Milnacipran Hydrochloride (MIL) Uses in Medicine

Milnacipran Hydrochloride ( cubic centimeter) Uses in MedicineMilnacipran hydrochloride ( knot) is a selective serotonin and norepinephrine re ingestion inhibitor. It was originally developed and manufactured by capital of South Dakota Fabre Medicament in France, and was approved in that country as an antidepressant medicate in 1997 1. It has since been approved for this reading material in bigeminal countries and currently marketed for this indication in over 45 countries worldwide including several European countries. cypress Bioscience bought the exclusive rights for approval and marketing of the drug for fibromyalgia purpose in the United States and Canada in 2003 from the manufacturer Pierre Fabre Laboratories 2-3.In January 2009 the U.S. Food and dose Administration (FDA) approved international nautical mile only for the intercession of fibromyalgia, making it the leash medication approved for this purpose in the United States 4.Some of the drug information and propert ies argon listed below2.1 Physical and chemical propertiesChemical propose MIL is chemically designated as (1R,2S)-rel-2(Amino-methyl)-N,N-diethyl-1-phenyl-cyclopropanecarboxamide hydrochloride and its structure is shown in Figure 2.1.Synonyms F-2207 Ixel Toledomin Dalcipran Milnacipran Hydrochloride.empirical formula C15H22N2O. HClMolecular weight 282.8CAS No. 101152-94-7Melting point 179CPhysical description MIL is a white to off-white, odourless, crystalline powder.disassociation constant (pKa) 9.65Permeability coefficient (Log P) 1.42Solubility It is freely soluble in aqueous buffers over the entire physiological pH domain. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and sparingly soluble in diethyl ether 5-6.BCS class partitioning I, highly soluble and highly permeable drug.2.2 Pharmacological propertiesMechanism of treatMilnacipran blocks 5-HT and norepinephrine (NE) reuptake into the neuron, thereby change magnitude 5- HT and NE extracellular concentrations. This activates 5-HT and NE auto and heteroreceptors culminating in a decreasing 5-HT and NE neuronal paper bag rates, synthesis, and release. On Chronic use MIL continues to block 5-HT and NE transporters without desensitization, notwithstanding 5-HT and NE auto- and heteroreceptors are desensitized and thus, down regulated. Firing rates of 5-HT and NE show to normal, and the amount of 5-HT and NE released per nerve impulse is increased 7.MIL has no significant affinity for - and -adrenergic, muscarinic (M1-5), histamine (H1-4), dopamine (D1-5), opiate, benzodiazepine, or -aminobutyric acid (GABA) receptors. MIL has no significant affinity for Ca2+, K+, Na+ and Cl channels and does not inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase 8-9.One of the main differences amid the various antidepressants and MIL is its equal preference and activity on the uptake of NE and 5-HT. The exact mechanism of th e central pain inhibitory reach and effectiveness in fibromyalgia symptom are unknown in adult male 10-11.2.3 Therapeutic Indications sermon of clinical depressionMajor Depression, also known as major depressive disorder or unipolar depression, is a highly weaken disorder that has been estimated to affect up to 21% of the world population 12. It is a CNS disorder characterised by a combination of symptoms that interfere with a persons ability to work, sleep, study, eat, and enjoy pleasurable activities 7,12.Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both(prenominal) efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are many combination t herapies and novel targets that possess been identified that may demonstrate improvements in one or more areas 12.Management of FibromyalgiaFibromyalgia (FM) is a complex syndrome characterized by continuing musculoskeletal pain which is often accompanied by multiple other symptoms, including fatigue, sleep disturbances, decreased physical functioning, and dyscognition. Due to these multiple symptoms, as well as high rates of comorbidity with other related disorders, patients with FM have a reduced quality of life. The reduced serotonin and norepinephrine levels observed in patients with FM suggest that medications which increase the levels of these neurotransmitters, such as serotonin and norepinephrine reuptake inhibitors (SNRIs), may have clinically advantageous effects in FM and other chronic pain conditions. MIL is an SNRI that has been approved for the management of FM 8, 13. MIL was viewed as a howling(prenominal) new weapon in the fight against both depression and pain. Treatment of LupusRecent studies proved that MIL is also useful against lupus. Lupus is a chronic autoimmune disease in which the immune system turns against the body and harms honorable cells and tissues. It is a rheumatic disease which can affect many separate of the body including the joints, skin, kidneys, lungs, heart or brain. Some of the most common symptoms intromit extreme fatigue, painful or swollen joints, unexplained fever, skin rashes, and kidney problems. scientific evidence indicates that lupus is beatd by a combination of genetic and environmental factors. Lupus is characterized by periods of increased or intensified disease activity, called flares 14-15.Tolerability and side effectsMILhas present numerous unbecoming reactions in human clinical trials with tolerability decreasing with an increasing dose. In the placebo controlled trials in patients with fibromyalgia, the most frequent spontaneously inform adverse events were as follows nausea, palpitations, hea dache, constipation, increased heart rate and hyperhidrosis, vomiting, and dizziness 16. Discontinuation collect to adverse reactions was generally more common among patients treated with 200 mg/ daylight compared to blow mg/day. The adverse effects can bulge from the fluctuation in the plasma drug concentrations of an active substance following(a) administration and subsequent metabolism and/or elimination from the body. Most of the reported adverse events were reduced or disappeared with the discontinuation of treatment 17.2.4 PharmacokineticsThe pharmacokinetic profile of MIL is as summarized in Table 2.1 1,5.AbsorptionMIL is well-absorbed after oral administration. Absolute bioavailability is about 85-90 %. It is not affected by food intake. The government note plasma concentration is about 120 ng/ml achieved in 2 hours after a single 50 mg dose. Inter-subject divergence is low. Plasma concentrations are linearly proportional with dose over the range of single acute doses of 25 to 200 mg as shown in Table 2.2 1,2.DistributionProtein binding is low (13%) and not saturable. The volume of dispersion of MIL is about 5 litre/kg with a occur clearance of about 40 litre/hour. Renal and non-renal clearances are tantamount(predicate) 1.MetabolismMIL is metabolized mainly by conjugation (Glucoronisation). Active metabolites have been found at very low levels without clinical relevance. Cytochrome P450 2D6 is involved in the metabolism of many psychotropic drugs and its inhibition is frequently a cause of drug-drug interactions. This enzyme has no impact on the metabolism of MIL and no aerobic metabolites of MIL have been detected in humans 1-3.The pharmacokinetics of MIL are not modified in subjects who are deficient in the CYP2D6 isoenzyme (slow sparteine-like metabolisers). Furthermore, MIL does not interfere in-vivo with other isoenzymes of cytochrome P450 1, 18.EliminationPlasma elimination half life is about 8 hours. Elimination occurs mainly via the kidney with tubular secretion of the harvest-feast in unchanged form. After repeated doses, MIL is totally eliminated in 2 to 3 days after termination of therapy. The liver and kidneys are both involved in the elimination of MIL as illustrated by renal and non-renal clearances with values of 23.8 7.3 and 16.4 3.1 l/h, respectively. This balance between renal and non-renal clearances may be an advantage in patients presenting with moderate renal insufficiency 3,5.2.5 social disease and administrationThe recommended dose titration schedule for MIL is 12.5 mg once on Day 1, then 12.5 mg twice a day on Days 2-3, and then 25 mg twice a day on Days 4-7, and then 50 mg twice a day after Day 7. Recommended maintenance dose is 50 mg twice workaday. In clinical trials, MIL was evaluated with a dose titration schedule. The daily dose may be increased to 200 mg (or 100 mg twice a day) based on individual response. Dosing should be adjusted in patients with severe renal impairment (CrCl 2.6 Marketed formulationsThere are various brands of MIL are available with dose of 12.5 mg, 25 mg, 50 mg and 100 mg immediate release tablets or capsules as shown in Table 2.3 19-21.