Somatostatin

Somatostatin (also known as growth hormone-inhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF)) or somatotropin release-inhibiting hormone^{[citation needed]} is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferationvia interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.

Somatostatin has two active forms produced by alternative cleavage of a single preproprotein: one of 14 amino acids, the other of 28 amino acids.^[1]

In all vertebrates, there exists six different somatostatin genes that have been named SS1, SS2, SS3, SS4, SS5, and SS6. ^[2] The six different genes along with the five different somatostatin receptors allows somatostatin to possess a large range of functions.^[3] Humans have only one somatostatin gene, SST.^[4][5][6]

Production

Digestive system

Somatostatin is secreted in several locations in the digestive system:

§       stomach

§       intestine

§       delta cells of the pancreas^[7]

[Brain

Somatostatin is produced by neuroendocrine neurons of the periventricular nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamo-hypophysial system through neuron axons. Somatostatin is then carried to the anterior pituitary gland, where it inhibits the secretion of growth hormone from somatotrope cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatin neurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone.

Somatostatin is also produced by several other populations that project centrally, i.e., to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, there are populations of somatostatin neurons in the arcuate nucleus^{[citation needed]}, thehippocampus^{[citation needed]}, and the brainstem nucleus of the solitary tract^{[citation needed]}.

Actions

Somatostatin is classified as an inhibitory hormone,^[1] whose actions are spread to different parts of the body:

Anterior pituitary

In the anterior pituitary gland, the effects of somatostatin are:

§       Inhibit the release of growth hormone (GH)^[8] (thus opposing the effects of Growth Hormone-Releasing Hormone (GHRH))

§       Inhibit the release of thyroid-stimulating hormone (TSH)^[9]

§       It is induced by low pH.

§       Inhibit adenylyl cyclase in parietal cells.

Gastrointestinal system

§       Somatostatin is homologous with cortistatin (see somatostatin family) and suppresses the release of gastrointestinal hormones

§       Gastrin

§       Cholecystokinin (CCK)

§       Secretin

§       Motilin

§       Vasoactive intestinal peptide (VIP)

§       Gastric inhibitory polypeptide (GIP)

§       Enteroglucagon

§       Decrease rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine^[8]

§       Suppresses the release of pancreatic hormones

§       Inhibits insulin release when somatostatin is released from delta cells of pancreas^[10]

§       Inhibits the release of glucagon^[10]

§       Suppresses the exocrine secretory action of pancreas.

Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone and has a much longer half-life (approximately 90 minutes, compared to 2–3 minutes for somatostatin). Since it is absorbed poorly from the gut, it is administered parenterally (subcutaneously, intramuscularly, or intravenously). It is indicated for symptomatic treatment of carcinoid syndrome, acute variceal bleeding, and acromegaly. It is also finding increased use in polycystic diseases of the liver and kidney.

Lanreotide (INN) is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analogue of somatostatin, like octreotide.

Boceprevir

Boceprevir (INN, trade name Victrelis) is a protease inhibitor used as a treatment for hepatitis C genotype 1.^[1][2] It binds to HCV nonstructural 3 (NS3) active site.

It was being developed by Schering-Plough,^[3] but is now being developed by Merck since Schering was acquired in 2009. It was approved by the FDA on May 13, 2011

SPRINT-1 trial

The SPRINT-1 trial was a phase II trial of Boceprivir in difficult-to-treat patients with HCV genotype 1.^[3] Study results were announced at the 44th annual meeting of the European Association for the Study of the Liver in Copenhagen in April, 2009. When used in combination with peginterferon alfa-2b and ribavirin, boceprivir use resulted in significantly higher sustained viral response (SVR) rates in the most difficult-to-treat patients with genotype 1.

The phase 2 trial compared 3 different regimens: 4 weeks of peginterferon alfa-2b (1.5 micrograms/kg once weekly) plus ribavirin (800 to 1400 mg daily based on patient weight) followed by boceprevir (800 mg 3 times a day in addition to peginterferon and ribavirin) for 24 weeks or 44 weeks; boceprevir in combination with peginterferon alfa-2b plus ribavirin as above for 28 or 48 weeks (triple therapy); and peginterferon alfa-2b plus low-dose ribavirin (400 to 1000 mg/day) and boceprevir for 48 weeks.

The patients enrolled in the SPRINT-1 study were among the most difficult to treat, and were exclusively those with genotype 1. (The patients were all treatment naive.) Additionally, many of the patients had other difficult-to-treat indices, including cirrhosis (6-9%), high viral load (90%) and African-American ancestry (14-17%). An SVR after 24 weeks off of therapy of 75% was achieved in the group treated for 48 weeks with 4 weeks of lead-in therapy with peginterferon alfa-2b plus ribavirin followed by the addition of boceprivir. This represents a near doubling of the rate of SVR compared to standard therapy without boceprivir in this group.

Anemia was the most common adverse event. It occurred in half of the patients who received boceprivir and by about a third of the patients taking peginterferon alfa-2b plus ribavirin at the standard dose.

The lead investigator of the study was Dr. Paul Kwo, associate professor of medicine at the School of Medicine, Indiana University, in Indianapolis, Indiana, USA. ^[5]

SPRINT-2 trial

The SPRINT-2 trial ^[6] was a double-blind study which randomly assigned adults with untreated hepatitis C virus, genotype 1 to one of three groups. Each group received a month of peginterferon alfa-2b and ribavirin before being randomized to one of three arms. The first arm received placebo plus peginterferon-ribavirin for 44 weeks, the second arm received boceprevir plus plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus plus peginterferon-ribavirin for an additional 20 weeks, and the third arm received boceprevir plus plus peginterferon-ribavirin for 44 weeks. Black patients and non-black patients were enrolled and analyzed separately, since black patients have been shown to respond less well to antiviral therapy with peginterferon plus ribavirin than nonblacks.^[7] 938 nonblack and 159 black patients were enrolled in the study.

At 44 weeks, among the nonblack cohort, there was a 40% sustained virologic response (125 of 311 patients) in the placebo group, a 67% response (211 of 316 patients) in the response-guided boceprevir group, and a 68% response (214 of 311 patients) in the fixed-duration therapy group. Important side effects included anemia and dysgeusia (distortion of the sense of taste).

RESPOND-2 trial

The RESPOND-2 trial^[8] studied patients with chronic hepatitis C genotype 1 who did not have a sustained response to therapy with peginterferon-ribavirin therapy. All patients received a month of peg-interferon alfa-2b and ribavirin before being randomized to one of three arms. The first arm received placebo plus peginterferon-ribavirin for 44 weeks. The second group received boceprevir plus peginterferon-ribavirin for 32 weeks, and those with a detectable HCV RNA level at week 8 received peginterferon-ribavirin and placebo for an another 12 weeks. The third group received boceprevir and peginterferon-ribavirin for 44 weeks.

403 people were treated in the trial. At 44 weeks, the control group had a lower sustained virologic response rate (21%) than either of the groups treated with boceprevir - 59% sustained viral response for the group with response-guided therapy and 66% response for the group with fixed-duration therapy

Bisoprolol

Bisoprolol is a drug belonging to the group of beta blockers, a class of drugs used primarily in cardiovascular diseases. More specifically, it is a selective type β1adrenergic receptor blocker. The FDA approved Duramed Pharmaceutical's application for Zebeta Oral Tablets (Bisoprolol Fumarate) as a new molecular entity on July 31, 1992. It has since been approved by the FDA for manufacture by Teva, Mylan, Sandoz, and Mutual Pharmaceutical Company.^[3]

Clinical use

Bisoprolol is beneficial in treatment for: high blood pressure (hypertension), reduced blood flow to the heart (cardiac ischemia); preventative treatment before and primary treatment after heart attacks decreasing the chances of recurrence.^[4] During hypertension there is an elevated blood pressure, which is what Bisoprolol targets.^[5][6]While in cardiac ischemia the drug is used to reduce the activity of the heart muscle and therefore reduce oxygen and nutrient demand, so reduced blood supply can still transport sufficient amounts of oxygen and nutrients. [24][27][30]

Many beta-blockers are now available and in general they are all equally effective. There are, however, differences between them which may affect choice in treating particular diseases or individual patients.

Beta-blockers with a relatively short duration of action have to be given two or three times daily. Many of these are, however, available in modified-release formulations so that administration once daily is adequate for hypertension. For angina twice-daily treatment may sometimes be needed even with a modified-release formulation. Some beta-blockers such as atenolol, bisoprolol, carvedilol, celiprolol, and nadolol have an intrinsically longer duration of action and need to be given only once daily.

Mechanism of action

Bisoprolol is cardioprotective because it selectively and competitively blocks catecholamine (adrenalin) stimulation of beta-1 adrenergic receptors (β1 adrenoreceptor) mainly found in the heart muscle cells and heart conduction tissue (cardio specific) but also found in juxtaglomerular cells in the kidney [24]. Normally adrenalin and noradrenalin stimulation of the β1 adrenoreceptor activates a signalling cascade (Gs protein and cAMP) which ultimately lead to increased contractility and increased heart rate of the heart muscle and heart pacemaker respectively [23]. Bisoprolol competitively blocks the activation of this cascade and therefore decreases the adrenergic tone/stimulation of the heart muscle and pacemaker cells. Decreased adrenergic tone shows less contractility of heart muscle and lowered heart rate of heart pacemaker [25][28][29].

These are the favourable factors that are decreased and treat hypertension, heart attacks and ischemia. The decreases in contractility and heart rate are beneficial for hypertension because they reduce blood pressure^[5][27] but for preventive measures for heart attacks and cardiac ischemia these decreases in heart rate and contraction decrease the hearts demand for oxygen and nutrients; primary treatment post heart attacks is to prevent recurrence of the infarction [27][30]^[6].

Cautions

Beta-blockers can precipitate asthma and this effect can be dangerous. Beta-blockers should be avoided in patients with a history of asthma or bronchospasm; if there is no alternative, a cardioselective beta-blocker can be used with extreme caution under specialist supervision. Atenolol, bisoprolol, metoprolol, nebivolol, and (to a lesser extent) acebutolol, have less effect on the beta2 (bronchial) receptors and are, therefore, relatively cardioselective, but they are not cardiospecific. They have a lesser effect on airways resistance but are not free of this side effect.

Side effects

Overdose of bisoprolol leads to fatigue, hypotension[27], low blood sugar [29], bronchospasms and bradycardia [27]. Bronchospasms and low blood sugar because at high doses drug can be an antagonist for β2 adrenergic receptors located in lung and in liver. Bronchspasm due to blockage in lungs of β2 receptor and low blood sugar because of decreased stimulation of glycogenolysis and gluconeogenesis in the liver via β2 receptor.

Dose:5-10mg once in a day

TAMSULOSIN

Tamsulosin (rINN) ( /tæmˈsuːlɵsɨn/ or /tæmsʉˈloʊsɨn/) is an α_1a-selective alpha blocker used in the symptomatic treatment of benign prostatic hyperplasia (BPH). Tamsulosin was developed by Yamanouchi Pharmaceuticals (now part of Astellas Pharma) and was first marketed under the trade name Flomax. It is now marketed by various companies under licence, including Boehringer-Ingelheim and CSL.

Tamsulosin hydrochloride extended-release capsules are marketed under the trade names Flomax, Flomaxtra, Contiflo XL and Urimax, although generic, non-modified-release capsules are still approved and marketed in many countries (such as Canada). In Colombia, it is marketed under Uripur from Laboratorios Bussié and under Harnal D in Japan and Indonesia.^[1] In Egypt^[2], Italy and Iceland, it is marketed under the trade name Omnic by Astellas Pharma Europe.

The U.S. patent for Flomax expired in October 2009.^[3] The U.S. Food and Drug Administration (FDA) approved generic Flomax in March 2010.^[4]

Mechanism

Tamsulosin is a selective α₁ receptor antagonist that has preferential selectivity for the α_1A receptor in the prostate versus the α_1B receptor in the blood vessels.^[5]

Clinical uses

Tamsulosin is primarily used for benign prostatic hyperplasia, but is sometimes used for the passage of kidney stones by the same mechanism of smooth muscle relaxation via alpha antagonism.^{[citation needed]}

Adverse effects

Two ADRs (Adverse Drug Reactions) have been reported:

§       Immunologic: It contains a sulfa moiety, thus causing typical reactions to sulfa drugs.^{[citation needed]}

§       Ophthalmologic: Patients taking tamsulosin are prone to a complication known as floppy iris syndrome during cataract surgery. Adverse outcomes of the surgery are greatly reduced by the surgeon's prior knowledge of the patient's history with this drug, and thus having the option of alternative techniques.^[6]

Tamsulosin has also affected the sexual function in men. Tamsulosin can cause males to experience retrograde ejaculation.^[7] In males, retrograde ejaculation occurs when the fluid to be ejaculated, which would normally exit the body via the urethra, is redirected to the urinary bladder. Normally, the sphincter of the bladder contracts and the ejaculate goes to the urethra, the area of least pressure. In retrograde ejaculation, this sphincter does not function properly.

Occasionally, tamsulosin can cause a drop in blood pressure, rarely resulting in dizziness or fainting.^{[citation needed]} Other reported side effects include headache, dizziness, nasal congestion, and palpitations.^{[citation needed]}

Clinical comparison

Although prostate specific, it does not have the prostate apoptotic effects of other alpha-blockers such as doxazosin and terazosin.^{[citation needed]}

Use in combination therapy

The results of the CombAT (Combination of Avodart and Tamsulosin) trial in 2008 demonstrated that treatment with the combination of dutasteride (Avodart) and tamsulosin provides greater symptom benefits compared to monotherapy with either agent alone for treatment of benign prostatic hyperplasia. ^[8]

Dose: 0.4mg every morning once. Doesn’t require renal adjust.