Ovanac Plus

Uses

Alfacalcidol is used for:

• It is used to increase the amount of vitamin D in your body. This often increases calcium levels as well which can help in treatment of certain illnesses.
• In general this drug is used to treat diseases where the amount of calcium and phosphate (which is controlled by the level of vitamin D) in your body needs changing.
• Benefits of being on this drug can include control of the levels of calcium and phosphate in your body.
• Treat and prevent bone conditions that are caused by kidney failure (osteodystrophy)
• Treat illnesses and abnormalities affecting the parathyroid glands which make a substance called the parathyroid hormone.
• Correct low levels of calcium in the blood of newborn babies (hypocalcaemia)
• Treat the softening and deformity of the bones due to lack of calcium (rickets or osteomalacia)

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

Indicated for use as a supplement to intravenous solutions given for total parenteral nutrition (TPN), to maintain chromium serum levels and to prevent depletion of endogenous stores and subsequent deficiency symptoms .

Melatonin is used for numerous conditions but is showing the most promise in short-term regulation of sleep patterns, including jet lag.

Insomnia: Melatonin helps to induce sleep in people with-

• Disrupted circadian rhythms (such as those suffering from jet lag or poor vision or those who work the night shift)
• Low melatonin levels (such as some elderly and individuals with schizophrenia)
• Children with learning disabilities who suffer from insomnia.

Osteoporosis: Melatonin stimulates cells called osteoblasts that promote bone growth.

In Menopause:

Melatonin helps peri- or postmenopausal women to regulate sleep patterns.

Eating disorders: Melatonin levels may play a role in the symptoms of anorexia.

Sarcoidosis:

Sarcoidosis is an inflammatory disease that affects multiple organs in the body, but mostly the lungs and lymph glands.

Attention Deficit Hyperactivity Disorder (ADHD): It may be effective in managing sleep disturbances in children with this condition

Ovanac Plus is also used to associated treatment for these conditions: Hypocalcemia, Hypophosphatemic Rickets, Hypovitaminosis D, Nutritional Rickets, Osteodystrophy, Osteomalacia, Secondary Hyperparathyroidism (SHPT), Hypophosphatemic osteomalaciaMineral supplementationInsomnia

How Ovanac Plus works

In conditions like chronic renal failure, renal bone disease, hypoparathyroidism, and vitamin D dependent rickets, the kidneys' capacity for 1α-hydroxylation is impaired, leading to reduced production of endogenous 1,25-dihydroxyvitamin D and aberrated mineral metabolism. As an active and potent analog of vitamin D, alfacalcidol works to restore the functions and activities of endogenous 1,25-dihydroxyvitamin D.

Chromium is an essential nutrient involved in the metabolism of glucose, insulin and blood lipids. Its role in potentiating insulin signalling cascades has been implicated in several studies. Chromium upregulates insulin-stimulated insulin signal transduction via affecting effector molecules downstream of the insulin receptor (IR). IR-mediated signalling pathway involves phoshorylation of multiple intracellular domains and protein kinases, and downstream effector molecules . Upon activation by ligands, intracellular β-subunit of IR autophosphorylates and activates tyrosine kinase domain of the IR, followed by activation and phosphorylation of regulatory proteins and downstream signalling effectors including phosphatidylinositol 2-kinase (PI3K). PI3K activates further downstream reaction cascades to activate protein kinase B (Akt) to ultimately promote translocation of glucose transporter-4 (Glut4)-vesicles from the cytoplasm to the cell surface and regulate glucose uptake . Chromium enhances the kinase activity of insulin receptor β and increases the activity of downstream effectors, pI3-kinase and Akt.

Under insulin-resistant conditions, chromium also promotes GLUT-4 transporter translocation that is independent of activity of IR, IRS-1, PI3-kinase, or Akt; chromium mediates cholesterol efflux from the membranes via increasing fluidity of the membrane by decreasing the membrane cholesterol and upregulation of sterol regulatory element-binding protein . As a result, intracellular GLUT-4 transporters are stimulated to translocate from intracellular to the plasma membrane, leading to enhanced glucose uptake in muscle cells . Chromium attenuates the activity of PTP-1B in vitro, which is a negative regulator of insulin signaling. It also alleviates ER stress that is observed to be elevated the suppression of insulin signaling. ER stress is thought to activate c-Jun N-terminal kinase (JNK), which subsequently induces serine phosphorylation of IRS and aberration of insulin signalling . Transient upregulation of AMPK by chromium also leads to increased glucose uptake .

Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.

Dosage

Ovanac Plus dosage

Adults: The usual starting dose is 1 microgram each day. People usually take between 1 and 3 micrograms each day. Most people take between 0.25 and 1 microgram each day once the blood test results show the medicine is working.

If you have very low levels of calcium in your blood, your doctor may prescribe between 3 and 5 microgram each day. Your doctor may prescribe another medicine called a calcium supplement to take as well as Alfacalcidol. This will help to keep the right amount of calcium level in your blood.

Elderly: The usual starting dose is 0.5 microgram each day.

Children:

• Newborn and premature babies: The usual starting dose is 0.05 to 0.1 microgram per kilogram of body weight each day. If the level of calcium in their blood is very low, up to 2 micrograms per kilogram of body weight may be needed each day. A dose of 0.1 microgram per kilogram body weight each day is used to stop low blood calcium levels in premature babies.
• Children weighing less than 20 kilograms: The usual starting dose is 0.05 microgram per kilogram body weight each day.
• Children weighing more than 20 kilograms: The usual starting dose is 1 microgram each day.

Adult-

Insomnia: 3-6 mg one hour before bedtime

Jet lag: 0.50 to 5 mg one hour prior to bedtime at final destination or, 1 to 5 mg 1 hour before bedtime for 2 days prior to departure and for 2 to 3 days upon arrival at final destination.

• Eastbound travel: Take a preflight early evening treatment followed by treatment at bedtime for 4 days after arrival.
• Westbound travel: Take for 4 days at bedtime when in the new time zone.

Sarcoidosis:

20 mg per day for 4 to 12 months.

Depression: 0.125 mg twice in the late afternoon, each dose 4 hours apart.

Difficulty falling asleep: 5 mg 3 to 4 hours before an imposed sleep period over a 4-weeks period.

Children-

6 months to 14 years of age with sleep disorders: 0.30 mg/day

Side Effects

Anorexia, nausea, vomiting, diarrhoea, lassitude, polyuria, sweating, headache, thirst, vertigo, pruritus, rash, urticaria. Hypercalcaemia, hypercalciuria and ectopic calcification.

In case of renal impairment, hyperphosphataemia. In hypercalcaemic dialysis patients, possibility of calcium influx from the dialysate should be considered.

Increased seizure activity; drowsiness, headache. Disruption of normal circadian rhythm. May worsen symptoms for individuals with depression.

Toxicity

There is a discrepancy across a number of reported LD₅₀ values for alfacalcidol, which can be attributed to differences in the procedures used in laboratories. Oral LD₅₀ in mice ranges from 440 to 490 mcg/kg. Intravenous in mice was 290 mcg/kg; however, another source presented 56 mcg/kg in female mice and 71 mcg/kg in male mice. Oral LD₅₀ in rats ranges from 340 to 720 mcg/kg.

In case of an acute accidental overdose following oral administration, emesis or gastric lavage can be induced to prevent further drug absorption. Mineral oil may be used to promote fecal drug elimination in instances where the drug was already absorbed in the stomach.

Alfacalcidol overdose can lead to hypercalcemia, hypercalciuria, and hyperphosphatemia. Similarly, a high intake of calcium and phosphate concurrently with a therapeutic dose of alfacalcidol can result in those conditions. Hypercalcemia most commonly presents with headache, weakness, hypertension, somnolence, dizziness, sweating, anorexia, nausea, vomiting, diarrhea, constipation, polyuria, polydipsia and muscle and bone pain, and metallic taste. Hypercalcemia should be responded to with discontinuation of alfacalcidol, a low calcium diet and withdrawal of calcium supplements. Prolonged hypercalcemia can lead to nephrocalcinosis, nephrolithiasis, and reduced kidney function. In cases of severe hypercalcemia, general supportive measures are recommended, which may include forced diuresis and close monitoring of renal function, electrolytes, and electrocardiographs. Monitoring for abnormalities is especially critical in patients receiving digitalis glycosides. Management with glucocorticosteroids, loop diuretics, bisphosphonates, and calcitonin, as well as hemodialysis with low calcium content, may be considered.

Oral LD50 for Cr (VI) is 135 - 175 mg/kg in mouse and 46 - 113 mg/kg in rat . Oral LD50 for Cr (III) in rat is >2000 mg/kg . LD50 of chromium (III) oxide in rats is reported to be > 5g/kg . Other LD50 values reported for rats include: 3.5 g/kg (CI 3.19-3.79 g/kg) for chromium sulphate; 11.3 g/kg for chromium (III) acetate; 3.3 g/kg for chromium nitrate; and 1.5 g/kg for chromium nitrate nonahydrate .

Acute overdose of chromium is rare and seriously detrimental effects of hexavalent chromium are primarily the result of chronic low-level exposure . In case of overdose with minimal toxicity following acute ingestion, treatment should be symptomatic and supportive . There is no known antidote for chromium toxicity.

Hexavalent chromium is a Class A carcinogen by the inhalation route of exposure and Class D by the oral route . The oral lethal dose in humans has been estimated to be 1-3 g of Cr (VI); oral toxicity most likely involves gastrointestinal bleeding rather than systemic toxicity . Chronic exposure may cause damage to the following organs: kidneys, lungs, liver, upper respiratory tract . Soluble chromium VI compounds are human carcinogens. Hexavalent chromium compounds were mutagenic in bacteria assays and caused chromosome aberrations in mammalian cells. There have been associations of increased frequencies of chromosome aberrations in lymphocytes from chromate production workers . In human cells in vitro, Cr (VI) caused chromosomal aberrations, sister chromatid exchanges and oxidative DNA damage .

Generally well-tolerated when taken orally. The most common side effects, day-time drowsiness, headache and dizziness, appear to occur at the same frequency as with placebo. Other reported side effects include transient depressive symptoms, mild tremor, mild anxiety, abdominal cramps, irritability, reduced alertness, confusion, nausea, vomiting, and hypotension. Safety in Adults: Evidence indicates that it is likely safe to use in oral and parenteral forms for up to two months when used appropriately. Some evidence indicates that it can be safely used orally for up to 9 months in some patients. It is also likely safe to use topically when used appropriately. Safety in Children: Melatonin appeared to be used safely in small numbers of children enrolled in short-term clinical trials. However, concerns regarding safety in children have arisen based on their developmental state. Compared to adults over 20 years of age, people under 20 produce high levels of melatonin. Melatonin levels are inversely related to gonadal development and it is thought that exogenous administration of melatonin may adversely affect gonadal development. Safety during Pregnancy: High doses of melatonin administered orally or parenterally may inhibit ovulation. Not advised for use in individuals who are pregnant or trying to become pregnant. Safety during Lactation: Not recommended as safety has not be established.

Oral, rat: LD₅₀ ≥3200 mg/kg

Precaution

Pregnancy, lactation, renal impairment, infants, elderly. Monitor serum levels of calcium in patients with renal failure. Caution in hypercalciuria in those with history of renal calculi. Avoid in patients with hypersensitivity to inj. containing propylene glycol.

Caffeine and fluvoxamine may increase the effects of melatonin, while melatonin may decrease the antihypertensive effect of nifedipine.

Interaction

Thiazides may increase the risk of hypercalcaemia. Some antiepileptics e.g. carbamazepine, phenobarbital, phenytoin and primidone may increase vitamin D requirements. Rifampicin, isoniazid and corticosteroids may reduce the efficacy of vitamin D.

Antidepressant Medications: Melatonin reduces the antidepressant effects of desipramine and fluoxetine. In addition, fluoxetine leads to measurable depletion of melatonin in people.

Antipsychotic Medications: People with schizophrenia and tardive dyskinesia taking antipsychotic medications with melatonin has significantly reduced mouth movements compared to those who did not take the supplements.

Benzodiazepines: The combination of melatonin and triazolam improves sleep quality. In addition, there have been a few reports suggesting that melatonin supplements may help individuals stop using long-term benzodiazepine therapy.

Blood Pressure Medications: Melatonin may reduce the effectiveness of blood pressure medications like methoxamine and clonidine. In addition, calcium channel blockers (such as nifedipine, verapamil, diltiazem, amlodipine, nimodipine, felodipine, nisoldipine, and bepridil) may decrease melatonin levels. Use of beta-blockers (propranolol, acebutolol, atenolol, labetolol, metoprolol, pindolol, nadolol, sotalol, and timolol) may reduce melatonin production in the body.

Blood-Thinning Medications, Anticoagulants: Melatonin may increase the risk of bleeding from anticoagulant medications such as warfarin.

Interleukin 2: In one study of 80 cancer patients, use of melatonin in conjunction with interleukin-2 led to more tumor regression and better survival rates than treatment with interleukin-2 alone.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs such as ibuprofen may reduce the levels of melatonin in the blood.

Steroids and Immunosuppressant Medications: People should not take melatonin with corticosteroids or other medications used to suppress the immune system because the supplement may cause them to be ineffective.

Tamoxifen: Preliminary research suggests that the combination of tamoxifen (a chemotherapy drug) and melatonin may benefit certain patients with breast and other cancers.

Other Substances: Caffeine, tobacco, and alcohol can all diminish levels of melatonin in the body while cocaine and amphetamines may increase melatonin production.

Volume of Distribution

Absorbed chromium is distributed to all tissues of the body and its distribution in the body depends on the species, age, and chemical form . Circulating Cr (III) following oral or parenteral administration of different compounds can be taken up by tissues and accumulates in the liver, kidney, spleen, soft tissue, and bone .

Elimination Route

Alfacalcidol is absorbed passively and almost completely in the small intestine.

Chromium compounds are both absorbed by the lung and the gastrointestinal tract. Oral absorption of chromium compounds in humans can range between 0.5% and 10%, with the hexavalent (VI) chromium more easily absorbed than the trivalent (III) form . Absorption of chromium from the intestinal tract is low, ranging from less than 0.4% to 2.5% of the amount consumed . Vitamin C and the vitamin B niacin is reported to enhance chromium absorption .

Most hexavalent Cr (VI) undergoes partial intragastric reduction to Cr (III) upon absorption, which is an action mainly mediated by sulfhydryl groups of amino acids . Cr (VI) readily penetrates cell membranes and chromium can be found in both erythrocytes and plasma after gastrointestinal absorption of Cr (IV). In comparison, the presence of chromium is limited to the plasma as Cr (III) displays poor cell membrane penetration . Once transported through the cell membrane, Cr (VI) is rapidly reduced to Cr (III), which subsequently binds to macromolecules or conjugate with proteins. Cr (III) may be bound to transferrin or other plasma proteins, or as complexes, such as glucose tolerance factor (GTF).

The absorption and bioavailability of melatonin varies widely.

Half Life

The half-life of alfacalcidol ranges from three to four hours.

The elimination half-life of hexavalent chromium is 15 to 41 hours .

35 to 50 minutes

Clearance

Excretion of chromium is via the kidneys ranges from 3 to 50 μg/day . The 24-hour urinary excretion rates for normal human subjects are reported to be 0.22 μg/day .

Elimination Route

Absorbed chromium is excreted mainly in the urine, accounting for 80% of total excretion of chromium; small amounts are lost in hair, perspiration and bile . Chromium is excreted primarily in the urine by glomerular filtration or bound to a low molecular-weight organic transporter .

Pregnancy & Breastfeeding use

FDA has not yet classified the drug into a specified pregnancy category.

Information regarding safety and efficacy in pregnancy and lactation is not available.

Contraindication

Hypercalcaemia, metastatic calcification, hyperphosphataemia (except when occurring with hypoparathyroidism), hypermagnesaemia.

Melatonin should not be used by patients who have autoimmune diseases.

Acute Overdose

There is little or no evidence of any major toxicities with melatonin, even at high doses.

Storage Condition

Store in a cool & dry place, protected from light & moisture.

Innovators Monograph

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