winstrol cycle

Mechanism of action winstrol cycle is an L-valyl ester (pro-drug) of ganciclovir after oral administration is rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir – a synthetic analogue of 2′-deoxyguanosine, which inhibits the proliferation of herpes viruses in vitro group and in vivo. For human viruses, sensitive to ganciclovir, include cytomegalovirus (CMV), herpes simplex virus-1 and -2 (herpes simplex 1 and 2), human herpes virus type 6, 7 and 8 (HHV-6, HHV-7, HHV- 8), Epstein-Barr virus (EBV), varicella zoster virus (varicella / zoster) and hepatitis B. The CMV-infected cells by the action of the viral protein kinase UL97 ganciclovir is initially phosphorylated to ganciclovir monophosphate form. Further phosphorylation occurs by cellular kinases to form ganciclovir triphosphate, which is then subjected to slow intracellular metabolism. It is shown that this metabolism occurs in cells infected with CMV and herpes simplex virus, wherein after the disappearance of ganciclovir from the extracellular fluid intracellular half-life period is suitably 6-24 and 18 hours. Since the phosphorylation of ganciclovir to a large extent depends on the action of viral kinases, it occurs primarily in the infected cells. Virostatic activity ganciclovir caused inhibition of viral DNA synthesis by: (1) competitive inhibition of incorporation of deoxyguanosine triphosphate into DNA by a viral DNA polymerase, (2) inclusion of ganciclovir triphosphate into viral DNA, resulting in the termination of viral DNA elongation or its very limited elongation. Typical antiviral IC 50 against CMV determined in vitro, is in the range from 0.14 mM (0.04 g / ml) to 14 mM (3.5 mg / ml).

Pharmacodynamics The clinical antiviral effect Valtsita was proved decrease isolation of CMV from the body of AIDS patients from the original 46% (32/69) and 7% (4/55) after 4 weeks of treatment Valtsitom.

Efficiency Application Valtsita allows to obtain the same systemic exposure of ganciclovir, as when using the recommended doses of intravenous ganciclovir, effective in the treatment of CMV retinitis. It is shown that the area under the curve, “concentration-time” (AUC) of ganciclovir correlates with the time to progression of CMV retinitis. CMV disease incidence within the first 6 months after transplantation was 12.1% in patients treated mill (900 mg daily) and 15.2% – patients receiving oral ganciclovir (1000 mg three times a day) from 10 to 100 days after transplantation. The frequency of acute rejection within the first 6 months was 29.7% in the group of patients and 36% of winstrol cycle – ganciclovir group.

Viral resistance Chronic administration of winstrol cycle may receive a virus that is resistant to ganciclovir, which is caused by selection of mutations in the gene or viral kinase (UL97), responsible for monophosphorylation ganciclovir or gene viral polymerase (UL54). The virus having only the mutation UL97 gene resistant only to ganciclovir, whereas mutations UL54 gene of a virus can have cross-resistance to other antiviral drugs with the same mechanism of action, and vice versa. Genotyping CMV in polymorphonuclear leukocytes, it showed that at 3, 6, 12 and 18 months of treatment, winstrol cycle, respectively, 2%, 7%, 14% and 18% of leukocytes identified UL97 mutation. Phenotypic resistance was not, however, an analysis was conducted on a very small number of CMV cultures.

Preclinical safety data winstrol cycle ganciclovir and mutagenic effects in mouse lymphoma cells and clastogenic effect in mammalian cells. These results are consistent with the positive results of the carcinogenicity studies in mice ganciclovir. As ganciclovir, winstrol cycle is a potential carcinogen. Studies of reproductive toxicity with winstrol cycle not be repeated because of the rapid and complete conversion of the drug ganciclovir. For both drugs include the same warning about a possible reproductive toxicity (see. “Special instructions”). In animals, ganciclovir violates fertility and teratogenic effect.Given the animal experiments in which systemic exposure to ganciclovir concentrations below therapeutic caused spermatoschesis very likely that ganciclovir and winstrol cycle can inhibit spermatogenesis in man. The data obtained in a model for human placenta ex vivo, show that ganciclovir crosses the placenta, probably by simple transfer. In the concentration range from 1 to 10 mg / ml of the drug crossing the placenta saturable bore and character carried out by passive diffusion.

 

Pharmacokinetics
The pharmacokinetic characteristics of winstrol cycle have been studied in HIV and CMV-seropositive patients and in patients with AIDS and CMV retinitis and after organ transplantation.
The bioavailability and renal function are responsible for the exposure of ganciclovir after administration of winstrol cycle. Ganciclovir Bioavailability was similar in all patients receiving winstrol cycle.Systemic exposure of ganciclovir to heart transplant recipients, kidney, liver was similar to that after administration of oral winstrol cycle according to the dosing schedule, depending on renal function.

Absorption
winstrol cycle is a pro-drug ganciclovir is well absorbed from the gastrointestinal tract and the intestinal wall and liver rapidly converted to ganciclovir. The absolute bioavailability of ganciclovir after administration of winstrol cycle is approximately 60%. Systemic concentrations of winstrol cycle low and stay awhile. The area under the curve, “concentration-time” (AUC 24 ), and the maximum concentration (C max ) are, respectively, about 1% and 3% of those of ganciclovir.
The proportional relationship AUC ganciclovir dose after winstrol cycle in doses ranging from 450 to 2625 mg shown only in the case of taking the medication after a meal. If winstrol cycle administered during a meal in the recommended dosage of 900 mg increases the average AUC 24 (about 30%) and the average C max (approximately 14%) of ganciclovir. Therefore, Valcyte is recommended to be taken with food (see. “Dosing and dosing regimen”).

Distribution
Due to the rapid metabolism of winstrol cycle to ganciclovir, winstrol cycle binding proteins was not determined. Ganciclovir Plasma protein binding of the drug at concentrations from 0.5 to 51 micrograms / ml is 1-2%. The equilibrium volume of distribution of ganciclovir after intravenous administration was equal to 0.680 0.161 l / kg.

Metabolism
winstrol cycle is rapidly hydrolyzed to produce ganciclovir; other metabolites were found. After a single oral 1000 mg radiolabeled ganciclovir none of the metabolites was not more than 1-2% of the radioactivity detected in the faeces or urine.

Excretion The main route of elimination of winstrol cycle, ganciclovir as is glomerular filtration and active tubular secretion. In renal clearance accounts for 81.5% 22 systemic clearance of ganciclovir.

Pharmacokinetics in special populations Patients with renal insufficiency. Deterioration of renal function leads to a decrease in clearance of ganciclovir, winstrol cycle formed from, with a corresponding increase in half-life of terminal phase. Therefore, in patients with impaired renal function dose adjustment is required (see. “Special instructions for dosage” and “Cautions”). Patients on hemodialysis. Patients receiving hemodialysis (creatinine clearance less than 10 mL / min) is not recommended for Valcyte. This is due to the fact that these patients need individual dose Valtsita less than 450 mg per tablet (see. “Special instructions for dosage” and “Cautions”). Patients with hepatic impairment. The pharmacokinetics of winstrol cycle was studied in patients with stable graft functioning liver. The absolute bioavailability of ganciclovir from winstrol cycle is formed, was approximately 60%, which coincides with the index of the other groups of patients. The area under “concentration-time” curve (AUC 0-24 ) ganciclovir was comparable with that after intravenous ganciclovir 5 mg / kg of patients who had undergone a liver transplant.

 

Indications
Treatment of CMV retinitis in AIDS patients.
Prophylaxis of CMV – infection in patients after organ transplantation.

Contraindications
: Hypersensitivity to winstrol cycle, ganciclovir or to any component of the drug. Due to the similar chemical structure Valtsita and aciclovir and valaciclovir possible reaction cross-sensitivity to these drugs.
An absolute neutrophil count below 500 cells in 1 mm, the platelet count is less than 25,000 cells in 1 mm, the level of hemoglobin below 80 g / l, creatinine clearance less than 10 ml / min.
Pregnancy, lactation, children under 12 years.

Precautions
Kidney failure, older age (safety and efficacy have not been established).

Pregnancy and lactation
studies reproductive toxicity with winstrol cycle not be repeated because of the rapid and complete conversion of the drug ganciclovir. Ganciclovir is penalized for fertility and is teratogenic in animals.
During treatment, should be recommended for women of childbearing age use reliable methods of contraception. Men are recommended to use a barrier method of contraception during treatment Valtsitom and not less than 90 days after the end (see. “Preclinical Safety Data”).
Safety Valtsita during pregnancy in humans has not been established. When pregnancy Valtsita destination should be avoided, unless the potential benefit to the mother justifies the potential risk to the fetus.
Peri- and postnatal development using winstrol cycle and ganciclovir has not been studied, but we can not exclude the possibility of elimination of ganciclovir in breast milk and developing serious adverse reactions in the infant . Therefore, taking into account the potential benefits of therapy Valtsitom to a nursing mother, you should decide on the abolition of the drug or the termination of breastfeeding.

Dosing and Administration
In order to avoid an overdose need to strictly observe the dosing recommendations.

The standard dosing regimen of Valcyte should be taken orally with meals (see. “Pharmacokinetics”, “Absorption”). Valcyte quickly and to a large extent transformed into ganciclovir. The bioavailability of ganciclovir from Valtsita 10 times higher than from ganciclovir capsules, so you need to strictly adhere to the below-described tablets Valtsita dosing regimen (see. “Cautions” and “Overdose”).

Induction therapy
in patients with active CMV retinitis Valtsita recommended dose is 900 mg (2 tablets of 450 mg) twice a day for 21 days. Prolonged induction therapy increases the risk of myelotoxicity (see. “Special instructions”).

Maintenance treatment
after induction therapy, or patients with CMV retinitis inactive recommended dose is 900 mg (2 tablets of 450 mg) once daily. If deteriorating for retinitis, induction therapy can be repeated (see. “Induction therapy”).

Prevention of CMV disease after organ transplantation
In patients undergoing transplantation, the recommended dose is 900 mg (2 tablets of 450 mg) once a day from 10th day, 100 days after transplant.

Specific guidance on dosing in patients with renal insufficiency. It is necessary to carefully monitor serum creatinine or creatinine clearance. Dose correction is carried out depending on the creatinine clearance, as shown in the table below (see “Pharmacokinetics in special populations” and “special instructions”.). Creatinine clearance was calculated based on serum creatinine using the following formula:

 

Men = (140 – age [years]) x body weight [kg]
______________________________________________
72 x 0.011 x serum creatinine [mmol / l]

Women x = 0.85 for males.

 

Creatinine clearance (ml / min) The dose for the induction treatment The dose for maintenance therapy / prophylaxis
≥ 60 900 mg 2 times a day 900 mg 1 time per day
40 – 59 450 mg 2 times a day 450 mg 1 time per day
25 – 39 450 mg 1 time per day 450 mg every 2 days
10 – 24 450 mg every 2 days 450 mg 2 times a week

Patients on hemodialysis
patients receiving hemodialysis (creatinine clearance less than 10 ml / min), Valcyte is not recommended (see. “Pharmacokinetics in special populations” and “Cautions”).

Patients with severe leucopenia, neutropenia, anemia, thrombocytopenia or pancytopenia
in patients receiving Valcyte (and ganciclovir), there have been cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia. Treatment should not be initiated if the absolute neutrophil count below 500 cells in 1 mm or less platelet count 25,000 cells in 1 mm, and if the hemoglobin level below 8 g / dL (cm. “Specific guidance” and “Side effect”).

Side effect

Data from clinical studies . The experience of Valtsita All adverse events reported in clinical studies Valtsita, previously experienced in the treatment of ganciclovir. The most common adverse events that occurred while taking winstrol cycle in patients with CMV retinitis and AIDS: diarrhea, neutropenia, fever, oral candidiasis ., headache, and weakness of the most frequent undesirable effects regardless of severity and connection with the reception of the drug in patients after organ transplantation: diarrhea, tremors, graft rejection, nausea, headache, lower limb edema, constipation, insomnia, back pain, hypertension, vomiting. Most of them were mild or moderate expressed. The most common undesirable effects regardless of severity of, but related to the drug intake (probable or possible relationship) in patients after solid organ transplantation were: leukopenia, diarrhea, nausea, neutropenia. Adverse events that occurred in patients after transplantation with a frequency of ≥ 2% and were not observed in the group of patients with CMV retinitis: hypertension, hypercreatininemia, hyperkalemia, abnormal liver function. Side effects identified by more than 5% of patients with CMV retinitis and after organ transplantation. digestive organs – intestinal tract: diarrhea, nausea, vomiting , abdominal pain, constipation, pain in the upper abdomen, indigestion, abdominal enlargement, ascites, hepatic dysfunction. body as a whole – fever, weakness, lower limb edema, peripheral edema, fatigue, weight loss, decreased appetite, anorexia, cachexia , dehydration, transplant rejection. Blood and lymphatic system – neutropenia, anemia, thrombocytopenia, leukopenia. Infectious complications – oral candidiasis, pharyngitis, nasopharyngitis, sinusitis, upper respiratory tract infection, pneumonia, Pneumocystis pneumonia, urinary tract infection. Nervous system – headache, insomnia, peripheral neuropathy, paresthesia, tremor, dizziness. Skin and appendages – dermatitis, night sweats, itching, acne. thorax organs – shortness of breath, productive cough, nasal discharge, pleural effusion. The bodies of – retinal detachment, . blurred vision mental health problems – depression. Musculoskeletal system – back pain, arthralgia, pain in extremities, muscle cramps. Genito-urinary system – kidney failure, dysuria. Cardio – vascular system – arterial hypertension, hypotension. Laboratory tests – hypercreatininemia , hyperkalemia, hypokalemia, hypomagnesemia, hyperglycemia, hypophosphatemia, hypocalcemia. surgery -. postoperative complications, pain after surgery, infectious complications of surgical wounds, increased wound drainage, poor wound healing following are serious adverse events associated with taking Valtsita, occurring with a frequency less than 5%, not mentioned above: Blood and lymphatic system: pancytopenia, bone marrow suppression function, aplastic anemia. Severe neutropenia (less than 500 cells / microliter) was more common in patients in the treatment of CMV retinitis (16%) than in the appointment of patients after organ transplantation (5%). Urogenital: decline in creatinine clearance, hypercreatininemia. Increase in serum creatinine observed more frequently in patients after organ transplantation compared with patients who received treatment for CMV retinitis. Renal impairment – typical complication in transplant patients. Bleeding – threatening bleeding life, perhaps associated with thrombocytopenia. Central and peripheral nervous system – convulsions, mental disorders, hallucinations, confusion, agitation. Body as a Whole – hypersensitivity to winstrol cycle.

. Experience with ganciclovir As Valcyte is rapidly converted to ganciclovir, the following are adverse events described in the treatment with ganciclovir, and not mentioned above. Digestive system: dry mouth, cholangitis, dysphagia, regurgitation, esophagitis, fecal incontinence, flatulence, gastritis, gastrointestinal intestinal disorders, gastro-intestinal bleeding, ulcerative stomatitis, pancreatitis, glossitis, hepatitis, jaundice. body as a whole: bacterial, fungal and viral infections, malaise, mucositis, tremors, sepsis. Skin and appendages: alopecia, exfoliative dermatitis, photosensitivity reactions , dry skin, sweating, urticaria. Central and peripheral nervous system: asthenia, headache, nightmares, amnesia, anxiety, ataxia, coma, emotional disorder, hyperkinesia, hypertonia, decreased libido, myoclonic jerks, nervousness, somnolence, disturbances of intelligence. Musculoskeletal -dvigatelny device: pain in the bones and muscles, myasthenic syndrome. Urogenital: hematuria, impotence, frequent urination.Laboratory indicators: increase in the activity of alkaline phosphatase, creatine kinase, lactate dehydrogenase in the blood, lowering blood glucose, hypoproteinemia. Special senses: amblyopia, blindness, pain in the ear, bleeding in the eyes, pain in eyeballs, deafness, glaucoma, disorders of taste perception, non-systemic dizziness, changes in the vitreous body. blood system and lymphatic system:eosinophilia, leukocytosis, lymphadenopathy, splenomegaly, bleeding. Cardiovascular system: arrhythmias, including ventricular, deep vein thrombophlebitis, phlebitis, tachycardia, vasodilatation. respiratory:stagnation in the paranasal sinuses. The endocrine system: diabetes.

Post-marketing experience of the drug Experience with ganciclovir. The following are the adverse events described in the spontaneous messages in the post-marketing use of ganciclovir not mentioned in any of the above sections, for which we can not exclude a causal relationship with the drug. Since Valcyte quickly and to a large extent converted to ganciclovir, such adverse events may develop and the treatment Valtsitom: anafilakciya, reduced fertility in men. Adverse events were described at the post-registration use of the drug are similar to those observed in clinical studies Valtsita and ganciclovir.

 

Overdosing
One adult patient to use the drug for several days, at doses at least 10 times higher than recommended for it based on kidney damage (decrease of creatinine clearance), developed bone marrow suppression (medullar aplasia) fatal.
Perhaps overdose of winstrol cycle may occur signs of renal toxicity (see. “Cautions” and “Dosage”).
Reduce winstrol cycle plasma concentrations in patients with an overdose can be achieved by dialysis and hydration (see. “pharmacokinetics, patients on hemodialysis”).

An overdose of ganciclovir when administered intravenously in clinical studies and post-marketing use of the drug overdose cases intravenous ganciclovir have been described. Some of them were not accompanied by adverse events. The majority of the patients had one or more of the following adverse events: Haematological toxicity: pancytopenia, bone marrow suppression function, medullary aplasia, leucopenia, neutropenia, granulocytopenia. Hepatotoxicity: hepatitis, liver dysfunction. Nephrotoxicity: strengthening of hematuria in patients with pre-existing lesion kidney, acute renal failure, increased creatinine. Gastrointestinal toxicity: abdominal pain, diarrhea, vomiting. Neurotoxicity: generalized tremor, convulsion.

Interaction

Drug interactions Valtsita The in situ model of intestinal permeability in rats interactions with winstrol cycle valacyclovir, didanosine, nelfinavir, cyclosporin, omeprazole and mycophenolate mofetil were found. Valcyte is converted to ganciclovir, so interactions specific to ganciclovir may be expected when using Valtsita.

Drug interactions ganciclovir Binding of ganciclovir to plasma proteins is only 1-2%, so the reactions associated with the replacement of protein binding should not be expected. Imipenem-cilastatin:patients receiving both ganciclovir and imipenem / cilastatin, convulsions were observed. Co-administration of these drugs should be avoided, unless the potential benefits do not exceed the risks.Probenecid: Simultaneous oral probenecid may be about 20% to reduce the renal clearance of ganciclovir and statistically significant (40%) to increase its area under “concentration-time” curve (AUC ). This is due to the interaction mechanism – competition for tubular renal excretion. Patients concurrently receiving probenecid and rollers must be closely monitored for toxicity of ganciclovir. Zidovudine: when assigning simultaneously with ganciclovir AUC oral zidovudine may slightly but statistically significant increase (17%); In addition, there is a trend, although not statistically significant, in lower concentrations of ganciclovir. Since both zidovudine and ganciclovir can cause anemia and neutropenia, some patients can not tolerate simultaneous reception of these drugs at full doses. Didanosine: found that the plasma concentration of didanosine while both intravenous and oral administration of ganciclovir increased firmness. When taken orally at a dose of ganciclovir 3 and 6 grams per day of ddI AUC increased by 84-124%, while for intravenous ganciclovir at doses of 5-10 mg / kg / day of ddI AUC increased by 38-67%. This increase can not be explained by competition for renal tubular excretion, as the percentage of elimination of didanosine is increased. The reason for this increase may be either increasing bioavailability or metabolism inhibition. No clinically significant effect on ganciclovir concentrations were noted.However, given the increase of plasma didanosine concentrations in the presence of ganciclovir should be carefully monitored patients for the emergence of symptoms of toxic action of didanosine.Mycophenolate mofetil: taking into account the results of the study on a single injection of the recommended dose in / ganciclovir and oral administration of mycophenolate mofetil and known influence renal impairment on the pharmacokinetics of ganciclovir and mycophenolate mofetil can be expected that co-administration of these drugs, competing in the process of tubular secretion, lead to increased concentrations of ganciclovir and phenolic glucuronide of mycophenolic acid (MFKG). Significant changes pharmacokinetics mycophenolic acid (IFC) are not expected to adjust the dose of mycophenolate mofetil is required. In patients with impaired renal function, which simultaneously receive mycophenolate mofetil and ganciclovir, it is necessary to comply with the recommendations for the correction of the dose of ganciclovir and conduct careful observation. Zalcitabine: ddC increases the area under “concentration-time” curve (the AUC 0-8 ) oral ganciclovir by 13% . No significant changes in other pharmacokinetic parameters is not happening. Clinically significant changes in the pharmacokinetics of zalcitabine while oral ganciclovir were also absent, despite a slight increase in the elimination rate constant. Stavudine: no significant pharmacokinetic interactions were observed while taking stavudine and oral ganciclovir. Trimethoprim: Trimethoprim statistically significantly (by 16.3%) reduces renal clearance oral ganciclovir, which is accompanied by a statistically significant decrease in terminal elimination rate and increasing the half-life corresponding to 15%. However, the clinical significance of these changes is unlikely, because the AUC 0-8 and C max are not changed. The only statistically significant change in the pharmacokinetic parameters of trimethoprim while receiving ganciclovir was an increase in C min. However, this is unlikely to have clinical importance, therefore dose adjustment is required. Cyclosporine: when comparing cyclosporine concentrations before receiving the next data dose that ganciclovir alters the pharmacokinetics of cyclosporine, It has been received. Nonetheless, after the start of ganciclovir was a slight increase in the maximum level of serum creatinine. Other possible drug interactions. Assignment ganciclovir concurrently with other drugs that provide myelosuppressive effects or invasive kidney function (such as dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin , amphotericin B, nucleoside analogues and hydroxyurea), may enhance their toxicity. Therefore, these drugs can be used in conjunction with ganciclovir only if the potential benefits outweigh the risks.

Specific guidance

in animal experiments showed mutagenic, teratogenic, and carcinogenic spermicidal effect of ganciclovir. Valcyte should be considered a potential teratogen and carcinogen to humans, the use of which may cause birth defects and cancers (see. “Handling the drug”). In addition it is likely that Valcyte may temporarily or permanently suppress spermatogenesis (see. “Preclinical safety data”, “Side effects”, “Pregnancy”).
Patients treated with Valcyte (and ganciclovir), there have been cases of severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression and aplastic anemia. Treatment should not be initiated if the absolute neutrophil count below 500 cells in 1 mm or platelet count less than 25,000 cells in 1 mm, and if the hemoglobin level below 8 g / dL (cm. “Specific guidance on dosing” and “Side effect”) .
Do not appoint Valcyte children. Pharmacokinetic characteristics, safety and efficacy in this population have not been established.
The bioavailability of ganciclovir Valtsita 10 times higher than that of ganciclovir capsules. Ganciclovir is impossible to replace the drums in a ratio of 1: 1. Patients who are transferred to the capsule of ganciclovir should be informed about the risk of an overdose if they will accept a larger number of tablets Valtsita than recommended (see. “Dosage” and “Overdose”).
In the course of treatment is recommended on a regular basis to determine the complete blood count with platelets. Patients with severe leucopenia, neutropenia, anemia or thrombocytopenia, it is recommended to appoint hematopoietic growth factors and / or discontinue the drug (see. “Special instructions for dosage” and “Side effects”).
Patients with renal insufficiency Dosage adjustment based on the amount of creatinine clearance (see. “Special instructions for dosage” and “Farmakokinetka in special populations”).

Effects on ability to drive a car and work with machines and mechanisms Convulsions, sedation, dizziness, ataxia and confusion, which are described in the treatment of Valtsitom and ganciclovir, may impair the ability to perform tasks that require a certain level of consciousness, including driving and working with machines and mechanisms.

Handling drug tablets can not crush or pulverize. Since Valcyte is potentially teratogenic and carcinogenic to humans, caution should be exercised, if the tablet fractures. Avoid direct contact faults or crushed tablets with skin or mucous membranes. In cases such contact should be thoroughly washed it with soap and water, if eye contact with them thoroughly washed with plain water.

Release form and packing
Coated tablets 450 mg
60 tablets in a bottle made of polypropylene
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