Biopharmaceuticals Hypothalamo Pituitary Regulatory Hormones PDF

Biopharmaceuticals Hypothalamo Pituitary Regulatory Hormones Dr Elnaz Mehdizadeh Aghdam PharmD, PhD Assistant Professor Pharmaceutical Biotechnology Department Faculty of Pharmacy  Hypothalamo pituitary regulatory target organ axes  Hypo...

Biopharmaceuticals Hypothalamo Pituitary Regulatory Hormones Dr Elnaz Mehdizadeh Aghdam PharmD, PhD Assistant Professor Pharmaceutical Biotechnology Department Faculty of Pharmacy  Hypothalamo pituitary regulatory target organ axes  Hypothalamic-pituitary axis GnRH - gonadotrophin releasing hormone; CRH - Corticotrophin releasing hormone; TRH - Tirotrophin releasing hormone; PRH – Prolactin releasing hormone; GHRH - Growth hormone releasing hormone  GnRH - Gonadotrophin Releasing Hormone GnRH is a decapeptide (EHWSYGLRPG) synthesized as a 92-aa precursor GnRH acts through its cell surface receptor to increase intracellular calcium, hydrolyze phosphoinositides, and activate protein kinase C GnRH is released every 30–120 minutes to stimulate synthesis of LH and FSH The pentapeptide metabolite GnRH -(1-5) regulate neuronal migration during development  GnRH - Gonadotrophin Releasing Hormone Synthetic: Gonadorelin Analogues including Buserelin, Deslorelin, Goserelin, Histrelin, Leuprorelin, Nafarelin, & Triptorelin Antagonists Abarelix, Cetrorelix, & Ganirelix  GnRH Synthetic Gonadorelin / Lutrepulse Half life 10-40 min Diagnosis of hypothalamic- pituitary-gonadal dysfunction 100 micrograms by IV or SC Treatment of amenorrhoea and infertility associated intermittent pulse pump providing 5 to 20 micrograms over one minute every 90 minutes, either subcutaneously or intravenously, for up to 6 months or until conception Delayed and precocious puberty intermittent pulse pump providing 5 micrograms over one minute every 90 minutes up to 18th years old!  GnRH - Gonadotrophin Releasing Hormone low doses of GnRH given in pulses can induce LH & FSH, and high doses of GnRH given continuously inhibit these two hormones, GnRH analogs have been developed to modulate the GnRH effects for a number of clinical applications. These GnRH therapeutic analogs are modified with D amino acids and derivatives to make them resistant to peptidase and avoid being metabolized GnRH –Agonist Goserelin /Zoladex Palliative treatment of advanced carcinoma of the prostate Zoladex should be administered as a subcutaneous implant at the anterior abdominal wall below the navel line. Continuous release biodegradable 1.5 mm diameter cylinder implant containing either 3.6 or 10.8 mg goserelin acetate. Goserelin acetate is useful for in vitro fertilization and is possibly effective in controlling precocious puberty and early  GnRH –Agonist Leuprolide / Lupron Palliative treatment of advanced prostate cancer Lupron (leuprolide acetate) SC Injection 3.75 mg and Lupron Depot (7.5, 22.5, 30, and 45 mg) management of endometriosis Lupron Depot (3.75 mg and 11.25 mg) Lupron Depot-PED (7.5, 11.25, 15, 30 mg) is indicated in the treatment of children with central precocious puberty. GnRH –Agonist Triptorelin / Trelstar / Diphereline? Palliative treatment of advanced prostate cancer It is available at 3.75, 11.25, and 22.5 mg intramuscular injection The recommended dose is 3.75 mg every 4 weeks, 11.25 mg every 12 weeks, or 22.5 mg every 24 weeks. The evidence favors efficacy for use of triptorelin pamoate to treat CPP (50 microg/Kg) , endometrial hyperplasia (0.1 mg/day) , endometriosis (3.75 GnRH –Agonist Nafarelin / Synarel Management of endometriosis 400 μg/day Treatment of central precocious puberty 1600 μg/day 8 mL Synarel Nasal Solution 2 mg/mL (one spray is equal to 200 μg).  GnRH –Agonist Busereline/ Supprelin In advanced prostatic carcinoma doses of 500 micrograms are injected subcutaneously every 8 hours for 7 days. On the eighth day treatment is changed to the nasal route; 100 micrograms is sprayed into each nostril 6 times daily In endometriosis a dose of 150 micrograms is sprayed into each nostril three times daily. The usual duration of therapy is 6 months, which should not be exceeded. In infertility, pituitary desensitisation before ovulation induction  Therapy should be continued until pituitary downregulation occurs, which normally takes 1 to 3 weeks. 150 micrograms intranasally four times daily, beginning  GnRH –Antagonist Cetrorelix/Cetrotide Cetrorelix is given by subcutaneous injection as the acetate The half-life after a subcutaneous injection of 3 mg is about 60 hours Controls the release of LH and FSH in a dose- dependent manner Prevent LH surges and premature ovulation (infertility) 250 micrograms daily on day 5, and continued until ovulation induction. It has also been tried in benign prostatic hyperplasia, malignant neoplasms of the prostate, endometriosis, and for uterine fibroids.  GnRH –Antagonist Ganirelix It is used as a component of ovarian stimulation regimens for assisted reproduction in infertility 250 micrograms is given once daily, starting on day 6 of ovarian stimulation and continued until ovulation induction.  CRH - Corticotrophin releasing hormone 41 amino acids: Ser–Gln–Glu–Pro–Pro–Ile–Ser–Leu– Asp–Leu–Thr–Phe–His–Leu–Leu–Arg–Glu–Val–Leu–Glu–Met– Thr–Lys–Ala–Asp–Gln–Leu–Ala–Gln–Gln–Ala–His–Ser–Asn–Arg– Lys–Leu–Leu–Asp–Ile–Ala–NH2 with only the C-terminal blocked as an amide. it acts via the cAMP second messenger system Corticorelin  A single dose of 100 micrograms, or of 1 microgram/kg, is given by intravenous injection over 30  TRH - Tirotrophin releasing hormone TRH is a tripeptide with an N-terminal pyroglutamyl residue and a C-terminal prolineamide Acts directly on the anterior pituitary to stimulate release of thyroid-stimulating hormone (TSH), prolactin, and growth hormone (GH). Synthetic material (known as  TRH - Protirelin The diagnosis of mild hyperthyroidism or hypothyroidism is given intravenously, usually in doses of 200 to 400 micrograms Intranasal protirelin has been tried for stimulation of lactation, and in any case mechanical stimulation is preferable to drug treatment Neonatal respiratory distress syndrome?  TRH - Taltirelin Taltirelin is claimed to have Beneficial effects on CNS function. Taltirelin is used in the treatment of spinocerebellar degeneration.  TRH - Posatirelin It is claimed to have beneficial effects on CNS function, and has been investigated in the management of dementia of various causes.  PRH – Prolactin releasing hormone Dopamine is an inhibitor of prolactin secretion Dopamine works by stimulating the pituitary lactotroph D2 receptor to inhibit adenylate cyclase and consequently inhibits both prolactin synthesis and secretion. Several neuropeptides, including TRH, have prolactin-releasing properties, but there is little evidence for a physiologic GHRH - Growth hormone releasing hormone Synthesized as a 108 aa precursor and the active GHRH contains 44 aa residues (Somatorelin). the 44-amino acid form may possibly be converted to the smaller forms (40-, and 37-aa) but all are reported to be active, the activity residing in the first 29 amino-acid residues. Regulates receptor-mediated pulsatile release of growth hormone GHRH - Growth hormone releasing hormone GHRH was originally used as a diagnostic test to determine whether GH deficiency in children was a pituitary (GH release) or hypothalamic (GHRH) defect. Those children deficient in GHRH at the hypothalamic level can benefit from GHRH treatment. Due to the discovery that GHRH has a great effect on fat redistribution; lipolytic effect; (fat reduction) The lack of or lower effects on glycemic indices V.S. the GH  GHRH- Somatorelin; Sermorelin Sermorelin is a synthetic peptide corresponding to the 1–29 amino acid sequence of somatorelin. Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu- Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met- Ser-Arg-NH2 acetate hydrate Synonyms: GRF(1-29)NH2 (sermorelin); Growth Hormone-releasing Factor (Human)-(1-29)-peptide Amide (sermorelin);  GHRH- Sermorelin the diagnosis of growth hormone deficiency. The usual dose is the equivalent of sermorelin 1 microgram/kg by intravenous injection in the morning after an overnight fast. the treatment of growth hormone deficiency in children; doses equivalent to 30 micrograms/kg, as the acetate, may be given once daily at bedtime by subcutaneous injection Sermorelin has also been tried as an adjunct to gonadotrophin therapy in the induction of ovulation  GHRH analog- Egrifta (tesamorelin) Synthetic GHRH that is composed of 29 N-terminal aa residues of endogenous 44 aa GHRH. half-life of approximately 26–38 minutes. Egrifta is believed to cause pituitary somatotroph cells to synthesize and pulsatile release endogenous GH, which is both anabolic and lipolytic, and thus reduces lipodystrophy in HIV patients  Growth-hormone-release- inhibiting Hormone GH-RIF; GHRIH; Somatostatin It is synthesized as a 92-aa precursor and proteolytically cleaved into two active forms, SST-14 aa in hypothalamus and SST-28 aa in other tissues. Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe- Thr-Ser-Cys cyclic (3→14) disulphide (cyclic tetradecapeptide) Intra-disulfide bridge exposes the active biding epitope, Phe-Trp-Lys-Thr.  Growth-hormone-release- inhibiting Hormone GH-RIF; GHRIH; Somatostatin Somatostatin inhibits the release of Growth Hormone Thyrotrophin Corticotropin Glucagon & Insulin appears to have a role in the regulation of duodenal and gastric secretions. appears to play a role in the perception of pain in CNS.  GH-RIF; GHRIH; Somatostatin IV , or slow bolus Injection (250 mcg and 3 mg) can be used to provide relieve in the following condition: – Severe acute haemorrhage from oesophageal varices. – Severe acute haemorrhage from gastric or duodenal ulcers. – Adjuvant treatment in pancreatic, biliary and intestinal fistulae. – Prophylaxis and treatment of postoperative complications following pancreatic surgery. – Adjuvant treatment in diabetic ketoacidosis.  GHRIH- analogues: Octreotide; Lanreotide Somatostatin derivatives, Involves the active domain of Somatostatin with 8 aa residues and D isomeric forms of Trp to reduce susceptibility to proteasedependent SST inactivation (improved biological stability). For treatment of acromegaly or gigantism IM injection of 20–30 mg Octreotide once every 4 weeks or 30 mg Lanreotide once every 2 weeks. To reduce plasma GH level below 2.5 ng/mL.  GHRIH- analogues: Octreotide; Lanreotide SST also blocks secretion of other hormones and cytokines in a number of tissues and cells Is used to treat cancer patients with metastatic carcinoid tumors to inhibit the severe diarrhea and flushing symptoms to treat cancer patients with vasoactive intestinal peptide (VIP) tumors that elicit profuse watery diarrhea associated  Lanreotide Acetate Somatuline Depot Synthetic cyclical octapeptide analog of the natural hormone, somatostatin. Its Mw is 1.09 kDa. It is used to reduce growth hormone (GH) and insulin growth factor 1 (IGF-1) levels to normal. For the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy deep subcutaneous (SC) injection It is available at 60, 90, and 120 mg strengths  Octreotide Acetate Sandostatin, Sandostatin LAR Depot Octreotide acetate is a long acting cyclic octapeptide (Mw 1 kDa) Reduction of blood levels of growth hormone and insulin-like growth factor 1 (IGF-I) in acromegaly patients, symptomatic treatment of metastatic carcinoid tumors, and treatment of profuse water diarrhea associated with intestinal tumors 1 mL ampules / 50, 100, or 500 μg, and 5 mL multidose vials / 200 and 1,000 μg/mL.  Hypothalamo pituitary regulatory target organ axes