse plasma and urine by nano-liquid chromatography/high resolution mass spectrometry (nano-LC/HRMS) after immunoaffinity extraction with the objective of controlling the abuse of rhRLX-2 in horses. The limits of detection in plasma and urine are 2 pg/mL and 5 pg/mL, respectively. Two thoroughbred geldings were each administered one dose of 10 mg rhRLX-2 subcutaneously daily for 3 consecutive days. The rhRLX-2 could be detected and confirmed in the plasma and urine samples collected 105 h and 80 h, respectively, after the last dose of administration. For doping control purposes, rhRLX-2 ELISA could be used as a screening test to identify potential positive samples for further investigation using the nano-LC/HRMS methods.

Engineered Relaxin as theranostic nanomedicine to diagnose and ameliorate liver cirrhosis.

Hepatic cirrhosis is a growing health problem with increasing mortality worldwide. So far, there is a lack of early diagnosis and no clinical therapy is approved for the treatment. In this study, we developed a novel theranostic nanomedicine by targeting relaxin (RLX) that is known to possess potent anti-fibrotic properties but simultaneously has poor pharmacokinetics and detrimental off-target effects. We conjugated RLX to PEGylated superparamagnetic iron-oxide nanoparticles (RLX-SPIONs) and examined hepatic stellate cells (HSCs) specific binding/uptake. Thereafter, we assessed the therapeutic efficacy of RLX-SPIONs on human HSCs in vitro and in vivo in CCl4-induced liver cirrhosis mouse model. RLX-SPIONs showed specific binding and uptake in TGFß-activated HSCs, and inhibited TGFß-induced HSCs differentiation, migration and contraction. In vivo, RLX-SPIONs strongly attenuated cirrhosis and showed enhanced contrast in MR imaging. Altogether, this study presents RLX-SPIONs as a novel theranostic nanomedicine that provides new opportunities for the diagnosis and treatment of liver cirrhosis.

Design and Synthesis of Potent, Long-Acting Lipidated Relaxin-2 Analogs.

Peptide hormone relaxin-2, a member of the insulin family of peptides, plays a key role in hemodynamics and renal function and has shown preclinical efficacy in multiple disease models, including acute heart failure, fibrosis, preeclampsia, and corneal wound healing. Recently, serelaxin, a recombinant version of relaxin-2, has been studied in a large phase 3 clinical trial (RELAX-AHF-2) for acute decompensated heart failure patients with disappointing outcome. The poor in vivo half-life of relaxin-2 may have limited its therapeutic efficacy and long-term cardiovascular benefit. Herein, we have developed a semisynthetic methodology and generated potent, fatty acid-conjugated relaxin analogs with long-acting pharmacokinetic (PK) profile in rodents. The enhanced PK properties translated into improved and long-lasting pharmacodynamic effect in pubic ligament elongation (PLE) studies. The resultant novel relaxin analog, R9-13, represents the first long-acting relaxin-2 analog and could potentially improve the clinical efficacy and outcome for this important peptide hormone. This semisynthetic methodology could also be applied to other cysteine-rich peptides and proteins for half-life extension.

Population pharmacokinetics of serelaxin in patients with acute or chronic heart failure, hepatic or renal impairment, or portal hypertension and in healthy subjects.

AIMS: Serelaxin is a recombinant human relaxin-2 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients. METHODS: Serum concentration-time data for 613 subjects from nine phase I and II studies were analysed using a nonlinear mixed-effects model to estimate population pharmacokinetics and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from a phase III study. RESULTS: A three-compartment disposition model was established to describe serelaxin pharmacokinetics. Three out of 23 covariates, including baseline body mass index (BMI) and estimated glomerular filtration rate (eGFR) and study A1201, were identified as significant covariates for clearance but with a moderate impact on steady-state concentration, reducing the intersubject variability from 44% in the base model to 41% in the final model with covariates. The steady-state volume of distribution (Vss) was higher in patients with AHF (544 ml kg-1 ) or chronic heart failure (434 ml kg-1 ), compared with typical nonheart failure subjects (347 ml kg-1 ). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased serelaxin clearance by 9.2% or 5.2%, respectively. CONCLUSIONS: Patients with HF showed higher Vss but similar clearance (and therefore steady-state exposure) vs. non nonheart failure subjects. BMI and eGFR were identified as the main covariates explaining intersubject variability in clearance; however, the impact of these covariates on steady-state concentration was moderate and therefore unlikely to be clinically relevant.

Serelaxin in acute heart failure: Most recent update on clinical and preclinical evidence.

Heart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising healthcare costs and is one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long-term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone. Relaxin was discovered in pregnancy, but eventually found to have a number of other physiological actions, not only in pregnancy, but also in nonpregnant women and men. The actions of serelaxin are primarily via nitric oxide, leading to the observed vasodilatory effects, and increase in renal plasma flow. It has also been found to increase expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and MMP-9. The antifibrotic and antiinflammatory effects of the drug also play a role in heart failure. In Phase II studies, serelaxin has shown reduction in pulmonary arterial pressure, pulmonary capillary wedge pressure, and NT-proBNP. The recently published results of the RELAX-AHF, a phase III clinical trial on serelaxin, has opened new avenues into our understanding of its effects in heart failure. The trial showed improvement in short-term dyspnea scores and 180-day mortality, but, interestingly, failed to show any improvement of the secondary endpoints of death or readmission at 60 days. Ongoing Phase III trials like RELAX-AHF-2 and RELAX-AHF-ASIA would explain these data better and improve understanding of the use of serelaxin in clinical practice. This article summarizes the most updated published preclinical and clinical study data on serelaxin, including pharmacokinetic, pharmacodynamic, safety studies in hepatic, renal impaired patients, Phase II and Phase III trials.

Concentración de relaxina en pacientes con insuficiencia cardiaca aguda: comportamiento y determinantes clínicos / Relaxin concentrations in acute heart failure patients: kinetics and clinical determinants

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Serelaxin and acute heart failure.

Attempts at developing novel therapeutic agents for acute heart failure (AHF) over the past two decades have been marked by disappointment. Relaxin is a human peptide hormone believed to mediate many adaptive haemodynamic changes that occur during pregnancy. Because these effects may be useful for treating AHF, a recombinant version of human relaxin-2, serelaxin, has been developed as a novel therapeutic agent. Studies have confirmed serelaxin's haemodynamic effects of decreasing pulmonary and systemic resistance and increasing renal blood flow. A 1161-patient, placebo-controlled Phase III trial, RELAX-AHF, demonstrated significant improvement in symptoms, reduced worsening of heart failure, decreased hospital length of stay and increased 180-day survival after index hospitalisation. Additional Phase III trials (RELAX-AHF-2; RELAX-AHF-ASIA) are underway to further evaluate the efficacy of serelaxin in patients with AHF. This article will review the physiological function, mechanism of action, clinical trial results and future directions of serelaxin in the treatment of AHF.

Pharmacokinetics of serelaxin in patients with severe renal impairment or end-stage renal disease requiring hemodialysis: A single-dose, open-label, parallel-group study.

Serelaxin, a recombinant human relaxin-2 hormone, is in clinical development for treating acute heart failure. This open-label, parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-hour intravenous infusion (10 µg/kg) in patients with severe renal impairment (n = 6) or end-stage renal disease (ESRD) requiring hemodialysis (PK on the day of dialysis [n = 6] or during dialysis-free interval [n = 6]), compared with matched healthy subjects (n = 18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with mean terminal elimination half-life of 6.5-8.8 hours. Compared with healthy subjects, a moderate decrease in serelaxin systemic clearance (37%-52%) and increase in its exposure (30%-115%) were observed in all patients. During the 4-hour hemodialysis in ESRD patients, 30% serelaxin was removed, with hemodialysis clearance constituting approximately 52% of total systemic clearance. Serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. Antiserelaxin antibodies were not detected in any participant. Given the shallow dose-response relationship observed with serelaxin in clinical studies and its wide therapeutic window, the observed PK differences in patients with severe renal impairment compared with healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients.

Targeted biological therapies reach the heart: the case of serelaxin for heart failure.

Acute heart failure (AHF) is one of the most important causes of mortality, morbidity and rising healthcare costs. Despite this, there has been minimal advancement in the management of AHF and the treatment continues to focus on symptomatic improvement using vasodilators, diuretics and inotropes, none of which have shown any mortality benefits. Though originally thought of as a reproductive hormone, relaxin is now recognized as a potent vasodilator that modulates systemic and renal vascular tone, resulting in pre- and after-load reduction and a decrease in cardiac workload. A single intravenous infusion of relaxin over 48 hours has been shown to provide significant dyspnea relief among AHF patients, with an ongoing study to evaluate its potential for mortality benefit. This article provides an insight into the pharmacology of this novel therapy for AHF with an eye towards future clinical applications.

Multicenter, Randomized, Double-Blinded, Placebo-Controlled Phase II Study of Serelaxin in Japanese Patients With Acute Heart Failure.

BACKGROUND: Serelaxin, a recombinant form of human relaxin-2, is in development for treating acute heart failure (AHF) and a Phase II study in Japanese AHF patients was conducted. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study of serelaxin at 10 and 30 µg·kg(-1)·day(-1)continuous intravenous infusion for up to 48 h, added to standard care for Japanese AHF patients. Primary endpoints were adverse events (AEs) through Day 5, serious AEs (SAEs) through Day 14, and serelaxin pharmacokinetics. Secondary endpoints included changes in systolic blood pressure (SBP) and cardiorenal biomarkers. A total of 46 patients received the study drug and were followed for 60 days. The observed AE profile was comparable between the groups, with no AEs of concern. Dose-dependent increase in the serum concentration of serelaxin was observed across the 2 dose rates of serelaxin. A greater reduction in SBP was observed with serelaxin 30 µg·kg(-1)·day(-1)vs. placebo (-7.7 [-16.4, 1.0] mmHg). A greater reduction in NT-proBNP was noted with serelaxin (-50.8% and -54.9% for 10 and 30 µg·kg(-1)·day(-1), respectively at Day 2). CONCLUSIONS: Serelaxin was well tolerated in this study with Japanese AHF patients, with no AEs of concern and favorable beneficial trends on efficacy. These findings support further evaluation of serelaxin 30 µg·kg(-1)·day(-1)in this patient population.

Safety and tolerability of serelaxin, a recombinant human relaxin-2 in development for the treatment of acute heart failure, in healthy Japanese volunteers and a comparison of pharmacokinetics and pharmacodynamics in healthy Japanese and Caucasian populations.

Serelaxin, a recombinant form of the human relaxin-2 hormone, is currently under clinical investigation for treatment of acute heart failure. This double-blind, placebo-controlled, dose-ranging study investigated the effect of Japanese ethnicity on the pharmacokinetics (PK), pharmacodynamics (PD), and safety and tolerability of serelaxin. Japanese healthy subjects (n = 32) received 10, 30, or 100 µg/kg/day of serelaxin, or placebo, administered as a 48-hour intravenous infusion. A Caucasian cohort (n = 8) receiving 30 µg/kg/day open-label serelaxin was included for comparison. In all subjects, serum serelaxin concentrations increased rapidly after the start of infusion, approached steady state as early as 4 hours, and declined rapidly upon treatment cessation. Serum exposure to serelaxin increased with increasing doses. Statistical dose proportionality was shown for AUC(inf) over the entire dose range. A significant increase in estimated glomerular filtration rate from baseline to Day 2 (30 and 100 µg/kg/day) and to Day 3 (10 and 100 µg/kg/day) was observed compared with placebo. Serelaxin was well tolerated by all subjects. In conclusion, PK, PD, and safety profiles of serelaxin were generally comparable between Japanese and Caucasian subjects, suggesting that no dose adjustment will be required in Japanese subjects during routine clinical use of this agent.

Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study.

AIMS: Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. METHODS: This was an open-label, parallel group study (NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 µg kg(-1) day(-1) ) between patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve AUC(0-48 h) and AUC(0-∞) and serum concentration at 24 h post-dose (C24h )] were compared between each hepatic impairment group and healthy controls. RESULTS: A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 h and then declined following completion of infusion, with a mean terminal half-life of 7-8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. CONCLUSIONS: The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment.

Negative cooperativity in H2 relaxin binding to a dimeric relaxin family peptide receptor 1.

H2 relaxin, a member of the insulin superfamily, binds to the G-protein-coupled receptor RXFP1 (relaxin family peptide 1), a receptor that belongs to the leucine-rich repeat (LRR)-containing subgroup (LGRs) of class A GPCRs. We recently demonstrated negative cooperativity in INSL3 binding to RXFP2 and showed that this subgroup of GPCRs functions as constitutive dimers. In this work, we investigated whether the binding of H2 relaxin to RXFP1 also shows negative cooperativity, and whether this receptor functions as a dimer using BRET(2). Both binding and dissociation were temperature dependent, and the pH optimum for binding was pH 7.0. Our results showed that RXFP1 is a constitutive dimer with negative cooperativity in ligand binding, that dimerization occurs through the 7TM domain, and that the ectodomain has a stabilizing effect on this interaction. Dimerization and negative cooperativity appear to be general properties of LGRs involved in reproduction as well as other GPCRs.

Stable serum levels of relaxin throughout the menstrual cycle: a preliminary comparison of women with premenstrual dysphoria and controls.

Serum levels of relaxin in 25 women with premenstrual dysphoria and 25 age-matched controls were determined at three time points during the menstrual cycle. At the same time, levels of estradiol, progesterone, 17-beta-OH-progesterone, free testosterone, total testosterone, sex hormone binding hormone, androstenedione, dehydroepiandrosterone sulphate, and 3-alpha-androstanediol glucuronide were determined. Detectable levels of relaxin were found in all women in both the follicular and luteal phase as well as around ovulation, the inter-individual variations being larger than intra-individual differences. The levels of relaxin were not influenced by the fluctuation of the other reproductive hormones. A significant difference between the two groups of women was observed, subjects with premenstrual dysphoria displaying reduced levels of relaxin (p < 0.05) compared to controls. Also, when analysed with respect to a variable number of tandem repeats polymorphism (CT repeats followed by GT repeats) in the promotor region of the relaxin H2 gene, women with premenstrual dysphoria (n = 29) were found to display significantly longer GT repeats than controls (n = 35).

Comparative localization of leucine-rich repeat-containing G-protein-coupled receptor-7 (RXFP1) mRNA and [33P]-relaxin binding sites in rat brain: restricted somatic co-expression a clue to relaxin action?

Relaxin is a polypeptide hormone with established actions associated with reproductive physiology, but until recently the precise nature of the relaxin receptor and its transmembrane signaling mechanisms had remained elusive. In 2002 however, the leucine-rich-repeat-containing G-protein-coupled receptor-7 (now classified as RXFP1) was identified as a cognate receptor for relaxin, with activation resulting in stimulation of intracellular cAMP production. These findings, along with the presence and putative actions of relaxin within the CNS and earlier descriptions of relaxin binding sites in brain, suggest the importance and feasibility of determining if these relaxin binding sites represent leucine-rich-repeat-containing G-protein-coupled receptor-7 and their precise comparative distribution. Thus, the current study reports the distribution of leucine-rich-repeat-containing G-protein-coupled receptor-7 mRNA throughout the rat brain using in situ hybridization histochemistry of [(35)S]-labeled oligonucleotides and the comparative distribution of [(33)P]-human relaxin binding sites. The extensive, topographical distribution of leucine-rich-repeat-containing G-protein-coupled receptor-7 mRNA throughout the adult rat brain correlated very closely to that of [(33)P]-relaxin binding sites. Leucine-rich-repeat-containing G-protein-coupled receptor-7 mRNA was expressed by neurons in several brain regions, including the olfactory bulb, cerebral cortex, thalamus, hippocampus, hypothalamus, midbrain, pons and medulla. Receptor transcripts were most abundant in areas such as the basolateral amygdala, subiculum, deep layers of the cingulate, somatosensory and motor cortices and intralaminar/midline thalamic nuclei. These areas also contained very high densities of [(33)P]-relaxin binding sites, suggesting a largely somatic localization of leucine-rich-repeat-containing G-protein-coupled receptor-7 protein and site of action for relaxin peptide. The central distribution of relaxin-producing neurons has been described, while data on the topography of nerve terminals that contain and secrete the peptide are currently lacking; but overall these findings strongly suggest that leucine-rich-repeat-containing G-protein-coupled receptor-7 is the cognate receptor for relaxin in the rat brain, and support a role for relaxin-leucine-rich-repeat-containing G-protein-coupled receptor-7 signaling in various somatosensory, autonomic and neurohumoral pathways, which warrants further investigation.

Relaxin receptor activation in the basolateral amygdala impairs memory consolidation.

The peptide-hormone relaxin has well-established actions in male and female reproductive tracts, and has functional effects in circumventricular regions of brain involved in neurohormonal secretion. In the current study, we initially mapped the distribution of mRNA encoding the relaxin receptor--leucine-rich repeat-containing G-protein-coupled receptor 7 (LGR7)- and [33P]-human relaxin-binding sites in extra-hypothalamic sites of male Sprague-Dawley rats. The basolateral amygdala (BLA) expressed high levels of LGR7 mRNA and relaxin-binding sites and, although relaxin peptide was not detected in the BLA, several brain regions that send projections to the BLA were found to contain relaxin-expressing neurons. As it is well established that the BLA is involved in regulating the consolidation of memory for emotionally arousing experiences, we investigated whether activation of LGR7 in the BLA modulated memory consolidation for aversively motivated inhibitory avoidance training. Bilateral infusions of human relaxin (10-200 ng in 0.2 microL) into the BLA immediately after inhibitory avoidance training impaired 48-h retention performance in a dose-dependent manner. Delayed infusions of relaxin into the BLA 3 h after training were ineffective, indicating that the retention impairment was due to influences on memory consolidation. Post-training infusions of relaxin into the adjacent central amygdala, which is devoid of LGR7, did not impair retention. These findings suggest a novel function for endogenous relaxin-LGR7 signalling in rat brain involving regulation of memory consolidation.

Potential binding sites for relaxin in pregnant rabbits.

The purpose of this study was to identify tissues in the day 25 pregnant rabbit that bind relaxin. First, the clearance half-life of relaxin from the rabbit (n = 6) was determined by injecting 10 g porcine relaxin via the marginal ear vein. One-milliliter blood samples were collected via a cannula in the central ear artery. Samples were collected at 10- and 5-min pre-relaxin and at 1-min intervals post-relaxin injection, and the relaxin concentrations determined by radioimmunoassay. The clearance half-life was 4 min. Next, pregnant rabbits were infused with [125I]-relaxin. Control rabbits (n = 3) received 10 g radio-inert relaxin via the marginal ear vein in order to saturate endogenous receptors. Ten minutes later, 10 ng [125I]-relaxin was similarly injected. Treated rabbits (n = 3) received only [125I]-relaxin. After allowing sufficient time for clearance (24 min), a 1-mL blood sample was removed via the central ear vein. Rabbits were euthanized, tissues of maternal and fetal origin excised, and cpm/mg of tissue divided by cpm/mL of blood was determined. Differences in uptake of [125I]-relaxin between control and treated animals, using the Student paired t test, were found for the uterus (P < .05), uterine cervix (P < .03), and mammary gland (P < .05). These data suggest potential rabbit tissues with the LGR-7 receptor.

Recombinant relaxin: a review of pharmacology and potential therapeutic use.

Use of recombinant relaxin in the treatment of systemic sclerosis (or scleroderma) has been explored and determined as ineffective. However, continued research has revealed that relaxin is not limited to its role as a hormone. Relaxin has also been shown to decrease collagen formation and secretion, increase collagenase production, influence renal vasodilation, increase vascular endothelial growth factor expression and angiogenesis, promote dilation of blood vessels, and inhibit release of histamine. Further studies to discover other potential uses of relaxin are well-justified.

Safety and pharmacokinetics of recombinant human relaxin in systemic sclerosis.

OBJECTIVE: To investigate the safety and pharmacokinetics of a 28 day continuous subcutaneous infusion of recombinant human relaxin in patients with systemic sclerosis with diffuse scleroderma. METHODS: Thirty patients with stable diffuse scleroderma of moderate severity received recombinant human relaxin at 6, 12, 50, 100, and 200 microg/kg/day or placebo in a double blind, sequential panel, dose escalation study. RESULTS: All patients completed 28 days of study treatment. Steady state concentrations of serum relaxin were achieved by the 3rd day of infusion and were dose proportionate. Patients receiving 200 microg/kg/day achieved levels about 50-fold those of normal pregnancy. Pharmacokinetics of relaxin were nonlinear with hyperbolic increases of both t1/2 and volume of distribution and parallel decrease of elimination rate coefficient. An elimination transport system was suggested with saturation at serum relaxin concentration of 45 ng/ml. Adverse events included local infusion site rash and pain, minor bleeding episodes, and decreased hemoglobin concentration (mean reduction 1.1 g/dl). Standard measures of scleroderma were unchanged, although global assessment favored relaxin over placebo. CONCLUSION: Recombinant human relaxin in the doses used was safe and well tolerated. Longer term controlled trials are warranted to define the potential efficacy of relaxin in patients with diffuse scleroderma.