CN111632150A - Pharmaceutical composition for treating nephrotic syndrome - Google Patents
Pharmaceutical composition for treating nephrotic syndrome Download PDFInfo
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- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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Abstract
The invention discloses a pharmaceutical composition for treating nephrotic syndrome, which comprises the following components: glucocorticoids, calcineurin inhibitors and mycophenolic acid or a pharmaceutically acceptable salt, prodrug thereof. The pharmaceutical composition can not only act in multiple links of immunosuppression and achieve better effect by synergism of drug effects in the process of treating nephrotic syndrome, particularly idiopathic membranous nephropathy, but also can obviously reduce the dosage of each drug and reduce respective adverse reactions and toxic and side effects.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a pharmaceutical composition for treating nephrotic syndrome.
Background
Nephrotic syndrome is a disease seriously harming human health, and has the main clinical manifestations of a large amount of proteinuria, hypoproteinemia, edema, hypertension, even renal insufficiency and the like. Membranous nephropathy is one of the most common types of pathology for nephrotic syndrome, a group of diseases characterized pathologically by immune complex deposition under glomerular basement membrane epithelial cells with diffuse thickening of the basement membrane. The membranous nephropathy is divided into idiopathic membranous nephropathy and secondary membranous nephropathy, wherein the idiopathic membranous nephropathy accounts for about 80% of patients with membranous nephropathy.
The exact pathogenesis of idiopathic membranous nephropathy is unclear, but it may be damaged by autoantibodies directed against certain antigens on the glomerular epithelial cell membrane that bind to the antigen and shed and deposit under the epithelial cells, reactivating complement. Although immune complex mediated diseases, the renal histopathology was concentrated in the epithelial cells of the glomerular visceral layer (podocytes). Podocytes are located outside the glomerular basement membrane and have important physiological functions, including maintaining the permeability of the glomerular filtration membrane, synthesizing the constituents of the glomerular basement membrane, supporting the capillary structure, and the like. Due to the compartmentalization of the glomerular basement membrane, the laterally deposited immune complexes are not readily accessible to circulating inflammatory mediators and generally do not elicit an inflammatory response, more importantly through activation of complement, podocyte lesion formation leading to proteinuria and renal tissue damage.
The simple osmanthus fragrans and the like use a glucocorticoid and cyclophosphamide treatment method in the observation on the curative effect of primary membranous nephropathy treated by hormone and cyclophosphamide impact (Chinese clinical medicine, 2004, 12(11): 1064-1065), so that patients can benefit both in a long term and a short term. However, cyclophosphamide has large toxic and side effects, limits the use to a certain extent and is not suitable for long-term use.
YaoXiaodan et al, in contrast research on Cyclosporin A treatment of idiopathic membranous nephropathy (nephropathy and dialysis kidney transplant, 1997, 6(2): 122-. However, in the treatment of idiopathic membranous nephropathy, cyclosporine and tacrolimus have the side effects of high recurrence rate, nephrotoxicity, new onset diabetes and the like, and the side effects are in direct proportion to the dosage.
Zhao Ming Hui et al in "clinical Observation of mycophenolate mofetil for treating Primary nephrotic syndrome" (J.Zhonghua Med., 2001, 81(9): 528-one 531.) and Lu Fu Ming et al in "clinical Observation of mycophenolate mofetil for treating Primary nephrotic syndrome" (J.Zhonghua Med.Med., 2001, 81(9): 134-one 145.) used glucocorticoid + mycophenolate mofetil for treating idiopathic membranous nephropathy in combination with Primary nephrotic syndrome. However, evidence-based medicine for this regimen is inadequate, and generally the effect is not significant and can only be achieved for more than half a year.
In summary, the current major treatment options for idiopathic membranous nephropathy are: glucocorticoid + cyclophosphamide, or glucocorticoid + calcineurin inhibitor. However, in either case, there are limitations: 1. glucocorticoid has many side effects, such as hypertension, hyperglycemia, infection, osteoporosis, induced gastric ulcer, etc., and is obviously related to dosage; 2. cyclophosphamide has great toxic and side effects, is not suitable for long-term use, and has risk of reproductive toxicity, bone marrow suppression, induction of malignant tumor, etc.; 3. calcineurin inhibitors have nephrotoxicity and diabetes-inducing side effects that are dose-dependent and that are susceptible to relapse after treatment.
The invention is improved on the basis of glucocorticoid and calcineurin inhibitors, reduces the dosage of glucocorticoid and calcineurin inhibition, increases mycophenolate mofetil, and forms three medicaments for combined treatment of idiopathic membranous nephropathy, thereby achieving the purpose of treating membranous nephropathy, reducing toxic and side effects of medicaments, reducing complications, reducing medical and health burden, and improving the life quality of patients.
Disclosure of Invention
The invention aims to solve the problems of more glucocorticoid side effects, large cyclophosphamide toxic and side effects, unobvious calcineurin inhibitor and mycophenolate mofetil effects and the like in the current clinical treatment of nephrotic syndrome.
In order to achieve the object of the present invention, the present invention discloses a pharmaceutical composition for treating nephrotic syndrome, comprising: glucocorticoids, calcineurin inhibitors and mycophenolic acid or a pharmaceutically acceptable salt, prodrug thereof.
Further, the pharmaceutical composition is a compound preparation consisting of glucocorticoid, calcineurin inhibitor and mycophenolic acid or pharmaceutically acceptable salt and prodrug thereof, or a compound preparation consisting of glucocorticoid single preparation, calcineurin inhibitor single preparation and mycophenolic acid or pharmaceutically acceptable salt and prodrug single preparation thereof, or a compound preparation consisting of glucocorticoid and calcineurin inhibitor and mycophenolic acid or pharmaceutically acceptable salt and prodrug single preparation thereof, or a compound preparation consisting of calcineurin inhibitor, mycophenolic acid or pharmaceutically acceptable salt and prodrug thereof and glucocorticoid single preparation thereof, or a compound preparation consisting of glucocorticoid, mycophenolic acid or pharmaceutically acceptable salt and prodrug thereof and a compound preparation consisting of glucocorticoid and calcineurin inhibitor single preparation thereof.
Further, the glucocorticoid is selected from the group consisting of: one or the combination of more than two of prednisone or the pharmaceutically acceptable salt thereof, prednisolone or the pharmaceutically acceptable salt thereof, and methylprednisolone or the pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salts include prednisone acetate, prednisolone acetate, methylprednisolone sodium succinate, and the like.
Further, the glucocorticoid is prednisone or its pharmaceutically acceptable salt.
Further, the calcineurin inhibitor is selected from one or a combination of two of cyclosporine or pharmaceutically acceptable salt thereof, tacrolimus or pharmaceutically acceptable salt thereof.
Still further, the calcineurin inhibitor may optionally be any one of cyclosporine or tacrolimus.
Further, the mycophenolic acid or the pharmaceutically acceptable salt and the prodrug thereof are selected from mycophenolic acid, mycophenolate sodium or mycophenolate mofetil.
Further, the mycophenolic acid or the pharmaceutically acceptable salt and the prodrug thereof are mycophenolate.
Further, the pharmaceutical composition contains 2.5-60mg of glucocorticoid, preferably 2.5-30mg of glucocorticoid.
Furthermore, the pharmaceutical composition contains 2.5-60mg of prednisone, preferably 2.5-30mg of prednisone.
Further, the pharmaceutical composition comprises a calcineurin inhibitor: the cyclosporin is 25-300mg, preferably, the cyclosporin is 25-100mg, and the dose is adjusted according to the blood concentration.
Further, the pharmaceutical composition comprises a calcineurin inhibitor: the amount of tacrolimus is 0.5-6mg, preferably 0.5-3mg, and the dosage is adjusted according to the blood concentration.
Further, the pharmaceutical composition contains 0.25-3g of mycophenolic acid or a pharmaceutically acceptable salt or prodrug thereof, and preferably, 0.25-1g of mycophenolic acid or a pharmaceutically acceptable salt or prodrug thereof.
Further, the pharmaceutical composition contains 0.25-3g of mycophenolate mofetil, preferably 0.25-1g of mycophenolate mofetil.
Further, the pharmaceutical composition may be in any dosage form or administration form, and those skilled in the art may select it according to circumstances, including, but not limited to, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), troches, syrups, solutions, controlled release preparations (e.g., immediate release preparations, sustained release microcapsules), injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), intravenous drip, transdermal absorption preparations, or oral preparations.
In preparing the above dosage forms, those skilled in the art can select suitable adjuvants for the pharmaceutical composition of the present application according to the general knowledge in pharmacy, and the pharmaceutical composition can include one or more of sweeteners (specifically, sucrose, xylitol, fructo-oligosaccharide, sodium cyclamate, stevioside, aspartame, etc.), aromatics (such as flavors, essences, etc.), preservatives (specifically, benzoic acid and its salt, sorbic acid and its salt, nipagin series, etc.), disintegrants (specifically, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, croscarmellose sodium, starch, etc.), stabilizers (specifically, citric acid, fumaric acid, succinic acid, etc.), fillers (specifically, starch, sucrose, lactose, microcrystalline cellulose, etc.), and the like.
The invention also provides the use of the pharmaceutical composition in the manufacture of a medicament for simultaneous, partial simultaneous, separate or sequential use.
Further, the medicament is used for treating nephrotic syndrome.
Furthermore, the medicine is used for treating primary glomerular diseases, secondary glomerulonephritis, hereditary nephropathy, urinary system infectious nephropathy and the like.
Further, the medicament is used for treating idiopathic membranous nephropathy and secondary membranous nephropathy.
Preferably, said medicament is for the treatment of idiopathic membranous nephropathy.
The invention also provides the application of the pharmaceutical composition in preparing a medicament for treating nephrotic syndrome, wherein the dosage of glucocorticoid in the pharmaceutical composition is 2.5-60 mg/day; the calcineurin inhibitor is 25-300 mg/day cyclosporin or 0.5-6 mg/day tacrolimus, and is administered in two times, with dosage adjusted according to blood concentration; the dose of mycophenolic acid or its medicinal salt and prodrug is 0.25-3 g/day, and the mycophenolic acid or its medicinal salt and prodrug is taken in two times.
Further, the dosage of prednisone is 2.5-60 mg/day; the dosage of the cyclosporine is 25-300 mg/day or 0.5-6 mg/day of tacrolimus, the cyclosporine is taken in two times, and the dosage is adjusted according to the blood concentration; the mycophenolate mofetil is administered in an amount of 0.25-3 g/day in two divided doses.
Further, the dose of prednisone is 0.5 mg/kg/day, and the maximum dose is 30 mg/day. The initial dosage of cyclosporin is 100 mg/day, and the dosage is adjusted according to blood drug concentration by two times, wherein target range of cyclosporin valley concentration is 80-120ng/ml, and maximum dosage is 300 mg/day. The mycophenolate mofetil is administered in a dose of 1 g/day in two divided doses.
Preferably, the initial dose of prednisone is 0.5 mg/kg/day and the maximum dose is 30 mg/day for 8 weeks. Then every 4 weeks, 5 mg/day. When the dosage is reduced to 20 mg/day, 2.5 mg/day is reduced every 8 weeks, and the dosage is reduced to 5 mg/day for 4-6 months.
The initial dosage of cyclosporin is 100 mg/day, and the dosage is adjusted according to blood drug concentration by two times, wherein target range of cyclosporin valley concentration is 80-120ng/ml, and maximum dosage is 300 mg/day. If the disease condition is completely relieved, after the disease condition is maintained for 2 weeks, the dosage is reduced to 25 mg/day and 50 mg/day every 8 weeks, the dosage is reduced again after the maintenance treatment for 12 months, and the total treatment course is maintained for 60 months at 25 mg/day. If the disease is only partially alleviated or not, the maximum dose is maintained for 18 months before gradual reduction.
The initial mycophenolate mofetil dose was 1 g/day and was administered in two divided doses. If the disease condition is completely relieved, the disease condition is gradually reduced after being maintained for 2 weeks, the disease condition is reduced by 0.25 g/day every 8 weeks, and when the dosage is 0.5 g/day, the disease condition is maintained for 12 months. If the disease is only partially alleviated or not alleviated, the disease is gradually reduced after 18 months of maintenance treatment.
Further, the dose of prednisone is 0.5 mg/kg/day, and the maximum dose is 30 mg/day. The initial dose of the tacrolimus is 1 mg/day, the tacrolimus is taken by two times, the dose is adjusted according to the blood concentration, and the target concentration range is 4-6 ng/mL. The mycophenolate mofetil is administered in a dose of 1 g/day in two divided doses.
Preferably, the initial dose of prednisone is 0.5 mg/kg/day, the maximum dose is 30 mg/day for 8 weeks, and the subsequent dose is reduced by 5 mg/day every 4 weeks, 2.5 mg/day every 8 weeks when the dose is reduced to 20 mg/day, and for 4-6 months when the dose is reduced to 5 mg/day;
the initial dosage of the tacrolimus is 1 mg/day, the tacrolimus is taken in two times, the dosage is adjusted according to the blood concentration, the target range of the tacrolimus valley concentration is 4-6ng/ml, and the maximum dosage is 3 mg/day. If the disease condition is completely relieved, the weight is reduced by 0.5 mg/day every 8 weeks after the maintenance treatment for 2 weeks, and the maintenance treatment is carried out for 12 months when the weight is reduced to 1 mg/day. Reducing to 0.5 mg/day, and maintaining the total treatment course for 60 months. If the disease condition is only partially relieved or not relieved, the disease condition is gradually reduced after the treatment is maintained for 18 months at 1 mg/day.
The initial mycophenolate mofetil dose was 1 g/day and was administered in two divided doses. If the disease condition is completely relieved, after maintaining the treatment for 1 g/day for 2 weeks, the disease condition is gradually reduced, and the disease condition is reduced by 0.25 g/day every 8 weeks, and when the dosage is 0.5 g/day, the disease condition is reduced again by 12 months in the maintenance treatment and is maintained at 0.25 g/day. If the disease condition is only partially relieved or not relieved, the disease condition is gradually reduced after the treatment is maintained for 18 months at 1 g/day.
The invention also provides application of the pharmaceutical composition in preparing a medicament for treating idiopathic membranous nephropathy, wherein the dosage of glucocorticoid in the pharmaceutical composition is 2.5-60 mg/day; the calcineurin inhibitor is 25-300 mg/day cyclosporin or 0.5-6 mg/day tacrolimus, and is administered in two times, with dosage adjusted according to blood concentration; the dose of mycophenolic acid or its medicinal salt and prodrug is 0.25-3 g/day, and the mycophenolic acid or its medicinal salt and prodrug is taken in two times.
Further, the dosage of prednisone is 2.5-60 mg/day; the dosage of the cyclosporine is 25-300 mg/day or 0.5-6 mg/day of tacrolimus, the cyclosporine is taken in two times, and the dosage is adjusted according to the blood concentration; the mycophenolate mofetil is administered in an amount of 0.25-3 g/day in two divided doses.
Further, the dose of prednisone is 0.5 mg/kg/day, and the maximum dose is 30 mg/day. The initial dosage of cyclosporin is 100 mg/day, and the dosage is adjusted according to blood drug concentration by two times, wherein target range of cyclosporin valley concentration is 80-120ng/ml, and maximum dosage is 300 mg/day. The mycophenolate mofetil is administered in a dose of 1 g/day in two divided doses.
Preferably, the initial dose of prednisone is 0.5 mg/kg/day and the maximum dose is 30 mg/day for 8 weeks. Then every 4 weeks, 5 mg/day. When the dosage is reduced to 20 mg/day, 2.5 mg/day is reduced every 8 weeks, and the dosage is reduced to 5 mg/day for 4-6 months.
The initial dosage of cyclosporin is 100 mg/day, and the dosage is adjusted according to blood drug concentration by two times, wherein target range of cyclosporin valley concentration is 80-120ng/ml, and maximum dosage is 300 mg/day. If the disease condition is completely relieved, after the disease condition is maintained for 2 weeks, the dosage is reduced to 25 mg/day and 50 mg/day every 8 weeks, the dosage is reduced again after the maintenance treatment for 12 months, and the total treatment course is maintained for 60 months at 25 mg/day. If the disease is only partially alleviated or not, the maximum dose is maintained for 18 months before gradual reduction.
The initial mycophenolate mofetil dose was 1 g/day and was administered in two divided doses. If the disease condition is completely relieved, the disease condition is gradually reduced after being maintained for 2 weeks, the disease condition is reduced by 0.25 g/day every 8 weeks, and when the dosage is 0.5 g/day, the disease condition is maintained for 12 months. If the disease is only partially alleviated or not alleviated, the disease is gradually reduced after 18 months of maintenance treatment.
Further, the dose of prednisone is 0.5 mg/kg/day, and the maximum dose is 30 mg/day. The initial dose of the tacrolimus is 1 mg/day, the tacrolimus is taken by two times, the dose is adjusted according to the blood concentration, and the target concentration range is 4-6 ng/mL. The mycophenolate mofetil is administered in a dose of 1 g/day in two divided doses.
Preferably, the initial dose of prednisone is 0.5 mg/kg/day, the maximum dose is 30 mg/day for 8 weeks, and the subsequent dose is reduced by 5 mg/day every 4 weeks, 2.5 mg/day every 8 weeks when the dose is reduced to 20 mg/day, and for 4-6 months when the dose is reduced to 5 mg/day;
the initial dosage of the tacrolimus is 1 mg/day, the tacrolimus is taken in two times, the dosage is adjusted according to the blood concentration, the target range of the tacrolimus valley concentration is 4-6ng/ml, and the maximum dosage is 3 mg/day. If the disease condition is completely relieved, the weight is reduced by 0.5 mg/day every 8 weeks after the maintenance treatment for 2 weeks, and the maintenance treatment is carried out for 12 months when the weight is reduced to 1 mg/day. Reducing to 0.5 mg/day, and maintaining the total treatment course for 60 months. If the disease condition is only partially relieved or not relieved, the disease condition is gradually reduced after the treatment is maintained for 18 months at 1 mg/day.
The initial mycophenolate mofetil dose was 1 g/day and was administered in two divided doses. If the disease condition is completely relieved, after maintaining the treatment for 1 g/day for 2 weeks, the disease condition is gradually reduced, and the disease condition is reduced by 0.25 g/day every 8 weeks, and when the dosage is 0.5 g/day, the disease condition is reduced again by 12 months in the maintenance treatment and is maintained at 0.25 g/day. If the disease condition is only partially relieved or not relieved, the disease condition is gradually reduced after the treatment is maintained for 18 months at 1 g/day.
The invention also provides the application of the pharmaceutical composition in treating nephrotic syndrome, wherein the nephrotic syndrome is selected from: primary glomerular disease, secondary kidney disease, and the like.
Further, the nephrotic syndrome is idiopathic membranous nephropathy and secondary membranous nephropathy.
Preferably, the nephrotic syndrome is idiopathic membranous nephropathy.
The invention also provides the curative effect of the pharmaceutical composition on patients with refractory idiopathic membranous nephropathy, and the curative effect is good for patients with refractory idiopathic membranous nephropathy who are not effective on classical schemes in Beijing friendship hospital since 2016 by adopting example 6 or example 8. So far, the total application of example 6 or example 8 in the department of China treats 32 patients with refractory idiopathic membranous nephropathy, blood albumin is obviously increased after treatment, urine protein is quantitatively and obviously reduced, and the effective rate can reach 81.3%. More importantly, the more appropriate therapeutic dose is found out in clinical practice. For patients with idiopathic membranous nephropathy, the cyclosporin trough concentration is controlled at 80-120ng/mL, the maximum dose is 300 mg/day or tacrolimus trough concentration is 4-6ng/mL, and the maximum dose is 6 mg/day. Mycophenolate mofetil was dosed at 1 g/day. Within this range, cyclosporin is less nephrotoxic and no serious adverse events such as infection occur.
The invention also provides the curative effect of the pharmaceutical composition on patients with idiopathic membranous nephropathy. Since 7 months of 2019, the Beijing friendship hospital started exploring the application of example 6 or example 8 to treat patients with idiopathic membranous nephropathy, and 16 patients were treated, of which 12 patients were relieved within 6 months of treatment, until no adverse events occurred. In the other 4 cases, no efficacy evaluation was performed due to short treatment time. In 14 patients in the same period, the standard scheme (cyclophosphamide) is applied to treat membranous nephropathy, and as a result, the 14 patients with membranous nephropathy in the standard scheme (cyclophosphamide) have 10 partial remission results, and in addition, 4 patients have short treatment time and are still in the observation period. However, in the standard protocol group, 1 patient had herpes zoster, and 1 patient had a significant drop in lymphocytes, and the lymphocytes were recovered to be normal after cyclophosphamide reduction. In preliminary evaluation, both were similarly effective, but the multi-target protocol had fewer adverse events.
The pharmaceutical composition of the invention has two advantages: 1. multiple immunosuppressive agents are combined to play a role in multiple links of immunosuppression (namely multiple targets), and the drug effects are synergistic, so that a better effect is achieved; 2. the combination of multiple immunosuppressions can obviously reduce the dosage of each drug and reduce respective adverse reactions and toxic and side effects.
Drawings
FIG. 1 shows the therapeutic effect of the pharmaceutical composition of the present invention on patients with refractory idiopathic membranous nephropathy.
FIG. 2 shows the therapeutic effect of the pharmaceutical composition of the present invention on patients with idiopathic membranous nephropathy.
Detailed Description
The present invention is further described in the following description of the specific embodiments, which is not intended to limit the invention, but various modifications and improvements can be made by those skilled in the art according to the basic idea of the invention, within the scope of the invention, as long as they do not depart from the basic idea of the invention.
EXAMPLE 1 use of the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of nephrotic syndrome
The prednisone dose is 0.5 mg/kg/day, and the maximum dose is 30 mg/day.
The dose of cyclosporin is 100 mg/day, and the preparation is administered in two times, and the dose is adjusted according to blood concentration.
The mycophenolate mofetil is administered in a dose of 1 g/day in two divided doses.
Example 2 use of a pharmaceutical composition of the invention in the preparation of a medicament for the treatment of nephrotic syndrome
The initial dose of prednisone was 0.5 mg/kg/day and the maximum dose was 30 mg/day for 8 weeks. The subsequent dose is reduced by 5 mg/day every 4 weeks, reduced to 20 mg/day, reduced by 2.5 mg/day every 8 weeks, and reduced to 5 mg/day for 4-6 months.
The initial dose of cyclosporin was 100 mg/day and was administered in two divided doses. The dosage is adjusted according to the blood concentration, the target range of the cercosporin valley concentration is 80-120ng/ml, and the maximum dosage is 300 mg/day. If the disease condition is completely relieved, the weight is reduced by 25 mg/day every 8 weeks after the disease condition is maintained for 2 weeks. Reducing to 50 mg/day, maintaining the treatment at 50 mg/day for 12 months, then reducing to 25 mg/day, and maintaining the total treatment course for 60 months. If the disease is only partially alleviated or not, the target dose is maintained for 18 months and then gradually reduced.
The initial mycophenolate mofetil dose was 1 g/day and was administered in two divided doses. If complete remission is achieved, gradual reduction is initiated 2 weeks after maintenance therapy, with a reduction of 0.25 g/day every 8 weeks. When the dosage is reduced to 0.5 g/day, the dosage is reduced again for 12 months of maintenance treatment, and the dosage is maintained for 12 months at 0.25 g/day. If the disease is only partially alleviated or not, the target dose is maintained for 18 months and then gradually reduced. EXAMPLE 3 use of the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of nephrotic syndrome
The prednisone dose is 0.5 mg/kg/day, and the maximum dose is 30 mg/day.
The dosage of the tacrolimus is 1 mg/day, the tacrolimus is taken in two times, and the dosage is adjusted according to the blood concentration.
The mycophenolate mofetil is administered in a dose of 1 g/day in two divided doses.
EXAMPLE 4 use of the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment of nephrotic syndrome
The initial dose of prednisone is 0.5 mg/kg/day, the maximum dose is 30 mg/day for 8 weeks, and the dose is reduced by 5 mg/day every 4 weeks, 2.5 mg/day every 8 weeks when the dose is reduced to 20 mg/day, and the dose is reduced to 5 mg/day for 4-6 months.
The initial dosage of the tacrolimus is 1 mg/day, the tacrolimus is taken in two times, the dosage is adjusted according to the blood concentration, the target range of the blood tacrolimus valley concentration is 4-6ng/ml, and the maximum dosage is 6 mg/day. If the disease condition is completely relieved, the weight is reduced to 0.5 mg/day and then to 0.5 mg/day every 8 weeks after the maintenance treatment for 2 weeks. The total treatment period is maintained at 0.5 mg/day for 60 months. If the disease is only partially alleviated or not alleviated, the disease is gradually reduced after 18 months of maintenance treatment.
The initial mycophenolate mofetil dose was 1 g/day and was administered in two divided doses. If complete remission is achieved, gradual reduction is initiated 2 weeks after maintenance therapy, with a reduction of 0.25 g/day every 8 weeks. When the dosage is reduced to 0.5 g/day, the treatment is maintained for 12 months, and the dosage is reduced to 0.25 g/day. If the disease is only partially alleviated or not alleviated, the disease is gradually reduced after 18 months of maintenance treatment.
Example 5 use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of idiopathic membranous nephropathy
The prednisone dose is 0.5 mg/kg/day, and the maximum dose is 30 mg/day.
The dose of cyclosporin is 100 mg/day, and the preparation is administered in two times, and the dose is adjusted according to blood concentration.
The mycophenolate mofetil is administered in a dose of 1 g/day in two divided doses.
Example 6 use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of idiopathic membranous nephropathy
The initial dose of prednisone is 0.5 mg/kg/day, the maximum dose is 30 mg/day, the maintenance period is 8 weeks, the dose is reduced by 5 mg/day every 4 weeks, reduced to 2.5 mg/day every 8 weeks when the dose is 20 mg/day, and reduced to 5 mg/day, the maintenance period is 4-6 months;
the initial dose of cyclosporin was 100 mg/day and was administered in two divided doses. The dosage is adjusted according to the blood concentration, the target range of the cercosporin valley concentration is 80-120ng/ml, and the maximum dosage is 300 mg/day. If the disease condition is completely relieved, the weight is reduced by 25 mg/day every 8 weeks after the disease condition is maintained for 2 weeks. Reducing to 50 mg/day, maintaining for 12 months at 50 mg/day, reducing to 25 mg/day, and maintaining until the total treatment period reaches 60 months. If the disease is only partially alleviated or not, the target dose is maintained for 18 months and then gradually reduced.
The initial mycophenolate mofetil dose was 1 g/day and was administered in two divided doses. If the disease condition is completely relieved, the weight is gradually reduced after the maintenance treatment is carried out for 2 weeks, the weight is reduced by 0.25 g/day every 8 weeks, and when the weight is reduced to 0.5 g/day, the weight is reduced again after the maintenance treatment is carried out for 12 months, and the maintenance treatment is carried out at 0.25 g/day. If the disease is only partially alleviated or not, the target dose is maintained for 18 months and then gradually reduced.
Example 7 use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of idiopathic membranous nephropathy
The prednisone dose is 0.5 mg/kg/day, and the maximum dose is 30 mg/day.
The dosage of the tacrolimus is 1 mg/day, the tacrolimus is taken in two times, and the dosage is adjusted according to the blood concentration.
The mycophenolate mofetil is administered in a dose of 1 g/day in two divided doses.
Example 8 use of a pharmaceutical composition of the invention in the preparation of a medicament for the treatment of idiopathic membranous nephropathy
The initial dose of prednisone is 0.5 mg/kg/day, the maximum dose is 30 mg/day for 8 weeks, and the dose is reduced by 5 mg/day every 4 weeks, 2.5 mg/day every 8 weeks when the dose is reduced to 20 mg/day, and the dose is reduced to 5 mg/day for 4-6 months.
The initial dosage of the tacrolimus is 1 mg/day, the tacrolimus is taken in two times, the dosage is adjusted according to the blood concentration, the target range of the tacrolimus valley concentration is 4-6ng/ml, and the maximum dosage is 6 mg/day. If the disease condition is completely relieved, after maintaining treatment for 2 weeks, the dosage is reduced to 0.5 mg/day and 0.5 mg/day every 8 weeks, and the total treatment period is maintained at 0.5 mg/day for 60 months. If the disease is only partially alleviated or not alleviated, the disease is gradually reduced after 18 months of maintenance treatment.
The initial mycophenolate mofetil dose was 1 g/day and was administered in two divided doses. If complete remission is achieved, gradual reduction is initiated 2 weeks after maintenance therapy, with a reduction of 0.25 g/day every 8 weeks. Reducing to 0.5 g/day, maintaining for 12 months, reducing to 0.25 g/day, and maintaining for 12 months. If the disease is only partially alleviated or not alleviated, the disease is gradually reduced after 18 months of maintenance treatment.
EXAMPLE 9 therapeutic Effect of the pharmaceutical composition of the present invention
Curative effect of multi-target group on patients with refractory idiopathic membranous nephropathy
Since 2016, patients with refractory idiopathic membranous nephropathy who were not under the classical protocol by the Beijing friendship Hospital, obtained good therapeutic effects using either example 6 or example 8. So far, the total application of example 6 or example 8 in the family of the inventor treats 32 patients with refractory idiopathic membranous nephropathy, blood albumin is obviously increased after treatment, urine protein is quantitatively and obviously reduced, and the effective rate can reach 81.3 percent (table 1 and figure 1). More importantly, a more appropriate treatment dose is explored in clinical practice, and in the case of patients with idiopathic membranous nephropathy, the cyclosporine valley concentration is controlled to be 80-120ng/mL, the maximum dose is 300 mg/day or the tacrolimus valley concentration is 4-6ng/mL, and the maximum dose is 6 mg/day in a multi-target scheme. Mycophenolate mofetil was dosed at 1 g/day. Within this range, cyclosporin is less nephrotoxic and no serious adverse events such as infection occur.
TABLE 1 therapeutic Effect of the Multi-target regimen on refractory idiopathic membranous nephropathy
Curative effect of multi-target group on patients with idiopathic membranous nephropathy
Since 7 months of 2019, the beijing friendship hospital started to explore the application of example 6 or example 8 to treat idiopathic membranous nephropathy naive patients, 16 patients (baseline characteristics of patients are shown in table 2) are treated, and 12 patients get remission within 6 months of treatment (table 3 and fig. 2), until no adverse events appear. In the other 4 cases, no efficacy evaluation was performed due to short treatment time. In 14 patients in the same period, the standard scheme (cyclophosphamide) is applied to treat membranous nephropathy, and as a result, the 14 patients with membranous nephropathy in the standard scheme (cyclophosphamide) have 10 partial remission results, and in addition, 4 patients have short treatment time and are still in the observation period. However, in the standard protocol group, 1 patient had herpes zoster, and 1 patient had a significant drop in lymphocytes, and the lymphocytes were recovered to be normal after cyclophosphamide reduction. In preliminary evaluation, both were similarly effective, but the multi-target protocol had fewer adverse events.
TABLE 2 Baseline characteristics of patients with idiopathic membranous nephropathy
TABLE 3 efficacy of the Multi-target and Standard regimens (Cyclophosphamide) on Primary treatment of idiopathic membranous nephropathy
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A pharmaceutical composition for treating nephrotic syndrome, said pharmaceutical composition comprising: glucocorticoids, calcineurin inhibitors and mycophenolic acid or a pharmaceutically acceptable salt, prodrug thereof.
2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a combination of a glucocorticoid, a calcineurin inhibitor, and mycophenolic acid or a pharmaceutically acceptable salt or prodrug thereof, or a composition of glucocorticoid single preparation, calcineurin inhibitor single preparation and mycophenolic acid or pharmaceutically acceptable salt and prodrug single preparation, or a composition consisting of a compound preparation consisting of glucocorticoid and calcineurin inhibitor and mycophenolic acid or medicinal salt and a prodrug single preparation, or a composition consisting of a compound preparation consisting of a calcineurin inhibitor, mycophenolic acid or medicinal salt and a prodrug thereof and a glucocorticoid single preparation, or a composition consisting of a compound preparation consisting of glucocorticoid, mycophenolic acid or medicinal salt and prodrug thereof and a single preparation of a calcineurin inhibitor.
3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the glucocorticoid is selected from the group consisting of prednisone, prednisolone, methylprednisolone, prednisone acetate, prednisolone acetate, and methylprednisolone sodium succinate, the calcineurin inhibitor is selected from the group consisting of cyclosporine and tacrolimus, and the mycophenolic acid or a pharmaceutically acceptable salt or prodrug thereof is selected from the group consisting of mycophenolic acid, mycophenolate sodium, and mycophenolate mofetil.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises: 2.5-60mg of prednisone, 25-300mg of cyclosporine and 0.25-3g of mycophenolate mofetil.
5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises: prednisone 30mg, cyclosporin 100mg, mycophenolate mofetil 1 g.
6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises: 2.5-60mg of prednisone, 0.5-6mg of tacrolimus and 0.25-3g of mycophenolate mofetil.
7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises: prednisone 30mg, tacrolimus 1mg, mycophenolate mofetil 1 g.
8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, pills, powders, granules, capsules, lozenges, syrups, solutions, controlled release formulations, injections, intravenous drip, transdermal absorption formulations and oral formulations.
9. Use of a pharmaceutical composition according to any one of claims 1 to 8 in the manufacture of a medicament for simultaneous, partial simultaneous, separate or sequential use.
10. Use of a pharmaceutical composition according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of nephrotic syndrome, preferably idiopathic membranous nephropathy.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747743A (en) * | 2003-02-10 | 2006-03-15 | 诺瓦提斯公司 | Pharmaceutical combinations comprising corticoids and immunosuppressants for treating corticoid- and/or calcineurin inhibitors-resistant diseases |
| CN1767836A (en) * | 2003-04-01 | 2006-05-03 | 诺瓦提斯公司 | Parenteral formulation of mycophenolic acid, a salt or prodrug thereof. |
| WO2008008549A2 (en) * | 2006-07-14 | 2008-01-17 | Boston Medical Center Corporation | Combination of an immunosuppressive agent and nonsteroidal anti -inflammatory drugs to treat neoplasia |
| WO2017100722A1 (en) * | 2015-12-09 | 2017-06-15 | Cedars-Sinai Medical Center | Methods for treating nephrotic syndrome |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1747743A (en) * | 2003-02-10 | 2006-03-15 | 诺瓦提斯公司 | Pharmaceutical combinations comprising corticoids and immunosuppressants for treating corticoid- and/or calcineurin inhibitors-resistant diseases |
| CN1767836A (en) * | 2003-04-01 | 2006-05-03 | 诺瓦提斯公司 | Parenteral formulation of mycophenolic acid, a salt or prodrug thereof. |
| WO2008008549A2 (en) * | 2006-07-14 | 2008-01-17 | Boston Medical Center Corporation | Combination of an immunosuppressive agent and nonsteroidal anti -inflammatory drugs to treat neoplasia |
| WO2017100722A1 (en) * | 2015-12-09 | 2017-06-15 | Cedars-Sinai Medical Center | Methods for treating nephrotic syndrome |
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