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Biomedical subjects

K Raun

Publications and source records attributed to K Raun.

17 recordsLinked to original sources
PubMed2005

Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight.

OBJECTIVE: This study was conducted to elucidate whether antagonistic targeting of the histamine H3 receptor increases hypothalamic histamine levels, in parallel with decreases in food intake and body weight. METHODS: The competitive antagonist potency of a recently synthesized histamine H3 receptor antagonist, NNC 38-1049, was studied in intact HEK293 cells expressing human or rat histamine H3 receptor, in which NNC 38-1049 was allowed to antagonize the effect of the H3 receptor agonist R-alpha-methylhistamine on isoprenaline-induced accumulation of cAMP. The affinity of NNC 38-1049 for a number of variants of the histamine receptor was also determined. Following single dosing of normal rats with NNC 38-1049, hypothalamic histamine levels were assessed by means of microdialysis. Plasma and brain levels of NNC 38-1049 and acute effects on food intake and energy expenditure were followed after oral doses of 3-60 mg/kg. Potential side effects were examined with rat models of behaviour satiety sequence (BSS), pica behaviour and conditioned taste aversion (CTA). Intakes of food and water together with body weight were recorded for 15 days during daily dosing of dietary obese rats. RESULTS: NNC 38-1049 was found to be a highly specific and competitive antagonist towards both human and rat histamine H3 receptors, and measurable amounts of NNC 38-1049 were found in the plasma of rats following single oral doses of 3-60 mg/kg and in the brain after 15-60 mg/kg. Following single intraperitoneal injections of NNC 38-1049 (20 mg/kg), significant increases in extracellular histamine concentrations were observed. The same dose did not change BSS or pica behaviour acutely, nor did it induce CTA following repeated administration for 7 days. Reductions in food intake were seen very soon after administration, and occurred in a dose-dependent fashion. Energy expenditure was unchanged, but the respiratory quotient (RQ) tended to decrease at higher doses, indicating an increase in lipid oxidation. Twice daily administration of 20 mg/kg of NNC 38-1049 in old and dietary obese rats resulted in sustained reduction of food intake throughout a 2-week study, and was associated with a highly significant (P<0.01) decrease in body weight compared with controls (-18.4+/-3.4 vs +0.4+/-2.7 g). The same dose of NNC 38-1049 produced an acute decrease of water intake, but 24 h intakes were not significantly changed. CONCLUSIONS: The results of this study strongly support the idea that an increase in the hypothalamic concentration of histamine produces a specific reduction of food intake and that this effect can be translated into a decrease in body weight.

Administration, Oral↗
PubMed2004

Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.

Animals↗
PubMed2003

Absorption and systemic availability of two synthetic growth hormone secretogogues and transport of glucose by the proximal small intestine of anestrus dogs after administering estradiol.

Pharmacokinetics for one growth hormone secretogogue (NNC 26-0722), but not for another (NN703), differ between dogs in estrus or anestrus. We examined if the differences could be mimicked by administering estradiol during anestrus and if there was a relationship with rates of small intestine absorption. Pharmacokinetics for oral doses of NN703 (1.0-1.6 mg kg(-1)) did not differ among dogs in estrus, anestrus, or anestrus and given estradiol for 1 week (days 1, 3, and 6; 40 micro g kg(-1)), whereas plasma concentrations of NNC 26-0722 increased from undetectable in untreated, anestrus dogs to several hundred nanograms per milliliter in dogs given estradiol, with maximal concentrations measured 5 min after oral dosage. Estradiol treatment increased small intestinal absorption of NNC 26-0722 by 100% (P<0.05), but did not increase absorption of NN703, and caused a 64% increase in carrier-mediated glucose transport at 50 mmol l(-1) (P<0.05) due to increased densities of transporters. These findings indicate estrus and estradiol enhance absorptive functions of the dog proximal small intestine and can affect pharmacokinetics for some orally administered drugs.

Administration, Oral↗
PubMed2003

Homologous growth hormone accelerates bone healing--a biomechanical and histological study.

The purpose of this study was to prove whether homologous growth hormone has a beneficial effect in the early phase of bone healing. Therefore the left tibias of 24 Yucatan micropigs were osteotomized and stabilized by plate fixation. The treatment group (12 animals) received 100 microg of recombinant porcine growth hormone (rpGH)/kg body w/day sc, whereas the control pigs (12 animals) received 1 ml sodium chloride as placebo. After a healing period of 4 weeks the animals were sacrificed and destructive torsional testing was performed. For histological evaluation 6 microm serial slices of the tibiae were stained with von Kossa. The total area of callus formation (CA) and the mineralized bone area (BA) were quantified by image analysis. The fraction of mineralized bone tissue within the callus area, the bone density (BD), was calculated as follows: BD = (BA/CA) x 100. Torsional failure load was 91% higher and torsional stiffness 61% higher in the treatment group than in the control group (P < 0.05). The histomorphometric measurements revealed an advance for the CA (GH: 127.6 +/- 38.9 mm(2); placebo: 75.9 +/- 50.7 mm(2); P < 0.005) as well as for the BA (GH: 89.3 +/- 25.8 mm(2); placebo: 55.9 +/- 38.5 mm(2); P < 0.001) for the GH-treated animals in comparison to the control animals. The BD was similar in both groups (GH: 70.6 +/- 8.4%; placebo: 74.0 +/- 6.24%; P = 0.28). These data indicate that administration of homologous GH stimulates callus formation and ossification in the early phase of bone healing, which consequently results in an increased mechanical strength and stiffness.

Animals↗
PubMed2002

Recombinant species-specific growth hormone increases hard callus formation in distraction osteogenesis.

The effect of growth hormone (GH) on secondary fracture healing and callus formation has been demonstrated in several previously investigated animal models. The aim of this study was to investigate and quantify the effects of GH on bone regenerates in a distraction osteogenesis model. In 20 mature female Yucatan micropigs, the tibia and fibula were osteotomized, stabilized with an external fixator, and distracted at 2 mm/day for 10 days after a 4 day latency period. The regenerates were allowed to consolidate for 10 days. Micropigs in the study group (ten animals) received a daily injection of 100 microg per kilogram body weight of recombinant porcine growth hormone (r-pGH). Micropigs in the control group (ten animals) received sodium chloride as placebo. After killing on day 25, a quantitative histomorphometrical analysis of the formed callus and the adjacent cortical bone was performed and the results of polychrome in vivo labeling were assessed. The regenerates of the r-pGH-treated animals showed a significantly larger callus area but no change in callus structure. We found islands of cartilage tissue in the regenerates of both groups; the calli from the control group exhibited a higher fraction of cartilage compared with the r-pGH group, but this was not significant. Quantification of the fluorescent in vivo labeling revealed that the distraction gap in GH-treated group showed significant ossification even during distraction. These results demonstrate that growth hormone can accelerate the maturation of the regenerate in distraction osteogenesis without changing the callus microstructure. This may prove to be a useful clinical tool for shortening the healing time in limb lengthening and bone segment transport.

Animals↗
PubMed2001

Highly potent growth hormone secretagogues: hybrids of NN703 and ipamorelin.

A series of NN703 analogues with lysine mimetics combined with naphthyl- or biphenylalanine in the core has been prepared and tested in vitro in a rat pituitary cell based assay and subsequently in vivo in pigs in a single dose at 50 nmol/kg. Re-introduction of certain pharmacophores in the C-terminal of NN703, which were originally removed during optimisation for oral bioavailability, led to unexpectedly potent compounds in vitro as well as in vivo.

Administration, Oral↗
PubMed2001

The effect of growth hormone on insulin-like growth factor I and bone metabolism in distraction osteogenesis.

Limb lengthening in the left tibia of 30 mature female Yucatan micropigs was performed using distraction osteogenesis. A treatment group of 15 animals received recombinant porcine growth hormone (r-pGH) (100 microg/kg/day) while the others served as controls. Serial serum measurements of total insulin-like growth factor I (IGF-I), free IGF-I, IGF binding proteins -1, -2, -3 and -4 (IGFBP-1 to -4) were performed. Bone-specific alkaline phosphatase (bone-ALP) and the serum carboxyl-terminal telopeptide of type I collagen (ICTP) were measured as bone turnover markers. The GH-treated animals showed a significant increase in total IGF-I, free IGF-I and IGFBP-3 after surgery (P<0.001). Similarly, the treated animals showed a significantly higher level of bone-ALP (P<0.001) throughout the experiment compared to the controls. There was a significant correlation between bone-ALP and total IGF-I (r=0.76) in the GH-treated group and an even higher correlation for free IGF-I (r=0.90). There was no difference in the ICTP serum levels between the two groups. These data indicate that the application of species-specific growth hormone results in a stimulation of bone formation in distraction osteogenesis which may be mediated by IGF-I. The stronger correlation between free IGF-I and bone-ALP indicates that the anabolic effect of IGF-I may be regulated through the IGFBPs by binding and inactivating IGF-I.

Alkaline Phosphatase↗
PubMed2000

[Recombinant growth hormone accelerates regenerate consolidation in distraction osteosynthesis].

Distraction osteogenesis is a good model for evaluation of fracture healing with intramembranous bone formation. The purpose of the present study was to investigate whether homologous GH has a stimulating effect on bone healing in distraction osteogenesis. The left tibiae of 30 micropigs were osteomized and distracted with an external fixator 2 mm daily over a period of 10 days. Animals were killed after an additional healing time of 10 days. The treatment group received 100 micrograms r-pGH per kg bodyweight per day. A newly developed device allowed non-destructive torsional biomechanical evaluation of the regenerate strength as in vivo measurements. After killing, destructive torsional strength testing of the sites of distraction was performed. To determine the endocrine response to the administration of r-pGH, serum levels of IGF-I were determined. The non-destructive in vivo testing showed that torsional stiffness of the regenerate was significantly higher in the treatment group than in the control group. Final regenerate torsional failure load was 131% higher and ultimate torsional stiffness was 231% higher in the treatment group than in the control group. The mean serum level of IGF-I increased to 440% of the preoperative base level in the treatment group and remained unchanged in the control group. Our data indicate that systemic administration of recombinant homologous growth hormone significantly accelerates ossification of bone regenerate in distraction osteogenesis.

Animals↗
PubMed2000

Growth hormone secretagogues derived from NN703 with hydrazidesas c-terminal.

A series of GH secretagogues based on modifications in the C-terminal of NN703 is reported. The C-terminal N-methyl amide of NN703 has been replaced with alkylated hydrazides in order to decrease the volume of distribution and identify GH secretagogues with shorter duration of action. Most of the prepared compounds show high potency in a rat pituitary assay. Subsequent to an initial in vivo screening in dogs, four compounds were selected for further pharmacological and pharmacokinetic evaluation. The four compounds showed oral bioavailability around 35% and equipotency in vitro compared to NN703. The relationship between lipophilicity and volume of distribution is discussed and it is speculated whether the lower volume of distribution is attributed to the observed higher in vivo potency and shorter plasma elimination half-life.

Animals↗
PubMed2000

New highly potent dipeptidic growth hormone secretagogues with low molecular weight.

Based on NN703, low molecular weight growth hormone secretagouges (GHSs) with a reduced number of hydrogen binding sites were designed by removal of the C-terminal amide group. The compounds were highly potent in combination with high efficacy in a rat pituitary cell assay, being characterized with EC(50) values down to 0.8 nM. Selected compounds were tested in in vivo animal models. The oral bioavailability in dogs was 16-44%. Also, the ED(50) values of the compounds were determined both in dog and swine.

Administration, Oral↗
PubMed1999

Recombinant growth hormone accelerates bone regenerate consolidation in distraction osteogenesis.

The purpose of the present study was to prove whether homologous GH has a stimulating effect on bone healing. Therefore, left tibiae of 30 micropigs were osteomized and distracted over an external fixator at the rate of 2 mm/day on each of 10 consecutive days. Animals were killed after a healing period of another 10 days. The treatment group received 100 microg of recombinant porcine growth hormone (rpGH) per kilogram of body weight per day. Serial torsional nondestructive biomechanical tests were performed in vivo using a newly developed measurement device. After killing, destructive torsional strength testing of the sites of distraction was performed. To determine the endocrine response to the administration of rpGH, serum levels of insulin-like growth factor-I (IGF-I) were determined. Nondestructive in vivo testing showed that torsional stiffness of the regenerate was significantly higher in the treatment group than in the control group. Final regenerate torsional failure load was 131% higher and ultimate torsional stiffness was 231% higher in the treatment group than in the control group. The mean serum level of IGF-I increased to 440% of preoperative basal level in the treatment group and remained unchanged in the control group. Our data indicate that systemic administration of recombinant homologous growth hormone greatly accelerates ossification of bone regenerate in distraction osteogenesis.

Animals↗
PubMed1999

Pharmacological characterisation of a new oral GH secretagogue, NN703.

NN703 is a novel orally active GH secretagogue (GHS) derived from ipamorelin. NN703 stimulates GH release from rat pituitary cells in a dose-dependent manner with a potency and efficacy similar to that of GHRP-6. The effect is inhibited by known GHS antagonists, but not by a GH-releasing hormone antagonist. Binding of (35)S-MK677 to the human type 1A GHS receptor (GHS-R 1A) stably expressed on BHK cells was inhibited by GHRP-6 and MK677 as expected. NN703 was also able to inhibit the binding of (35)S-MK677. However, the observed K(i) value was lower than expected, as based on the observed potencies regarding GH release from rat pituitary cells. Similarly, the effect of NN703 on the GHS-R 1A-induced inositol phosphate turnover in these cells showed a lower potency, when compared with GHRP-6 and MK677, than that observed in rat pituitary cells. The effect of i.v. administration of NN703 on GH and cortisol release was studied in swine. The potency and efficacy of NN703 on GH release were determined to be 155+/-23 nmol/kg and 91+/-7 ng GH/ml plasma respectively. A 50% increase of cortisol, compared with basal levels, was observed for all the tested doses of NN703, but no dose-dependency was shown. The effect of NN703 on GH release after i. v. and oral dosing in beagle dogs was studied. NN703 dose-dependently increased the GH release after oral administration. At the highest dose (20 micromol/kg), a 35-fold increase in peak GH concentration was observed (49.5+/-17.8 ng/ml, mean+/-s.e.m.). After a single i.v. dose of 1 micromol/kg the peak GH plasma concentration was elevated to 38.5+/-19.6 ng/ml (mean+/-s.e.m.) approximately 30 min after dosing and returned to basal level after 360 min. The oral bioavailability was 30%. The plasma half-life of NN703 was 4.1+/-0.4 h. A long-term biological effect of NN703 was demonstrated in a rat study, where the body weight gain was measured during a 14-day once daily oral challenge with 100 micromol/kg. The body weight gain was significantly increased after 14 days as compared with a vehicle-treated group. In summary, we here describe an orally active and GH specific secretagogue, NN703. This compound acts through a similar mechanism as GHRP-6, but has a different receptor pharmacology. NN703 induced GH release in both swine and dogs after i.v. and/or p.o. administration, had a high degree of GH specificity in swine and significantly increased the body weight gain in rats.

Administration, Oral↗
PubMed1998

A new series of highly potent growth hormone-releasing peptides derived from ipamorelin.

A new series of GH secretagogues derived from ipamorelin is described. In an attempt to obtain oral bioavailability, by reducing the size and the number of potential hydrogen-bonding sites of the compounds, a strategy using the peptidomimetic fragment 3-(aminomethyl)benzoic acid and sequential backbone N-methylations was applied. Several compounds from this series release GH with high in vitro potency and efficacy in a rat pituitary cell assay and high in vivo potency and efficacy in anesthetized rats. The tetrapeptide NNC 26-0235 (3-(aminomethyl)benzoyl-D-2Nal-N-Me-D-Phe-Lys-NH2) shows, following iv administration, comparable in vivo potency to ipamorelin, GHRP-2, and GHRP-6 with an ED50 in swine at 2 nmol/kg. NNC 26-0235 demonstrated a 10% oral bioavailability in dogs, and NNC 26-0235 and ipamorelin were able to increase basal GH level by more than 10-fold after oral administration of a dose of 1.8 and 2.7 mg/kg, respectively. The tripeptide NNC 26-0323 (3-(aminomethyl)benzoic acid-N-Me-D-2Nal-N-Me-D-Phe-ol) which showed moderate in vitro potency but lacked in vivo potency demonstrated a 20% oral bioavailability in rats.

Administration, Oral↗
PubMed1998

Novel orally active growth hormone secretagogues.

A novel class of growth hormone-releasing compounds with a molecular weight in the range from 500 to 650 has been discovered. The aim of this study was to obtain growth hormone secretagogues with oral bioavailability. By a rational approach we were able to reduce the size of the lead compound ipamorelin (4) and simultaneously to reduce hydrogen-bonding potential by incorporation of backbone isosters while retaining in vivo potency in swine. A rat pituitary assay was used for screening of all compounds and to evaluate which compounds should be tested further for in vivo potency in swine and oral bioavailability, fpo, in dogs. Most of the tested compounds had fpo in the range of 10-55%. In vivo potency in swine after iv dosing is reported, and ED50 was found to be 30 nmol/kg of body weight for the most potent compound.

Administration, Oral↗
PubMed1998

Ipamorelin, the first selective growth hormone secretagogue.

The development and pharmacology of a new potent growth hormone (GH) secretagogue, ipamorelin, is described. Ipamorelin is a pentapeptide (Aib-His-D-2-Nal-D-Phe-Lys-NH2), which displays high GH releasing potency and efficacy in vitro and in vivo. As an outcome of a major chemistry programme, ipamorelin was identified within a series of compounds lacking the central dipeptide Ala-Trp of growth hormone-releasing peptide (GHRP)-1. In vitro, ipamorelin released GH from primary rat pituitary cells with a potency and efficacy similar to GHRP-6 (ECs) = 1.3+/-0.4nmol/l and Emax = 85+/-5% vs 2.2+/-0.3nmol/l and 100%). A pharmacological profiling using GHRP and growth hormone-releasing hormone (GHRH) antagonists clearly demonstrated that ipamorelin, like GHRP-6, stimulates GH release via a GHRP-like receptor. In pentobarbital anaesthetised rats, ipamorelin released GH with a potency and efficacy comparable to GHRP-6 (ED50 = 80+/-42nmol/kg and Emax = 1545+/-250ng GH/ml vs 115+/-36nmol/kg and 1167+/-120ng GH/ml). In conscious swine, ipamorelin released GH with an ED50 = 2.3+/-0.03 nmol/kg and an Emax = 65+/-0.2 ng GH/ml plasma. Again, this was very similar to GHRP-6 (ED50 = 3.9+/-1.4 nmol/kg and Emax = 74+/-7ng GH/ml plasma). GHRP-2 displayed higher potency but lower efficacy (ED50 = 0.6 nmol/kg and Emax = 56+/-6 ng GH/ml plasma). The specificity for GH release was studied in swine. None of the GH secretagogues tested affected FSH, LH, PRL or TSH plasma levels. Administration of both GHRP-6 and GHRP-2 resulted in increased plasma levels of ACTH and cortisol. Very surprisingly, ipamorelin did not release ACTH or cortisol in levels significantly different from those observed following GHRH stimulation. This lack of effect on ACTH and cortisol plasma levels was evident even at doses more than 200-fold higher than the ED50 for GH release. In conclusion, ipamorelin is the first GHRP-receptor agonist with a selectivity for GH release similar to that displayed by GHRH. The specificity of ipamorelin makes this compound a very interesting candidate for future clinical development.

Adrenocorticotropic Hormone↗
PubMed1991

Respiratory tract distribution and bioavailability of spiramycin in calves.

Pharmacokinetic determinants of spiramycin and its distribution into the respiratory tract were studied in 2 groups of calves, 4 to 10 weeks old. Group-A calves (n = 4) were used to determine pharmacokinetic variables of spiramycin after IV (15 and 30 mg/kg of body weight) and oral administrations of the drug (30 mg/kg) and to measure distribution of spiramycin into nasal and bronchial secretions. Group-B calves (n = 4) were used to determine distribution of spiramycin into lung tissue and bronchial mucosa. Spiramycin disposition was best described by use of an open 3-compartment model. Mean (+/- SD) elimination half-life was 28.7 +/- 12.3 hours, and steady-state volume of distribution was 23.5 +/- 6.0 L/kg. Bio-availability after oral administration was 4 +/- 3%. High and persistent concentrations of spiramycin were achieved in the respiratory tract tissues and fluids. Tissue-to-plasma concentration ratio was 58 for lung tissue and 18 for bronchial mucosa at 3 hours after spiramycin administration and 137 and 49, respectively at 24 hours. Secretion-to-plasma concentration ratio was 4 for nasal secretions and 7 for bronchial secretions, and remained almost constant with time. Thus, spiramycin penetrates well into the respiratory tract, although the value in bronchial secretions is lower than that in lung tissues and bronchial mucosa. Calculations indicate that a loading dose of 45 mg/kg, administered IV, followed by a maintenance dose of 20 mg/kg, IV, once daily is required to maintain active concentrations of spiramycin against bovine pathogens in bronchial secretions.

Animals↗