Noliprel a forte pills coated 5 mg + 1.25 mg N30
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Active ingredients
Indapamide + Perindopril
Release form
Pills
Composition
Active ingredient: Perindopril arginine (Perindopril arginine), Indapamide (Indapamide) Active ingredient concentration (mg): Perindopril arginine - 5 mg, Indapamide - 1.25 mg
Pharmacological effect
Noliprel A forte is a combination product containing perindopril arginine and indalam. The pharmacological properties of the drug Noliprel A forte combine the individual properties of each of the components. Mechanism of Action in angiotensin II (ACE inhibitor). ACE, or kininase II, is an exopeptidase that performs both the conversion of angiotensin I into a vasoconstrictor substance angiotensin II, and the destruction of bradykinin, which has a vasodilating effect, to inactive heptapeptide. As a result, perindopril: - reduces the secretion of aldosterone; renin activity in the blood plasma; - with long-term use, it reduces OPSS, which is mainly due to the effect on the vessels in the muscles and kidneys. These effects are not accompanied by the retention of sodium ions and fluids or the development of reflex tachycardia. Perindopril normalizes myocardial work by reducing preload and afterload. When studying hemodynamic parameters in patients with chronic heart failure, it was revealed: - a decrease in filling pressure in the left and right ventricles of the heart; - a decrease in OPSS; - an increase in cardiac output; - increased muscle peripheral blood flow.IndapamideIndaptami belongs to the group of sulfonamides, pharmacological properties similar to thiazide diuretics. Indapamide inhibits the reabsorption of sodium ions in the cortical segment of the loop of Henle, which leads to an increase in kidney excretion of sodium ions, chlorine and to a lesser extent potassium and magnesium ions, thereby enhancing diuresis and reducing blood pressure. Antihypertensive effect Noliprel A fornoliprel A forte has a dose-dependent antihypertensive effect diastolic and systolic blood pressure in the standing and lying position. The antihypertensive effect lasts for 24 hours.A stable therapeutic effect develops in less than 1 month from the start of therapy and is not accompanied by tachycardia. Termination of treatment does not cause withdrawal. Noliprel A Forte reduces the degree of left ventricular hypertrophy (GTLZH), improves the elasticity of arteries, reduces the round neck, does not affect lipid metabolism (total cholesterol, HDL cholesterol, LDL, triglycerides). The effect of the use of perindopril and indapamide on GTLZH in comparison with enalapril. In patients with arterial hypertension and GTLV who received perindopril erbumin 2 mg (equivalent to 2.5 mg perindopril arginine) / indapamide 0.625 mg or enalapril at a dose of 10 mg 1 time / day, and with an increase in perindopril erbumine dose to 8 mg (equivalent to 10 mg perindopril arginine) and indapamide up to 2.5 mg, or enalapril up to 40 mg 1 time / day, there was a more significant decrease in the left ventricular mass index (LVMI) in the perindopril / indapamide group compared with the enalapril group. At the same time, the most significant effect on LVMI is observed when perindopril erbumine 8 mg / indapamide 2.5 mg is used. A more pronounced antihypertensive effect was also observed on the background of combined therapy with perindopril and indapamide compared with enalapril. In patients with type 2 diabetes mellitus (average age 66 years, BMI - 28 kg / m2, glycated hemoglobin (HbA1c) 7.5%, BP 145/81 mm Hg) studied the effect of the fixed perindopril / indapamide combination on the main micro- and macrovascular complications in addition to . Artney therapy glycemic control, as well as the strategy of intensive glycemic control (IUC) (target HbA1c <6.5%) in 83% of patients had hypertension, 32% and 10% - of macro- and microvascular complications, 27% - microalbuminuria. The majority of patients at the time of inclusion in the study received hypoglycemic therapy, 90% of patients received hypoglycemic agents for oral administration (47% of patients - in monotherapy, 46% - therapy with two drugs, 7% - therapy with three drugs). 1% of patients received insulin therapy, 9% - only diet therapy. Sulfonylurea derivatives took 72% of patients, 61% metformin. As concomitant therapy, 75% of patients received antihypertensive drugs, 35% of patients received hypolipidemic agents (mainly HMG-CoA reductase inhibitors (statins) —28%), acetylsalicylic acid as an antiplatelet agent, and other antiplatelet agents (47%). After 6 weeks of the introductory period,during which patients received perindopril / indapamide therapy, they were distributed to the standard glycemic control group or to the IHC group (Diabeton MB with the possibility of increasing the dose to a maximum of 120 mg / day or adding another hypoglycemic agent). In the IHC group (average observation duration 4.8 years , average HbAlc 6.5%) compared with the standard control group (average HbAlc 7.3%) showed a significant 10% decrease in the relative risk of the combined frequency of macro- and microvascular complications. Advantage was achieved due to a significant reduction in relative risk: major microvascular complications by 14%, the onset and progression of nephropathy by 21%, microalbuminuria by 9%, macroalbuminuria by 30% and the development of kidney complications by 11%. The benefits of antihypertensive therapy did not depend on the benefits, PerindoprilPerindopril is effective in the treatment of hypertension of any severity. The antihypertensive effect of the drug reaches a maximum 4-6 h after a single ingestion and preserving within 24 hours. 24 hours after taking the drug, a pronounced (about 80%) residual inhibition of ACE is observed. Perindopril has an antihypertensive effect in patients with both low and normal renin activity in the blood plasma. Simultaneous administration of thiazide diuretics increases the severity of antihypertensive actions. In addition, the combination of an ACE inhibitor and a thiazide diuretic also leads to a reduction in the risk of hypokalemia in patients receiving diuretics. Indapamide The antihypertensive effect is manifested when the drug is used in doses that have a minimal diuretic effect. The antihypertensive effect of indapamide is associated with an improvement in the elastic properties of large arteries, a decrease in CRPS. Indapamide reduces GTZH, does not affect the concentration of lipids in blood plasma: triglycerides, total cholesterol, LDL, HDL; carbohydrate metabolism (including in patients with concomitant diabetes).
Pharmacokinetics
The pharmacokinetic characteristics of perindopril and indapamide do not change when combined with their separate use. Perindopril Absorption and metabolism After oral administration, perindopril is rapidly absorbed.Bioavailability is 65-70%. Approximately 20% of the total amount of absorbed perindopril is converted to the active metabolite of perindopril. Cmax of perindoprilat in blood plasma is reached after 3-4 hours. When taking the drug during a meal, the metabolism of perindopril to perindoprilat decreases (this effect does not have a significant clinical significance). . The dissociation of perindoprilat associated with ACE is slowed down. As a result, the effective half-life (T1 / 2) is 25 hours. Reappointment of perindopril does not lead to its cumulation, and T1 / 2 of perindoprilat when taken again corresponds to the period of its activity, thus the equilibrium state is reached after 4 days. by the kidneys. T1 / 2 metabolite is 3-5 hours. Pharmacokinetics in special clinical situations. Perindoprilat release slows down in elderly patients, as well as in patients with renal insufficiency and heart failure. Perindoprilaty clearance is 70 ml / min. cirrhosis of the liver: hepatic clearance of perindopril is reduced by 2 times. However, the amount of perindoprilat formed does not change, therefore, dose adjustment of the drug is not required. Perindopril crosses the placental barrier. Indapamide Absorption Indapamide is rapidly and completely absorbed from the gastrointestinal tract. Cmax in the blood plasma is achieved 1 hour after ingestion. Distribution: Plasma protein binding to the blood plasma is 79%. Repeated administration of the drug does not cause its accumulation in the body. Excretion of T1 / 2 is 14-24 hours (19 hours on average). Excreted mainly by the kidneys (70% of the administered dose) and through the intestine (22%) in the form of inactive metabolites. Pharmacokinetics in special clinical situations. The pharmacokinetics of indapamide does not change in patients with renal insufficiency.
Indications
Essential hypertension.
Contraindications
Hypersensitivity to perindopril, angioedema in history; hereditary / idiopathic angioedema, hypokalemia, severe renal failure, stenosis of the artery of a single kidney,bilateral renal artery stenosis, severe liver failure (including with encephalopathy), simultaneous administration of drugs that prolong the QT interval, simultaneous use with antiarrhythmic drugs that can cause arrhythmia such as "pirouette", pregnancy and breastfeeding.
Precautionary measures
Do not exceed recommended doses.
Use during pregnancy and lactation
The drug is contraindicated during pregnancy. When planning a pregnancy or when it occurs while taking the drug Noliprel A, forte should immediately stop taking the drug and prescribe another antihypertensive therapy. Do not use Noliprel A forte in the first trimester of pregnancy. Relevant controlled studies on the use of ACF inhibitors in no pregnant women. The limited data available on the effects of ACE inhibitors in the first trimester of pregnancy indicate that taking ACE inhibitors did not lead to fetal malformations associated with fetotoxicity, but to completely eliminate the phototoxic effect of the drug is impossible. Noliprel A is contraindicated in the second and third trimesters of pregnancy. It is known that long-term effects of ACE inhibitors on the fetus in the second and third trimesters of pregnancy can lead to impairment of its development (reduced renal function, oligohydramnios, delayed ossification of the skull bones) and the development of complications in the newborn (renal failure, arterial hypotension, hyperkalemia). Prolonged use of thiazide diuretics in the third trimester of pregnancy can cause hypovolemia in the mother and a decrease in uteroplacental blood flow, which leads to fetoplacental ischemia and delayed fetal development. In rare cases, on the background of diuretic administration, shortly before birth, newborns develop hypoglycemia and thrombocytopenia. If the patient received the drug Noliprel A Forte in the II or III trimester of pregnancy, it is recommended to conduct an ultrasound examination of the newborn to assess the state of the skull and kidney function. In newborns whose mothers received therapy with ACE inhibitors, hypotension may occur, and therefore the newborns must be under careful medical supervision. Noliprel A forte is contraindicated during lactation.It is not known whether perindopril is excreted in breast milk. Indapamide is excreted in breast milk. Reception of thiazide diuretics causes a decrease in the amount of breast milk or suppression of lactation. A newborn may develop hypersensitivity to sulfonamide derivatives, hypokalemia, and nuclear jaundice. Since the use of perindopril and indapamide during lactation can cause severe complications in the infant, it is necessary to evaluate the importance of therapy for the mother and decide to stop breastfeeding or to stop taking drug.
Dosage and administration
Inside, preferably in the morning, before eating.
Side effects
Thrombocytopenia, leukopenia / neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia, paresthesia, headache, dizziness, asthenia, vertigo, sleep disturbance, mood lability, confusion, fainting, blurred vision, tinnitus, marked decrease in blood pressure, heart rhythm disturbance including bradycardia, ventricular tachycardia, atrial fibrillation, dry cough, shortness of breath, bronchospasm, eosinophilic pneumonia, rhinitis, dry oral mucosa, nausea, vomiting, abdominal pain, epigastric pain, pain taste perception, loss of appetite, dyspepsia, constipation, diarrhea, angioedema, cholestatic jaundice, pancreatitis, hepatic encephalopathy in patients with hepatic, skin rash, pruritus, maculopapular rash, angioedema, edema of the liver, pruritus, maculopapular rash, angioedema, edema of the liver, pruritus, maculopapular rash, angioedema, eruption of the gut folds and / or larynx; urticaria, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, muscle spasms, renal failure, acute renal failure, impotence, asthenia, increased sweating.
Overdose
Symptoms: the most likely overdose syndrome is a pronounced decrease in blood pressure, sometimes in combination with nausea, vomiting, convulsions, dizziness, drowsiness, confusion, oliguria, which can turn into anuria (as a result of hypovolemia), impaired water and electrolyte balance (hyponatremia, hypokalemia ). Treatment: emergency measures are reduced to the removal of the drug from the body - gastric lavage and / or the appointment of activated carbon, followed by restoration of water and electrolyte balance. With a significant decrease in blood pressure should be transferred to the patient in a horizontal position with raised legs.If necessary, correction of hypovolemia (for example, by intravenous infusion of 0.9% sodium chloride solution) should be carried out. Perindopril, the active metabolite of perindopril, can be removed from the body through dialysis.
Interaction with other drugs
Combinations that are not recommended for use. Lithium preparations: with the simultaneous use of lithium preparations and ACE inhibitors, a reversible increase in plasma lithium concentration and associated toxic effects may occur. The additional administration of thiazide diuretics may further increase the concentration of lithium and increase the risk of manifestations of toxicity. The simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. If such therapy is necessary, the lithium content in the blood plasma should be constantly monitored. Preparations, the combination with which requires special attention and cautionBaclofen: an increase in the hypotensive effect is possible. Blood pressure and kidney function should be monitored, and, if necessary, dose adjustment of antihypertensive drugs is required. With significant fluid loss, acute renal failure may develop (due to a decrease in glomerular filtration rate). Before starting treatment with a drug, it is necessary to replenish fluid loss and regularly monitor kidney function at the beginning of treatment. Drug combination requiring attention decrease in antihypertensive effect (fluid retention and sodium ions as a result of corticosteroids). Other hypotensive cf Units: May increase antihypertensive effect. PerindoprilCombinations not recommended for useKalis-saving diuretics (amiloride, spironolactone, triamterene) and potassium preparations: ACE inhibitors reduce the loss of potassium by the kidneys caused by the diuretic.Potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride), potassium preparations and potassium-containing substitutes for edible salt can lead to a significant increase in serum potassium up to a fatal outcome. If you need simultaneous use of an ACE inhibitor and the above drugs (in the case of confirmed hypokalemia), care should be taken to regularly monitor the potassium content in the blood plasma and ECG parameters. A combination of drugs that require special attention. Hypoglycemic agents for oral administration (sulfonylurea derivatives) and insulin: The effects below have been described for captopril and enalapril. ACE inhibitors can enhance the hypoglycemic effect of insulin and sulfonylurea derivatives in patients with diabetes. The development of hypoglycemia is very rare (due to increased glucose tolerance and reduced insulin requirements). A combination of drugs requiring attention Allopurinol, cytostatic and immunosuppressive drugs, corticosteroids (with systemic use) and procainamide: simultaneous use with ACF inhibitors may be accompanied by an increased risk of leukopenia. General anesthesia drugs: the simultaneous use of ACE inhibitors and general anesthesia agents can lead to increased antihypertensive effect. iuretics (thiazide and loop): the use of high-dose diuretics can lead to hypovolemia, and the addition of perindopril to therapy can lead to arterial hypotension. Gold preparations: with the use of ACE inhibitors, including perindopril by patients receiving IV gold medication (sodium aurothiomalate), a symptom complex was described, including: flushing of the skin of the face, nausea, vomiting, arterial hypotension. Indapamide A combination of drugs that require special attention. Preparations that can cause arrhythmia pirouette: due to cause development of hypokalemia should be careful while using indapamide with drugs that can cause arrhythmia such as pirouette, for example, antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, amioda ron, dofetilide, ibutilid, bretily tosylate, sotalol); some neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine,trifluoperazine); benzamides (amisulpride, sulpiride, sultopride, tiapride); butyrophenones (droperidol, haloperidol); other neuroleptics (pimozide); other drugs, such as bepridil, cisapride, difemanil methyl sulfate, erythromycin IV, halofantrine, mizolastine, moxifloxacin, pentamidine, sparfloxacin, vincamine IV, methadone, astemizole, terfenadine. It is necessary to avoid simultaneous use with the above preparations; the risk of hypokalemia, if necessary, carry out its correction; control the QT interval. Drugs that can cause hypokalemia: amphotericin B (w / w), gluco- and mineralocorticosteroids (for systemic use), tetracosactide, laxatives that stimulate intestinal motility: an increased risk of hypokalemia (additive effect). It is necessary to control the content of potassium in the blood plasma, if necessary - its correction. Particular attention should be paid to patients simultaneously receiving cardiac glycosides. Laxatives that do not stimulate intestinal motility should be used. Cardiac glycosides: hypokalemia increases the toxic effect of cardiac glycosides. With simultaneous use of indapamide and cardiac glycosides, potassium in the blood plasma and ECG parameters should be monitored and, if necessary, therapy should be adjusted. A combination of drugs requiring attentionMetformin: functional renal failure, which may occur while taking diuretics, especially loopback, while simultaneously administering metformin increases the risk of lactic acidosis. Metforminum should not be used if the concentration of creatinine in the blood plasma exceeds 15 mg / l (135 μmol / l) in men and 12 mg / l (110 μmol / l) in women. Iodine-containing contrast agents: dehydration of the body while taking diuretic drugs increases the risk of acute renal failure, especially when using high doses of iodine-containing contrast agents. Patients need to compensate for fluid loss before using iodine-containing contrast agents. Calcium salts: with simultaneous administration, hypercalcemia may develop due to a decrease in the excretion of calcium ions by the kidneys. Cyclosporine: an increase in plasma creatinine may occur without changing the plasma cyclosporine concentration, even with normal water content and sodium ions.
special instructions
Noliprel A forte The use of the drug Noliprel A forte is not accompanied by a significant reduction in the incidence of side effects, with the exception of hypokalemia, compared with perindopril and indapamide at the lowest permitted doses. At the beginning of therapy with two antihypertensive drugs that the patient has not previously received, an increased risk of idiosyncrasy cannot be excluded. To minimize this risk, the patient’s condition should be carefully monitored. Renal impairment in patients with severe renal insufficiency (CC <30 ml / min) is contraindicated. In some patients with arterial hypertension without prior obvious renal impairment during therapy Noliprel A Forte may show laboratory signs of functional renal failure. In this case, treatment should be discontinued. In the future, you can resume combination therapy using low doses of drugs, or use drugs in monotherapy mode. Such patients need regular monitoring of the level of potassium and creatinine in the blood serum - 2 weeks after the start of therapy and thereafter every 2 months. Renal failure often occurs in patients with severe chronic heart failure or an initial renal dysfunction, including with renal artery stenosis. Arterial hypotension and impaired water and electrolyte balanceHyponatremia is associated with the risk of sudden development of arterial hypotension (especially in patients with arterial stenosis of the single kidney and bilateral stenosis of the renal arteries). Therefore, when monitoring patients, one should pay attention to possible symptoms of dehydration and a decrease in the level of electrolytes in the blood plasma, for example, after diarrhea or vomiting. Such patients require regular monitoring of plasma electrolyte levels. In case of severe arterial hypotension, a 0.9% solution of sodium chloride may be required by intravenous infusion. Transient arterial hypotension is not a contraindication to continue therapy. After the restoration of BCC and blood pressure, you can resume therapy using low doses of drugs, or use drugs in monotherapy mode. Potassium content The combination of perindopril and indapamide does not prevent the development of hypokalemia, especially in patients with diabetes mellitus or renal failure.As with the admission of any antihypertensive drug in combination with a diuretic, in the treatment of this combination should regularly monitor the content of potassium in the blood plasma. Auxiliary substances It should be noted that lactose monohydrate is included in the excipients of the drug. Noliprel A forte should not be prescribed to patients with hereditary intolerance to galactose, lactase deficiency and the creatures of the glucose-galactose malabsorption. Lithium preparations Simultaneous use of a combination of perindopril and indapamide with lithium preparations is not recommended. drugs and the presence of concomitant diseases. Neutropenia rarely occurs in patients without comorbidities, but the risk increases in patients with impaired renal function, especially against the background of systemic connective tissue diseases (including SLE, scleroderma). After the abolition of ACE inhibitors, the symptoms of neutropenia disappear independently. In order to avoid the development of such reactions it is recommended to strictly follow the recommended dose. When prescribing ACE inhibitors, this group of patients should carefully relate the benefit / risk factor. Angioedema (Quincke edema) When taking ACE inhibitors, incl. perindopril, in rare cases, angioedema of the face, extremities, lips, tongue, glottis and / or larynx may develop. If symptoms occur, perindopril should be stopped immediately and the patient should be observed until the signs of edema disappear completely. If the edema affects only the face and lips, then the manifestations usually go away on their own, although antihistamines can be used to treat its symptoms. Angioedema, which is accompanied by laryngeal edema, can be fatal. Swelling of the tongue, pharynx, or larynx can lead to airway obstruction. In this case, epinephrine (adrenaline) s / c should be immediately administered at a dose of 1: 1000 (0.3 to 0.5 ml), ensure airway patency and other emergency measures should be taken.Patients with a history of angioedema, not associated with taking ACE inhibitors, have an increased risk of developing angioedema while taking these drugs. In rare cases, ACE inhibitors develop angioedema of the bowel. Anaphylactoid reactions during desensitization There are separate reports of development prolonged, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy with venom of the hymenoptera (including bee insects, o blue) ACE inhibitors should be carefully prescribed to patients prone to allergic reactions and undergoing desensitization procedures. The administration of the drug to patients receiving immunotherapy with hymenoptera poison should be avoided. However, anaphylactoid reactions can be avoided by temporarily discontinuing the drug at least 24 hours before the start of a course of desensitization therapy. Anaphylactoid reactions during aplyresis of LDL are rare cases in patients receiving ACE inhibitors when performing apheresis of LDL using dextran sulfate in patients life-threatening anaphylactoid reactions may develop during hemodialysis using high-flow membranes. To prevent an anaphylactoid reaction, an ACE inhibitor therapy should be temporarily discontinued at least 24 hours before the apheresis procedure. Cough A dry cough may occur during therapy with an ACE inhibitor. Coughing persists while taking this group of drugs and disappears after they are canceled. When a patient has a dry cough, you should be aware of the possible iatrogenic nature of this symptom. If the attending physician believes that ACE inhibitor therapy is necessary for the patient, the drug can be continued. The risk of hypotension and / or renal failure (including in the case of heart failure, water and electrolyte deficiency) In some pathological conditions, significant activation can be observed RAAS, especially with severe hypovolemia and a decrease in the level of electrolytes of blood plasma (against the background of a salt-free diet or long-term use of diuretics), in patients with initially low blood pressure, with bilateral renal stenosis arteries or with stenosis of a single kidney artery, chronic heart failure, or liver cirrhosis with edema and ascites.The use of an ACE inhibitor causes blockade of this system and therefore may be accompanied by a sharp decrease in blood pressure and / or an increase in plasma creatinine level, indicating the development of functional renal failure. These phenomena are more often observed when taking the first dose of the drug or during the first two weeks of therapy. Sometimes these conditions develop acutely and in other periods of therapy. In such cases, when resuming therapy, it is recommended to use the drug at a lower dose and then gradually increase the dose. Atherosclerosis The risk of arterial hypotension exists in all patients, but the drug should be used with particular caution in patients with IHD or cerebrovascular insufficiency. In such cases, treatment should begin with a low dose. Renovascular hypertension A method of treating renovascular hypertension is revascularization. However, the use of ACE inhibitors has a beneficial effect in this category of patients, both awaiting surgery, and in the case when surgery is impossible. Treatment with Noliprel A forte in patients with diagnosed or suspected bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney should be started with a low dose of the drug in a hospital setting, monitoring kidney function and plasma concentration of potassium. Some patients may develop functional renal failure, which disappears when the drug is withdrawn. Other risk groups In patients with severe heart failure (stage IV) and patients with insulin-dependent diabetes mellitus (the risk of spontaneous increase in potassium levels), treatment with the drug should be started with low doses and constant monitoring by a physician. In patients with arterial hypertension and heart failure, beta-blockers should not be canceled: ACE inhibitors should be used together with ta-blockers. Anemia Anemia can develop in patients who have had a kidney transplant, or in patients on hemodialysis. The higher the initial level of hemoglobin, the more pronounced its decline. This effect, apparently, is not dose-dependent, but may be associated with the mechanism of action of ACE inhibitors. The decrease in hemoglobin is insignificant, it occurs during the first 6 months of treatment, and then stabilizes. With the abolition of treatment, hemoglobin level is fully restored.Treatment can be continued with regular hematological tests. Surgical intervention / General anesthesia The use of ACE inhibitors in patients undergoing surgery with general anesthesia can lead to a pronounced decrease in blood pressure, especially when using agents for general anesthesia that have a hypotensive effect. It is recommended to stop taking long-acting ACE inhibitors, incl. perindopril, one day before surgery. An anesthesiologist should be warned that the patient is taking ACE inhibitors. Aortic stenosis / Hypertrophic cardiomyopathy ACE inhibitors should be used with caution in patients with obstruction of the left ventricular output tract. With the progression of this syndrome, possible rapid development of liver necrosis, sometimes with a fatal outcome. The mechanism for the development of this syndrome is unclear. With the appearance of jaundice or a significant increase in activity