Mexican Pharmacy Blog

A total of 100 mg/day is given in divided doses. The recommended dose-titration schedule for milnacipran is:

• Day 1: 12.5 mg once daily
• Days 2–3: 25 mg/day (12.5 mg twice daily)
• Days 4–7: 50 mg/day (25 mg twice daily)
• After day 7: 100 mg/day (50 mg twice daily)

The manufacturer recommends an initial dose of 12.5 mg/day given once daily on day 1. On days 2 and 3, the dose should be increased to 25 mg/day, taken as 12.5 mg twice daily. On days 4 to 7, the dose should be further increased to 50 mg/day, taken in divided doses of 25 mg twice daily. After day 7, the dose should reach 100 mg/day, taken as 50 mg twice daily. The dose may be increased to reach 200 mg/day, given as 100 mg twice daily; however, doses should not exceed 200 mg/day because of the lack of evidence for the drug’s efficacy and because of an increased risk of AEs.
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Dose adjustments should be made for each patient. As commonly seen with other SNRIs, tapering of the dose is needed when the drug is discontinued. Patients should not stop milnacipran therapy abruptly because of the potential for the development of withdrawal symptoms.

Renal Insufficiency

No dose adjustments are needed for patients with mild renal impairment (a creatinine clearance [CrCl] of 50–80 mL/minute); caution should be applied in patients with moderate renal impairment (CrCl, 30–49 mL/minute). For patients with severe renal insufficiency (CrCl, 5–29 mL/minute), the maintenance dose should be reduced by 50% to 50 mg/day in divided doses of 25 mg twice daily. Milnacipran should not be prescribed for patients with end-stage renal disease.

Hepatic Insufficiency

No dosage adjustments are necessary for patients with hepatic impairment; however, caution should be taken in this patient population.

Elderly Patients

In the phase 3 studies of the safety and efficacy of milnacipran for treating FM, no overall differences were observed in patients 60 years of age or older in comparison with younger patients. Specific trials involving milnacipran for geriatric patients with FM have not been published, although safety has been analyzed in older patients with depression. In a study comparing milnacipran with imipramine (Tofranil, Malinckrodt), milnacipran was associated with lower withdrawal rates and fewer AEs (except for nausea) in patients 65 years of age and older. Although there were fewer AEs in the milnacipran group, dry mouth was the only statistically more frequent AE seen with imipramine.

Pregnant and Lactating Women

Milnacipran has been designated as a Pregnancy Category C agent, implying positive fetal risks in animal studies, but studies involving humans are lacking. The manufacturer states that no adequate or well-controlled studies have been reported for pregnant women. Milnacipran should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.
Controlled studies of milnacipran have not been performed in nursing mothers. Milnacipran is excreted in animals, and simultaneous nursing is therefore not recommended.

Pediatric Populations
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No controlled studies involving milnacipran for FM have included patients younger than 17 years of age. Consequently, the drug’s safety and efficacy have not been established in this patient population.

The chemical name of milnacipran HCl is (±)-[1R(S),2S(R)]-2-(amino-methyl)-N,N-diethyl-1-phenylcyclopane-carboxamide HCl. Its empirical formula is C15H23ClN2O; the molecular weight is 282.8 g/mol. Milnacipran is a white to off-white crystalline powder with a melting point of 179° C. It is freely soluble in water, methanol, ethanol, chloroform, and methylene chloride and is sparingly soluble in diethyl ether.

Milnacipran savella is sold as orally administered, film-coated tablets in dosages of 12.5, 25, 50, and 100 mg of the active ingredient. It is also supplied in a dose-titration pack for patients starting treatment. According to the manufacturer, the tablets should be stored between 59°F and 86°F.

Milnacipran is a SNRI that inhibits the reuptake of both norepinephrine and serotonin; it also has a mild affinity for inhibiting N-methyl-D-aspartate (NMDA).5 Milnacipran exerts higher selectivity for norepinephrine reuptake than venlafaxine (Effexor generic price, Wyeth) or duloxetine.

The exact mechanism of milnacipran and its efficacy in FM are unknown, but it is hypothesized that the effects on regulating dysfunctional noradrenergic and serotonergic pathways contribute to its therapeutic properties. The selectivity for norepinephrine over serotonin has yet to show an overall clinical advantage, since both neurotransmitters have effects on pain modulation.

Milnacipran does not affect the reuptake of dopamine, and it has no significant affinity for serotonergic (5-HT1–7), dopaminergic (D1–5), opiate, benzodiazepine, and gamma-aminobutyric acid (GABA) receptors in vitro.

Because milnacipran lacks affinity for adrenergic, cholinergic, and histaminergic receptors, it does not exhibit many of the expected adverse effects (AEs) seen with the tricyclic antidepressants (TCAs). It has no significant affinity for Ca2+, K+, Na+, or Cl− channels, and it does not inhibit the activity of the monoamine oxidases (MAO-A and MAO-B) or acetylcholinesterase.

Absorption and Distribution
The pharmacokinetic properties of milnacipran are summarized in Table 1. Following oral administration, the drug is rapidly absorbed, exhibiting maximal concentrations at two to four hours and a mean peak concentration (Cmax) of 150 ng/mL after a single 50-mg dose. As a result of its favorable absorption profile, milnacipran exhibits high bioavailability of approximately 85% to 90%. First-pass elimination is limited, especially since there is low variability among subjects tested.10,11 Administration following a meal has no effect on peak plasma levels.

Table 1: Pharmacokinetics of Milnacipran

Milnacipran exhibits low, nonsaturable, plasma protein binding (13%), which is lower than the other approved SNRIs (venlafaxine and duloxetine). Because of its low protein binding, milnacipran is free to diffuse, and it is widely distributed in the body (5.3 ± 0.4 L/kg).

HGH or human growth hormone is a protein hormone of 190 amino acids, which is synthesized and secreted by the Somatotroph cells (hence called Somatotropin) in the anterior pituitary. The genes for human growth hormone are localized in the q22-24 region of chromosome 17. The structure of HGH includes four helices necessary for functional interaction with the GH receptor. Structurally, HGH is homologous to prolactin and chorionic somatomammotropin and it appears as if the three share some evolutionarily connection. The triad is known to promote growth and aid the lactogenic activity.

Human Growth Hormone Secretion

Synthesis and secretion of HGH is controlled by many factors such as exercise, nutrition, sleep, stress and sometimes even by growth hormone itself. The control, however, are wielded by two hypo-thalamic hormones (Growth hormone-releasing hormone or GHRH and Somatostatin or SS) and one hormone present in the stomach (Ghrelin).

Functions of HGH
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Human growth hormone contributes in the building up of the human body. HGH has two different types of effects on the human tissues and the human system as a whole – direct and indirect. The direct effects are the upshot of the growth hormone binding its receptor to the target cells. Indirect effects are stimulated by an insulin-like growth factor-I (IGF-I), a hormone secreted by the liver and other tissues in response to growth hormone action. In fact, most of the growth promoting effects of HGH are the consequence of IGF-I acting on the target cells.

Thus, it is apparent that HGH or Somatotropin plays a vital role in major physiological processes, including growth and metabolism.

HGH & Growth

The major role of growth hormone in effecting body growth is to stimulate the liver and various other tissues to secrete IGF-I. IGF-I. This, in-turn, it provokes proliferation of Chondrocytes (cartilage cells), resulting in bone growth.

HGH & Metabolism

Human growth hormone has been found to have important effects on protein, lipid and carbohydrate metabolism. These effects in some are direct, others indirect and a few showing mixed effects.

Although height growth is an all-too-manifest effect of HGH on the human system, it has several other specific and essentially functions. These functions range from protein synthesis to building muscle mass, calcium retention to mineralization of bones, stimulating the immune system to maintaining fuel homeostasis, etc.

This is all about real human growth hormone. Biosynthetic human growth hormone, also known as recombinant human growth hormone and abbreviated as rHGH was first used for remedial use in the U.S. in 1985. Since then, the biosynthetic variety of HGH has nearly sidelined the pituitary-prompted human growth hormone, especially in therapeutic use.