Permivit

Uses

Black cohosh is a herbal product indicated in the symptomatic treatment of menopause.

Treatment of menopausal symptoms and menstrual dysfunction .

Currently Genistein is being studied in clinical trials as a treatment for prostate cancer.

Vitamin D is an ingredient found in a variety of supplements and vitamins.

Vitamin D is indicated for use in the treatment of hypoparathyroidism, refractory rickets (also known as vitamin D resistant rickets), and familial hypophosphatemia .

Permivit is also used to associated treatment for these conditions: Menopausal Symptoms, Menopause SymptomsCalcium Deficiency, Deficiency, Vitamin D, Osteodystrophy, Osteomalacia, OsteoporosisDeficiency, Vitamin D

How Permivit works

Although the mechanism by which black cohosh relieves menopausal symptoms is unknown, several hypotheses have been made. It is believed to act through the following mechanisms/effects:

1) as a selective estrogen receptor modulator 2) through serotonergic pathways 3) as an antioxidant 4) on inflammatory pathways

The primary active component of the black cohosh root is believed to be the terpene glycoside fraction, including actein and cimifugoside. The triterpenes are one of the most ubiquitous and diverse groups of plant natural products. They are classified as complex molecules that are beyond the reach of chemical synthesis in the laboratory. Simple triterpenes are constituents of surface waxes and specialized plant membranes and may possibly serve as signaling molecules. More complex glycosylated triterpenes (also known as saponins) provide protection against pathogens and pests. The rhizome (stem portion of the plant) also contains other potentially biologically active substances, including alkaloids, flavonoids, and tannins. The therapeutic activity of black cohosh was initially believed to be the activation of estrogen receptors; however, more recent studies show that although some components of the extract bind to at least one subtype of estrogen receptor, the receptor binding produces very little (if any) estrogenic effect, and may selectively block some of the effects.

An early study reported that treatment with black cohosh leads to a decrease in luteinizing hormone (LH) levels consistent with its purported estrogenic effect. Despite this, more recent studies have shown no effect on levels of LH, follicle-stimulating hormone (FSH), or prolactin. To this day it is unclear whether black cohosh exerts its effect via estrogen receptors or through another mechanism.

One study observed that while the most prominent triterpene in black cohosh, known as 23-epi-26-deoxyactein, inhibits cytokine-induced nitric oxide production in brain microglial cells, the complete black cohosh extract demonstrated to enhance this pathway. A variety of activities have been reported for black cohosh and its compounds, however, the absorption and tissue distribution of these compounds is not known.

Cimicifuga racemosa (black cohosh) is used most often to treat symptoms occurring during menopause. However, in recent years, several concerns regarding its safety have been voiced.

Genistein may inhibit cancer cell growth by blocking enzymes required for cell growth.

Genistein may decrease cardiovascular risk in postmenopausal women by interacting with the nuclear estrogen receptors to alter the transcription of cell specific genes. In randomized clinical trials, genistein was seen to increase the ratio of nitric oxide to endothelin and improved flow-mediated endothelium dependent vasodilation in healthy postmenopausal women . In addition, genistein may have beneficial effects on glucose metabolism by inhibiting islet tyrosine kinase activity as well as insulin release dependent on glucose and sulfonylurea .

Most individuals naturally generate adequate amounts of vitamin D through ordinary dietary intake of vitamin D (in some foods like eggs, fish, and cheese) and natural photochemical conversion of the vitamin D3 precursor 7-dehydrocholesterol in the skin via exposure to sunlight.

Conversely, vitamin D deficiency can often occur from a combination of insufficient exposure to sunlight, inadequate dietary intake of vitamin D, genetic defects with endogenous vitamin D receptor, or even severe liver or kidney disease . Such deficiency is known for resulting in conditions like rickets or osteomalacia, all of which reflect inadequate mineralization of bone, enhanced compensatory skeletal demineralization, resultant decreased calcium ion blood concentrations, and increases in the production and secretion of parathyroid hormone . Increases in parathyroid hormone stimulates the mobilization of skeletal calcium and the renal excretion of phosphorus . This enhanced mobilization of skeletal calcium leads towards porotic bone conditions .

Ordinarily, while vitamin D3 is made naturally via photochemical processes in the skin, both itself and vitamin D2 can be found in various food and pharmaceutical sources as dietary supplements. The principal biological function of vitamin D is the maintenance of normal levels of serum calcium and phosphorus in the bloodstream by enhancing the efficacy of the small intestine to absorb these minerals from the diet . At the liver, vitamin D3 or D2 is hydroxylated to 25-hydroxyvitamin D and then finally to the primary active metabolite 1,25-dihydroxyvitamin D in the kidney via further hydroxylation . This final metabolite binds to endogenous vitamin d receptors, which results in a variety of regulatory roles - including maintaining calcium balance, the regulation of parathyroid hormone, the promotion of the renal reabsorption of calcium, increased intestinal absorption of calcium and phosphorus, and increased calcium and phosphorus mobilization of calcium and phosphorus from bone to plasma to maintain balanced levels of each in bone and the plasma .

Toxicity

The oral LD50 for rats is 17,000 to 27,211 mg/kg.

Clinical trials using a variety of black cohosh formulas to manage menopausal symptoms have shown that its use is associated with a low incidence of adverse effects. The most commonly reported side effects are gastrointestinal discomfort and rashes, both of which have shown to be mild and transient. Some other adverse effects in clinical trials have included breast pain or enlargement, infection, vaginal bleeding or spotting, and musculoskeletal discomfort. The incidence of these symptoms, however, was similar in women taking black cohosh and those taking a placebo.

Reports have been made globally of at least 83 cases of liver damage—including hepatitis, liver failure, elevated liver enzymes, and various other liver injuries—associated with black cohosh use. However, no evidence of a causal relationship exists. It is possible that a subset of reported cases of hepatotoxicity were due to impurities, adulterants, or incorrect Acteae species in the black cohosh products used. However, no independent analysis of these drugs has been done to confirm the existence of these problems.

The American Herbal Products Association recommends that pregnant women not ingest black cohosh, except under the supervision of their healthcare provider because studies have not thoroughly evaluated its use during pregnancy. The U.S. Pharmacopeia advises that individuals with liver disorders should also avoid the use of black cohosh. In addition, users who develop symptoms of liver disease, such as abdominal pain, dark urine, or jaundice, while taking the supplement should discontinue use and contact their healthcare provider.

As with other drugs believed to have potential estrogenic effects, there has been concern about the safety of black cohosh in women with a personal history or family history of breast cancer. Though further research is warranted, at least one tissue-culture study showed no stimulation of estrogen receptor-positive breast cancer cell lines by black cohosh extract. This study found that black cohosh extract amplified the inhibitory action of tamoxifen (Nolvadex) on breast cancer cell lines. Because this question has not yet been fully answered, physicians should discuss this issue with their patients who are at risk of breast cancer while considering taking black cohosh.

Black cohosh is contraindicated during pregnancy due to its potential ability to promote uterine contraction. The safety of black cohosh in breastfeeding mothers and the level of transmission of black cohosh in breast milk are both unknown.

The use of pharmacological or nutraceutical vitamin d and/or even excessive dietary intake of vitamin d is contraindicated in patients with hypercalcemia, malabsorption syndrome, abnormal sensitivity to the toxic effects of vitamin d, and hypervitaminosis D .

Hypersensitivity to vitamin d is one plausible etiologic factor in infants with idiopathic hypercalcemia - a case in which vitamin d use must be strictly restricted .

As vitamin d intake is available via fortified foods, dietary supplements, and clinical drug sources, serum concentrations and therapeutic dosages should be reviewed regularly and readjusted as soon as there is clinical improvement . Dosage levels are required to be individualized on an individual patient by patient basis as caution must be exercised to prevent the presence of too much vitamin d in the body and the various potentially serious toxic effects associated with such circumstances .

In particular, the range between therapeutic and toxic doses is quite narrow in vitamin d resistant rickets . When high therapeutic doses are used, progress should be followed with frequent blood calcium determinations .

When treating hypoparathyroidism, intravenous calcium, parathyroid hormone, and/or dihydrotachysterol may be required .

Maintenance of normal serum phosphorus levels by dietary phosphate restriction and/or administration of aluminum gels as intestinal phosphate binders in those patients with hyperphosphatemia as frequently seen in renal osteodystrophy is essential to prevent metastatic calcification .

Mineral oil interferes with the absorption of lipid-soluble vitamins, including vitamin d preparations .

The administration of thiazide diuretics to hypoparathyroid patients who are concurrently being treated with vitamin d can result in hypercalcemia .

At this time, no long term animal studies have been performed to evaluate vitamin potential for carcinogens, mutagenesis, or fertility .

As various animal reproduction studies have demonstrated fetal abnormalities in several species associated with hypervitaminosis D, the use of vitamin d in excess of the recommended dietary allowance during normal pregnancy should be avoided . The safety in excess of 400 USP units of vitamin d daily during pregnancy has not been established . The abnormalities observed are similar to the supravalvular aortic stenosis syndrome described in infants that is characterized by supravalvular aortic stenosis, elfin facies, and mental retardation .

In a nursing mother given large doses of vitamin D, 25-hydroxycholecalciferol appeared in the milk and caused hypercalcemia in her child. Caution is subsequently required when contemplating the use of vitamin d in a nursing woman, and the necessity of monitoring infants' serum calcium concentration if vitamin d is administered to a breastfeeding woman .

Adverse reactions associated with the use of vitamin d are primarily linked to having hypervitaminosis D occurring [FDA Lanel]. In particular, hypervitaminosis D is characterized by effects specific effects on specific organ systems. At the renal system, hypervitaminosis D can cause impairment of renal function with polyuria, nocturne, polydipsia, hypercalciuria, reversible asotemia, hypertension, nephrocalcinosis, generalized vascular calcification, or even irreversible renal insufficiency which may result in death . Elsewhere, hypervitaminosis D can also cause CNS mental retardation . At the level of soft tissues, it can widespread calcification of the soft tissues, including the heart, blood vessels, renal tubules, and lungs . In the skeletal system, bone demineralization (osteoporosis) in adults can occur while a decline in the average rate of linear growth and increased mineralization of bones, dwarfism, vague aches, stiffness, and weakness can occur in infants and children . Finally, hypervitaminosis D can also lead to nausea, anorexia, and constipation at the gastrointestinal level as well as mild acidosis, anemia, or weight loss via metabolic processes .

The LD(50) in animals is unknown .

Elimination Route

Vitamin D3 and D2 are readily absorbed from the small intestine (proximal or distal) .

Half Life

Approximately 2h.

Although certain studies suggest the half-life of 1,25-hydroxyvitamin D3 may be approximately 15 hours, the half-life of 25-hydroxyvitamin D3 appears to have a half-life of about 15 days . Intriguingly however, the half-lives of any particular administration of vitamin d can vary and in general the half-lives of vitamin D2 metabolites have been demonstrated to be shorter overall than vitamin D3 half-lives with this being affected by vitamin d binding protein concentrations and genotype in particular individuals .

Clearance

Some studies propose an estimated clearance rate for 1,25-dihydroxyvitamin D as 31 +/- 4 ml/min in healthy adults .

Elimination Route

The primary excretion route of vitamin D is via the bile into the feces .

Innovators Monograph

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