CN104490873A - Child tuberous sclerosis treatment drug - Google Patents
Child tuberous sclerosis treatment drug Download PDFInfo
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- CN104490873A CN104490873A CN201410687617.5A CN201410687617A CN104490873A CN 104490873 A CN104490873 A CN 104490873A CN 201410687617 A CN201410687617 A CN 201410687617A CN 104490873 A CN104490873 A CN 104490873A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Abstract
The present invention relates to the field of medicines, and in particular discloses a child tuberous sclerosis treatment drug including rapamycin, the child tuberous sclerosis includes child tuberous sclerosis combined intractable epilepsy, child tuberous sclerosis combined cardiac rhabdomyoma, child tuberous sclerosis combined depigmentation, facial steatadenoma, and child tuberous sclerosis combined renal angioleiomyolipoma, and the drug use method is as follows: the initial dose of the rapamycin is 1mg / (m2.d), and the blood drug concentration is maintained at 5-10ng / mL.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of medicine for the treatment of tuberous sclerosis in pediatric patients disease.
Background technology
Tuberous sclerosis (tuberous sclerosis complex, TSC) be a kind of autosomal dominant inherited disease, sickness rate is about 1:6000, the ratio of men and women is approximately 1.44:1, be more common in child, Disease-causing gene is respectively TSC1 and TSC2, and domestic and international multinomial larger samples research is all presented at non-selective TSC and enters to organize in case, and pathogenic mutation recall rate is at 69%-89%.Infant often shows as multiple organ clinically and gets involved (as skin, brain, eye, kidney, liver and heart etc.), with facial angiofibroma, epilepsy and hypophrenia for main clinical characteristics.
Tuberous sclerosis nervous system complication is the modal death of infant and the reason that disables, and the infant psychomotor development obstacle of 44%, the case IQ of 30% is lower than 21.Wherein epilepsy is the main cause that infant is gone to a doctor.The patient of the tuberous sclerosis of 80% ~ 90% can merge epilepsy, how childhood period early stage or infancy stage morbidity.Current without special treatment, have convulsions person to use Antiepileptic Drugs, electroencephalogram can use thyroliberin (ACTH) in the person that highly do not lose a war, and excision has cerebral cortex and the cortex inferior thyroid tubercle of pathological changes, epilepsy can be made to stop, but be only applicable to single focus and the better person of intelligence.The epilepsy of tuberous sclerosis infant, because focus is constantly in progress, so often develop into intractable epilepsy.But at present for the dermatosis of epiloia, the renal cystis, angiomyoliopma and nervous system complication (as bad in intractable epilepsy, cortical development, ependyma inferior thyroid tubercle, subependymal giant cell astrocytoma), except symptomatic treatment, if desired excision, not etiotropic treatment.
TSC1 and TSC2 gene is encoded TSC1 hamartin and tuberin respectively, and these two kinds of albumen suppress mTOR to activate, TSC1 and TSC2 gene mutation destroys this inhibit feature, causes mTOR excessive activation.Mammal rapamycin target protein (mammalian target of rapamycin, mTOR) is a kind of protein serine/threonine, plays an important role in many aspects such as Growth of Cells, propagation, differentiation, cell cycle regulatings.MTOR signal path is the signal of interest path of regulating cell growing multiplication and protein synthesis.MTOR kinases is the key molecule in this signal path, is controlled by protein kinase P13K and Akt; If remove the active suppression to mTOR of TSC1/TSC2 complex, the S6K in mTOR and downstream will be activated, make ribosomal protein S6 phosphorylation, cause protein synthesis and cell proliferation and differentiation; This is the principal causative mechanism that development occurs TSC.At nervous system, mTOR signal path regulates neuronal development and synaptic plasticity.
Rapamycin (also known as sirolimus) is mTOR specific inhibitor, the anti-rejection drugs of Novel macrocyclic lactone, it is potent immunosuppressant inhibitor up-to-date in the world at present, clinically for the anti-rejection of organ transplantation and the treatment of autoimmune disease, children is safe and reliable.
Summary of the invention
For problems of the prior art, the object of this invention is to provide a kind of medicine for the treatment of tuberous sclerosis in pediatric patients disease.
For achieving the above object, technical scheme of the present invention realizes like this.
(1) treat a medicine for tuberous sclerosis in pediatric patients disease, it is characterized in that, described pharmaceutical pack is containing rapamycin.
(2) purposes of rapamycin in the medicine for the treatment of tuberous sclerosis in pediatric patients disease, described tuberous sclerosis in pediatric patients disease comprises tuberous sclerosis in pediatric patients disease merging intractable epilepsy, tuberous sclerosis in pediatric patients disease merges rhabdomyoma of heart, tuberous sclerosis in pediatric patients disease merges depigmentation speckle, tuberous sclerosis in pediatric patients disease merges facial sebaceous tumor and tuberous sclerosis in pediatric patients disease merges renal blood vessels smooth muscle lipoma.
(3) include the using method of the medicine of the described treatment tuberous sclerosis in pediatric patients disease of rapamycin, wherein, the initial dose of described rapamycin is 1mg/ (m
2and to maintain blood drug level be 5-10ng/mL d).
Rapamycin (also known as sirolimus) is mTOR specific inhibitor, the anti-rejection drugs of Novel macrocyclic lactone, potent immunosuppressant inhibitor up-to-date in the world at present, clinically for the anti-rejection of organ transplantation and the treatment of autoimmune disease.But, research finds that mTOR signal path is all by abnormal activation in several diseases such as epiloia, focal cortical development exception, glioma and cerebral hemisphere increase disease, and this several disease all with epilepsy height correlation, prompting mTOR signal path take part in the generation of epilepsy, and proves that mTOR signal path is the main bridge connecting TSC1/TSC2 gene mutation and tuberous sclerosis phenotype.
The present invention is found by a large amount of clinical experiment: the children taking rapamycin suffering from tuberous sclerosis, and all clinical symptoms are all improved, and guardian to the overall improvement of patient and toleration evaluation good.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further details, but the invention is not restricted to these embodiments.
Embodiment: the clinical research utilizing rapamycin treatment tuberous sclerosis in pediatric patients disease
This clinical research is research that is open, perspective, own control.
Concrete research method and observed result as follows:
(1) case selection
The TSC with complete data is selected to merge intractable epilepsy infant, inclusive criteria: at less than 14 years old age, men and women does not limit in PLA General Hospital outpatient service and ward; TSC diagnostic criteria is according to the tuberous sclerosis diagnostic criteria of diagnostic criteria committee of US National TSC association revision in 1998; To enter before group monthly epilepsy number of times >=4 time, use the infant that Antiepileptic Drugs is invalid; Read experimenter's notice, guardian agrees to and signs Written informed consent; Minimumly complete the treatment of 24 weeks and follow up a case by regular visits to.
Exclusion standard: the current patient just participating in other clinical researches or participated in other clinical researches in nearly 1 month; Serious hepatorenal disease, disease in the blood system, autoimmune disease or other chronic serious infections etc. are suffered from except TSC.
Enter the routine tuberous sclerosis of group 52 altogether according to inclusive criteria and exclusion standard and merge intractable epilepsy infant, complete and followed up a case by regular visits at least 24 weeks.Wherein man 34 example, female 18 example, infant age of onset median is 4.8 months (4 days-49 months), medical 24 months (the 4-170 month) of median age.
In this research, have 10 examples to have TSC family history in 52 routine infants, 2 examples have epilepsy family history.Enter the front 10 routine infants of group and take 5 kinds of antiepileptics, 7 routine infants take 4 kinds of antiepileptics, and 14 routine infants take 3 kinds of antiepileptics, and 15 routine infants take 2 kinds of antiepileptics, and 6 routine infants take a kind of antiepileptic.The 3 kinds of antiepileptics entering to organize the most informal dress of infant are followed successively by: topiramate (29%), sodium valproate (24%) and vigabatrin (9%).24 routine infants have carried out TSC gene test, and 4 examples are TSC1 sudden change, and 20 examples are TSC2 sudden change.Other phenotypic characteristic situations of TSC are, cutaneous manifestations: depigmentation speckle (48/52 example), facial angiofibroma (7/52), sharkskin sample speckle (2/52); Manifestations of nervous system: Cortical tuber (50/52), ependyma inferior thyroid tubercle (51/52), SEGA (1/52); Kidney shows: renal angiomyolipoma (1/40), cyst of kidney/polycystic kidney (5/40); Cardiac Manifestation: rhabdomyoma of heart (14/40).In this research 52 routine infants, wherein once diagnosed in the 31 routine courses of disease or be diagnosed as infantile spasms (59.6%) at present.Enter to organize patient episode's type and show as convulsion 23 example (diagnosis infantile spasms) successively, partial seizures 22 example (wherein extensive 2 examples of partial seizures, complex partial seizures 5 example), convulsion 3 example, grand mal 3 example, 1 example shows as spasm, tetanic and atypical absences (diagnosis Lennox-Gastaut syndrome).
(2) Therapeutic Method
Enter to organize patient adds with rapamycin (trade name: Sai Mosi, specification 50mg/50mL, listing authentication code: the accurate word H20051081 of traditional Chinese medicines, Zhongmei Huadong Pharmaceutical Co., Ltd. Hangzhou) on the basis using former antiepileptic, oral, once a day.Patient takes medicine 24-96 week continuously.Initial dose 1mg/ (m
2d), be titrated to blood drug level gradually and reach 5-10ng/mL, body surface area computational methods are as follows:
Body weight≤30kg body weight (kg) × 0.0375+0.1
Body weight > 30kg [body weight (kg)-30] × 0.02+1.05
(3) observation index
When entering group (0 week) and following up a case by regular visits to for 12 weeks, 24 weeks, 36 weeks and 48 weeks, record epilepsy number of times and duration of seizure (bunchiness spasm is as the criterion with the number of times of spasm) between following up a case by regular visits to for twice, and observing toxic and side effects, the adverse events that record occurs and guardian improve and the evaluation of toleration overall patient.Every 3 months routines of having a blood test before medication and after medication, hepatic and renal function, rapamycin blood drug level, electroencephalogram (video or dynamically) and head B-sonography, followed up a case by regular visits to at least 24 weeks.
(4) curative effect evaluation:
Leading indicator: the improvement of intractable epilepsy in tuberous sclerosis in pediatric patients disease
1. epilepsy Outcome measure:
Calculate the epilepsy decline percentage rate before and after patient treatment:
General curative effect is evaluated by 5 grades of curative effects divisions according to epilepsy decline fraction values.Control completely: 100%, effective: >=75% and < 100%, effectively: >=50% and < 75%, invalid: >=0 and < 50%, increase the weight of < 0.Former three is effectively, total effective rate=control rate+obvious effective rate+effective percentage completely.
2. electroencephalogram evaluation: be divided into according to the performance of electroencephalogram after treatment: A. is normal: the electric discharge of epilepsy sample disappears completely; B. be clearly better: reduce more than 50%; C. take a turn for the better: reduce 25-49%; D. unchanged; E. the electric discharge of epilepsy sample increases.
Secondary index: the improvement of other symptoms that tuberous sclerosis is adjoint
1. the improvement degree of depigmentation speckle and/or facial sebaceous tumor
Curative effect judging standard: be clearly better, for area reduces more than 50%; Take a turn for the better, for area reduces 25-49%; Unchanged, for area reduces 0-25%.
2. rhabdomyoma of heart improves degree
Curative effect judging standard: be clearly better, for volume reduces more than 50%; Take a turn for the better, for volume reduces 25-49%; Unchanged, for volume reduces 0-25%.
3. renal blood vessels smooth muscle lipoma
Curative effect judging standard: be clearly better, for volume reduces more than 50%; Take a turn for the better, for volume reduces 25-49%; Unchanged, for volume reduces 0-25%.
4. improve and the evaluation of toleration overall: by patient monitoring people overall patient improved and the observed result of toleration, be divided into very satisfied, satisfied, generally, be not too satisfied with, very dissatisfied five grades.
All data analysiss adopt SPSS18.0 statistical package to data analysis, and the measurement data meeting normal distribution represents with (x ± s).The normality of Kolmogorov-Smirnov testing data, related application Spearman between ranked data is correlated with (sex, age of onset, the course of disease disobey normal distribution), different follow up time point efficient comparison adopts Friedman inspection, and P < 0.05 has statistical significance for difference.
(5) result of study
Leading indicator: the control situation of intractable epilepsy in tuberous sclerosis in pediatric patients disease
1. epilepsy curative effect: epilepsy curative effect evaluation data are in table 1.To latter 24 weeks for the treatment of, within 48 weeks, 72 weeks and 96 weeks, follow up a case by regular visits to, total effective rate was respectively 73%, 74%, 76% and 74%.24 weeks, within 48 weeks, 72 weeks and 96 weeks, when following up a case by regular visits to, before total effective rate and treatment, all there is significant difference (P<0.01).
Before utilizing rapamycin treatment, the average attack times of infant 70.27 times/d, average use antuepileptic species 1.30 kinds; When treating half a year, 1 year, 2 years, infant average attack times 1.94-2.8 time/d, average use antuepileptic species 0.83-0.97 kind; Along with the minimizing of patient's attack times, the antuepileptic species that patient uses also reduces simultaneously.
Table 1 epilepsy curative effect evaluation
The patient 52 examples, the 23 routine tuberous sclerosis entering to organize in patient being merged to infantile spasm carries out subgroup analysis.23 routine tuberous sclerosis merge the basic condition of infantile spasm patient in table 2.
Table 2 tuberous sclerosis in pediatric patients disease merge infantile spasm infant take rapamycin last as characteristics of incidence
All complete 23 routine tuberous sclerosis merging infantile spasm patients and follow up a case by regular visits to for 24 weeks, wherein 13 examples complete and follow up a case by regular visits to for 48 weeks, and 7 examples complete follows up a case by regular visits to for 72 weeks, and 5 examples complete follows up a case by regular visits to for 96 weeks.Add up 23 routine infants to take before rapamycin treatment and 12 weeks, 24 weeks seizure trequency and antiepileptic (AEDs) kind after treatment.Result display, seizure frequency and the AEDs kind comparatively front obviously minimizing (p<0.01) of medication after treatment.After treatment, seizure frequency the results are shown in Table 3, AEDs kind in table 4, and curative effect evaluation is in table 5.
The infant that table 3 tuberous sclerosis merges infantile spasm takes the comparison that before and after rapamycin treatment, epilepsy controls
Table 4 tuberous sclerosis merges the comparison of taking antiepileptic (AEDs) kind after the infant of infantile spasm takes rapamycin
Different follow up time curative effect evaluation before and after the infant rapamycin treatment of table 5 tuberous sclerosis merging infantile spasm
Result shows, and the patient that rapamycin merges infantile spasm for tuberous sclerosis in pediatric patients disease has positive therapeutical effect.After taking rapamycin, the refractory epilepsy frequency that tuberous sclerosis in pediatric patients disease merges the patient of infantile spasm significantly reduces, and the antuepileptic species used also significantly reduces.
2. electroencephalogram assessment: to treat 24 weeks for time point, 8 routine epilepsy sample electric discharges disappear completely, and 22 routine electroencephalograms are clearly better, and 8 examples take a turn for the better, and 14 routine electroencephalograms are unchanged.
Hyperarrhythmia is the characteristic EEG of infantile spasm.When entering to organize, seizure types is that 23 routine infants of infantile spasm all show as hyperarrhythmia.During to treatment 24 weeks, 14 routine infant electroencephalogram hyperarrhythmias disappear, wherein 3 routine infant electroencephalogram no abnormality seens.
Secondary index: the improvement of other symptoms that tuberous sclerosis in pediatric patients disease is adjoint
In this research, 16 examples are with the patient of heart rhabdomyosarcoma, and 12 examples take a turn for the better, and wherein the swollen thing of 1 example disappears completely, and the swollen thing of 11 example reduces.10 routine patients are with renal blood vessels smooth muscle lipoma, and 8 examples all take a turn for the better (the swollen thing disappearance of 3 example, the swollen things of 5 example reduce), and the swollen thing of 2 example is in progress.1 routine patient has optical fundus hamartoma, and 1 routine patient has nasopharynx part to swell thing, all take a favorable turn after treatment.The results are shown in Table 6.
Table 6 tuberous sclerosis accompanies the improvement situation of other symptoms
3. improve and the evaluation of toleration overall: Effect of follow-up visit by telephone is carried out to complete rapamycin treatment more than 48 weeks 31 routine infant guardians, sum up the overall improvement situation of rapamycin to infant and the evaluation of toleration, obtain feedback as follows: 12 examples (38.7%) infant guardian is to rapamycin treatment very satisfaction, 17 examples (54.84%) infant guardian is satisfied to rapamycin treatment, and 2 examples (6.45%) infant guardian thinks that rapamycin treatment is general.
(6) untoward reaction
Enter to organize infant before taking rapamycin, complete routine blood test, hepatic and renal function and lipids detection, and after taking medicine periodic review, infant routine blood test, hepatic and renal function Non Apparent Abnormality.Rapamycin blood concentration maintains below 10ng/mL (average 6.5ng/mL).
Take the infant of rapamycin, there is transient oral ulcer in 23% (12/52 example), oral ulcer continues to die away for 2-3 days.There is upper respiratory tract infection in 17.2% (9/52 example).There is two lower limbs edema when taking rapamycin 3 months in 1 routine infant, edema extinction after drug withdrawal, but outbreak increases, and cognition falls back, and the head of a family takes rapamycin to infant again, and after taking medicine 4 months, the two lower limb of infant occur edema again, disappear after drug withdrawal.
(7) research conclusion
Suffer from the oral rapamycin of child of tuberous sclerosis, once a day, initial dose 1mg/ (m
2d), maintenance blood drug level is 5-10ng/mL, effectively, and safety.The clinical symptoms accepting the infant of 52 routine rapamycin treatment all is all improved.Particularly tuberous sclerosis merges intractable epilepsy patient, and its outbreak obviously improves before comparatively entering group; Particularly 16 examples are with the patient of heart rhabdomyosarcoma, and 12 examples take a turn for the better (wherein the swollen thing of 1 example disappears completely, and the swollen thing of 11 example reduces).10 routine patients are with renal blood vessels smooth muscle lipoma, and wherein 8 people take a turn for the better (the swollen thing of 3 example disappears, and the swollen thing of 5 example reduces), the swollen thing progress of 2 example.1 example has optical fundus hamartoma, and 1 example has nasopharynx part to swell thing, all take a favorable turn after treatment.
Therapeutic effect is stablized, and in the dosage range of research setting, infant is for the better tolerance of rapamycin treatment.
The pharmaceutical pack that treatment tuberous sclerosis in pediatric patients disease of the present invention is closed contains rapamycin, this medicine can make Common drugs dosage form well known in the art with pharmaceutically acceptable carrier, as oral liquid, capsule, tablet, granule or pill by rapamycin together with excipient.
Although be described embodiment of the present invention above, the present invention is not limited to above-mentioned specific embodiments, and above-mentioned specific embodiments is only schematic, guiding, instead of restrictive.Those of ordinary skill in the art is under the enlightenment of this description, and when not departing from the scope that the claims in the present invention are protected, can also make a variety of forms, these all belong to the row of the present invention's protection.
Claims (4)
1. treat a medicine for tuberous sclerosis in pediatric patients disease, it is characterized in that, described pharmaceutical pack is containing rapamycin.
2. the medicine for the treatment of tuberous sclerosis in pediatric patients disease according to claim 1, it is characterized in that, described tuberous sclerosis in pediatric patients disease comprises tuberous sclerosis in pediatric patients disease and merges intractable epilepsy, tuberous sclerosis in pediatric patients disease merging rhabdomyoma of heart, tuberous sclerosis in pediatric patients disease merging depigmentation speckle, tuberous sclerosis in pediatric patients disease merging facial sebaceous tumor and tuberous sclerosis in pediatric patients disease merging renal blood vessels smooth muscle lipoma.
3. the using method of the medicine for the treatment of tuberous sclerosis in pediatric patients disease according to claim 1, is characterized in that, the initial dose of described rapamycin is 1mg/ (m
2and to maintain blood drug level be 5-10ng/mL d).
4. the purposes of rapamycin in the medicine for the treatment of tuberous sclerosis in pediatric patients disease.
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Cited By (8)
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| CN105560619A (en) * | 2015-09-18 | 2016-05-11 | 范月辉 | Traditional Chinese medicine formula for treating tuberous sclerosis |
| WO2018234811A1 (en) * | 2017-06-23 | 2018-12-27 | GW Research Limited | Use of cannabidiol in the treatment of tuberous sclerosis complex |
| US11065209B2 (en) | 2014-10-14 | 2021-07-20 | GW Research Limited | Use of cannabidiol in the treatment of epilepsy |
| CN113181367A (en) * | 2021-03-30 | 2021-07-30 | 首都医科大学附属北京儿童医院 | Preparation method of medicine for treating nodular sclerosis angiofibroma |
| US11160795B2 (en) | 2020-02-27 | 2021-11-02 | GW Research Limited | Methods of treating tuberous sclerosis complex with cannabidiol and everolimus |
| CN114555081A (en) * | 2019-10-16 | 2022-05-27 | 国立大学法人大阪大学 | External preparation for treating epilepsy or for treating autism spectrum disorder |
| US11963937B2 (en) | 2014-06-17 | 2024-04-23 | GW Research Limited | Use of cannabinoids in the treatment of epilepsy |
| US12064399B2 (en) | 2015-06-17 | 2024-08-20 | Jazz Pharmaceuticals Research Uk Limited | Use of cannabinoids in the treatment of epilepsy |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11963937B2 (en) | 2014-06-17 | 2024-04-23 | GW Research Limited | Use of cannabinoids in the treatment of epilepsy |
| US11065209B2 (en) | 2014-10-14 | 2021-07-20 | GW Research Limited | Use of cannabidiol in the treatment of epilepsy |
| US11400055B2 (en) | 2014-10-14 | 2022-08-02 | GW Research Limited | Use of cannabidiol in the treatment of epilepsy |
| US12064399B2 (en) | 2015-06-17 | 2024-08-20 | Jazz Pharmaceuticals Research Uk Limited | Use of cannabinoids in the treatment of epilepsy |
| CN105560619A (en) * | 2015-09-18 | 2016-05-11 | 范月辉 | Traditional Chinese medicine formula for treating tuberous sclerosis |
| WO2018234811A1 (en) * | 2017-06-23 | 2018-12-27 | GW Research Limited | Use of cannabidiol in the treatment of tuberous sclerosis complex |
| CN114555081A (en) * | 2019-10-16 | 2022-05-27 | 国立大学法人大阪大学 | External preparation for treating epilepsy or for treating autism spectrum disorder |
| EP4046637A4 (en) * | 2019-10-16 | 2023-11-01 | Osaka University | External preparation for treating epilepsy or autism spectrum disorder |
| US11160795B2 (en) | 2020-02-27 | 2021-11-02 | GW Research Limited | Methods of treating tuberous sclerosis complex with cannabidiol and everolimus |
| US11406623B2 (en) | 2020-02-27 | 2022-08-09 | GW Research Limited | Methods of treating tuberous sclerosis complex with cannabidiol and everolimus |
| CN113181367A (en) * | 2021-03-30 | 2021-07-30 | 首都医科大学附属北京儿童医院 | Preparation method of medicine for treating nodular sclerosis angiofibroma |
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