Evidence of feedback regulation of C-type natriuretic peptide during Vosoritide therapy in Achondroplasia

AbstractEvidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown. In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and then related to skeletal growth. Before treatment NTproCNP SDS was raised. Within the first 3 months of accelerating growth, levels were significantly reduced. Across the 5 years of sustained growth, levels varied widely and were markedly increased in some subjects during adolescence. Plasma NTproCNP was suppressed at 4 h post-injection in proportion to the prevailing level of hormone resistance as reflected by SDS before injection. We conclude CNP remains subject to regulation during growth promoting doses of Vosoritide. Fall in CNP during accelerating growth is consistent with an indirect feedback whereas the fall at 4 h is likely to be a direct effect from removal of intra cellular CNP resistance.

Download Full-text

Human placental lactogen inhibits growth without changing serum levels of IGF-1 in rats: an apparent specific action of the hormone

Acta Endocrinologica ◽

10.1530/acta.0.1270146 ◽

1992 ◽

Vol 127 (2) ◽

pp. 146-151 ◽

Cited By ~ 4

Author(s):

Mimi H Chiang ◽

Charles S Nicoll

Keyword(s):

Epiphyseal Plate ◽

Skeletal Growth ◽

Female Rats ◽

Placental Lactogen ◽

Total Serum ◽

Inhibitory Effects ◽

Growth Inhibitory ◽

Growth Promoting ◽

Tibial Epiphyseal ◽

Plate Width

Previous work in our laboratory has shown that the internal environment of rats has reduced growth-promoting activity during the second half of gestation and this condition is associated with resistance to the anabolic effects of GH. The placenta appears to be responsible for this condition but injections of estradiol plus progesterone into virgin females did not mimic it. Accordingly, it seemed worthwhile to test the effects of a placental lactogen (PL) for possible growth inhibitory effects. In the present study the effects of human (h)PL on skeletal growth in young female rats and on the growth of embryonic tissue transplants under their kidney capsules were investigated. Human (h) and bovine (b) GH, and ovine prolactin (oPRL) were also tested to determine whether the results obtained with hPL were specific. Twice daily subcutaneous injections of a high dose of hPL (10mg/day), but not of oPRL (5 mg/day) for 7 days inhibited both host tail growth and tibial epiphyseal plate width, and growth of whole 10-day embryo transplants. Injections of hGH at 1 mg/day for 8 days significantly increased host skeletal growth and growth of 12-day embryonic head transplants; at the same dose, neither bGH nor oPRL affected growth of the embryonic heads or of the host tibial epiphyseal plate width, but the bGH increased host tail growth. By contrast, the 1 mg/day dose of hPL significantly reduced the host's tibial epiphyseal plate width, tail growth, and transplant growth; lower doses of hPL (10 and 100 μg/day) were also inhibitory. Although all the hormone treatments increased total serum IGF-1 levels in the females, none of them had a significant effect when compared to saline injected control animals. Thus, the growth-inhibitory effects of hPL treatment appear to be specific to that hormone and they are not mediated by depression of serum IGF-1 levels. If these effects of hPL are mimicked by one or more of the rodent PLs, then the reduced growth-promoting activity and resistance to GH action that occurs in pregnant rats could be due to the rat PLs. These results indicate that in addition to having glucose-sparing effects in the mother, PLs could promote fetal growth by inhibiting growth of maternal tissues, which would thus spare other metabolites, such as amino acids and vitamins, for the conceptus.

Download Full-text

Rivaroxaban for Thromboprophylaxis in Patients Undergoing Total Hip Replacement: Comparison of Pharmacokinetics and Pharmacodynamics with Once- and Twice-Daily Dosing.

Blood ◽

10.1182/blood.v108.11.903.903 ◽

2006 ◽

Vol 108 (11) ◽

pp. 903-903 ◽

Cited By ~ 3

Author(s):

Wolfgang Mueck ◽

Bengt I. Eriksson ◽

Lars C. Borris ◽

Ola E. Dahl ◽

Sylvia Haas ◽

...

Keyword(s):

Confidence Intervals ◽

Total Hip Replacement ◽

Hip Replacement ◽

Plasma Concentrations ◽

Dose Finding ◽

Total Daily Dose ◽

Time Curve ◽

Mixed Effect ◽

Total Hip ◽

Daily Dose

Abstract Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Two phase IIb, dose-finding studies with rivaroxaban for the prevention of venous thromboembolism (VTE) after total hip replacement (THR) were conducted: one with twice-daily (bid), and one with once-daily (od) rivaroxaban dosing. In the bid study, rivaroxaban total daily doses of 5–20 mg had similar efficacy and safety to enoxaparin (40 mg od), and the od study identified a dose within this range (10 mg od) as the appropriate dose for further investigation. This analysis compared the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban when given od or bid, using non-linear, mixed-effect population modeling. The analysis was restricted to the rivaroxaban 5, 10, and 20 mg total daily dose groups from each study, and used samples from 758 patients. In both studies, rivaroxaban PK were well described by an oral, one-compartment model, and were affected by anticipated factors: age and renal function influenced clearance, and body weight influenced volume of distribution. These effects were moderate, within the variability of the patient population, and suggested that no dose adjustment would be necessary, in this population. In both studies, the maximum and minimum plasma concentrations (Cmax and Ctrough, respectively) of rivaroxaban increased dose dependently (Table). Cmax values were higher, and Ctrough values were lower, in the od study than in the bid study; however, the 90% confidence intervals for Cmax and Ctrough in the two studies overlapped. These findings are as expected, and suggest that od dosing with rivaroxaban should not expose patients to a greater risk of bleeding (at Cmax) or VTE (at Ctrough) than bid dosing. Estimates for area under the rivaroxaban plasma-concentration time curve (AUC) were 20–28% higher in the od study than the bid study. In the PD analysis, prolongation of prothrombin time correlated with rivaroxaban plasma concentrations in a linear fashion in both studies. In conclusion, this analysis of rivaroxaban in patients undergoing THR suggested that the PK and PD of rivaroxaban are predictable after od or bid dosing, allowing selection of a convenient od dosing regimen. Median predicted rivaroxaban PK parameters in THR patients at steady state (with 90% confidence intervals) Rivaroxaban total daily dose Parameter 5 mg 10 mg 20 mg n (bid/od) 122/124 122/140 118/132 bid Cmax (μg/L) 39.7 (29.2–73.4) 65.2 (46.2–105) 141 (101–218) od Cmax (μg/L) 69.0 (49–112) 124 (88.1–194) 222 (160–360) bid Ctrough (μg/L) 8.61 (1.71–26.5) 15.4 (4.65–46.2) 34.9 (7.85–99.7) od Ctrough (μg/L) 4.50 (0.7–37.7) 9.12 (1.34–37.8) 22.4 (4.3–95.7) bid AUC (μg·h/L) 531 (304–1188) 915 (583–1637) 1982 (1139–3757) od AUC (μg·h/L) 670 (377–1283) 1170 (767–2077) 2374 (1366–4858)

Download Full-text

Age and Sex Impact Clozapine Plasma Concentrations in Inpatients and Outpatients With Schizophrenia

American Journal of Geriatric Psychiatry ◽

10.1097/jgp.0b013e3182118318 ◽

2012 ◽

Vol 20 (1) ◽

pp. 53-60 ◽

Cited By ~ 23

Author(s):

Zahinoor Ismail ◽

Alette M. Wessels ◽

Hiroyuki Uchida ◽

Wenzie Ng ◽

David C. Mamo ◽

...

Keyword(s):

Plasma Concentrations ◽

Age And Sex

Download Full-text

Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth

Hormone Research in Paediatrics ◽

10.1159/000496544 ◽

2018 ◽

Vol 90 (6) ◽

pp. 345-357 ◽

Cited By ~ 6

Author(s):

Eric Espiner ◽

Tim Prickett ◽

Robert Olney

Keyword(s):

Clinical Practice ◽

Natriuretic Peptide ◽

Bone Growth ◽

Plasma Concentrations ◽

Skeletal Growth ◽

Height Velocity ◽

Long Bone ◽

Blood Levels ◽

Growth Disorders ◽

Reference Ranges

Although studies in experimental animals show that blood levels of C-type natriuretic peptide (CNP) and its bioinactive aminoterminal propeptide (NTproCNP) are potential biomarkers of long bone growth, a lack of suitable assays and appropriate reference ranges has limited the application of CNP measurements in clinical practice. Plasma concentrations of the processed product of proCNP, NTproCNP – and to a lesser extent CNP itself – correlate with concurrent height velocity throughout all phases of normal skeletal growth, as well as during interventions known to affect skeletal growth in children. Since a change in levels precedes a measurable change in height velocity during interventions, measuring NTproCNP may have predictive value in clinical practice. Findings from a variety of genetic disorders affecting CNP signaling suggest that plasma concentrations of both peptides may be helpful in diagnosis, provided factors such as concurrent height velocity, feedback regulation of CNP, and differential changes in peptide clearance are considered when interpreting values. An improved understanding of factors affecting plasma levels, and the availability of commercial kits enabling accurate measurement using small volumes of plasma, can be expected to facilitate potential applications in growth disorders including genetic causes affecting the CNP signaling pathway.

Download Full-text

Rivaroxaban Has Predictable Pharmacokinetics (PK) and Pharmacodynamics (PD) When Given Once or Twice Daily for the Treatment of Acute, Proximal Deep Vein Thrombosis (DVT).

Blood ◽

10.1182/blood.v110.11.1880.1880 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1880-1880 ◽

Cited By ~ 3

Author(s):

Wolfgang Mueck ◽

Giancarlo Agnelli ◽

Harry Buller

Keyword(s):

Confidence Intervals ◽

Plasma Concentrations ◽

Demographic Factors ◽

Dose Finding ◽

Phase Iii ◽

Total Daily Dose ◽

Efficacy And Safety ◽

Time Curve ◽

Mixed Effect ◽

Mean Values

Abstract Introduction: Rivaroxaban is an oral, direct Factor Xa inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. Two large, phase IIb, dose-finding studies investigating rivaroxaban for the treatment of acute, proximal DVT, showed that rivaroxaban once daily (od) and twice daily (bid) had similar efficacy and safety profiles to standard therapy. In order to characterize the population PK/PD of rivaroxaban for DVT treatment, a population model was developed based on data from healthy subjects. Methods: Sparse PK/PD samples from 870 patients across the two studies were analyzed using non-linear, mixed-effect population modeling (NONMEM), version V level 1.1. The program analyzed population data to give estimates of mean values and variability in the population. Prothrombin time (PT) was determined at a central laboratory and was used in the PD investigation. For the PK profile, data was pooled from both clinical trials and specific exposure parameters for rivaroxaban, such as area under the plasma concentration-time curve (AUC), maximum and minimum plasma concentrations (Cmax and Ctrough, respectively) were predicted for each patient according to the dosing regimen received. Results: The PK of rivaroxaban were well described by an oral, one-compartment model, with demographic factors influencing clearance (age, renal function) and volume of distribution (age, body weight, gender); variations due to these factors were moderate, suggesting fixed dosing may be possible. Co-medications (e.g. diuretics, NSAIDs, aspirin) had no relevant effects on the PK of rivaroxaban. Rivaroxaban Cmax and Ctrough concentrations increased dose dependently (Table). As expected, Cmax was higher and Ctrough was lower after od dosing compared with bid dosing, at equivalent total daily doses; however, 90% confidence intervals overlapped, suggesting that od dosing with rivaroxaban should not expose patients to a greater risk of bleeding (at Cmax) or VTE (at Ctrough) than bid dosing. Clinically relevant rivaroxaban plasma concentrations correlated linearly with PT, confirming that it would be suitable for measuring rivaroxaban exposure, if necessary. Conclusions: The PK and PD of rivaroxaban were predictable with od and bid dosing, and affected by expected demographic factors in patients receiving it for DVT treatment. Combined with efficacy and safety results, this analysis aided the selection of an initial, intensified bid regimen followed by convenient, long-term rivaroxaban 20 mg od, for investigation in phase III studies in this indication. Predicted rivaroxaban PK parameters Parameter Rivaroxaban total daily dose *Values are shown as means (90% confidence intervals) 20 mg 30 mg 40 mg 60 mg n (od/bid) 134/117 134/- 252/114 -/119 od Cmax (μg/L)* 270.6 (189.1–418.7) 324.6 (234.2–491.3) 406.5 (268.4–599.9) - bid Cmax (μg/L)* 211.5 (130.3–360.7) - 320.9 (209.9–517.9) 400.6 (244.2–749.5) od Ctrough (μg/L)* 25.5 (5.9–86.9) 33.8 (8.4–132.9) 42.3 (9.7–161.8) - bid Ctrough (μg/L)* 65.1 (17.2–193.6) - 104.2 (31.3–277.8) 143.1 (46.6–347.9)

Download Full-text

Molecular mechanism for feedback regulation of C4 biosynthesis in guinea pig peritoneal macrophage.

Journal of Experimental Medicine ◽

10.1084/jem.159.6.1750 ◽

1984 ◽

Vol 159 (6) ◽

pp. 1750-1761 ◽

Cited By ~ 15

Author(s):

H S Auerbach ◽

R D Baker ◽

W J Matthews ◽

H R Colten

Keyword(s):

Guinea Pig ◽

Messenger Rna ◽

Molecular Mechanisms ◽

Plasma Concentrations ◽

Major Histocompatibility Complex Gene ◽

Feedback Regulation ◽

Fluid Phase ◽

Biologically Active ◽

Class Iii ◽

Factor B

Previous reports have shown that regulation of local extrahepatic production of complement may not reflect the regulation of plasma concentrations of the corresponding proteins and, further, that alteration of the tissue microenvironment can affect local macrophage protein synthesis. This report describes the molecular basis for control of the biosynthesis and secretion of a class III major histocompatibility complex gene product, the fourth component of complement (C4), from guinea pig macrophages by extracellular native C4 protein. The effect is specific for C4 synthesis, since production of C2 and total secreted protein was unaffected by fluid phase C4. C4 synthesis by extracellular C4 is regulated at a pretranslational level, without an effect on posttranslational proteolytic cleavage, glycosylation, or secretion. Specific C4 and factor B cDNA probes were used to demonstrate, by dot hybridization and Northern blot analysis, a decrease in messenger RNA coding for C4 that paralleled the inhibition of C4 biosynthesis, while the amount of total RNA and mRNA specific for factor B remained constant. Inhibition of C4 biosynthesis and the disappearance of mRNA encoding C4 occurred between 4 and 6 h after exposure of the macrophages to biologically active or methylamine-inactivated C4 protein. These data demonstrate that regulation of C4 biosynthesis by guinea pig macrophages serves as a model for the study of the molecular mechanisms of macrophage activation as well as the control of production of a component of the inflammatory response.

Download Full-text

Growth-promoting properties of the internal milieu of pregnant and lactating rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.1.e98 ◽

1990 ◽

Vol 258 (1) ◽

pp. E98-E102

Author(s):

M. Chiang ◽

S. M. Russell ◽

C. S. Nicoll

Keyword(s):

Serum Insulin ◽

Tail Length ◽

Skeletal Growth ◽

Internal Environment ◽

Kidney Capsule ◽

Rat Embryos ◽

Factor I ◽

Internal Milieu ◽

Igf I ◽

Growth Promoting

The growth-promoting properties of the internal milieu of pregnant and lactating rats were investigated using transplanted whole rat embryos or fetal paws. When placed under the kidney capsule of intact nonpregnant hosts and incubated for 12 days, such transplants grow rapidly, and tissues differentiate normally. Thus they provide an accurate means of assessing the growth-promoting properties of the internal environment of host animals in different physiological states. Transplant growth during days 0-11 of pregnancy was similar to that observed in age-matched virgin control hosts during an equivalent 12-day period. However, growth of transplants was decreased by 40% in hosts during days 10-22 of pregnancy and by approximately 30% in hosts during days 1-13 or days 11-23 of lactation. Increase in tail length, which was used as an index of maternal skeletal growth, was reduced by 50% during the second half of pregnancy and the early and late periods of lactation compared with age-matched virgin females. No such inhibition was recorded during the first half of pregnancy. Compared with virgins, serum insulin-like growth factor I (IGF-I) levels were reduced by approximately 20% on days 6 and 10 of pregnancy, and by 63-66% during the second half of gestation. Serum IGF-I levels rose during lactation to reach prepregnancy levels by day 12, but a second decline occurred by day 18 postpartum.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

The Effect of Overweight and Obesity on Liver Biochemical Markers in Children and Adolescents

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz010 ◽

2019 ◽

Vol 105 (2) ◽

pp. 430-442 ◽

Cited By ~ 5

Author(s):

Magnus J Johansen ◽

Julie Gade ◽

Stefan Stender ◽

Christine Frithioff-Bøjsøe ◽

Morten A V Lund ◽

...

Keyword(s):

Children And Adolescents ◽

Biochemical Markers ◽

Liver Enzymes ◽

Plasma Concentrations ◽

Age Groups ◽

Fat Content ◽

Overweight And Obesity ◽

Resonance Spectroscopy ◽

Age And Sex ◽

Overweight Or Obesity

Abstract Background Elevated plasma concentrations of liver enzymes are routinely used as markers of liver injury in adults and children. Currently, the age- and sex-specific effects of adiposity on pediatric liver enzyme concentrations are unclear. Methods We included participants from 2 cohorts of Danish children and adolescents: 1858 from a population-based cohort and 2155 with overweight or obesity, aged from 6 to 18 years. Age- and sex-specific percentile curves were calculated for fasting plasma concentrations of alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), bilirubin, and alkaline phosphatase (ALP) in both cohorts. Hepatic fat content was assessed by proton magnetic resonance spectroscopy in 458 participants. Results Concentrations of ALT, AST, LDH, and ALP decreased with age in both girls and boys, while GGT and bilirubin were comparable across age groups in girls and increased slightly with age in boys. Children and adolescents with overweight or obesity exhibited higher concentrations of ALT in all age groups. Concentrations of ALT, and to a lesser degree GGT, increased with age in boys with overweight or obesity. Optimal ALT cut-points for diagnosing hepatic steatosis (liver fat content > 5%) was 24.5 U/L for girls (sensitivity: 55.6%, specificity: 84.0%), and 34.5 U/L for boys (sensitivity: 83.7%, specificity: 68.2%). Conclusions Pediatric normal values of liver enzymes vary with both age and sex. Overweight and obesity is associated with elevated biochemical markers of liver damage. These findings emphasize the need for prevention and treatment of overweight and obesity in children and adolescents. (J Clin Endocrinol Metab XX: 0-0, 2019)

Download Full-text

A double-blind, placebo-controlled, randomised, multicentre, proof-of-concept and dose-finding phase II clinical trial to investigate the safety, tolerability and efficacy of adrecizumab in patients with septic shock and elevated adrenomedullin concentration (AdrenOSS-2)

BMJ Open ◽

10.1136/bmjopen-2018-024475 ◽

2019 ◽

Vol 9 (2) ◽

pp. e024475 ◽

Cited By ~ 9

Author(s):

Christopher Geven ◽

Alice Blet ◽

Matthijs Kox ◽

Oliver Hartmann ◽

Paul Scigalla ◽

...

Keyword(s):

Clinical Trial ◽

Septic Shock ◽

Phase Ii ◽

Plasma Concentrations ◽

Biologically Active ◽

Dose Finding ◽

Proof Of Concept ◽

Double Blind ◽

Major Health Problem ◽

Double Blind Placebo

IntroductionSepsis remains a major health problem with an increasing incidence, high morbidity and high mortality. Apart from treatment with antibiotics and organ support, no approved specific adjunct therapies currently exist. Adrenomedullin (ADM) is a vasoactive peptide. High plasma concentrations of ADM correlate with worse outcome in sepsis patients. Preclinical work with the non-neutralising ADM-binding antibody adrecizumab showed promising effects in animal models of septic shock, including improved vascular barrier function, reduced vasopressor demand and organ dysfunction and increased survival. Therapeutic use of adrecizumab may therefore improve outcome in critically ill patients with septic shock and high ADM plasma concentrations. Phase I studies in healthy volunteers did not reveal any safety concerns. In this biomarker-guided trial, the safety and efficacy of adrecizumab will be investigated in patients with septic shock.Methods and analysisWe describe a phase II, randomised, double-blind, placebo-controlled, biomarker-guided, proof-of-concept and dose-finding clinical trial in patients with early septic shock and high concentration of circulating ADM. A total of 300 patients will be enrolled at approximately 30 sites within the European Union. Patients are randomised to receive active treatment (2 and 4 mg/kg adrecizumab) or placebo, in a 1:1:2 ratio. Patient selection is guided by clinical parameters, and biomarker-guided by measurement of circulating biologically active ADM concentration at admission. Primary endpoint is safety and tolerability of adrecizumab over a 90-day period. A key secondary endpoint is the Sepsis Severity Index over a 14-day period.Ethics and disseminationThis study is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, the European Medicines Agency guidelines of Good Clinical Practice and all other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal.Trial registration numberNCT03085758; Pre-results.

Download Full-text