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Growth Hormone And The Hypothalamicpituitarysomatotrophic Axis

Growth hormone (GH) or somatotropin is another stress-sensitive neuroendocrine system. GH is synthesized by the anterior pituitary, and although it can be used as an endpoint in itself for neuroendocrine research in psychiatry, its predominant use is as a marker of the integrity of the noradrenergic system following challenge. The hypothalamic-pituitary-somatotrophic (HPS) axis is under complex regulatory control that is not yet fully understood since cross-species variations in GH regulation make it difficult to extrapolate to humans from animal studies. It is well established, however, that the final common pathways for control of GH release from the pituitary are hypothalamic growth hormone-releasing hormone (GHRH) (stimulation) and somatostatin (inhibition). The wide variety of metabolic, endocrine, and neural influences that alter GH secretion do so primarily through effects on GHRH and or somatostatin. Neural influences may be mediated by noradrenergic, cholinergic,...

Growth hormone monoclonal antibodies factor XI erythropoietin

Artificial cell encapsulated mouse fibroblasts with a human growth hormone (hGH) fusion gene continue to secrete and deliver human growth hormone (hGH) when implanted into animals in an animal model of dwarfism (Al-Hendy et al., 1996). Implantation of microencapsulated SK2 hybridoma cells that secreted anti-hIL-6 monoclonal antibodies (SK2 mAb) into transgenic mice (hIL-6 Tgm) suppressed IgG1 plasmacytosis, resulting in significant increases in survival time of these mice (Okada et al., 1997). Artificial cell encapsulated genetically engineered mouse myoblasts that secrete human factor XI have also been studied for potential use in hemophilia B (Basic etal., 1996). Artificial cell encapsulated myoblasts have been used to deliver erythropoietin in mouse thalasemia (Dalle etal., 1999).

Growth Hormone

Growth hormone, the most abundant anterior pituitary hormone, is synthesized and secreted by somatotropes, which account for about 40 of hormone-secreting cells of the anterior pituitary. Due to alternative splicing of the GH gene, the anterior pituitary secretes a heterogeneous mixture of GH peptides an appreciable fraction of which circulates bound to a protein corresponding to the extracellular domain of the GH receptor. Bound GH has a biological t1 2 ten times that of unbound GH, suggesting that the binding protein may provide a reservoir that dampens acute fluctuations in GH levels associated with its pulsatile secretion. Obesity and estrogen treatment increase circulating levels of GH binding proteins and thus may affect the clinical response to exogenous GH. Regulation of Growth Hormone Secretion

Human Growth Hormone

Human growth hormone (hGH) is a 191-amino-acid polypeptide that is released from anterior pituitary somatotrope cells. The hormone functions to promote linear growth during adolescence and modulate many physiological functions after completion of growth. Since 1984, somatropin (recombinant DNA-derived hGH) therapy has been applied in the treatment of growth hormone-deficient children. hGH is known to exhibit a distinct conformation at an acidic pH when compared to neutral pH 53 . Although the molecular conformations at acid and neutral pH share virtually identical extents of secondary structure, differences in the tertiary structure have been observed. The less stable acidic conformation is also implicated as the intermediate for undesirable aggregation 53 .

Role Of The Orphan Drug

Products such as human insulin, growth hormone, or interferons and (2) focusing on treating individuals with rare medical conditions so that the NME in development can be qualified for grant and tax benefits under the 1983 Orphan Drug Act. Factors influencing the choice of which indication of an NME to develop first include consideration of (1) market potential, (2) competition, (3) patents and proprietary advantages, (4) qualification as an orphan drug, and (5) reimbursement by third-party payers (i.e., Medicare, Medicaid, and insurance companies). By targeting the indications of a new drug candidate to diseases that affect fewer than 200,000 individuals in the United States, a company also receives seven years of market exclusivity. The market exclusivity discourages other companies from developing any product for the target indication. In the

Pharmacology and pharmaceutics

Clinical pharmacology Interleukin-11 is a member of a family of human growth factors that includes human growth hormone, granulocyte colony-stimulating factor (G-CSF), and other growth factors. It is produced by fibroblasts, as well as by bone marrow stromal cells, and directly stimulates the proliferation of hematopoi-etic stem cells and megakaryocyte progenitor cells, as well as lymphoid cells. IL-11 also induces the differentiation of megakaryocytes into platelets. Platelets produced in response to IL-11 are normal morphologically and functionally, and possess normal life spans.

The Recombinant DNA Era Today

Growth hormone (GH) 22,000 GH synthesis and secretion does not disappear when linear growth is complete. In fact isolation of hGH from cadaver pituitary glands would not have been possible if it did. Physicians caring for adult patients with pituitary disease began to realize that even with optimum replacement of other hormones, patients who acquired GH deficiency in adulthood complained bitterly about diminished quality of life. Studies from Europe also documented increased cardiovascular morbidity and mortality in these patients 13 . Because it was no longer necessary to conserve scarce supplies of hGH for use in children, physicians were able to study GH effects in adults with growth hormone deficiency. These studies have shown that GH improves body composition (decreases fat mass and increases lean body mass) and decreases risk factors for cardiovascular disease 14 .

Somatropin Recombinant

Indications Long-term treatment of pedi-atric patients who have growth failure due to an inadequate secretion of endogenous growth hormone (Genotropin, Humatrope, Norditropin, Nutropin, Saizen) or to Prader-Willi syndrome (Genotropin). Treatment of short stature associated with Turner's syndrome (Humatrope, Nutropin). Treatment of growth failure in children associated with chronic renal insufficiency up to the time of renal transplantation (Nutropin). Long-term replacement therapy in adults with growth hormone deficiency (Genotropin, Humatrope, Nutro-pin). Treatment of AIDS wasting or cachexia (Serostim). A. General description Somatropin (rDNA origin) is a polypeptide hormone of recombinant DNA origin. It has 191 amino-acid residues and a molecular weight of about 22kDa. The amino-acid sequence of the product is identical to that of human growth hormone of pituitary origin. Huma-trope and Genotropin are synthesized in a strain of Escherichia coli that has been mod ified by the...


Indications Treatment of growth hormone deficiency in children A. General description Somatrem is a polypeptide hormone produced by DNA technology. It has 192 amino-acid residues and a molecular weight of 22kDa. Soma-trem contains the sequence of 191 amino acids constituting pituitary-derived human growth hormone plus an additional amino acid, methionine, on the N-terminus of the molecule. Somatrem is synthesized in a strain of Escherichia coli bacteria modified by the addition of the gene for human growth hormone production. B. Indications and use Protropin is administered to children with documented lack of human growth hormone.

Developmental stages of studies on biofunctional molecules

Let us first consider the process by which the investigation of a biofunctional molecule develops. As shown in Figure 1.1, the careful observation of a biological phenomenon together with speculation on the cause of that phenomenon make up the first step in the discovery of a biofunctional molecule. In the studies on the plant-growth hormone gibberellin, the first step was the observation in Japan in 1898 that the infection of rice seedlings by fungus Gibberella fujikuroi causes elongation of the seedlings to bring about the so-called bakanae ( foolish seedlings)1 disease, a destructive pest that reduces the yield of rice in Asia.1

Biopharmaceuticals market value

From a zero starting point in the edarly 1980s, the world-wide sales value of biopharmaceuticals reached US 5 billion by 1993. (The first biopharmaceutical to gain marketing authorization was recombinant human Insulin in 1982). By 1997, the global market value had surpassed the 7 billion mark. By 2003, this figure is projected to be in the region of 35 billion, which will represent some 15 of the total global pharmaceutical market (1-3). Biopharmaceuticals are amongst the most expensive of therapeutic agents. The annual cost of erythropoietin, for example, per patient per year is in the region of 4000- 6000, while that of human growth hormone can be 12,000- 18,000. In monetary terms, erythropoietin is the single largest selling biopharmaceutical product, and was the first such product to surpass an annual sales value of 1 billion. The estimated sales value of some notable biopharmaceutical products is presented in Table 4.

O Biotechnology And Pharmaceutical Care

As it affects medicine and pharmaceutical care, biotechnology has forever altered the drug discovery process and the thinking about patient care. Extensive screening programs once drove drug discovery on natural or synthetic compounds. Now, the recombinant DNA (rDNA)-driven drug discovery process is beginning to yield new avenues for the preparation of some old drugs. For example, insulin, once prepared by isolation from pancreatic tissue of bovine or porcine species, can now be prepared in a pure form identical with human insulin. Likewise, human growth hormone (hGH), once isolated from the pituitary glands of the deceased, can now be prepared in pure form. Recombinant systems, such as these, provide high-yielding, reproducible batches of the drug and uniform dosing for patients.

O Expression Of Cloned

Other examples in which the expression of cloned human genes offers alternatives to previously existing products include human insulin, which is now a viable replacement for purified bovine and porcine insulin for the treatment of diabetes, and hGH, which is used for the treatment of growth hormone deficiency in children (dwarfism). Unlike insulin, growth hormones from other animal species are ineffective in humans thus, until human recombinant growth hormone became available, the only source of hGH was the pituitary glands of cadavers. This obviously limited the supply of hGH and, like factor VIII, exposed patients to potential contamination by human pathogens. Recombinant hGH (rhGH) can now be produced by expression in bacterial cells.

Developments In Molecular Genetics

The chronology of the developments in molecular genetics reveals a fascinating story of scientific discoveries, many of which were recognized by Nobel Prizes in medicine or physiology or chemistry. In the 1950s experiments showed that bacterial recombination (splicing foreign DNA into own DNA) is possible in nature, and researchers began to perform similar recombination experiments in the laboratory. Gradually this led to development of recombinant DNA technology, pioneered by Arber, Smith, and Nathan's discovery of restriction enzymes and their application to molecular genetics. After recombinant DNA technology was established in the mid- and late 1970s as a standard molecular tool, the DNA molecule was transformed from the most difficult to the easiest to study. In 1983 the first transgenic mouse, carrying the gene for rat growth hormone in its cells, was generated. This was soon followed in 1988 by the generation of a mouse with severe combined immunodeficiency and a cancer-prone...

Unconventional Transmitters Focus On Gases

Many of the unconventional transmitters do not fit the well-accepted neurotransmitter criteria mentioned at the beginning of this chapter. A handful of unconventional transmitters have been characterized and may ultimately prove to have relevance for neuropsychiatric disorders here, we limit ourselves to a discussion of the gases nitric oxide (NO) and carbon monoxide (CO), which have been demonstrated to exhibit neurotransmitter-like properties in the brain (Dawson and Snyder 1994). The gases, as a result of being small and uncharged, are able to permeate the lipid bilayer and enter the neuron and directly affect certain second-messenger generating systems directly.

Alterations in Physiological Function Circardian Rhythms Sleep Pain Perception and Appetite

As part of circadian effects, there are normal 24-h fluctuations in neuroendocrine secretion, especially cortisol, growth hormone, TSH, and melatonin, as already noted above. These hormonal systems are often disrupted in depression thought to be due to heightened arousal. With shorter daylight hours, some individuals who experience the aforementioned have recurring autumn and winter depression (seasonal affective disorder, SAD) thought to be related to phase delay in the sleep-wake cycle (186, 188).

Mechanism of Receptor Internalization

In addition to the linear primary sequence, the trafficking of GPCR can be regulated by three-dimensional signals. Covalent modification of the GPCR by conjugating polypeptides such as ubiquitin could establish such signals by the subsequent recruitment of other proteins within the endocytosis pathway. Ubiquitin molecule, a 76 amino acid polypeptide, is expressed in all eukaryotic cells. The conjugation of this polypeptide to the target proteins by the multienzyme cascade involving the E1s, E2s, and E3s enzymes has long been known to direct the degradation of cytosolic and nuclear proteins by proteasomes see review in 181 . Normally, this involves the addition of multiubiquitin chains, i.e., the carboxy-termini glycine of ubiquitin is linked to the Lys48 of the preceding ubiquitin, to the e-amino group of the lysine residue of the target protein. However, there is accumulating evidence to suggest a role ofmonoubiquitination in the endocytosis ofplasma membrane proteins and their...

Targeting Drugs to the Lungs via the Bloodstream

Various studies deal with gene targeting, e.g. as a treatment modality for cystic fibrosis or to induce mucosal immune responses. To determine delivery and expression efficiency, plas-mids encoding reporter genes such as chloramphenicol acetyltransferase (CAT), luciferase or alkaline phosphatase are used. DODAC DOPE (dioleoyldimethylammonium-Cl di-oleoylphosphatidyl-ethanolamine) liposomes complexed with reporter plasmid DNA, deposited DNA in the alveolar region in the lung after i.v. administration. In comparison, intra-tracheal administration of the same formulation predominantly led to the deposition of DNA in epithelial cells lining the bronchioles 138 . A similar result was obtained with a formulation that consisted of DNA encoding CAT complexed with a ninth generation polyami-doamine (PAMAM) dendrimer. This polymer is a 467-kDa spherical molecule with a diameter of 114 A. Repeated i.v. administration allowed prolonged transgene expression 139 . Macroaggregated albumin can also...

AP2Binding Accessory Proteins Defining Cargo Selective Pathways

In recent years, it has become clear that covalent modification of cargo by mono- or multi-ubiquitination, usually following ligand-induced receptor activation and perhaps phosphorylation, can also function as an endocytosis signal. As with the examples described above, ubiquitinated cargo is not recognized by AP-2 directly, but instead associates with ubiquitin-binding accessory proteins including the UIM (ubiquitin-interacting motif)-containing factors eps15 and epsin. Examples of cargo undergoing regulated ubiquitination and clathrin-dependent internalization include the EGF and growth hormone receptors, epithelial sodium channels (ENaC), and Notch (Stang et al. 2004 Gupta-Rossi et al. 2004 Wang et al. 2006). Other accessory factors may also function in cargo-selective clathrin-dependent internalization pathways. These include HIP1 1R, dishevelled (Dvl), and numb.

PEG Proteins As Human Therapeutics

The FDA has approved the PEGylated forms of the protein therapeutics adenosine deaminase, asparaginase, a-interferon (IFN) and a growth hormone antagonist3. Linear PEGs with molecular weights of 12 000, including succinimidyl succinate (SS-PEG) and succinimidyl carbonate (SC-PEG) have been used on the first approved PEG-protein products. They possess the disadvantages of weak linkages between PEG and protein, side reactions, low-molecular-weight and diol contamination (HO-PEG-OH)1. The SS-PEG linkage used for asparaginase is susceptible to hydrolysis after the polymer has been attached to the protein1. An advantage of SC-PEG relative to SS-PEG is that SC-PEG does not contain a degradable ester linkage that can lead to hydrolytic removal of the PEG from the PEG-protein conjugate1. The linkage formed between SC-PEG and a protein lysine is a urethane linkage, stable to hydrolysis. However, SC-PEG couples at low pH to histidine moieties in a hydrolytically unstable linkage4. SC chemistry...

Central nervous system and the pituitary

Cytochrome P-450 metabolism of arachidonic acid also occurs in the pituitary. Microsomes of rat anterior pituitary formed 20-HETE and at least three epoxides of arachidonic acid (5,6-, 11,12- and 14,15-EETs) 178 . These cytochrome P-450-derived metabolites affect anterior pituitary cells at relatively high concentrations. Inhibitors of cytochromes P-450 (proadifen and piperonyl butoxide) blocked the release of corticotropins in response to a variety of secretagogs in mouse pituitary tumor cells 179 . 5,6-EET (1 pM) caused efflux of calcium and release of luteinizing hormone 180 . At 50 pM concentration, it stimulated the release of prolactin from a rat anterior pituitary cell line GH3 181 and stimulated the release of growth hormone from pituitary cells in culture at 20 pM 182 , In addition, 5,6-, 8,9-, 11,12- and 14,15-EETs (3 pM) all stimulated release of growth hormone from a population of enriched somatotrophs, with 5,6-EET and 14,15-EET more potent than the other two regioisomers...

Growth Metabolism and the Stress Response

The hormones secreted by the thyroid thyroxine (T4) and triiodothyronine (T3) and adrenal (cortisol and adrenaline) tissues are identical in both fish and mammals. In fish, however, these tissues do not form discrete glands the thyroid is scattered around the ventral aorta, while adrenal tissue is dispersed within the kidney. This makes it very difficult to measure the changes induced in their structure by chemical pollutants. The hormones of the thyroid regulate general metabolic rate, growth and possibly embryonic development, while those of the adrenal are involved in the stress response, osmoregulation and carbohydrate metabolism. Growth in fish is continuous and does not cease at puberty as in mammals. Fish size is therefore not only dependent on secretion of growth hormone by the pituitary gland as in mammals, but on age and the rate of metabolic activity and energy utilisation as determined by both the thyroid and interrenal glands. Thyroid and adrenal activities are also...

[29 Cloning and Characterization of Soluble Decoy Receptors

We have constructed a chimeric fusion protein that consists of the bovine growth hormone signal sequence and the human MSR AI extracellular domains.18,19 This soluble decoy MSR (sMSR) was cloned into an adenoviral vector, and sMSR recombinant adenoviruses were produced. It was found that sMSR inhibits the degradation of modified LDL by 70-80 and inhibits foam cell formation in vitro. Tail vein injection of 1 x 109 PFU of sMSR adenoviruses reduced atherosclerotic lesion formation in hypercholesterolemic LDL receptor knockout mice, which is an example of the therapeutic use of antagonistic soluble receptors. A similar approach would be useful for blocking the action of several growth factors and cytokines. In this chapter we present general guidelines for the cloning, production, and characterization of soluble decoy receptors, using sMSR and adenoviral gene transfer as an example. sMSR, consisting of the bovine growth hormone signal sequence and the extracellular parts of the human...

Product Characteristics

Impurities may influence immunogenicity. The immunogenicity of products as human growth hormone, insulin, and interferon a-2 have declined over the years due to improved downstream processing and formulation, reducing the level of impurities. There are studies showing the induction of antibodies by

Prediction Of Immunogenicity In Animals

Also, antibody-positive animals may provide sera for the development and validation of antibody assays and the evaluation of an antibody response in animals is important to evaluate the safety and pharmacokinetic data in conventional laboratory animals. Nonhuman primates have been advocated as better models to predict the immunogenicity of human proteins because of a high sequence homology between the product and the monkey native molecule to which the animal is immune tolerant. Immunogenicity studies in nonhuman primates have, however, also shown mixed results. Products with a high immunogenicity in monkeys sometimes do not induce antibodies in human patients. The opposite has also been observed, although these studies may have been too limited in length of treatment or number of animals to be truly predictive. A good example of the possible use of monkeys was a study to determine the immunogenicity of different human growth hormone (hGH) preparations using a hyper-immunization...

Abnormal Thyroid Activity

The hormones of the thyroid, in concert with those of the adrenal gland and growth hormone from the pituitary, regulate energy utilisation, metabolic rate and growth. Since thyroid hormones are incorporated into the developing egg from maternal sources, they may also be involved in larval development, although their role in this is still far from clear. The main thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are tetra- and triiodinated derivatives of 4-hydroxydiphenyl ether and as such have close structural similarities to other planar halogenated aromatic compounds such as PCBs, dioxins and DDT. It is therefore not surprising that such chemicals are those most suspected of inducing thyroid dysfunction by competing for receptors. As in mammals, thyroid function can be disrupted by action of pollutants at several sites, including production of thyrotrophin releasing hormone (TRH) from the hypothalamus, release of thyroid stimulating hormone (TSH) from the pituitary,...

Avoidance Conditioning Paradigms Selected Studies I Selected Studies

Experiment 2 tested the effects on extinction of a single injection of the following peptides oxytocin (1 g rat, subcutaneous), angiotensin II (1 g rat, subcutaneous), insulin (1 g rat, subcutaneous), and growth hormone (1 Ug rat, subcutaneous), using the same training procedure and injection schedule as for experiment 1. Extinction testing occurred 2,4, and 24 h after the injection. None of these peptides, at this dose level, influenced extinction of the avoidance response. Taken together, the results of this study led to the following conclusions (1) vasopressin is the peptide in the pitressin extract that facilitated retention (i.e., prolonged extinction) of the conditioned avoidance response (2) in contrast to the immediate and relatively brief effects of ACTH(4-10), the long-term effect of vasopressin on the maintenance of the avoidance response suggests an influence on memory consolidation (3) the effect is highly specific because, at the same dose level, the structurally...

G a Protein Subunit Disrupted in Disease

Inactivating Gsa variants lead to Albright's hereditary osteodystrophy (AHO) in the heterozygote, suggesting that Gsa haploinsufficiency causes the disorder. AHO is characterized by short stature, obesity, brachydactyly (shortening of metacarpal and metatarsal bones), subcutaneous ossifications, and mental or developmental deficits (86,87). The severity of the phenotype is variable. Some patients with Gsa mutations have few or no symptoms. The GNAS1 gene imprinting causes patients who have inherited Gsa mutations from their fathers to develop only AHO or pseudopseudohypoparathyroidism (PPHP). On the other hand, patients who inherited mutations from their mothers develop both AHO and resistance to a variety of hormones, including parathyroid hormone (PTH), thyrotropin (TSH formerly called thyroid-stimulating hormone), growth hormone-releasing hormone, and gonadotropins. This array of hormone resistance that results from Gsa insufficiency is known as pseudohypoparathyroidism (PHP) type...

Lossoffunction Models

Used gamma-crystallin promoter, elastase I promoter and growth hormone promoter, respectively (Breitman et al., 1987 Palmiter et al., 1987 Behringer et al., 1988). An incomplete penetrance of toxicity and a highly variable expression of the toxin gene constructs make interpretations difficult. However, certain pathological conditions where particular cell types are reduced or absent may well be mimicked by genetic cell ablation in transgenic animals.

Discovery of Ubiquitin Based Sorting

Apparently the major endocytic signal in budding yeast, in higher organisms ubiquitin addition also regulates the internalization of certain transmembrane proteins. One of the first indications came from studies on the growth hormone (GH) receptor in the CHO-ts20 cell line that exhibits a temperature-sensitive E1 ubiquitin-activating enzyme. At the nonpermissive temperature, no uptake or lysosomal degradation of transfected GH receptor occurs (172). Mutation of 327Phe in the cytosolic domain of the receptor blocks endocytosis and also inhibits receptor ubiquitination (173). Specific inhibitors of the proteasome, which cause depletion of free ubiquitin within the cell, abrogate ligand-stimu-lated destruction of the GH receptor, but transferrin receptor endocytosis is unaffected (174, 175). Also, blocking endocytosis by cyclodextran-mediated cholesterol depletion, or with a dominant-negative dynamin mutant, causes ubiquitinated GH receptor to accumulate on the plasma membrane (176)....

Activation of Endocannabinoid Biosynthesis

The orexigenic hormone ghrelin was shown to cause retrograde release of 2-AG, but not AEA, leading to suppression of excitation in the PVN, an effect that was prevented by blockade of DAG lipase (Kola et al., 2008). Even though PKC involvement was not tested by this study, ghrelin is known to be an agonist of the growth hormone secretagogue receptor type 1a, which is a Gaq 11-PKC pathway-coupled receptor. In this case, however, intracellular application of BAPTA did block the synaptic effects of ghrelin (Kola et al., 2008). Hence, it was proposed that ghrelin causes an increase on the intracellular levels of Ca2+, leading downstream to Ca2+-and or PKC-mediated activation of membrane DAG lipase and subsequent

Transient Cotransfection Assay for Exocytosis 1631 General Remarks

The cloning of stable cell lines expressing the protein under study is time consuming, especially when a number of different mutations are being investigated. In contrast, transient transfection is a rapid approach but will lead to (over)expression only in a limited percentage of cells. Therefore a reporter gene for secretion exocytosis must be cotransfected. A first description using growth hormone in chromaffin cells to monitor secretion and exocytosis of large dense core vesicles demonstrated the feasibility of this approach (Holz et a ., 1994, Selden et a ., 1986), using a commercially available kit to determine the release of growth hormone (Nicholls). Each cell line may, however, handle a given secretory product in a distinct fashion. Indeed, the use of growth hormone as a reporter signal is not very efficient in insulin-secreting cells (Lang, 1995b). This is most probably due to differences in postranslational modifications, precursor processing, packing or sorting of the...

Signal transduction and receptor modulation

Key 5HT serotonin ACh acetylcholine AEA anandamide ACTH adrenocorticotrophic hormone CCK cholecystokinin CGRP calcitonin gene-related peptide CRF corticotropin-releasing factor DA dopamine GABA y-aminobutyric acid GH growth hormone Glu glutamate GnRH gonadotropin-releasing hormone LH luteinizing hormone NA noradrenaline PRL prolactin Test testosterone THC tetrahydrocannabinol f increase stimulation decrease inhibition no effect.

Use of Cyclodextrins to Formulate Peptides or Proteins

Aachmann and co-workers reported different effects of CD on different proteins aggregation suppression (if residues responsible for aggregation are highly solvent accessible e.g., insulin 120 , growth hormone 121 , interleukin -2 122 ), protection against degradation (if point of attack of a protease is sterically 'masked' by CD) and alteration of function (if residues involved in the function are 'masked' by CD) 123 . Peptide and protein-CD interactions determine a change in the chemical and biological properties of the peptides and proteins as they are able to alter their three-dimensional structure 124 .

Brain Pituitary Axis

CBs are also involved in neuroendocrine regulation of hormone secretion since cannabinoid exposure affects reproduction, lactation, food intake, and stress. Exposure to D9-THC inhibits the release of gonadotro-phin (LH), prolactin, growth hormone, thyroid-stimulating hormone, and stimulates the release of the stress hormone corticotrophin (for review Murphy et al., 1998 Pagotto et al., 2006). Effects of eCBs on endocrine axis involve several actors. For example, GH inhibition is mediated through somatostatin activation while AEA suppresses prolactin release in male rat through the activation of the tuberoinfundibular dopaminergic system (Pagotto et al., 2006). Direct effect on thyroid gland has been reported (Porcella et al., 2002) the colocalization of CB1 and corticotrophin-releasing hormone (CRH) mRNA, reported in hypothalamic neurons of

Applications of twophoton microscopy

As well as for mapping network organization of neuronal electrical activity, intra-vital two-photon microscopy has been used to map the 3D network organization of pituitary growth hormone (GH)-secreting cells (Bonnefont et al. 2005). Utilizing GFP-GH transgenic mice, GH cells were observed to be highly networked it was shown that the interconnected network organizes during the pubescent stage of mouse development. Observing this development would have been significantly more challenging through conventional imaging of serial sections. It was also possible to measure the electrical activity in individual GH cells through Ca2+ levels and the team discovered extensive inter-cellular electrical coupling coordinating in vivo GH secretion. Observing this 3D network activity would have been possible from serial sections alone furthermore, two-photon microscopy was necessary to resolve subcellular morphology and electrical activity that was at a depth of hundreds of micrometers.

Small Molecule Modulators of Protein Protein Interactions PPI

However, in 1995 a landmark study based on alanine scanning mutagenesis of human growth hormone and its receptor demonstrated that the main contribution to the binding energy derives from contacts with a small fraction of amino acids (hotspots) constituting the protein-protein interface (Clackson and Wells 1995). For the first time it seemed feasible for small molecules to access such hotspots, and it was subsequently shown that small-molecule inhibition of protein-protein interactions is possible (Fischer and Lane 2004 He et al. 2005 Oltersdorf et al. 2005). Another strategy is exemplified by binding of a small molecule to the cytokine IL-2 which induces changes in the protein surface via low-energy rearrangement of some hotspot side chains, thereby interfering with receptor binding of the cytokine (Arkin et al. 2003). In these cases, the discovery of small-molecule inhibitors of PPIs has depended on applied screening methods rather than on in silico approaches based on the target...

Brattleboro Rat Retention Deficit I A Primary or Secondary Effect of VP Deficiency

Bailey and Weiss (1981) suggest that the HODI retention deficits that have been observed in avoidance tasks may represent secondary rather than primary effects of chronic VP deficiency. These include increased plasma levels of OT (released by the chronic state of mild dehydration), deficiency in growth hormone (may be responsible for the smaller size of HODI rats), and decreased responsiveness of the pituitary-adrenocortical system to some stressors associated with decreased release of corticotropin-releasing factor (CRF) and reduced anterior pituitary responsiveness to CRF, both of which are reversed by VP treatment . For example, a PA retention deficit could be due to a reduced pituitary-adrenal response to FS in the learning trial (Weiss et al., 1969, 1970). However, the finding that a single injection of DG-AVP promptly reversed the PA retention deficit without correcting the diabetes insipidus disorder suggested that the VP deficiency had a primary effect on retention (De Wied et...

Formulation Applications

Pharmaceutically viable formulation applications include topical, pulmonary, depot and implantable drug delivery systems (Bhardwaj and Blanchard, 1996 Cleland andJones, 1996 Schwendeman etal., 1996 Johnson etal., 1997 Schwendeman et al., 1997 Carrasquillo et al., 1999 Stevenson et al., 1999 Wright et al., 2001 Kikwai et al., 2004). Simple depot formulations, designed to decrease dissolution rates, have used non-aqueous conditions to achieve controlled release. Growth hormone has also been suspended in oil for depot injections (Yu etal., 1996).

Role Of Heteromerization In Functional Interactions Of Gpcrs

Somatostatin (SST) was first characterized as an inhibitor of pituitary secretion of growth hormone, but some evidence suggests that this peptide is nociceptive. SST is released in the spinal cord in response to thermal (82) or inflammatory (83) stimuli. Intracerebrovascular injection of SST decreased the threshold to thermal stimulus (84), whereas i.t. administration of antagonist (85) or antibody (86) was antinociceptive against thermal or inflammatory pain, respectively. However, other studies have challenged the notion that SST has nociceptive effects at subtoxic doses (87), and one study reported that SST administered intrathecally reduced pain in two cancer patients (88).

Perspective of the Market

The market for animal health products is often divided into two main areas pharmaceuticals and biologicals. In simple terms, pharmaceuticals are medicines to treat and cure animals, while biologicals are vaccines to prevent diseases. However, things can get muddled. Protein drugs like bovine growth hormone are not vaccines but often can be called a biological and may be classified as pharmaceuticals. Sometimes a third class is nutritionals, which cover products like selenium supplements for livestock or vitamins for companion animals. Medicinal and nutritional feed additives can be another designation. In addition there is the pet food and pesticide herbicide industries and their respective products. Therefore, it is important when examining sales figures for companies that an understanding of what is being reported is clear. For example, in 2001, the reported animal health market was 17 billion (this figure includes pharmaceuticals, biologicals, feed additives, and nutritionals) (1)....

Pituitary Hormones And Their Hypothalamic Releasing Hormones

Anterior pituitary hormones are classified into three different groups based on their structural features. Growth hormone (GH) and prolactin (PRL) belong to the somatotropic family, which in humans also includes placental lactogen. The glycoprotein hormones thyroid-stimulating hormone (TSH, also called thyrotropin), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) share a common a-subunit but have different (3-subunits that determine their distinct biological activities. Placenta-derived human chorionic gonadotropin (hCG) also is a member of the glycoprotein hormone family. Corticotropin (adrenocorticotropic hormone ACTH) and a-melanocyte-stimulating hormone (a-MSH) are part of a family of peptides derived from pro-opiomelanocortin (POMC) by proteolytic processing (see Chapter 21). Hypothalamic releasing hormones, peptides released by hypothalamic neurons in the median eminence, positively regulate the secretion of anterior pituitary hormones. These releasing factors...

Manufacturing Methods For Nanoparticles

Nanoelectromechanical systems (NEMS) and microelectromechanical systems (MEMS) are emerging technologies for generating electrical or mechanical devices in the nanometer to micrometer size range. Use of biocompatible polymers like polymethylmethacrylate (PMMA) and polydimethylsiloxane (PDMS) as alternatives to silicon in NEMS MEMS has made these technologies available for biological applications such as controlled drug delivery (46). NEMS and nanotechnology in general have laid the foundation for nanosur-gery, biological prostheses, imaging, biological tagging, biotechnology, and drug delivery. NEMS has the potential to address the unmet need in the programmed delivery of biological macromolecules. Indeed, slow zero-order release of radiolabeled bovine serum albumin has been achieved with a 13 nm nanopore membrane loaded with the protein (47). The release follows non-Fickian diffusion kinetics as pore diameter approaches the hydro-dynamic diameter of the solute. Further, a...

Physiology and disease relevance

Galanin has been found to influence several physiological processes, such as cognition and memory, the release of various neurotransmitters and hormones, feeding, motility of the digestive tract, nociception, nerve regeneration, and sexual behaviour and reproduction (Bartfai etal. 1993 Crawley 1996, 1999). In most cases, galanin acts as a hyperpolarizing peptide, like in pancreatic P-cells, where it suppresses the release of insulin. The only reported stimulatory action of galanin on the release of a signal substance is on the release of growth hormone in the anterior pituitary, where growth hormone release is increased after i.v. galanin injection in humans. Judging from the intracellular coupling and widespread distribution observed for rat GalR2 mRNA, there are many suggested roles for this receptor. GalR2 may mediate the effects of galanin on the release of prolactin and growth hormone, and regulate lactation, feeding, memory, emotion, nociception, nerve regeneration,...

Neuroendocrine Alterations

Hormones such as cortisol, growth hormone (GH), and thyroid hormone can be affected particularly in patients with an altered HPA axis. Studies have reported increased levels of adrenocortical trophic hormone (ACTH) and decreased levels of insulin-like growth factor (IGF-1), triiodothyronine (T3), GH, estrogen, and urinary cortisol.44

Prolactin Physiology Regulation and Secretion

PRL a hormone in the regulation of lactation, named by Riddle et al. 2 , is today known to have over 300 separate biological activities 1 including reproduction (lactation, leuteal function, reproductive behaviour) and homeostasis (immune response, osmoregulation, angiogenesis). Human PRL consists of 199 amino acids and has similar structure, binding and functional properties as growth hormone 1 . PRL synthesis and secretion in humans is mainly from lactotrope cells in the anterior pituitary gland and is largely regulated by dopamine (inhibitory), although thyrotropin-releas-ing hormone (PRL release) plays a small role. To a much lesser extent, PRL can be synthesised in several other locations such as the hypothalamus, placenta and mammary gland. The links between the hypothalamus and pituitary gland are important for normal PRL secretion 8 and interference with this linkage will break the inhibitory effect of dopamine resulting in HPRL.

Immune Alterations In Depressed Patients

Compared to healthy out-patient controls, although this reduction was not correlated with severity of depression as reflected by Hamilton scores. Despite the well known inhibitory action of glucocorticoids on immune activity, the decrease in lymphoprolif-eration was not related to the HPA axis hyperactivity (Cosyns, Maes, Vandewoude, Stevens, De Clerk, & Schottel, 1989 Kronfol & House 1985), as assessed by the dexamethasone suppression test (DST). Indeed, depression of lymphoproliferation was equally found in both DST positive and DST negative patients (Albrecht, Helderman, Schlesser, & Rush, 1985). However, others authors (Maes, Bosmans, Suy, Minner, & Raus, 1989 Maes, Bosmans, Suy, Vandervorst, Dejonckheere, Minner, & Raus, 1991) did find an inverse correlation between lymphocyte proliferation and Cortisol levels. The decrease of mitogenesis has also been found to be inversely correlated to the turn-over of norepinephrine and the age of the patients (Maes et al.,...

Shark Novel Antigen Receptors Hie Next Generation of Biologic Therapeutics

The world of pharmaceutical development and the treatment of disease were revolutionized in 1982 when the first recombinant protein drug, insulin, was approved for human use. This event was the direct result of previous momentous achievements, notably in 1972 when Paul Berg at Stanford produced the first recombinant DNA (rDNA) and the following year when Herbert Boyer first transformed E. coli bacteria with a rDNA plasmid that included a gene encoding a human protein. Boyer went on to establish Genentech, the worlds largest Biotechnology Company. The reason that this was possible at all is that the same genetic code is shared by all living organisms, reflecting their common ancestry. Initially clinical developments concentrated on generating recombinant versions of human proteins for the treatment of deficiencies, such as Factors VII, VIII and IX for blood clotting disorders andhuman growth hormone (hGH). Other popular products were cytokines, eg. interleukins, interferons and

Muscarinic M3 Receptors

Brain muscarinic M3 knockout mice exhibit a dwarf phenotype associated with a pronounced hypoplasia of the anterior pituitary gland and a marked decrease in pituitary and serum growth hormone (GH) and prolactin. These data suggest critical role for central M3 receptors in promoting longitudinal growth (Gautam et al.

Role of Hippocampus and Amygdala in Glucocorticoid Negative Feedback

There are several types of inherited enzymatic defects in Cortisol synthesis which result in congenital adrenal hyperplasia (CAH), also known as the adrenogenital syndrome (Orth et al., 1992). By far the most common form is due to a deficiency of P-45021 (21hydroxylase see Figure 4). Excessive androgen secretion results from a failure of glucocorticoid negative feedback and consequent high ACTH secretion. High androgen levels may lead to virilization of females in utero. About two-thirds of patients also have mineralocorticoid deficiency resulting in salt wasting. If not obvious during the neonatal period, androgen excess may appear in early infancy, resulting in sexual precocity in boys and clitoral enlargement and pubic hair growth in girls. Excess androgen accelerates linear growth and epiphyseal closure leading ultimately to diminished adult height. In adult women with untreated CAH, reproductive function is impaired due to (1) disturbance of normal menstrual cycles as a...

Features of Prader Willi Syndrome

Prader-Willi syndrome is a congenital disease with an incidence of about 1 in 8,000 to 20,000 live births. Prader-Willi syndrome is the most common genetic cause of marked obesity in humans. The excess weight causes type II diabetes as a major complication. This makes PWS the most frequent genetic cause for type II diabetes (Butler et al. 2006). Early PWS is characterized by a failure to thrive, feeding difficulties and hypogonadism. Later, the patients are characterized by short stature and develop mild to moderate mental retardation, behavioral problems and hyper-phagia that leads to severe obesity. Children with PWS show low levels of growth hormone, Insulin-like growth factor 1 (IGF-I), and insulin as well as elevated levels of ghrelin (Eiholzer et al. 1998a, b Cummings et al. 2002) and often exhibit central adrenal insufficiency (de Lind van Wijngaarden et al. 2008). Subsequently, growth hormone substitution was approved for treatment of children with PWS (Carrel et al. 2006)....

O Recombinant Drug Products Hormones

HUMAN GROWTH HORMONE, RECOMBINANT105-106 hGH is a protein that is essential for normal growth and development in humans. hGH affects many aspects of human development and metabolism including longitudinal growth, regulation (increase) of protein synthesis and lipol-ysis, and regulation (decrease) of glucose metabolism. hGH has been used as a drug since the 1950s, and it has been extremely successful in the treatment of classic growth hormone deficiency, chronic renal insufficiency, Turner syndrome, failure to lactate in women, and Prader-Willi syndrome. In its long history, the hormone has been remarkably successful and free of side effects.

Hypothalamic Pituitary Adrenal HPA Axis in Depression CRF

Neurotransmitters Concentration

CRF, which is increased in cerebral spinal fluid (CSF) and plasma in some depressed patients, activates the sympathetic nervous system and inhibits gastric emptying as well as gastric acid secretion. CRF also inhibits the secretion of growth hormone (35). After injection of CRF, the amount of ACTH released is less in depressed patients than in normal subjects (44, 45). This blunted ACTH secretion suggests that there is increased central CRF release (46, 47), since, in animals, stress and adrenalectomy lead to hypersecretion of CRF and downregulation of receptors in the anterior pituitary (48). The Hypothalamus-Pituitary-Thyroid (HPT) Axis, Growth Hormone, Somatostatin, and Prolactin in Depression Growth hormone (GH) and somatostatin, the hypothalamic GH suppressing factor, regulation have also been found to be altered in depression. A change in the diurnal rhythm of GH may be reflected by increased plasma concentrations (91), a finding that is opposite in direction to what would be...

The Macrophage Theory Of Depression

What causes the adrenal steroid abnormalities in depression One possibility is that the elevated proinflammatory cytokine IL-1 is at least partly responsible. It is known that IL-1 has a direct action on the hypothalamus leading the increased release of CRF. In vitro, IL-1 has been shown to stimulate ACTH and growth hormone secretion (Goetzl, Screedharan, and Harkonen, 1988) these effects are not shared by the

Neuroendocrine Effects

The administration of m agonists increases the concentration of prolactin in plasma, probably by reducing the dopaminergic inhibition of its secretion. The administration of morphine or b-endorphin has little effect on the concentration of growth hormone in plasma. With chronic administration, tolerance develops to the effects of morphine on hypothalamic releasing factors. Patients maintained on methadone reflect this phenomenon in women, menstrual cycles that had been disrupted by intermittent use of heroin return to normal in men, circulating concentrations of LH and testosterone return to the normal range.

Radiological Contrast Agents

Severe reactions are those that are life-threatening. They include sudden cardiovascular collapse and death, as well as severe hypotension severe shortness of breath, wheezing, or laryngoedema loss of consciousness massive hives and an-gioneurotic edema ventricular cardiac arrhythmias angina and myocardial infarction. Treatment depends on the patient's signs and symptoms and includes intravenous fluids, oxygen, various drugs (including epinephrine, diphenhydramine, and atropine), and possible cardiopulmonary resuscitation (CPR).

Eicosanoid Catabolism

ENDOCRINE SYSTEM A number of endocrine tissues respond to PGs. In a number of species, the systemic administration of PGE2 increases circulating concentrations of adrenocorti-cotropic hormone (ACTH), growth hormone, prolactin, and gonadotropins. Other effects include stimulation of steroid production by the adrenals, stimulation of insulin release, and thyrotropin-like effects on the thyroid. The critical role of PGF2a in parturition relies on its ability to induce an oxytocin-dependent decline in progesterone levels. PGE2 works as part of a positive-feedback loop to induce oocyte maturation required for fertilization during and after ovulation.

Classic Neurotransmitters and the Monoamine Hypothesis of Depression

Increased glucocorticoid activity leads to altered or decreased prefrontal cortical DA metabolism (149, 150) and increased mesolimbic DA activity (149). DA is also known to be a prolactin (PRL) release-inhibiting factor since it is released by the arcuate nucleus of the hypothalamus where it binds to the D2 receptor inhibiting the activity of the acidophilic cells of the anterior pituitary, thereby blocking PRL and also growth hormone release. Thus, the blunted PRL response to a serotonergic agent, seen in depressed patients, could involve a dopaminergic component, especially in light of well-known 5-HT-DA interactions (96).

Recombinant therapeutic hormones

An additional recombinant hormone preparation which gained regulatory approval in the 1980s was Protropin (recombinant human growth hormone, hGH). It was approved by the FDA in 1985 for the treatment of growth deficiency in children. Since then, various additional recombinant hGH preparations have gained approval for this and additional supplementary indications (Table 7) (33, 34). The approval of a recombinant form of hGH in 1985 coincided with the banning of the use of hGH preparations extracted directly from the pituitaries of deceased human donors. In that year, it was discovered that a young man who had died from Creutzfeldt-Jacob disease contracted this fatal condition from an infected batch of pituitary-derived hGH. (Unlike insulin, for example, growth hormone is relatively species specific, so animal-derived preparations exhibit little or no biological activity when administered to humans). Growth hormone Growth hormone Growth hormone

Fc Engineering to Modulate Pharmacokinetics

While encouraging in principal, these studies suffered from the heterogeneous preparations that were generated. Glutaraldehyde conjugation to albumin was random, and stoichiometry was difficult to control. Further, bio-activity of the conjugated protein was often compromised. For example, in a study conjugating porcine growth hormone (GH) to albumin, the average complex consisted of two molecules of albumin and six molecules of GH and although the conjugate increased the half-life of GH from five minutes to two to three hours, it did not stimulate growth in hypophysectomized rats (109).

Hypothalamic PituitaryAdrenal Axis Dysfunction in Schizophrenia

Dexamethasone leads to growth hormone release in healthy controls a response dependent upon dexamethasone acting on GR located within the hypothalamus 33 . In schizophrenia, Thakore et al. 34 have shown that dexamethasone-induced growth hormone responses are blunted, indicating either a central reduction or dysfunction of GR.

Transport Across the Epithelial Barrier

Harris (27) reported that nasal administration of biopharmaceuticals (polypeptides) resulted in bioavailabilities of the order 1 to 20 of administered dose, depending on the molar mass and physiochemical properties of the drug. It is widely accepted that macromolecules with a molar mass of less than 10,000 can be absorbed from the nasal epithelium into the systemic circulation in sufficient amounts without the need for added materials, except for bioadhesives (28). Larger molecules, such as proteins e.g., interferon, granulocyte colony-stimulating factor (G-CSF), and human growth hormone , however, require both a penetration enhancer (e.g., bile salts and surfactants) and a bioadhesive. Since the entire dose passes through one tissue, these flux enhancers may cause deleterious effects to the nasal mucosa and muciliary function. Cyclodextrins (29) and phospholipids (30) have been reported to significantly increase the absorption of macromolecules without causing any damage to the nasal...


Pharmacological Effects of Ethanol on the Nervous System, 1996, Richard A. Deitrich Immunopharmaceuticals, 1996, Edward S. Kimball Chemoattractant Ligands and Their Receptors, 1996, Richard Horuk Pharmacological Regulation of Gene Expression in the CNS, 1996, Kalpana Merchant Experimental Models of Mucosal Inflammation, 1995, Timothy S. Gaginella Human Growth Hormone Pharmacology Basic and Clinical Aspects, 1995,

Family 2 GPCRs

The secretin receptor family or the glucagon VIP calcitonin receptor family (Family 2) comprises receptors for secretin, glucagon, VIP, calcitonin, PTH, PTHrP, glucagon-like peptide 1, gastric inhibitory polypeptide, growth hormone-releasing hormone, corticotropin-releasing factor, and pituitary adenylate cyclase-activating peptide (see Part 3). The GPCR Family 2, the second largest family, recruits about 60 members and is characterized not only by the lack of the structural signature sequences present in the Family 1, but also by the presence of a large N-terminal ectodomain. The long and complex disulfide-bonded amino-terminal ecto-domain of these receptors plays an important role in agonist binding. Six cysteine residues within the N terminus, two cysteine residues connecting the e1 and e2 loops and about a dozen residues within the TMD core are well conserved among members of this family (Ulrich et al. 1998). Typically these receptors couple to more than one G protein, with the Gs...


Although the underlying mechanisms are largely unknown, steroids have been administered for their appetite-stimulating and weight-enhancing properties. The best example is megasterol acetate (a synthetic form of the hormone progesterone), which is reported to improve appetite and promote weight gain in patients with cystic fibrosis, AIDS, and cancer, as well as in the frail elderly (Chinuck et al. 2007). Treatment often involves very high doses (up to 800 mg per day) and is associated with a wide range of, often serious, side effects, with the consequent risks to the patient potentially overriding any desired clinical benefits. In addition, the weight gain that accompanies improved appetite with megasterol may result primarily from an increase in adipose mass rather than of lean tissues, the loss of which is a critical factor in the wasting associated with disease and aging. Growth hormone and testosterone have been shown in some trials to promote increases in lean body mass. However,...

Ogene therapy

Gene therapy arguably represents the ultimate application of rDNA technology to the treatment of disease. There are two ways to envision gene therapy (a) the replacement of a defective gene with a normal gene or (b) the addition of a gene whose product can help fight a disease such as a viral infection or cancer. In the former case, replacement of a defective gene, an actual cure can be effected instead of just treating the symptoms. For example, in CF, a defective gene has been clearly identified as the cause of the disease. It is possible that replacement of the defective gene with a corrected one could produce a cure. Similar possibilities exist for other inherited genetic disorders such as insulin-dependent diabetes, growth hormone deficiency, hemophilia, and sickle cell anemia.

Therapeutic Uses

The capacity of clonidine to activate postsynaptic a2 receptors in vascular smooth muscle has been exploited in a limited number of patients whose autonomic failure is so severe that reflex sympathetic responses on standing are absent postural hypotension is thus marked. Since the central effect of clonidine on blood pressure is unimportant in these patients, the drug can elevate blood pressure and improve the symptoms of postural hypotension. Among the other off-label uses of clonidine are atrial fibrillation, attention-deficit hyperactivity disorder (ADHD), constitutional growth delay in children, cyclosporine-associated nephrotoxicity, Tourette's syndrome, hyper-hidrosis, mania, posthepatic neuralgia, psychosis, restless leg syndrome, ulcerative colitis, and allergy-induced inflammatory reactions in patients with extrinsic asthma.


Drome, GI hypermotility of carcinoid syndrome, and migraine prophylaxis. Cyproheptadine is not, however, a preferred treatment for these conditions. Side effects of cyproheptadine include those common to other Hj receptor antagonists, such as drowsiness. Weight gain and increased growth observed in children have been attributed to impaired regulation of growth hormone secretion.


Variety of species manganese deficiency results in skeletal defects of decreased length and thickened long bones and swollen, enlarged joints.16 The primary etiological factor is a defect in the synthesis of proteoglycans as a result of diminished glycosyltransferase activities. In manganese-depleted rats given subcutaneous implants of bone particles, both osteogenesis and osteoclastic activities were impaired. In humans, women with osteoporosis have been reported to exhibit low concentrations of the mineral in plasma16 and an enhanced response to an oral load. Serum levels of manganese also have been correlated with bone density. When supplements containing manganese, calcium, zinc and copper were given for 2 years to postmenopausal women, the combination was more effective in improving spinal bone mineral density than either calcium or trace minerals alone.69 Also, a case study reported that a young girl on a manganese-free TPN since day 9 after birth exhibited short stature,...

Growth on the KD

Vining and colleagues (26), who reported prospectively on the growth of 237 children treated with the KD, found that the oldest children appear to grow taller almost normally but there was a suggestion that younger children fell more than 2 SD below the mean in height or stature change that is, they grew poorly.

Ronald A Hill

A large and growing number of medicinal substances act on endocrine systems. Many are steroid analogs (i.e., ligands for estrogen, progestin, and androgen receptors), and, as suggested by the title of this chapter, will not be considered herein, but instead in Chapter 25. Neither will all nons-teroidal endocrine modulators be considered in the present chapter, however. Medicinals acting to modulate calcium deposition and resorption, particularly within bone, are discussed in Chapter 21 (including ligands for vitamin D receptors, parathyroid hormone receptors, and calcitonin receptors). Coverage of thyroid hormones, and of agents for treating hyperthyroid states, has been retained in Chapter 19 for this edition of the text. Numerous other endocrine system interventions are, at present, solely accomplished by administering a naturally occurring human protein produced by artificial means. For now, agents of this nature receive primary consideration within a chapter dedicated to biologics...

Reporter Based Assays

Depending on the target of interest and their endogenous expression levels in the cell, transfection with additional genes may be necessary, e.g. a specific GTP-ase interacting with a distinct GPCR in the signaling cascade. Usually, the reporter gene construct consists of a gene encoding a reporter molecule that can easily be measured and quantified. The reporter gene is under the control of a promoter sequence linked to the transcriptional control region of interest. Specificity and sensitivity of the system are controlled by the choice of the promoter and the transcriptional control region, which determine the basal expression level and the degree of transcriptional response. Other factors influencing the sensitivity of the system are the stability of the reporter molecule in the cell and the dynamic range of the reaction. A short half-life of the reporter molecule is important for minimal baseline accumulation of the signal and hence a high dynamic range....


Although plasma protein binding of macromolecules is generally not considered to be an issue that is sufficiently important to be automatically evaluated, there are studies that do indicate that there are binding proteins for macromolecules (5). For example, six specific binding proteins were identified for insulin-like growth factor 1 (IGF-1), with IGFBP-3 (insulin-like growth factor binding protein-3) being the most important binding protein. The elimination half-life of bound IGF-1 was comparatively longer (three to four hours) than that of unbound IGF-1 (10 minutes). For growth hormone (GH), at least two binding proteins have been identified one with high binding affinity and the other with low affinity. The clearance of unbound GH is 10 times faster than that of bound GH (5). There are many other drugs such as IFN, interleukins (ILs), and tumor necrosis factor (TNF) for which specific binding proteins have been identified (5).


Current data do not support a significant effect on a-adrenergic receptor affinity or density by the SSRIs. Studies using radiolabeling to investigate fluoxetine (Wong et al. 1985) have shown relative inactivity at this site. Fluoxetine has been reported to reduce desipramine-induced release of growth hormone after 4 weeks of treatment (O'Flynn et al. 1991). This effect suggests a possible indirect activity at the 1 2-adrenergic receptor.


Prolactin belongs to a large family of proteins known as group I of the helix bundle protein hormones 15 , other members of which include growth hormone, placental lactogen and a multitude of prolactin-related proteins. All genes encoding this group share a certain degree of homology (e.g. 40 homology between PRL and GH genes) due to their evolution from a single common ancestral gene approximately 400 million years ago 16 . Such homogeneity leads to a certain degree of functional overlap between group members, such as the capability of human GH to bind to the PRL receptor and thus to mimic some of PRL's actions. PRL, however, has a much more diverse spectrum of action compared to GH, being involved in a broad array of functions extending from reproduction and lactation to roles in metabolism, behaviour, immunoregulation and osmoregulation 17 .

Pituitary Hormones

The pituitary gland, or the hypophysis, is located at the base of the skull and is attached to the hypothalamus by a stalk. The pituitary gland plays a major role21 in regulating activity of the endocrine organs, including the adrenal cortex, the gonads, and the thyroid. The neurohypophysis (posterior pituitary), which originates from the brain, and the adenohy-pophysis (anterior pituitary), which is derived from epithelial tissue, are the two embryologically and functionally different parts of the pituitary gland. The adenohypophysis is under the control of hypothalamic regulatory hormones, and it secretes adrenocorticotropic hormone (ACTH), growth hormone (GH), LH, FSH, prolactin, and others. The neurohypophysis is responsible for the storage and secretion of the hormones vasopressin and oxytocin, controlled by nerve impulses traveling from the hypothalamus.


Glycosaminoglycans are also often termed proteoglycans however, this latter term actually refers to a protein that is modified by one or more glycosamino-glycan chains. Glycosaminoglycans are comprised of four distinct types of sulfated, linear oligosaccharide polymers (Figure 5). Glycosaminoglycan synthesis may be generally characterized by chain initiation, polymerization, and modification, via the actions of different glycosyltransferases, sulfotransferases, and epimerase and deacetylase activities. Glycosaminoglycans are implicated in growth factor binding, presentation, and internalization, as well as in cell adhesion and the maintenance of extracellular matrix integrity reviewed in (128-130) . Mutational inactivation of genes required for glycosaminoglycan synthesis currently involves those relevant to heparan sulfate synthesis. EXT1 and EXT2 are GlcNAc and GlcA glycosyltransferases that contribute to the biosynthesis of heparan sulfate (HS) glycosaminoglycans (131-133)....

Class B GPCRs

Growth Hormone-Releasing Hormone Receptor Nine distinct inactivating mutations have been described in the growth hormone-releasing hormone receptor (GHRHR). Loss-of-function of GHRHR leads to severe growth retardation, associated with isolated growth hormone deficiency. Six of the nine currently identified mutations are missense and were found to be defective in signaling, though the mechanism for the dysfunction is not clear due to the lack of detailed binding and subcellular localization studies 215 .

Hormonal Regulation

During the 1990s, different studies described the existence of a highly conserved evolutionary pathway that would regulate longevity the insulin IGF-I axis 256-259 . Dietary restriction is characterized by a reduction in insulin, growth hormone (GH), IGF-I, leptin and thyroid hormone levels in plasma, whereas glucocorticoids, cate-cholamines and glucagon concentrations increase during dietary restriction 260 .

SIRT1 and T2D

In this regard, the function of SIRT1 in the brain is interesting. In the hypothalamus, SIRT1 protein levels increase in the DMH, LH, and SCN (Satoh et al. 2010) under CR. Increasing SIRT1 in the brain of transgenic mice (brain-specific Sirt1-overexpressing transgenic mice BRASTO mice) enhances neural activity in the DMH and LH, maintains body temperature, and promotes physical activity by increasing the expression of orexin type-2 receptor, a G protein-coupled receptor that binds to the neuropeptide hormone orexin. Moreover, BRASTO mice are more responsive to ghrelin, a gut hormone whose plasma level is increased under CR, than wildtype littermate, suggesting the function of SIRT1 in the hypothalamus, particularly in the DMH and LH, as a key mediator of the central adaptive response to CR (Satoh et al. 2010). These results support the idea that increasing hypothalamic SIRT1 activity mediates neurobehavioral adaptation to CR. Additionally, it has been reported that SIRT1 in the brain...


Appetitive behavior is complex and multifaceted. Stress reactivity, both physiological and psychological, may distinguish overeaters from underea-ters 196 . There is much evidence from animal studies that HPA axis function can profoundly influence expression of appetite and regulation of body weight 6 . The recently discovered new gut peptide, ghrelin, an endogenous ligand for the growth hormone secretagogue receptor 197 , seems to be involved in the control of food intake and energy balance. in fact, centrally injected ghrelin produces a sustained food intake in rodents, and ghrelin blood concentrations and mRNA expression in the stomach are increased by fasting and decreased by feeding 198 . Recent data have suggested a possible stimulatory effect of ghrelin on the HPA axis activity in experimental animals 199 . In humans, gherlin has a positive effect on glucose levels and negative effects on insulin concentrations 200 . Ghrelin concentrations are decreased in human obesity 201 .

Physical Stability

One way to describe the unfolding process is the two-state model shown in Figure 4. It is an equilibrium, a single-transition step between the folded native (N) and the disordered, unfolded or denatured (D) species (36-38). An intermediate step, the formation of possible intermediates (I), can be present between the transformation from N to D. The intermediate state (I) has often been described as the molten globule, for example, for growth hormone (39). It is a stable compact, partly denatured species, which retains some ordered secondary structure but not the tertiary structure of the native protein (35,36,40,41). The aggregate (A) formed may occur from irreversible changes to the unfolded species (18,42 14).

Acute Inflammation

Chronic inflammation is also seen in injection sites where cell-mediated immune reactions are elicited by the bioactive agent, which functions as an antigen to initiate this response. Figure 6 demonstrates the expected response when an antigen, recombinant human growth hormone, is released into another FIGURE 6 Chronic inflammatory response secondary to release of a bioactive agent from PLGA microparticles at 14 days' implantation. (A) Marked focal chronic inflammatory response (arrows) with monocytes and lymphocytes at the tissue particle aggregate interface of recombinant human growth hormone-containing (Nutropin ) PLGA microparticles. (B) Focal macrophage and foreign body giant cell responses to placebo PLGA microparticles. Hematoxylin and eosin stain. Abbreviation PLGA, polylactic acid-glycolic acid. FIGURE 6 Chronic inflammatory response secondary to release of a bioactive agent from PLGA microparticles at 14 days' implantation. (A) Marked focal chronic inflammatory response...


The neuropeptide somatostatin was first identified in the hypothalamus as a tetradecapeptide (Brazeau et al. 1973). Other peptides of the somatostatin family, all of which are derived from the prosomatostatin protein, include somatostatin-28 and somatostatin-281-12 (Benoit et al. 1982). The hypothalamus and limbic regions such as the amygdala and hippocampus have large numbers of somatostatin-containing neurons. A small number of somatostatin neurons are localized to the cerebral cortex and are particularly abundant in layers 2-3 and layers 5-6 (Epelbaum et al. 1994). Somatostatin-containing neurons in the cerebral cortex have a nonpyramidal morphology and contain GABA (Hendry et al. 1984). The principal somatostatinergic tract projects from the anterior periventricular nucleus of the hypothalamus to the median eminence (Patel 1999). This projection inhibits secretion of growth hormone, thyroid-stimulating hormone, and prolactin from the adenohypophysis (Epelbaum et al. 1994). The...

Breast Biology

These cycles are controlled by a combination of hormones and locally produced growth factors. The pubertal growth phase is stimulated by estrogens from the ovaries, which become active at this time, and by growth hormone and its 'somatomedin' mediators IGF1 and IGF2. The monthly cycles are controlled mainly by estradiol and progesterone, supported by insulin and further hormones. During the first phase of the monthly cycle, follicle cells secrete mostly estrogens. After release of the oocyte gestagens like progesterone are the major product. Unless fertilization takes place, the follicle degenerates and minimal estrogen and progesterone levels elicit an involution phase in the breast and, more pronounced, in the uterus endometrium. The pregnancy growth phase is stimulated by several hormones, including gestagens, estrogens, growth hormone and insulin, but also glucocorticoids and, of course, prolactin. As in other tissues, proliferation of epithelial cells in the breast is supported...

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