A combined drug formulation that prevents atorvastatin-induced myopathy, hepatotoxicity, and nephrotoxicity.

Abstract

The invention relates to a combined drug formulation and its preparation method, developed to prevent serious side effects such as myopathy, hepatotoxicity, and nephrotoxicity that occur during atorvastatin treatment for high blood lipid levels. The formulation contains atorvastatin, N-acetylcysteine, and coenzyme Q10. N-acetylcysteine ​​protects the liver and kidneys by reducing oxidative stress, while coenzyme Q10 increases energy production in muscle cells, thereby reducing the risk of myopathy. Thus, this drug combination prevents potential side effects without compromising the effectiveness of atorvastatin treatment.

Description

1 TARIFF MYOPATHY, HEPATOTOXICITY AND ATORVASTATIN-INDUCED SYNDROME. A COMBINED DRUG FORMULATION THAT PREVENTS NEPHROTOXICITY. Technical Area 5 The invention involves the active ingredient atorvastatin, used to treat high blood lipid levels (blood fats). the occurrence of myopathy, hepatotoxicity and nephrotoxicity caused by the substance a combined drug formulation for inhibition and the preparation of this formulation It is related to the method. The drug formulation in question contains atorvastatin, N-acetylcysteine, and It contains coenzyme Q10 as an active ingredient. The aforementioned combined drug formulation contains 10 ingredients. with atorvastatin treatment without interruption, all three of the aforementioned side effects occurred. This is prevented from happening. State of the Art Atorvastatin is a 15-year-old drug belonging to the class of medications known as HMG-CoA reductase inhibitors (statins). It is a compound. Statins inhibit cholesterol production in the body, particularly... It inhibits the activity of the HMG-CoA reductase enzyme in the liver. This enzyme, It plays a key role in cholesterol production, therefore inhibiting it is crucial. It reduces the synthesis of low-density lipoprotein (LDL). Atorvastatin specifically targets low-density lipoprotein (LDL) synthesis. It is used to lower cholesterol; LDL cholesterol is 20 cholesterol deposits in the walls of blood vessels. accumulated conditions such as atherosclerosis (hardening of the arteries) and cardiovascular diseases This can lead to its development. Additionally, atorvastatin also lowers triglyceride levels. It can lower high-density lipoprotein (HDL) cholesterol levels. It can increase [the risk of heart attack], stroke, and peripheral artery disease. Thanks to these effects, atorvastatin can increase the risk of heart attack, stroke, and peripheral artery disease. a broad 25 to reduce the risk of disease and other cardiovascular diseases It has a wide range of uses. In clinical studies, atorvastatin has been shown to be effective in coronary artery disease. It can prevent vascular blockage in individuals and treat existing vascular blockages. It has been observed that it can improve [the situation]. Furthermore, it is associated with high cholesterol levels and... diseases that threaten vascular health (for example, atherosclerosis and ischemic heart disease) It is also used in the treatment of diabetes. Atorvastatin is used in diabetic patients and those with high blood pressure (30°C). It is particularly beneficial for people at risk of cardiovascular disease, as these individuals have heart problems. The risk of diseases is higher. 2 Although atorvastatin provides an effective treatment in many respects, atorvastatin's... It also has some side effects; mild ones such as nausea, constipation, gas, and indigestion. Along with side effects, serious side effects can also occur. Serious side effects of atorvastatin... Three of the effects are myopathy, hepatotoxicity, and nephrotoxicity. Myopathy involves pain in the muscles, It begins with weakness and stiffness; if left untreated, it can lead to the breakdown of muscle tissue. It can lead to rhabdomyolysis and result in consequences such as kidney failure. Hepatotoxicity damages the liver through elevated liver enzymes, and If treatment continues, it leads to liver failure. Nephrotoxicity, muscle The accumulation of myoglobin, released as a result of its breakdown, in the kidneys impairs kidney function. It can damage kidney function and lead to permanent kidney failure. These three serious side effects, 10 Atorvastatin treatment requires careful monitoring, in some cases This leads to discontinuation of atorvastatin treatment. Myopathy caused by atorvastatin use is a side effect of statin class drugs. It manifests itself with symptoms such as pain, weakness, stiffness, and tenderness in muscle tissue. 15 This indicates a situation that shows that atorvastatin use causes muscle problems in some individuals [1]. It is known that it can affect myelin cells and lead to myopathy. Atorvastatin Statins, for example, are essential for energy production and cell membrane repair in muscle cells. It can affect molecules, which in turn causes structural damage to muscle fibers. and can ultimately lead to muscle weakness and pain. Statins weaken muscles 20 The exact mechanism by which it can cause damage to cells is still not clearly understood. However, high calcium influx into muscle cells increases oxidative stress. Factors such as mitochondrial dysfunction play a role in the development of myopathy. It can play a role. In addition, atorvastatin's effect on the lipid membrane structure of muscle It can cause structural and functional damage to cells. Myopathy, 25 It typically manifests as muscle pain, weakness, tenderness, and stiffness. Muscle weakness, usually in large muscle groups (especially the legs, back, and shoulders) This is felt. In addition, patients experience discomfort, stiffness, or pain in their muscles. Symptoms such as these are also reported. As the condition progresses, muscle tissue can be damaged and It can lead to rhabdomyolysis, which causes severe destruction of muscle cells and 30 It can cause toxic components like myoglobin to enter the bloodstream. Rhabdomyolysis is a serious condition that can also lead to kidney failure. Myopathy, Clinically, it is distinguished by pain and muscle weakness during muscle palpation. This can be done. In addition, patients may experience darkening of the urine color (myoglobinuria). 3 Symptoms may appear. In patients at risk of myopathy, atorvastatin treatment Certain precautions need to be taken during the process. The first step is to take precautions before treatment begins. review of patients' muscle history and any history of muscle disease The goal is to determine whether or not this occurs. Additionally, muscle pain and other symptoms may occur during atorvastatin treatment. It is important to monitor symptoms such as weakness. 5 of atorvastatin treatment After initiation, patients are regularly monitored for muscle function and liver enzymes. It needs to be monitored in terms of levels. Liver function tests and muscle Functional assessments (particularly creatine kinase levels) should be monitored. If If myopathy symptoms begin, atorvastatin treatment is immediately discontinued and alternative therapy is sought. Options are being evaluated. Several options are being considered for the treatment of atorvastatin-induced myopathy. There is an approach. The first step is to stop atorvastatin treatment or to discontinue treatment. It is necessary to change the course of action. If the symptoms of myopathy are severe, especially if there is a risk of rhabdomyolysis, Patients can be hospitalized and their kidney function can be improved with intravenous fluid therapy. It can be monitored. In cases of rhabdomyolysis, dialysis may be necessary. Atorvastatin There is no definitive cure for the myopathy it causes; because treatment usually lasts until 15 It is based on symptomatic treatment and modification of drug therapy. During treatment... Not all patients who develop myopathy will recover, and this situation, This can create hesitation about continuing treatment. Prevention of myopathy. and more research is needed to develop more effective methods for its treatment. It is heard. 20 Atorvastatin-induced hepatotoxicity is associated with the use of atorvastatin. Hepatotoxicity is a condition in which the liver is damaged and its functions are impaired. especially with long-term use of HMG-CoA reductase inhibitors such as atorvastatin or more commonly, during treatment with high doses of atorvastatin 25 can be seen [2]. The hepatotoxic effect of atorvastatin is largely due to the liver. This is due to its effect on the lipid metabolism and membrane structure of the cells. Atorvastatin improves hepatic lipid profile by inhibiting cholesterol synthesis in the liver. It alters mitochondria in liver cells. Furthermore, atorvastatin alters mitochondria in liver cells. by disrupting function, it leads to increased oxidative stress, and this situation affects the liver 30 it can also lead to consequences such as inflammation, damage and necrosis in the cells It is thought that atorvastatin also affects endoplasmic reticulum in the liver. causing stress in the reticulum, leading to intracellular protein folding disorders. It can increase the risk of death of hepatic cells. 4 Hepatotoxicity is usually accompanied by an increase in liver enzymes (especially AST and ALT). It begins with an increase in plasma levels of these enzymes, indicating liver damage. and is an indication that its functions have deteriorated. During atorvastatin treatment. If a significant increase in liver enzymes is detected, this is a sign of hepatic damage. This is possible. Furthermore, hepatotoxicity in more advanced stages can lead to jaundice, abdominal pain, and 5 symptoms include weakness, nausea, vomiting, and liver enlargement. This can manifest as liver failure if hepatotoxicity progresses further. This can have serious consequences and may threaten the patient's life. Patients with hepatotoxicity may also experience coagulopathy (bleeding disorder) and hypoglycemia. Systemic effects such as (low blood sugar) can also occur. 10 atorvastatin-related effects Various measures are taken to prevent and monitor hepatotoxicity. Treatment Before starting the procedure, patients' liver function tests (AST, ALT, bilirubin) were checked. (such as levels) should be evaluated. After ensuring that the liver is healthy... Then atorvastatin treatment should be started. During treatment, the liver... Liver functions should be monitored regularly. Monitoring liver enzymes, 15 This allows for the early detection of hepatotoxicity and treatment when necessary. Treatment with atorvastatin may be discontinued or dosage adjustments may be made. patients at risk of hepatic damage (e.g., those with a history of previous liver disease) (or those consuming alcoholic beverages) should be monitored especially. Atorvastatin-related In the treatment of hepatotoxicity, discontinuation of the drug and alternative treatment methods are recommended. These are the most important steps to implement. If hepatotoxicity is mild, atorvastatin Discontinuing treatment is usually sufficient, and liver function returns to normal. It is turning back. However, a serious deterioration in liver function (for example, jaundice, If liver failure occurs, hospitalization is required. In these patients Intravenous fluid therapy and electrolyte balance are attempted. Additionally, the treatment lasts 25 days. hepatoprotective treatment options that can protect hepatic cells during this process It is applicable. However, the hepatotoxicity caused by atorvastatin... There is no specific treatment protocol for its treatment. In addition, treatment is generally... It is symptomatic. These treatment methods may be incomplete and inadequate in some respects. There is still no definitive solution to prevent the hepatotoxic effects of atorvastatin. 30 There is no specific treatment available, and treatment is generally tailored to the patient's clinical condition. Treatment options, especially for patients with severely impaired liver function. It is limited. In addition, hepatotoxicity occurs in some patients despite atorvastatin treatment. Its progression cannot be stopped and liver failure may develop. Atorvastatin developing new drugs or developing existing treatments to prevent hepatotoxic effects More research is needed to make these methods more effective. It is heard. Atorvastatin-induced nephrotoxicity refers to the damage atorvastatin causes to the kidneys and 5 It describes dysfunction. Atorvastatin, especially at high doses or Long-term use can lead to toxic effects on the kidneys [3]. The exact mechanism of atorvastatin's nephrotoxic effects is not yet fully understood. However, this effect is largely due to muscle damage (myopathy) that develops as a result. It occurs as a result of rhabdomyolysis. Rhabdomyolysis is the process by which muscle tissue 10 proteins like myoglobin, which are released from muscle cells when they break down, enter the bloodstream. This leads to mixing. Myoglobin is filtered by the kidneys. When studied, it damages the renal tubules, which can lead to kidney failure. It can open up. In addition, atorvastatin can reduce oxidative stress and mitochondrial dysfunction. It is thought that these effects may also lead to inflammation in kidney cells. 15 Oxidative stress increases cellular damage, leading to damage to kidney tissue and This can lead to impaired functions. Caused by atorvastatin. Nephrotoxicity usually manifests as a darkening of the urine color. Muscle Myoglobin, released as a result of tissue breakdown, appears as a brown or brown substance in urine. It can cause a reddish discoloration. Additionally, patients may experience edema (swelling), 20 general symptoms of illness such as weakness, loss of appetite, nausea, vomiting, and abdominal pain This can manifest. As nephrotoxicity progresses, kidney function deteriorates and Elevated levels of kidney function tests such as creatinine and urea may be observed. These symptoms indicate that kidney failure is beginning to develop. Patients They usually experience pain due to muscle aches or weakness, 25 When the patient presents, neurological and renal functions should also be carefully monitored. Various measures are being taken to prevent atorvastatin-induced nephrotoxicity. Before starting treatment, patients' kidney function (creatinine, urea, glomerular) is assessed. parameters such as filtration rate) and muscle functions (enzymes such as creatine kinase) (levels) should be assessed, and those with pre-existing kidney disease, especially those over 30 should be monitored. During treatment, patients' kidney function should be regularly monitored. This will enable the early detection of nephrotoxicity. This can be achieved. Additionally, symptoms such as muscle pain, weakness, or changes in urine color may occur. If symptoms appear, atorvastatin treatment should be discontinued immediately and alternative treatment should be sought. 6 Options should be evaluated. In patients at risk of nephrotoxicity (especially more (those with a history of kidney disease or muscle disease) the treatment process will be more careful. should be monitored. Patients should be informed about the side effects of atorvastatin and any they will need to seek immediate medical attention if they notice any suspicious symptoms It should be noted that the treatment of atorvastatin-induced nephrotoxicity is generally symptomatic. and treatment continues by monitoring kidney function after treatment has started. If the signs of nephrotoxicity are mild, atorvastatin treatment should be discontinued. It is usually sufficient and kidney function returns to normal. However, advanced In these cases, patients need to be hospitalized for treatment. Treatment intravenous fluid therapy, electrolyte balance, and kidney function during this time. Functions should be closely monitored. When nephrotoxicity is severe, dialysis is usually necessary. Invasive treatment methods such as these are used. However, some of these treatment methods It is deficient and inadequate in these aspects. The nephrotoxicity caused by atorvastatin... There is no specific treatment or medication for its management, and treatment usually depends on the patient. It is determined depending on the clinical condition. If nephrotoxicity is very advanced, 15 And if kidney function is irreversibly damaged, this results in permanent kidney disease. This can lead to deficiency. Furthermore, each of the patients who were given atorvastatin... The response varies, which makes treatment strategies more based on genetic factors. This shows that personalization is needed. The full extent of the nephrotoxic effects of atorvastatin. Because the mechanisms are not yet fully understood, treatment methods are 20 Further research is needed to improve it. Myopathy, hepatotoxicity, and nephrotoxicity caused by atorvastatin. problems that occur are treated once symptoms begin to appear. In other words, during atorvastatin use, at least 25 of these 3 side effects are observed. current technique regarding a measure applied to prevent its occurrence from the outset is often insufficient. Therefore, the damage caused by these side effects is frequently overlooked. It is too late to address this. With the current technique, these side effects are not being addressed. Although some measures are being taken, none of these measures can be implemented simultaneously on all three sides. It is insufficient in preventing the occurrence of the effect. 30 In the known state of the art, the work done by Alshogran et al., Contrast-induced development in diabetic rats due to contrast agent administration To prevent induced renal injury (CIN), coenzyme Q10 (CoQ10) and this 7 the effects of combinations of N-acetylcysteine ​​(NAC) or atorvastatin with the substance [4]. In the said study, these combinations are investigating the kidney potential to improve functions and reduce damage to kidney tissue It has been evaluated. The contrast agent has been shown to affect the kidneys, especially in individuals with diabetes. It causes oxidative stress and other damage, and as a result, kidney 5 It is emphasized that its functions are impaired. The study in question highlights that CoQ10 alone alone or in combination with NAC and atorvastatin, kidney damage is not fully prevented. It could not prevent it, but the combination of CoQ10 and atorvastatin had some positive effects. The document indicates that it shows myopathy, hepatotoxicity, and nephrotoxicity. There is no information indicating that they can be blocked simultaneously. The study, 10 It focuses solely on nephrotoxicity and does not provide any data on other types of toxicity. It does not offer this. This deficiency means that treatment combinations could potentially involve multiple organs. This represents a significant gap in the assessment of their effects against toxicity. Furthermore, a more detailed explanation of the side effects of the therapeutic agents used in the study There is a deficiency. In addition, the effectiveness of treatment duration and dosages in the study is 15. There is insufficient information available on this topic. For example, the bioavailability of CoQ10 and its effects on the kidneys are not fully understood. The lack of studies on targeting efficiency, treatment methods This is a significant shortcoming in terms of optimization. Furthermore, there is a lack of longer-term understanding of the treatment. No assessment of the effects and toxicity risks has been carried out. The limitations and inadequacies of the solutions in the current technology, in the known state of the technology... the occurrence of atorvastatin-induced myopathy, hepatotoxicity, and nephrotoxicity The lack of a treatment method that prevents these side effects means that only symptoms can be addressed. Treatment is applied after the onset of symptoms, following the observation of side effects. High blood lipid levels due to discontinuation of atorvastatin treatment 25 interruption of treatment, commonly used in treating these side effects combinations of atorvastatin-induced myopathy, hepatotoxicity, and nephrotoxicity The fact that it cannot prevent all three at the same time, only treat the side effects that occur, any medication or other medical method that prevents the occurrence of all three side effects The absence of combinations that are effective against only one side effect in the literature is 30. reasons such as the fact that they are effective and there is insufficient data on their side effects. Therefore, it has become necessary to make improvements in this area. 8 Brief Description and Objectives of the Invention The invention investigates the cause of atorvastatin, which is used to treat high blood lipid (blood fat) levels. a treatment aimed at preventing myopathy, hepatotoxicity and nephrotoxicity The combined drug formulation and the method of preparing this formulation are described. The formulation in question contains atorvastatin, N-acetylcysteine ​​(NAC), and Coenzyme Q10 5. It contains active ingredients such as (CoQ10). The formulation subject to the invention is based on existing In this technique, the occurrence of 3 side effects during atorvastatin treatment It addresses a lack of treatment that is preventing this. This drug combination in question... Thanks to this treatment, all three of these side effects are prevented from occurring simultaneously. Its effectiveness can be maintained without interruption. 10 The main purpose of the invention is to identify three serious side effects associated with the use of atorvastatin. synergistic effects that prevent myopathy, hepatotoxicity, and nephrotoxicity all at once. It is the provision of a drug formulation. Atorvastatin is used for cardiovascular diseases. Although it is an effective drug in treatment, it can cause myopathy (muscle pain and weakness) and hepatotoxicity. serious side effects such as liver damage and nephrotoxicity (kidney dysfunction) This can lead to side effects. The invention prevents the occurrence of these side effects. To prevent this, atorvastatin is used in combination with N-acetylcysteine ​​(NAC) and coenzyme-10. The invention involves combining the active ingredients (CoQ10). The effectiveness of atorvastatin treatment is investigated in this invention. It does not cause deterioration; only the side effects are prevented. Atorvastatin, cholesterol lowering 20 and plays an important role in the treatment of cardiovascular diseases and therapy It needs to continue to be used effectively throughout the process. However, this drug When used for a long period or in high doses, it can affect muscles, liver, and kidneys. Toxic effects may occur in organs such as these. The combined drug that is the subject of this invention. Cholesterol treatment is performed with atorvastatin, which is included in the formulation, while NAC 25 And thanks to the synergistic effects of CoQ10, all three side effects (myopathy, hepatotoxicity, and (nephrotoxicity) is prevented. NAC helps with liver detoxification. While supporting these processes, CoQ10 increases energy production in muscle cells and muscles It helps preserve their functions; thus preventing nephrotoxicity. This prevents the formation of structures. Using these compounds together results in 30 It prevents organ damage by eliminating the toxic effects of atorvastatin and This makes the treatment process healthier. In this way, the potential of atorvastatin is reduced. By reducing the risks, the treatment process is made safer. Thus, the treatment Without disrupting the effectiveness of the treatment, patients can experience a healthier recovery process. 9 Another aim of the invention is to provide a combined atorvastatin treatment that is safe for patients. This is about ensuring the drug formulation. The safety of atorvastatin treatment (in other words Minimizing side effects is one of the most important factors in the treatment process. The invention, It improves drug safety by minimizing the side effects of atorvastatin. N- Acetylcysteine ​​and coenzyme Q10 protect the health of the liver and kidneys, respectively, and 5 These are compounds that support muscle function. The subject of this invention is a combined drug formulation. Thanks to this, the toxic effects that atorvastatin can cause are limited, and thus the treatment This ensures safer use during the process. This allows patients to adhere to the treatment. This helps them experience fewer complications and have a better treatment process. It provides comfort. 10 Explanation of the Figures Figure 1: Performance activity test of five groups of mice (A: Mean of falling delay, B: Average speed at the moment of falling and C: Average body weight of the mice) 15 Figure 2: Histopathological results (A: A+PAS stained kidney results, B: Suitable) (results of liver stained with dyes and C: results of muscle tissue stained with H&E) Figure 3: Histopathological analysis of kidney, muscle, and liver tissues (A: Kidney) A: Histopathological analysis of muscle tissue, B: Histopathological analysis of liver tissue. (analysis) 20 Figure 4: Biochemical marker analyses (A: Creatine kinase plasma levels, B: Blood levels) malondialdehyde levels and C: Glutathione peroxidase activity in blood, D: Catalase enzyme activity, E: Superoxide dismutase activity in blood) Detailed Description of the Invention 25 The invention is used to treat diseases characterized by high blood lipid levels (blood fats). Myopathy, hepatotoxicity, and nephrotoxicity can occur simultaneously with atorvastatin. a combined drug formulation that prevents the effects and this formulation It relates to the preparation method. The formulation in question is N- atorvastatin in combination with atorvastatin. It contains acetylcysteine ​​(NAC) and coenzyme Q10 (CoQ10). This combination contains 30 without affecting the effectiveness of atorvastatin treatment, by preventing the development of side effects. It provides patients with a safer experience during the treatment process. During atorvastatin treatment, which is used to treat high blood lipid levels. a combined drug that prevents the resulting myopathy, hepatotoxicity and nephrotoxicity formulation contains atorvastatin, N-acetylcysteine ​​(NAC) and Coenzyme Q10 (CoQ10) It includes. In an application of the invention, the drug formulation subject to the invention may be in the form of a suspension or tablet. It is in this form. In one application of the invention, the suspended combined drug formulation in question, 1% by weight atorvastatin suspension, 1% by weight NAC suspension and 10% by weight It contains 1% CoQ10 suspension. The subject of the invention is atorvastatin, NAC, CoQ10. The suspensions are prepared separately and then combined into a drug formulation. They are combined within. The ultimate of each of these three suspensions Its amount in the formulation is 1% by weight. During atorvastatin treatment, which is used to treat high blood lipid levels. a combined drug that prevents the resulting myopathy, hepatotoxicity and nephrotoxicity Method of preparing the suspension form of the formulation; i. Weighing 500 mg of carboxymethylcellulose (CMC) and sprinkling it into 50 Mixing with ml of distilled water, 20 ii. The mixture prepared in step (ii) is heated at 50 °C and 350 Mixing at rpm for 10 minutes, iii. Homogenization of the mixture using a sonicator to obtain 1% by weight CMC obtaining the mixture, iv. Prepare the atorvastatin suspension in a separate container and infuse for 2 minutes with 25... vortexing, v. Preparation of NAC suspension in a separate container and simmering for 2 minutes. vortexing, vi. Preparation of CoQ10 suspension in a separate container and simmering for 2 minutes. vortexing, 30 vii. atorvastatin suspension, NAC suspension and CoQ10 Adding and mixing 1% by weight of CMC to the suspensions vortexing It includes the steps involved in the process. 11 The preparation method for the combined drug formulation described in the invention initially involves 1% CMC. To prepare the solution, use 500 mg of CMC on a digital precision electronic balance. It is weighed. This step is of great importance in order to ensure an accurate and precise dosage. It is presented. Then, the weighed CMC solution is added to 50 ml of pure water, and this The process is carried out using a sprinkling technique. Sprinkling involves slowly adding CMC to the water in 5 increments. It ensures a homogeneous distribution, thus minimizing the possibility of clumping. It is then lowered. This mixture is then placed in a mixing and heating device and heated at 350 rpm. It is stirred at a constant speed and at a temperature of 50°C for 10 minutes. The heating process, By increasing the viscosity and homogeneity of the solution, it ensures better mixing and the full concentration of CMC. This allows it to dissolve. The use of a heating device also causes CMC to dissolve in 10 parts. increasing the solubility level to obtain a more homogeneous solution It provides this. In the next step, sonic analysis is performed to ensure the homogeneity of the mixture. A homogenizer is used. Sonic homogenizers provide homogenization at the micro level. It increases the volume and ensures an even distribution of the liquid at every point. After that, the atorvastatin, NAC, and CoQ10 suspensions to be added to the mixture are separated into 15... They are prepared in separate containers. These suspensions are added to the CMC mixture before... Each is vortexed for 2 minutes. This process ensures a homogeneous suspension. This ensures that the solution disperses evenly within the mixture, thus improving the effectiveness of the final formulation. It increases. Following this vortexing process, all suspensions are immersed in the CMC mixture. and thus the combined drug formulation that is the subject of the invention is obtained. 20 Thanks to the combined drug formulation described in this invention, atorvastatin treatment can be continued. However, side effects such as myopathy, hepatotoxicity, and nephrotoxicity may occur during this process. It is being prevented. Atorvastatin is a statin class of drug that inhibits cholesterol production. and are generally recommended for heart disease. However, statins have serious side effects. These serious side effects can include myopathy (muscle damage) and hepatotoxicity (liver damage). kidney damage) and nephrotoxicity (kidney damage). These serious side effects of atorvastatin are... NAC and CoQ10, used in the invention to prevent oxidative stress, are particularly effective. These are substances that have properties that reduce and repair cellular damage. The reason atorvastatin treatment can cause myopathy is because atorvastatin affects the muscles. It lowers the levels of coenzyme Q10 (CoQ10) in muscle cells. CoQ10 is essential for muscle cells. It plays an important role in energy production, and low levels can lead to muscle weakness and pain. and causes muscle damage. To reduce this side effect of atorvastatin, CoQ10 12 Supplementation is recommended. Coenzyme Q10 (CoQ10) is critical for cellular energy production. molecules, especially those in organs with high energy requirements such as the heart, liver, and kidneys. It is important in the organs. CoQ10 helps to counteract the energy deficiencies caused by atorvastatin and It reverses oxidative damage and reduces side effects such as myopathy, hepatotoxicity, and nephrotoxicity. It plays an important role in preventing this. N-acetylcysteine ​​(NAC) is a free 5 in the body. It is an antioxidant that reduces oxidative stress by neutralizing radicals. Oxidative stress, the underlying cause leading to both myopathy and hepatotoxicity and nephrotoxicity It is one of the mechanisms. NAC reduces oxidative stress by scavenging free radicals. It prevents the cellular damage it causes. This feature prevents conditions such as hepatotoxicity and nephrotoxicity. It is effective in preventing side effects, especially oxidative damage in the liver and kidneys. By reducing these side effects, NAC ensures that these organs function properly. It helps to prevent this and also improves the liver's detoxification function. It supports. The invention involves the combined use of the active ingredients atorvastatin, NAC, and CoQ10, these three 15 helps prevent side effects (myopathy, hepatotoxicity, nephrotoxicity) They create a synergistic effect. Each substance, on its own, does not have these side effects. While they can reduce intensity, when used together the effects are strengthened and become more comprehensive. Protection is provided. The mechanism by which atorvastatin causes muscle damage is due to CoQ10. It is associated with a decrease in levels. CoQ10 compensates for this deficiency and muscle 20 It meets the energy needs of the cells. In this way, the risk of myopathy is significantly reduced. NAC is reduced in liver cells due to its free radical scavenging properties. It provides protection against the oxidative stress that occurs. This is in contrast to the stress caused by atorvastatin. It helps prevent liver damage. CoQ10 helps kidney cells. It prevents kidney damage by increasing energy production. NAC reduces oxidative stress, thus preventing kidney damage. It minimizes damage to the kidneys. In this invention, these three active ingredients (atorvastatin, The combined use of NAC and CoQ10 may cause myopathy, hepatotoxicity, and nephrotoxicity. to prevent its formation and also to ensure the continuation of atorvastatin treatment This combination therapy provides patients with atorvastatin. While you can continue to benefit from its cardiovascular advantages, this serious side effect is 30 It is protected from the effects. To test the efficacy of the combined drug formulation described in the invention, on mice Experiments have shown the effectiveness of the formulation. The aforementioned formulation... 13 It is thoroughly mixed and vortexed before being administered to mice via oral gavage. This is being done. The stage of administering the formulation to mice via oral gavage has begun. When this is done, an insulin needle with a special 20 gauge oral gavage needle is used for this procedure. A syringe is used. This syringe ensures that the formulation is administered correctly and under control. This ensures that the dosages given to mice are calculated using Formula 1-5. The three formulas are given in section 3. These three formulations provide example values ​​for calculations. It has been given. Formula 1. Atorvastatin dose calculation (Values ​​given in the calculation are for illustrative purposes only) (This is given for a mouse weighing 30 grams.) 10  Daily dose = 100 mg / kg / day  Mouse weight = 0.03 kg  Total Atorvastatin dose = Daily dose x Mouse weight = 100 mg / Kg / day x 0.03 Kg = 3 mg Formula 2. NAC dose calculation (Values ​​given in the calculation are for illustrative purposes only) (This information is given for a mouse weighing grams.)  Daily dose = 200 mg / kg / day  Mouse weight = 0.03 kg  Total NAC dose = Daily dose x Mouse weight 20 = 200 mg / Kg / day x 0.03 Kg = 6 mg Formula 3. CoQ10 dose calculation (Values ​​given in the calculation are for illustrative purposes only) (This information is given for a mouse weighing 30 grams.)  Daily dose = 100 mg / Kg / day 25  Mouse weight = 0.03 kg  Total CoQ10 dose = Daily dose x Mouse weight = 100 mg / Kg / day x 0.03 Kg = 3 mg During mouse experiments, the application dose of the combined drug formulation in question was determined. The medication consists of 100 mg / kg / day atorvastatin, 200 mg / kg / day NAC, and 100 mg / kg / day CoQ10. Here, mg / kg / day refers to the number of milligrams of active ingredient per kilogram of body weight per day. 14 This means that the substance will be given. The animal's weight from the formulation that is the subject of the invention. Dose calculations are performed per dose (Formula 1-3). This dose will be drawn from the relevant formulation. It is located within the volume. Each mouse receives 10 ml / kg body weight, calculated accordingly. 0.3 ml of each suspension is administered. The important point here is that this is per mouse per day. The dosage should not exceed 0.9-1 ml. These dosages are sufficient for mice 5 This ensures that effective treatment is provided without jeopardizing their health. Ensure the formulation is thoroughly mixed before each dose. Vortex The homogeneity of the formulation is ensured by using the device, because the solution is administered orally. When delivering chemical substances, their even distribution directly affects treatment effectiveness. It has an impact. By carefully following these steps and using the right equipment, 10 Oral gavage can be performed safely and effectively on mice. In experiments, mice were administered a combination of atorvastatin, NAC, and CoQ10, and side effects were observed. Various biochemical and histological analyses were performed to observe the effects. The results of the analyses in question are given in Table 1. During these experiments, Coenzyme Q10 (CoQ10) and N-acetylcysteine ​​(NAC) are among the 15% most affected by atorvastatin-induced toxicity. Its potential for reduction has been investigated in a mouse model. Experiments To achieve this, male BALB / c mice were given high doses of atorvastatin (100 mg / kg / day), NAC (200 mg / kg / day) in combination with atorvastatin, in combination with atorvastatin CoQ10 (100 mg / kg / day), atorvastatin with NAC and CoQ10 combination or liquid (Carrier) control was applied for 14 days. Rotarod performance, body weight and 20 Tissue histopathology was evaluated. Additionally, creatine kinase (CK) and malondialdehyde levels were assessed. (MDA) and antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase. Biochemical parameters, including enzyme activities, were measured. The results (Table 1) show that atorvastatin administration alone significantly reduced body weight. that it reduced and impaired performance in the rotarod test (average delay time 29.327 25 (seconds and speed 7.08 RPM), severe degeneration in muscle, liver and kidney tissues This shows why. Furthermore, atorvastatin administration alone does not affect creatinine. It increased kinase (CK) levels and elevated oxidative stress markers. This... In contrast, atorvastatin inhibits NAC (N-acetylcysteine) and CoQ10 (Coenzyme Q10) The application of this combination improves rotarod performance (average delay time 30 With a time of 62.44 seconds and an average speed of approximately 11 RPM, this has resulted in significant improvements. The combination also reduced tissue damage, particularly to catalase and glutathione. It significantly increased the activities of peroxidase enzymes. This study showed that CoQ10 and The combination of NACs reduced atorvastatin-induced myopathy and oxidative stress in mice. This shows that it significantly reduces [the effects of the invention]. These results indicate that the combined drug discussed in the invention... Adjunctive therapy with this formulation improves atorvastatin tolerance and patient This shows that it could be a promising strategy for improving results. 16 Ta bl he 1. F ar hand er U ze Rin also Y ap with n D -most article S front fly la ri (a :K front tro l gr ub u (G ru p 1) = sa also ce % 1 ka rb ok if m and ils lü lo z, b : G ru p 2= A or rv and Yes today ( 0 m g / kg / g one ), c : G ru p 3= A or rv and Yes today (1 00 m g / kg / g one )+ N A C (2 00 m g / kg / g one ) the m The than in yes u, d: G ru p 4= A or rv and Yes today (1 00 m g / kg / g one )+ C oQ (1 00 m g / kg / g one ) the m The than in yes u, its : G ru p 5= A or rv and Yes today (1 00 m g / kg / g one )+ N A C (2 00 m g / kg / g one )+ C oQ (1 00 m g / kg / g a ) k man The No in yes u) F and and G ru pl and ı THE age is m to Ağ ırl ık (G they m ) THE age is m to G at from m and Sü king if (s I yes and) THE age is m to G at from m and Sü king yes (R PM ) C K- pl az m a U L1 62 -1 18 4 N or m al D eg er i A is to fence to lo jik a na liz , d ok u from yes ne day sy on u sk or day rı - The s Co n.t ro day (n =6 ) .7 6 41 .1 63 8. 49 6 79 0. 33 3 2. 3 At or va b (n =5 ) 27 .7 6 29 .3 27 7. 08 2 13 48 .6 8. 4 At or va +N AC c (n =3 ) 27 .2 50 .9 96 9. 88 3 60 5. 3 At or va +C oQ d (n =3 ) .2 6 47 .4 43 9. 33 18 60 4 At or va +N AC + C oQ e (n =3 ) .4 6 62 .4 4 .9 96 14 3 17 Pitch bl Oh 1. (D ev am he) Far re G ru pl ar he H is to pa to low jik I and liz , 1999 . do to d age en er as yo nu sk or the rı - B öb re k H is or Pa or on until and go from , d ok u of is and tender sy this u sk or The ry - Sour tender there to r Sour is The z I don't / m g pr house this n (K and ) G SH Px A kt iv item Bi rim cool ri / m g Pr house this n (K and ) O rta la m a M D A (n m ol / m l) (K an ) Ko nt ro la (n =6 ) 2 2. 0. 04 7 0. 17 0. 02 90 At or va b (n =5 ) 8. 8 9. 8 0. 03 2 0. 11 0. 04 7 At or va +N AC c (n =3 ) 6. 3 7. 3 0. 05 0. 21 0. 03 6 At or va +C oQ d (n =3 ) 4. 3 6 0. 05 9 0. 19 0. 03 7 At or va +N AC +C oQ e (n =3 ) 2. 7 2. 3 0. 4 0. 18 0. 02 4 (a :K on tro l gr ub u( G ru p 1) = sa dr ce % 1 ka rb ok if m and ils lü lo z, b : G ru p 2= A or rv and Yes today ( 0 m g / kg / g one ), c : G ru p 3= A or rv and Yes today (1 00 m g / kg / g one )+ N A C (2 00 m g / kg / g one ) the m The than in yes u, d: G ru p 4= A or rv and Yes today (1 00 m g / kg / g one )+ C oQ (1 00 m g / kg / g one ) the m The than in yes u, its : G ru p 5= A or rv and Yes today (1 00 m g / kg / g one )+ N A C (2 00 m g / kg / g one )+ C oQ (1 00 m g / kg / g reputation ) k om bi na sy front u) 18 In the experiments given in Table 1, mice were given oral gavage for two weeks. Then, the body weights of the mice were measured in grams at the end of the experimental study. The data was recorded. Average body weights were calculated for each group of mice. a sensitive and reliable method for assessing motor and cognitive abilities Rotarod performance activity test is performed on the rotarod device (ROTA-ROD / RS-5 (panlab / HARVARD APPARATUS) performed this test. The aim of the test was to observe how mice rotate. It is walking forward on a bar. The lowest performance activity average (this average fall delay per second and drop time per minute in the test (measured with two parameters, including average speed), the study that is the subject of the invention This case shows a high incidence of atorvastatin-induced myopathy. 10 Creatine kinase (CK) level, malondialdehyde (MDA) level, catalase (CAT) activity and Glutathione peroxidase (GSH-Px) levels indicate toxicity and antioxidant activity in the body. These are biomarkers used for investigation. High CK levels were detected in our study. muscle damage supporting the presence of atorvastatin-induced myopathy This shows that determining CAT and GSH-Px levels indicates the antioxidant activity in the body. the state of activity and the effectiveness of endogenous defense mechanisms This is reflected in the lower activity values ​​for these enzymes, indicating the effects of toxicity. Because they are consumed intensively in order to reduce their toxicity, they exhibit higher toxicity. MDA levels indicate lipid peroxidation, which serves as a marker for cellular toxicity; Higher MDA levels indicate increased cellular damage. These parameters are 20 When considered, the best result was obtained with atorvastatin-N-acetylcysteine-Coenzyme Q10. It was obtained through a combination of these methods. A person skilled in the technique (for example, an experienced person) pathologist), tissue damage according to the severity of lesion changes observed in each mouse. a semi-quantitative scoring system for evaluating (muscle, liver and kidney) It uses. Specifically, histopathological findings in each tissue range from 0 to 3 in 25 It is rated on a three-point scale; where 0 means no abnormality, 1 means minor damage, 2 indicates moderate damage and 3 indicates severe damage. These parameters should be taken into consideration. When taken, the best results are obtained with the atorvastatin-N-acetylcysteine-coenzyme Q10 combination. It has been obtained. Figure 1 shows five groups of mice (mouse groups given in Table 1) using a rotarod device. Performance activity test results and average body weights are shown. Falling The average delay (in seconds) is shown in Figure 1.A, and the average velocity at the moment of fall is also shown. The revolutions per minute (RPM) are shown in Figure 1.B. Any factor 19 The average fall delay of the mouse group that received the substance combination was 62.44. The average speed during the second and the moment of the fall was measured as approximately 11 RPM. In contrast, the mean latency to fall in the group receiving atorvastatin alone was 29.32 seconds. and the average speed was measured as 7.08 RPM (p < 0.05). In addition, 14 The mean body weight of mice after daily oral gavage is given in Figure 1.C. 5 Compared to the control group, both the group receiving atorvastatin alone and Significant weight loss was observed in the atorvastatin+NAC group (p < 0.05). Any The combination field mouse group had an average body weight similar to the control group. has shown. Histopathological tests performed on the mouse groups detailed in Table 1 The results are given in Figure 2. Histopathological results were obtained from 14-day oral gavage. It was obtained from selected mouse tissues after the application. Figure 1A-C, control and a total of 15 histopathological differences for kidney, liver and muscle tissue between treatment groups. It shows the damage score. Tissue samples were analyzed and the results are per mouse. Data is presented as mean ± standard deviation for each tissue type. Control, combination and between atorvastatin (Atorv) mouse groups, control and combination mouse groups compared to the group of mice treated with atorvastatin alone, severe tissue damage was observed. A highly significant difference characterized by degeneration was observed (***p < 20 0.001). Histopathological analyses of kidney, muscle, and liver tissues revealed differences between the two groups, as well as in the control group. This is also shown in Figure 3, which includes histological images from experimental mouse groups. Details of the control and experimental mouse groups subjected to these histopathological analyses are given in section 25. This is given in Table 1. In Figure 3A (Kidney histopathological analysis), the control mouse While the first group showed normal histological structures, the atorvastatin-treated mouse group showed abnormal kidney structures. It shows signs of degeneration in its tissue. In Figure 3A, the black arrow indicates bleeding. Black stars indicate areas of cell infiltration, while black arrowheads represent degenerated tubules. cells and the white arrow represents a renal corpuscle with disrupted boundaries 30 This shows the deterioration in their structures. In the control group, compared to the other groups. Areas of bleeding, degeneration, and infiltration have normal histological structures. In the atorvastatin group, however, these normal findings manifest as degeneration. Histopathology was reduced in the Atorva + NAC and Atorva + CoQ10 groups. This has been observed. In the Atorva + NAC + CoQ10 group, the observed pathological condition was... It has been observed that it has decreased. In Figure 3A, it was stained with hematoxylin and eosin. Scale bar, 200 micrometers in the upper quadrant images and 100 micrometers in the lower quadrant images. This is indicated in Figure 3B (Muscle histopathological analysis), the control mouse group. Normal histological structures without signs of degeneration, bleeding, or infiltration. 5 While this is shown, the atorvastatin-treated mouse group shows degeneration in muscle tissue. This The decrease was also evident in the Atorva + NAC and Atorva + CoQ10 mouse groups, and at least Pathological changes were observed in the Atorva + NAC + CoQ10 mouse group. (Figure 3B shows this.) The black arrow indicates bleeding, and the black star indicates areas of cell infiltration. Control In this group, compared to other groups, areas of bleeding, degeneration, and infiltration were normal (10). It has histological structures. In the atorvastatin group, these normal findings are accompanied by degeneration. This is evident in the Atorva + NAC and Atorva + CoQ10 groups. It was observed that the situation decreased in the Atorva + NAC + CoQ10 group. The pathological condition was observed to have decreased. Images with hematoxylin and eosin. It is painted. The scale bar is 200 micrometers in the upper quadrant images and 15 in the lower quadrant. In the images, it is stated as 100 micrometers. In Figure 3C (Liver) histopathological analysis), liver histological structures in the control mouse group It appears normal without degeneration, bleeding, or infiltration. This indicates that, in contrast, the atorvastatin mouse group experienced hepatocyte damage and bleeding, among other things. It shows significant degeneration, including Atorva + NAC and Atorva + CoQ10 20. Although the mouse groups showed some histopathological deterioration, this deterioration was observed in atorvastatin-treated mice. It was observed to be less severe compared to the group. Atorva + NAC + CoQ10 mouse The group shows the least visible pathological changes. In Figure 3C, the black arrow... hemorrhage, black star cell infiltration areas, black arrowhead degeneration The image shows damaged hepatocytes and white arrowhead edema. In the control group, the other 25 compared to the groups, areas of bleeding, degeneration, and infiltration were normal histologically. They have these structures. In the atorvastatin group, these normal findings manifest themselves with degeneration. This shows the histopathological status in the Atorva + NAC and Atorva + CoQ10 groups. A decrease was observed in the Atorva + NAC + CoQ10 group. The situation has been observed to have decreased. Images were stained with hematoxylin and eosin. Scale 30 The bar measures 200 micrometers in the upper quadrant images and 100 micrometers in the lower quadrant images. It is specified in micrometers. 21 The results of studies on biochemical markers are shown in Figures 4A-E. (Details of the control and experimental mouse groups are given in Table 1.) In Figure 4.A, creatine kinase (CK) plasma levels were shown in all four groups of treated mice. This indicates that it is at the upper limit of the normal range (162-1184 U / L), while the control group (Group 1) remains within the normal range. Specifically, compared to the control group and Atorvastatin+NAC, 5 There was a significant difference in CK levels among the treated group (Group 3). Figure 4.B shows the levels of malondialdehyde (MDA) in the blood. Only The group treated with atorvastatin (Group 2) had the highest MDA among all groups. This shows the levels. Conversely, the control group and the combination therapy group. (Group 5: Atorvastatin + NAC + CoQ10), lowest MDA 10 expressed in nmol / ml Figure 4.C shows the levels of glutathione peroxidase (GSH-Px) in the blood. It shows its activity by measuring it in units per mg of protein. This figure is for groups. This shows that there is a significant difference in GSH-Px activity between them. Only The atorvastatin group (Group 2), along with all other groups, including the control group. In comparison, it shows the lowest GSH-Px activity. In contrast, NAC 15 and all other groups treated with CoQ10 were more affected, with a significance level of ***P<0.05. It shows high GSH-Px activity. In Figure 4.D, the catalase (CAT) enzyme... Activity is expressed in Ku / mg protein. Combination therapy group (Group 5) There is a highly significant difference only between the atorvastatin group (Group 2) and the others. The combination group showed the highest CAT activity among all groups, 20 Only the atorvastatin group showed the lowest activity (***P<0.05). Finally, Figure 4.E shows superoxide dismutase (SOD) activity in blood, measured in U / mg protein. This indicates that there are differences in SOD activity between the groups. It is observed that the control group showed the highest SOD activity, while only The atorvastatin group showed the lowest SOD activity (25) when compared to all other groups. However, the difference in SOD activity was not statistically significant. (P>0.05). Statin-induced myopathy is a 30% severity of myopathy that occurs as a result of statin (atorvastatin) use. The series includes muscle-related symptoms, and these symptoms are related to creatine kinase (CK) They are classified according to the increase in their levels. Studies show that statin therapy... It can lead to a decrease in coenzyme Q10 (CoQ10) levels, and this situation with statins This suggests that it may be associated with the development of myopathy caused by CoQ10. However, 22 The effectiveness of supplements in alleviating these muscle symptoms is still being investigated. It is debated. Some studies suggest that CoQ10 supplementation may improve symptoms. While some point this out, others argue that it provides no significant benefit. This situation, Combination containing CoQ10 for the alleviation of atorvastatin-induced myopathy. This encourages further research into the treatments. The formulation subject to the invention, 5 atorvastatin-induced toxicity, particularly in terms of oxidative stress and myopathy. Coenzyme Q10 (CoQ10) and N-acetylcysteine ​​(NAC) help in reducing its effect. It is not only a combined drug formulation that ensures the effectiveness of treatments, but also... The effectiveness of the formulation has been proven through numerous detailed analyses (Table 1 and (Figures 1-4). CoQ10 is a critical component of the mitochondrial electron transport chain, 10 It is well known for its ability to reduce mitochondrial dysfunction and oxidative stress. This combination therapy restores mitochondrial function by replenishing depleted CoQ10 levels. It can increase and affect cellular activity in the liver and muscles, which are susceptible to statin-induced toxicity. It can provide protection. NAC, on the other hand, is an effective precursor of glutathione to reactive oxygen species. It contributes to better detoxification of ROS (respiratory pathogens) and delivers 15 to the cells. It reduces oxidative damage. The combination of these two components helps in atorvastatin-induced myopathy. and offers a multifaceted approach to mitigating organ toxicity. This The finding suggests that CoQ10 supplementation reduces statin-induced mitochondrial dysfunction and oxidative stress. This is consistent with previous studies showing that it can be effective against stress. Furthermore, the invention demonstrates that NAC enhances antioxidant defenses and 20 It has been proven to reduce cellular damage. The average weight loss in different groups of mice, There were no significant differences between the control group and the group treated with atorvastatin alone. This weight loss has been shown to be associated with muscle weakness and toxicity of high doses of atorvastatin. They may be related. However, the group treated with a combination of atorvastatin, NAC, and CoQ10, It showed similar weight change to the control group. In addition, the biomarker of muscle breakdown was 25 Plasma creatine kinase (CK) levels were normal in all treatment groups. While the values ​​exceeded those in the control group, they remained at normal levels, which means... Histopathological analysis shows that atorvastatin causes myopathy. The group of mice treated with atorvastatin had severe tissue damage in the muscles, liver, and kidneys. This observation reveals that it has undergone degeneration. This observation indicates that statin-induced toxicity is 30%. It leads to oxidative stress and mitochondrial dysfunction, especially on muscle cells. It is a condition known to cause myopathy and affect the liver and kidneys. Biochemical markers also present promising findings; lipid peroxidation and MDA, an indicator of oxidative stress, was only elevated in the group treated with atorvastatin. 23 At its highest level, antioxidant enzyme activities (SOD, CAT, GSH-Px) are at their peak. It was low. This indicates that severe oxidative stress in cellular response to atorvastatin toxicity was not present. It shows that it disrupts defenses. Statin-induced oxidative stress, increased MDA These levels can lead to tissue degeneration and dysfunction. This situation is associated with poor performance in the rotarod test. However, NAC and 5 The combination of CoQ10 leads to improvements in antioxidant levels and reduction of oxidative stress. positive results such as reduction and a significant decrease in tissue degeneration. These findings demonstrate that NAC and CoQ10 are involved in atorvastatin-induced oxidative damage. It emphasizes the protective synergistic effects. The Rotarod performance test, only The atorvastatin group showed motor dysfunction, with the worst performance being in the 10th grade. It reveals that it exhibits the following. The combination therapy that is the subject of the invention. (Atorva+NAC+CoQ10) shows the highest performance. Typical clinical doses of atorvastatin range from 10 mg to 80 mg daily. This indicates the generally used dose range for atorvastatin. In most clinical situations, 15 These doses are used to lower cholesterol levels and prevent cardiovascular disease. It is used for this purpose. The 100 mg / kg / day used in mouse experiments is much higher. A high dose can cause serious muscle damage (rhabdomyolysis), liver damage, and other side effects. It carries the risk of causing adverse effects. Here, attention is drawn to the possible side effects of high doses. It is being withdrawn. High doses of drugs like atorvastatin cause 20% pain, especially in the muscles. It can lead to serious side effects such as rhabdomyolysis, which causes destruction. Additionally, Liver damage is also a possibility. This high dose was administered to mice. In experiments, it was used to induce myopathy in a short period of time. In experiments, high doses of atorvastatin were used to induce myopathy (muscle weakness). This was used to quickly simulate muscle damage as part of the research. 25 It is the preferred method. Clinical doses of N-acetylcysteine ​​(NAC) depend on the condition being treated. It varies depending on the situation. For example, the doses of NAC given in acetaminophen overdose. The levels can be very high. Therefore, NAC dosages are carefully calculated and is being monitored. In other cases, the doses are much lower. A range of A dosage range is applied. NAC is available in 30 doses to treat many different medical conditions. It is used, but the requirements of each situation are different. For mouse experiments... The dose used is 200 mg / kg / day, which is a typical daily dose used in most clinical situations. This dosage is quite high. This dosage can cause nausea, vomiting, and other gastrointestinal problems. This can lead to [deviation]. This dose protects the body from oxidative stress and minimizes the side effect of myopathy. 24 It has been used to reduce [the effects of coenzyme Q10]. Finally, clinical doses for coenzyme Q10 (CoQ10) Daily doses range from 100 mg to 300 mg, but higher doses are sometimes used. It is used under medical supervision. The 100 mg / kg / day used in the experiments was very high. This is a high dose. This dosage can lead to gastrointestinal disturbances and other side effects. It can open. In an experiment conducted over 14 days, high doses of CoQ10 opened 5 By using antioxidant chemicals, the myopathy side effect of atorvastatin has been reduced. These doses were chosen in order to observe the maximum protective effect. Atorvastatin, NAC, and CoQ10 are already on the market, and various options are available depending on the patient's condition. It is available in therapeutic doses. The combined drug formulation described in this invention is intended for human use. The dosages given include atorvastatin, which ranges from 10 mg to 80 mg, and CoQ10, which is 10 mg. The amount is between 100-300 mg. NAC levels vary. Blood lipids. Dosages that can be used to treat high blood lipid levels are shown in Table 2. is provided. Table 2. Dosages of the combined drug formulation subject to the invention administered to humans. Examples of atorvastatin dosages Formulation Number Atovastatin Dose (mg / day) NAC Amount (mg / day) CoQ10 Amount (mg / day) 1 10 60 - 200 600 - 1200 2 20 3 40 4 80 Daily dosages of atorvastatin used to treat high blood lipid (blood fat) levels. The recommended daily dose of Coenzyme Q10 (CoQ10) is 100-200 mg, ranging from 10 to 80 mg per day. A dosage between [a certain range] is recommended. This helps maintain the body's natural CoQ10 levels. It is helpful. However, myopathy caused by atorvastatin. In this case, taking a daily supplement of 60-200 mg of CoQ10 can alleviate muscle pain. and rebalances CoQ10 levels. A 2018 study, Daily use of 200 mg ubiquinone (a form of CoQ10) increases the CoQ10 level in elderly men. It has been shown to be effective in increasing levels [5]. In addition, the ubiquinol form It has been found to be more effective than ubiquinone. For N-acetylcysteine ​​(NAC), 600 mg daily... A dosage between 1200 mg is common for providing overall health and antioxidant support. It is recommended that NAC and CoQ10 dosages be adjusted daily with the given atorvastatin. It should correspond to the dosage. 10 20 30 26 REFERENCES [1] Manoj K, Jain N, Madhu SV. “Myopathy in Patients Taking Atorvastatin: A Pilot Study”. Indian J Endocrinol Metab. 2017 Jul-Aug;21(4):504–509. [2] Björnsson Einar S. “Hepatotoxicity of statins and other lipid-lowering agents” Liver International, Volume 37, Issue 2, p. 173-178. 5 [3] Ahmadizar F, Rahmanian M, Jalali Z, Joseph A, Foroutan M. “Possible nephrotoxic effects of high dose statin therapy; current knowledge”. J Nephropharmacol. 2023; 12(1). [4] Alshogran OY, Nusair SD, El-Elimat T, Alzoubi KH, Obeidat A, Sweidan M. “Evaluation of coenzyme Q10 combined with or without N-acetyl cysteine or 10 atorvastatin for preventing contrast-induced kidney injury in diabetic rats”. Naunyn Schmiedebergs Arch Pharmacol. 2021 Jul;394(7):1403-1410. [5] Zhang Y, Liu J, Chen XQ, Chen CYO. “Ubiquinol is superior to ubiquinone to enhance Coenzyme Q10 status in older men”. Food Funct., 2018 Nov 14;9(11):5653- 5659. 15 25

Claims

27 REQUESTS 1. Atorvastatin is used to treat high blood lipid levels (blood fats). myopathy, hepatotoxicity and nephrotoxicity occurring during treatment It is a combination drug formulation that blocks atorvastatin, N-5. It contains acetylcysteine ​​(NAC) and Coenzyme Q10 (CoQ10).

2. To be used in the treatment of high blood lipid (blood fat) levels, according to Claim 1. It is a combined drug formulation and is available in suspension or tablet form. It is the fact that.

3. Atorvastatin 10 is used to treat high blood lipid levels (blood fat). myopathy, hepatotoxicity and nephrotoxicity occurring during treatment Claim 2 prohibits a suspension of a combined drug formulation. Its characteristic feature is the method of preparing the form; i. Weighing and sprinkling 500 mg of carboxymethylcellulose (CMC). Mixing with 50 ml of distilled water, 15 ii. The mixture prepared in step (ii) is heated at 50 °C and 350 Mixing at rpm for 10 minutes, iii. Homogenizing the mixture using a sonicator to obtain 1% by weight. Obtaining the CMC mixture, iv. Preparation of atorvastatin suspension in a separate container and 2 minutes 20 vortexing throughout, v. Preparation of NAC suspension in a separate container and simmering for 2 minutes. vortexing, vi. Preparation of CoQ10 suspension in a separate container and simmering for 2 minutes. vortexing, 25 vii. atorvastatin suspension, NAC suspension and CoQ10 Adding and mixing 1% by weight of CMC to the suspensions and vortexing It includes the steps of the process.

4. A 30-day course of treatment according to Order 3 for the treatment of high blood lipid levels (blood fat). atorvastatin, prepared using this method, is used in the treatment of high blood lipid levels. myopathy, hepatotoxicity and nephrotoxicity occurring during treatment A suspension-based combined drug formulation that blocks infection. 35

Images