Milnacipran Hydrochloride (MIL) Uses in Medicine

Milnacipran Hydrochloride (MIL) Uses in MedicineMilnacipran hydrochloride (MIL) is a selective serotonin and norepinephrine reuptake inhibitor. It was originally developed and manufactured by Pierre Fabre Medicament in France, and was approved in that country as an antidepressant in 1997 1. It has since been approved for this indication in quadruple countries and currently marketed for this indication in over 45 countries worldwide including several European countries. Cypress Bioscience bought the exclusive rights for acclaim 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 Drug Administration (FDA) approved MIL that for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States 4. nigh of the drug information and properties atomic number 18 listed below2.1 Physical and chemical substance propertiesCh emical name 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 usher 179CPhysical description MIL is a white to off-white, odourless, crystalline powder.Dissociation constant (pKa) 9.65Permeability coefficient (Log P) 1.42Solubility It is freely soluble in sedimentary buffers over the entire physiological pH range. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and sparingly soluble in diethyl ether 5-6.BCS class Class I, passing soluble and highly permeable drug.2.2 Pharmacological propertiesMechanism of ActionMilnacipran blocks 5-HT and norepinephrine (NE) reuptake into the neuron, thereby increasing 5-HT and NE extracellular c one timentrations. This activates 5-HT and NE auto a nd heteroreceptors culminating in a lessen 5-HT and NE neuronal firing rates, synthesis, and release. On Chronic use MIL continues to block 5-HT and NE transporters without desensitization, but 5-HT and NE auto- and heteroreceptors are desensitized and thus, pig regulated. Firing rates of 5-HT and NE return 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 non inhibit the activity of human monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase 8-9. maven of the main differences among the various antidepressants and MIL is its equal preference and activity on the uptake of NE and 5-HT. The exact mechanism of the central pain repressing action and effectiveness in fibromyalgia symptom are unknown i n Humans 10-11.2.3 Therapeutic IndicationsTreatment of depressionMajor Depression, also known as major depressive disorder or unipolar depression, is a highly debilitating disorder that has been estimated to affect up to 21% of the world population 12. It is a central nervous system 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 of necessity with respect to both efficacy and side cause. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To insure these needs, there are numerous combination therapies and novel targets that substantiate been identified that may demonstra te improvements in one or more areas 12.Management of FibromyalgiaFibromyalgia (FM) is a complex syndrome characterized by chronic 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 decreased 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 beneficial 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 wonderful new artillery 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 healthy cells and tissues. It is a rheumatic disease which can affect many parts of the body including the joints, skin, kidneys, lungs, heart or brain. Some of the most common symptoms include extreme fatigue, painful or swollen joints, unexplained fever, skin rashes, and kidney problems. Scientific evidence indicates that lupus is caused by a combination of communicable and environmental factors. Lupus is characterized by periods of increased or intensified disease activity, called flares 14-15.Tolerability and side effectsMILhas demonstrated numerous adverse 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 reported adverse events were as follows nausea, palpitations, headache, 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/ twenty-four hours compared to 100 mg/day. The adverse effects can originate from the variation in the plasma drug concentrations of an active substance following 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 afterward oral administration. Absolute bioavailability is about 85-90 %. It is not affected by food intake. The peak plasma concentration is about 120 ng/ml achieved in 2 hours after a integrity 50 mg dose. Inter-subject variability 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 distribution of MIL is about 5 litre/kg with a total clearance of about 40 litre/hour. Renal and non-renal clearances are equivalent 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 oxidative metabolites of MIL have been detected in humans 1-3.The pharmacokinetics of MIL are not circumscribed 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. body wastePlasma elimination half-life is about 8 hours. Elimination occurs mainly via the kidney with tubular secretion of the product in unchanged form. After repeated doses, MIL i s 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 Dosage and administrationThe recommended dose titration schedule for MIL is 12.5 mg once on Day 1, then 12.5 mg in two ways a day on Days 2-3, and then 25 mg doubly a day on Days 4-7, and then 50 mg twice a day after Day 7. Recommended maintenance dose is 50 mg twice daily. 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.