Buy Mimpara pills 30 mg, 28 pcs
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Mimpara® [Cinacalcet]

Amgen Manewackering Limited
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2019-09-19
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Clinical Pharmacology

Mimpara - Calcium Mimetic, which reduces the level of parathyroid hormone.

Pharmacodynamics

Calcium-sensitive receptors located on the surface of the main parathyroid cells are the main regulators of parathyroid hormone (PTH) secretion. Tsinakaltset has a calcimimetic effect, directly reducing the concentration of PTH, increasing the sensitivity of this receptor to extracellular calcium. A decrease in the PTH concentration is accompanied by a decrease in the calcium content in the blood serum.

The decrease in the concentration of PTH correlates with the concentration of cynacaltcet. Shortly after the introduction of cinaccetse, the PTH concentration begins to decrease; at the same time, the maximum decrease occurs approximately 2–6 hours after a dose, which corresponds to the maximum concentration of cynacaltce (Cmax). After that, the concentration of cynacaltseta begins to decrease, and the concentration of PTH increases within 12 hours after a dose, and then the suppression of PTH remains at about the same level until the end of the daily interval during the dosing regimen 1 time per day. The concentration of PTH in clinical studies of the drug Mimpara was measured at the end of the dosing interval.

After reaching a state of equilibrium, the concentration of calcium in the serum remains at a constant level during the entire interval between doses of the drug.

Secondary hyperparathyroidism

Three clinical studies lasting for 6 months (double-blind, placebo-controlled) included patients with end-stage renal disease who were on dialysis, with an uncontrolled form of secondary hyperparathyroidism (1136 patients). The average initial concentrations of intact parathyroid hormone (IPTG) in three clinical trials were 733 and 683 pg / ml (77.8 and 72.4 pmol / l) in cinnacrette and placebo groups, respectively, 66% of patients took vitamin D before being included in the study , and> 90% took phosphate binding drugs. Patients taking cinacalcet showed a significant decrease in serum concentration of IPTG, calcium and phosphorus, calcium-phosphorus product (Ca × P) compared with patients in the placebo group who received standard therapy. The decrease in the concentration of IPTG and Ca × P was maintained for 12 months of therapy. Tsinakaltset reduced the concentration of IPTG, calcium and phosphorus and Ca × P, regardless of the initial concentrations of IPTG or Ca × P, dialysis regimen (peritoneal dialysis compared to hemodialysis), the duration of dialysis, and whether or not vitamin D was used.

The decrease in PTH concentration was associated with an insignificant decrease in the concentrations of bone metabolism markers (specific bone alkaline phosphatase, N-telopeptides, bone renewal and bone fibrosis). When conducting a retrospective analysis of a pool of data collected from 6 and 12 months of clinical studies using the Kaplan-Meier method, the rates of bone fractures and parathyroidectomy were lower in the cynacalcet group compared with the control group.

Preliminary studies on patients with chronic kidney disease (CKD) and secondary hyperparathyroidism who are not on dialysis indicate that cynacalcet reduced PTH concentrations in a similar way as in patients diagnosed with end-stage renal disease (TSPN) and secondary hyperparathyroidism, being on dialysis. However, for patients with renal insufficiency in the pre-dialysis stage, the efficacy, safety, optimal dosages and target treatment values ​​have not been established. These studies have shown that patients with CKD who are not on dialysis and receiving cinacalcet have a greater risk of developing hypocalcemia compared with dialysis patients with end-stage renal failure who receive cinnacaltce, which may be due to a lower initial calcium concentration and / or residual kidney function.

Parathyroid carcinoma and primary hyperparathyroidism (GPT)

During the main study, 46 patients (29 patients diagnosed with parathyroid carcinoma, and 17 with primary GPT (in whom parathyroidectomy did not produce results or was contraindicated) received cinnacalce up to 3 years (an average of 328 days for patients with parathyroidal carcinoma and 347 days for patients with primary GPT).

Tsinakaltset was used in doses of 30 mg 2 times a day to 90 mg 4 times a day. The main goal of therapy was to reduce the serum calcium concentration by ≥1 mg / dL (≥0.25 mmol / L). In patients with parathyroid carcinoma, the average calcium concentration decreased from 14.1 to 12.4 mg / dL (3.5–3.1 mmol / l), while in patients with primary GPT serum calcium decreased from 12.7 to 10.4 mg / dl (3.2 to 2.6 mmol / l). In 18 patients out of 29 (62%) with parathyroid carcinoma and 15 out of 17 patients (88%) with primary GPT, serum calcium concentration decreased by ≥1 mg / dL (≥0.25 mmol / l).

Pharmacokinetics

After oral administration of the drug Mimpara, the maximum concentration (Cmax) tsynakaltseta in plasma is reached after approximately 2–6 hours. The absolute bioavailability of tsynakaltseta when taken on an empty stomach, established on the basis of a comparison of the results of various studies, was approximately 20–25%. Taking the drug Mimpara with food increased the bioavailability of tsinakaltseta by about 50-80%. A similar increase in plasma concentration of tsynakaltsete was observed regardless of the fat content in food. The decrease in the concentration of cynacaltsete occurs in two stages; the initial half-life is approximately 6 hours, the final half-life is 30 to 40 hours. The equilibrium state is reached within 7 days with a minimum cumulation. Increasing the area under the concentration-time curve (AUC) and Cmax tsynakalceta occurs almost linearly in the dosage range of 30–180 mg once a day. At dosages above 200 mg, saturation of absorption is observed, probably due to poor solubility. The pharmacokinetic parameters of cinnakaltse do not change with time. There is a high volume of distribution (approximately 1000 liters), which indicates an extensive distribution. Tsinakaltset about 97% binds to plasma proteins and is distributed at a minimum level in the erythrocytes. Tsinakaltset is metabolized by microsomal liver enzymes, mainly CYP3A4 and CYP1A2 (the role of CYP1A2 has not been confirmed by clinical methods). The major circulating metabolites are inactive. According to researchin vitro, cinacalcet is a potent inhibitor of CYP2D6, however, at concentrations reached in clinical conditions, cinacalcet does not inhibit the activity of other CYP enzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4, and also is not an inducer of CYP1A2, CYP2C19 and CYP3A4. After administration of 75 mg to a healthy volunteer using a dose radiolabelled dose, cynacalcet underwent a rapid and significant oxidative metabolism followed by conjugation. The excretion of radioactivity occurred mainly as a result of excretion of metabolites through the kidneys. Approximately 80% of the injected dose was found in the urine and 15% in the feces.

Elderly: in cincalcet pharmacokinetics, there were no clinically significant differences associated with the age of patients.

Renal failure:The pharmacokinetic profile of cinacalcet in renal insufficiency of mild, moderate and severe degrees, and in hemodialysis or peritoneal dialysis, is comparable to the pharmacokinetic profile of the drug in healthy volunteers.

Liver failure: A mild hepatic failure does not significantly affect the pharmacokinetics of cinakaltseta. Compared with the group with normal liver function, the average AUC of cinacaltsete was about 2 times higher in the group with moderately impaired liver function, and about 4 times higher with severe liver failure.The average elimination half-life of cinacalcet in patients with moderate and severe degrees of liver failure is prolonged, respectively, by 33 and 70%. Hepatic insufficiency does not affect the degree of binding of cinacalcet with proteins. Since the selection of doses is carried out on the basis of efficacy and safety parameters, for patients with hepatic insufficiency, no additional dose adjustment is required (see the sections “Dosage and administration”, “Special instructions”).

Floor: cinacaletta clearance may be lower in women than in men. Since the selection of doses is carried out individually, no additional dose adjustment is required depending on the gender of the patient.

Children: The pharmacokinetics of cinacalcet was studied in 12 children (6–17 years old) with CKD who are on dialysis, after a single oral dose of 15 mg. AUC and C average valuesmax (23.5 (range from 7.22 to 77.2) ng · h / ml and 7.26 (range from 1.80 to 17.4) ng / ml, respectively) were within approximately 30% of the mean AUC values and Cmaxobserved in one study in healthy adults after a single oral dose of 30 mg of the drug (33.6 (range from 4.75 to 66.9) ng · h / ml and 5.42 (range from 1.41 to 12.7) ng / ml, respectively). Due to limited data in children, a potentially more pronounced exposure to a certain dose of cinacalece in younger children with lower body weight is not excluded, compared with older children who have a greater body weight. The pharmacokinetics of repeated doses in children have not been studied.

Smoking: cinacaletta clearance is higher among smokers than non-smokers. Apparently, this is due to the induction of metabolism, passing with the participation of CYP1A2. If the patient stops or begins to smoke during therapy, plasma concentration of tsynakalcet may change and dose adjustment may be required.

Preclinical safety studies

In the course of preclinical studies, neither genotoxic nor carcinogenic potential of cinacaltsete was detected. The safe range, according to toxicological studies, is quite narrow, because in animal experiments the factor limiting the dose was hypocalcemia. The development of cataracts and clouding of the lens were observed during toxicological and carcinogenic studies in rodents with multiple doses. However, such phenomena were not observed in experiments on dogs or monkeys, or in clinical studies that were monitored for cataract formation. It is known that in rodents cataract may occur as a result of hypocalcemia.

Indications

Secondary hyperparathyroidism in patients with end-stage renal disease who are on dialysis, including as part of combination therapy, including drugs that bind phosphates and / or vitamin D; reduction of hypercalcemia in patients with parathyroid carcinoma.

Composition

1 tablet contains:

Active substance: cinakalceta hydrochloride;

Excipients: pregelatinized corn starch; MCC; Povidone; crospovidone; magnesium stearate; colloidal silicon dioxide; carnauba wax; Opadry II green (lactose monohydrate - 40%, hypromellose 15cP - 28%, titanium dioxide - 19.38%, triacetin - 8%, indigo carmine aluminum varnish - 2.78%, iron yellow oxide - 1.84%) opadry transparent (hypromellose 6cP - 90.9%, macrogol 400 - 9.1%).

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Mimpara® [Cinacalcet]

Dosage and Administration

For external use

The treatment process is carried out on an outpatient basis under the supervision of a physician. The procedure does not require anesthesia. The preparation is applied with a plastic spatula, cotton swab or with the help of a glass capillary on the surface of the pre-degreased 70% alcohol. Processing is carried out for 1-3 applications until the appearance of whitish-gray staining. The change in color of the fabric occurs within 2-3 minutes after application of the drug. In the presence of marked hyperkeratosis within 5-7 minutes. At the same time there is a change in the consistency of the tumor to a more dense. The dosage of the drug depends on the type, size, density and degree of hyperkeratosis and can be 0.02 ml-0.2 ml. The maximum daily dose is 0.2 ml.

The number of treatments varies from 1 st (flat warts) to 3–4 (plantar warts) until the element disappears with an interval of at least 24 hours between sessions. which disappears without a trace in 25-40 minutes after completion of the procedure. Any additional therapeutic measures after the application of the drug is not required. The next day after the application, the pathological focus is mummified, acquires a dark brown shade and decreases sharply in size. Mummified scabs are separated only after complete epithelialization spontaneously after 2-3 weeks. Healing goes without complications, especially in the absence of a secondary infection, leaving no significant scars, scars and deformities of the adjacent tissues or organ dysfunction.

For local use

Treatment of anogenital warts. The treatment is carried out on an outpatient basis under the supervision of a physician, the procedure does not require anesthesia. The drug is applied with a universal probe or applicator. After applying the drug, a change in the color of the tissue to a whitish-gray staining occurs. The volume of the applied preparation depends on the size of the formation and the area of ​​the lesion and can be from 0.02 ml to 0.2 ml. During each procedure no more than 2-3 lesions can be treated with a total area of ​​up to 3 cm2. The maximum daily dose is 0.2 ml. In the presence of more extensive lesions, treatment with the drug should be carried out in several stages with an interval of at least 24 hours. When applying the drug Mardil Zinc® Max there is a slight swelling of the mucous membrane. Within 2-3 days after using the drug, necrotic tissue is rejected. Full regeneration is observed within 10-14 days. In case of large anogenital warts, in case of incomplete necrotization, repeated application of the drug is possible in 5-7 days.

Adverse reactions

The use of the drug Mardil Zinc® Max in rare cases can lead to changes in skin pigmentation and the formation of superficial skin scars. With the normal course of the epithelialization process, the absence of a secondary infection and the separate separation of mummified scabs, the likelihood of such negative consequences is extremely insignificant. Swelling of the tissue may be observed, very rarely, with individual sensitivity to the components of the drug, allergic reactions in the form of pruritus may occur.

Contraindications

  • malignant neoplasms of the skin and mucous membranes;
  • pronounced tendency to form keloids;
  • pregnancy;
  • lactation period;
  • age up to 18 years;
  • hypersensitivity to the drug.

Drug interactions

The interaction of the drug Mardil Zinc® Max with other drugs of external action is not installed.

Special instructions

Before opening the bottle, shake and move the solution that fell into the top of the bottle to its bottom. The opened bottle should be in strictly vertical position.

Mardil Zinc® Max contains acid.Avoid contact with the healthy skin or mucous membrane. If an accidental hit of the drug Mardil Zinc® Max on healthy skin or mucous membranes occurred, it is necessary to remove the preparation as soon as possible with a cotton swab moistened with water.

When treating affected skin areas near the eye area, special precautions should be observed. Avoid contact with eyes. If an accidental hit of Mardil Zinc® Max in the eyes occurred in the eyes, it is necessary to immediately rinse them with a large amount of water and 1% sodium bicarbonate solution, and then consult a doctor.

Do not remove the mummified scab by scraping or by mechanical means. The eschar must separate from the healthy skin or mucous membrane itself, otherwise there may be a violation of tissue healing processes and the formation of scars.

Until complete healing of the skin or mucous membranes is achieved, it is not recommended to swim in pools and open ponds, and exposure to direct sunlight and ultraviolet radiation should be avoided. On the day of treatment, it is recommended to limit water treatments.

It is desirable to avoid traumatization and contamination of the treated pathological focus until complete epithelialization.

Before you throw away the bottle, you should wash off the remnants of the drug in running water. Empty vial can be thrown into the trash.

Overdosage

With the wrong use of the drug, the formation of erosion is possible.

In order to prevent acid burns, rinse the drug with running water. Healing can occur independently without the use of additional drugs or with the use of wound healing drugs.

  • Brand name: Mimpara
  • Active ingredient: Cinacalcet

Studies and clinical trials of Cinacalcet (Click to expand)

  1. Indirect reversed-phase high-performance liquid chromatographic and direct thin-layer chromatographic enantioresolution of (R,S)-Cinacalcet
  2. ChemInform Abstract: Efficient Synthesis of Cinacalcet Hydrochloride.
  3. ChemInform Abstract: Efficient Synthesis and Practical Resolution of 1-(Naphthalen-1-yl)ethanamine, a Key Intermediate for Cinacalcet.
  4. Synergistic effect of cinacalcet and active vitamin D in a dialysis patient with secondary hyperparathyroidism
  5. Persistent hypophosphathemia recovered with cinacalcet in a late renal transplanted patient
  6. A population pharmacokinetic (PK) and pharmacodynamic (PD) analysis of cinacalcet HCL in renal-dialysis patients with secondary hyperparathyroidism (HPT)
  7. Quantification of cinacalcet by LC–MS/MS using liquid–liquid extraction from 50 μL of plasma
  8. Synthesis of Cinacalcet congeners
  9. Practical synthesis of the calcimimetic agent, cinacalcet
  10. Reduction of whole PTH/intact PTH ratio as a predictor of bone metabolism in cinacalcet treatment of hemodialysis patients with secondary hyperparathyroidism
  11. Cinacalcet HCl SuppressesCyclin D1Oncogene-Derived Parathyroid Cell Proliferation in a Murine Model for Primary Hyperparathyroidism
  12. Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl
  13. Cinacalcet is efficacious in pediatric dialysis patients
  14. Cinacalcet for secondary hyperparathyroidism in children with end-stage renal disease
  15. Middle-term use of Cinacalcet in paediatric dialysis patients
  16. Beneficial effect of cinacalcet in a child with familial hypocalciuric hypercalcemia
  17. Effective use of cinacalcet for the treatment of secondary hyperparathyroidism in Austrian dialysis patients – Results of the Austrian cohort of the ECHO study
  18. Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels
  19. Bone metabolism after cinacalcet administration in patients with secondary hyperparathyroidism
  20. A patient undergoing chronic dialysis whose renal anemia was successfully corrected by treatment with cinacalcet
  21. Two cases of acute renal hemorrhage undergoing maintenance hemodialysis after concurrent administration of cinacalcet
  22. Cinacalcet as alternative treatment for primary hyperparathyroidism: achievements and prospects
  23. Cinacalcet hydrochloride in combination with alendronate normalizes hypercalcemia and improves bone mineral density in patients with primary hyperparathyroidism
  24. Cinacalcet bei Dialysepatienten?

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