Investigation of safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of a long-acting α-MSH analog in healthy overweight and obese subjects.

MC4-NN2-0453 is a novel, long-acting, selective, melanocortin-4-receptor agonist developed for treatment of obesity. This first-human-dose, randomized, double-blind, placebo-controlled trial investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of MC4-NN2-0453 in overweight to obese but otherwise healthy subjects. The trial included a single-dose part of ascending subcutaneous 0.

Identification and in vivo and in vitro characterization of long acting and melanocortin 4 receptor (MC4-R) selective α-melanocyte-stimulating hormone (α-MSH) analogues.

We report in vitro and in vivo data of new α-melanocyte-stimulating hormone (α-MSH) analogues which are N-terminal modified with a long chain fatty acid derivative. While keeping the pharmacophoric motif (d-Phe-Arg-Trp) fixed, we tried to improve selectivity and physicochemical parameters like solubility and stability of these analogues by replacing amino acids further away from the motif. Receptor specific changes in binding affinity to the melanocortin receptors were observed between the acetyl derivatives and the fatty acid analogues.

Serendipitous discovery of a new class of agonists for the melanocortin 1 and 4 receptors and a new class of cyclophanes.

A new class of melanocortin 4 receptor (MC4r) agonists was discovered from an unexpected sidereaction in which formaldehyde caused cyclization. These cyclophanes were found to be sub micromolar agonists of the MC1 and MC4 and were less potent on the MC3 and MC5 receptor. They were shown to compete with the peptidic antagonist SHU9119 for binding to the MC4 receptor.

Pegylated long-acting human growth hormone possesses a promising once-weekly treatment profile, and multiple dosing is well tolerated in adult patients with growth hormone deficiency.

Background: Recombinant human GH (rhGH) replacement therapy in children and adults currently requires daily sc injections for several years or lifelong, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed for once-weekly administration.

Objectives: Our objective was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of NNC126-0083 in adult patients with GH deficiency (GHD).

Mitochondrial uncouplers with an extraordinary dynamic range.

We have discovered that some weak uncouplers (typified by butylated hydroxytoluene) have a dynamic range of more than 10(6) in vitro: the concentration giving measurable uncoupling is less than one millionth of the concentration causing full uncoupling. They achieve this through a high-affinity interaction with the mitochondrial adenine nucleotide translocase that causes significant but limited uncoupling at extremely low uncoupler concentrations, together with more conventional uncoupling at much higher concentrations. Uncoupling at the translocase is not by a conventional weak acid/anion cycling mechanism since it is also caused by substituted triphenylphosphonium molecules, which are not anionic and cannot protonate.

Laparoscopic-assisted vaginal vs. abdominal surgery in patients with endometrial cancer stage 1.

Background: The development of new diagnostic and surgical methods has brought a differentiated approach to the surgery of endometrial cancer. The aim of this study was to verify the peri- and postoperative differences between laparoscopic and open procedures.

Methods: In the period from January 1995 to August 2001 a total of 86 patients were treated for endometrial cancer stage 1.

Immunohistochemical expression of p63 in human prenatal tooth primordia.

The aim of this study was to investigate the expression of the p63 gene in normal human tooth buds at different gestational stages. This is the first detailed study of p63 expression in normal human prenatal tooth primordia. The material consisted of sections of the midaxial tissue block from the cranial base of three human fetuses of gestational ages (GA) 11, 15, and 21 weeks.

Anthocyanins increase low-density lipoprotein and plasma cholesterol and do not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits.

Anthocyanin-rich beverages have shown beneficial effects on coronary heart disease in epidemiological and intervention studies. In the present study, we investigated the effect of black currant anthocyanins on atherosclerosis. Watanabe Heritable Hyperlipidemic rabbits (n = 61) were fed either a purified anthocyanin fraction from black currants, a black currant juice, probucol or control diet for 16 weeks.

Human prenatal nasal bone lengths: normal standards and length values in fetuses with cleft lip and cleft palate.

Objective: The aim of this study was to present prenatal autopsy standards for nasal bone length in normal fetuses, as well as to compare nasal bone lengths in human fetuses with cleft lip and palate with those standards.

Material And Methods: The material consisted of human fetuses investigated in connection with diagnosed and legally approved abortions and spontaneous abortions; 40 were normal and 26 had cleft lip and palate (7 isolated cleft lip, 12 isolated cleft palate, and 7 combined cleft lip and palate). Menstrual ages (MA) ranged from 12 to 25 weeks, crown-rump length (CRL) from 55 to 210 mm and foot length (FL) from 7 to 44 mm.

Fasting unmasks a strong inverse association between ghrelin and cortisol in serum: studies in obese and normal-weight subjects.

Administration of ghrelin, the endogenous ligand for the GH secretagogue receptor, stimulates not only GH secretion but also appetite and food intake in humans. Endogenous ghrelin levels display a distinct circadian rhythm, which is reciprocal to that of insulin and presumed to be meal dependent and not associated with GH secretion. We tested the hypothesis that food deprivation could impact circadian serum ghrelin levels and unmask meal-independent regulatory mechanisms.

Abnormal vomer development in human fetuses with isolated cleft palate.

Objective: The aim of this study was to elucidate the prenatal human development of the vomer with emphasis on the vomeral footplate and to assess vomeral morphology in fetuses with isolated cleft palate.

Material And Methods: Nine human fetuses of which four were normal (menstrual age [MA] 13 to 21 weeks) and five with isolated cleft palate (14 to 19 weeks MA) were studied. Midaxial cranial tissue blocks from the fetuses were cut frontally in 4microm serial sections.

Detection of Mycobacterium tuberculosis complex in formalin-fixed, paraffin-embedded tissue specimens with necrotizing granulomatous inflammation by strand displacement amplification.

Rapid, reliable diagnosis of tuberculosis is essential to initiate correct treatment, avoid severe complications, and prevent transmission. Conventional microbiological methods may not be an option if samples are formalin-fixed and paraffin-embedded (FFPE) for histopathological examination. With the demonstration of necrotizing granulomatous inflammation, tuberculosis becomes an important differential diagnosis, although it was not initially suspected.

Arylcyanoguanidines as activators of Kir6.2/SUR1K ATP channels and inhibitors of insulin release.

Phenylcyanoguanidines substituted with lipophilic electron-withdrawing functional groups, e.g. N-cyano-N'-[3,5-bis-(trifluoromethyl)phenyl]-N' '-(cyclopentyl)guanidine (10) and N-cyano-N'-(3,5-dichlorophenyl)-N' '-(3-methylbutyl)guanidine (12) were synthesized and investigated for their ability to inhibit insulin release from beta cells, to repolarize beta cell membrane potential, and to relax precontracted rat aorta rings.

Recognition of privileged structures by G-protein coupled receptors.

Privileged structures are ligand substructures that are widely used to generate high-affinity ligands for more than one type of receptor. To explain this, we surmised that there must be some common feature in the target proteins. For a set of class A GPCRs, we found a good correlation between conservation patterns of residues in the ligand binding pocket and the privileged structure fragments in class A GPCR ligands.

Parallel solid-phase synthesis of disubstituted (5-biphenyltetrazolyl) hydantoins and thiohydantoins targeting the growth hormone secretagogue receptor.

An efficient solid-phase protocol for the synthesis of substituted (5-biphenyltetrazolyl)-hydantoins and -thiohydantoins has been developed. Suzuki cross-coupling between resin-bound 2-(tetrazol-5-yl)-phenylborinane and 4-bromobenzaldehyde gave the corresponding tetrazolylbiphenyl aldehyde. Subsequent reductive amination using amino acid esters gave the pivotal resin bound amino acid esters which were transformed to hydantoins or thiohydantoins via two routes: (i) treatment with isocyanates or isothiocyanates or (ii) successive treatment with triphosgene and primary amines.

Sirenomelia sequence according to the distance between the first sacral vertebra and the ilia.

The development of the iliac bones and lower limbs are parallel processes depending on the normal ontogeny of the caudal blastema [O'Rahilly and Müller, 1989; Opitz, 1993; Opitz et al., 2000]. We hypothesized that the pathogenetic mechanisms leading to fused lower limbs would in parallel displace the ilia caudally and medially and that the degree of this displacement might correlate with the severity of the iliac and lower limb defects.

The influence of conformational restriction in the C-terminus of growth hormone secretagogues on their potency.

In order to obtain more potent growth hormone secretagogues, a comparison of ipamorelin and NN703 suggested the addition of a polar group at the C-terminus of NN703. A study was conducted using constrained amines for this purpose. Here, substituted 4-piperidinylamino- and 4-dimethylaminopiperidino-substituents were found to give the most active compounds.

Inhibition of the spontaneous apoptosis of neutrophil granulocytes by the intracellular parasite Leishmania major.

Macrophages are the major target cell population of the obligate intracellular parasites Leishmania. Although polymorphonuclear neutrophil granulocytes (PMN) are able to internalize Leishmania promastigotes, these cells have not been considered to date as host cells for the parasites, primarily due to their short life span. In vitro coincubation experiments were conducted to investigate whether Leishmania can modify the spontaneous apoptosis of human PMN.

Nateglinide, but not repaglinide, stimulates growth hormone release in rat pituitary cells by inhibition of K channels and stimulation of cyclic AMP-dependent exocytosis.

Objective: GH causes insulin resistance, impairs glycemic control and increases the risk of vascular diabetic complications. Sulphonylureas stimulate GH secretion and this study was undertaken to investigate the possible stimulatory effect of repaglinide and nateglinide, two novel oral glucose regulators, on critical steps of the stimulus-secretion coupling in single rat somatotrophs.

Methods: Patch-clamp techniques were used to record whole-cell ATP-sensitive K(+) (K(ATP)) and delayed outward K(+) currents, membrane potential and Ca(2+)-dependent exocytosis.

Histological examinations of bone and cartilage in the axial skeleton of human triploidy fetuses.

The aim of this study was to examine histologically bone and cartilage in vertebral corpora of axial skeletons of eight human triploid fetuses, gestational ages 14-25 weeks, CRL 100-200 mm. The results were compared to earlier studies on vertebral development in trisomies 21, 18, 13, and to normal corpora development. After radiography in frontal and lateral projections, the vertebral column was sectioned into cervical, thoracic and lumbar segments, decalcified, dehydrated, and embedded in paraffin.

Short bi-iliac distance in prenatal Ullrich-Turner syndrome.

The purpose of the present study is to evaluate the bi-iliac distance and the caudo-cranial position of the iliac bones in Ullrich-Turner syndrome (UTS) fetuses compared to recently published standards for normal fetuses. Whole-body radiographs in antero-posterior projections of 24 UTS fetuses (crown-rump lengths, 106-220 mm) were included in the study. From each radiograph, two horizontal (outer and inner bi-iliac distances) and two vertical (caudo-cranial) positions compared to the vertebral column were measured to estimate the position of the iliac bones.

Synthesis and pharmacological evaluation of novel cis-3,4-diaryl-hydroxychromanes as high affinity partial agonists for the estrogen receptor.

The syntheses and in vitro pharmacological evaluation of a number of cis-3,4-diaryl-hydroxy-chromanes are reported, along with the results of a thorough in vivo profiling of the tissue-selective estrogen partial-agonist NNC 45-0781 [3, (-)-(3S,4R)-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane]. These studies showed that NNC 45-0781 is a very promising candidate for the prevention of post-menopausal osteoporosis, and the treatment of other health issues related to the loss of endogenous estrogen production.

Synthesis and biological evaluation of novel thio-substituted chromanes as high-affinity partial agonists for the estrogen receptor.

Synthesis of (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-piperidinoethanethio)phenyl)chromane (13) and (+/-)-cis-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethanethio)phenyl)chromane (15) is presented. These compounds are representatives of a novel class of compounds with high in vitro binding affinity for the estrogen receptor (IC(50)=7-10 nM), and very low in vitro uterotrophic activity (max stim.=5-17% rel to moxestrol; EC(50)=0.