CN112546036A - Application of tretinoin in treatment of paroxysmal nocturnal hemoglobinuria - Google Patents
Application of tretinoin in treatment of paroxysmal nocturnal hemoglobinuria Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention relates to an application of tretinoin in treatment of paroxysmal nocturnal hemoglobinuria PNH. Based on the biogenic analysis and clinical verification, the invention proves that the retinoic acid can effectively relieve and even cure the clinical symptoms of intractable PNH patients, effectively reduce complications such as hemolysis, thrombus and the like of the PNH patients, recover the hematopoietic function of bone marrow, and has the advantages of good curative effect, good economy, high safety and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of tretinoin to treatment of paroxysmal nocturnal hemoglobinuria.
Technical Field
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal disease of acquired hematopoietic stem cell gene mutations, mainly characterized clinically by thrombosis, hemolytic anemia and bone marrow failure. The incidence of PNH is low, only 2.8/1000000, and the PNH is included in the first rare disease list in China. PNH pathogenesis is currently thought to be associated with mutations in the PIG-A gene on one or more hematopoietic stem cell X chromosomes. The gene product of PIG-A is necessary for synthesizing GPI anchor protein, and PIG-A mutation enables GPI anchor chain protein synthesis to be blocked, so that the membrane anchor chain protein is lost, the capability of resisting complement attack of cells is weakened, and the cells are easy to damage and cause hemolysis. However, this mechanism does not explain the full clinical picture of PNH including bone marrow failure and thrombus susceptibility.
Therapeutic strategies for PNH include terminal complement blockade and allogeneic hematopoietic stem cell transplantation. Allogeneic hematopoietic stem cell transplantation is the only radical treatment method, but the high treatment cost of the allogeneic hematopoietic stem cell transplantation is prohibitive for poor patients, and meanwhile, the treatment-related death caused by the large dose of chemotherapy during pretreatment and rejection reaction after transplantation is also a problem which cannot be ignored by the treatment. Since 2007, successful application of complement inhibitors represented by eculizumab is promising for PNH patients, but it is expensive, and a great burden is imposed on patients by lifelong medication and regular medication. Meanwhile, the medicine can only control hemolytic symptoms of patients and can not completely cure PNH. Once administered, the patient is infused biweekly until the patient dies or PNH disappears spontaneously (rarely occurs), followed by uncontrolled hemolysis and complications if treatment is discontinued. Meanwhile, in the current clinical treatment, the treatment contradiction caused by thrombocytopenia and easy thrombosis of PNH patients is lacked, and the targeted treatment measures are also lacked.
Currently, the drug development of PNH mostly takes well-known PNH pathogenesis-related molecules or signal pathways such as CD59, CD55, PIG-A gene mutation and the like as drug targets, and the drug development based on PNH pathogenesis functional genomics is not reported. Although domestic scholars apply a high-throughput sequencing technology to carry out complete transcriptomic research on T cells in PNH patients, the change of the PNH pathogenesis related functional genomics cannot be comprehensively and systematically clarified due to the limitation of the number and the cell types of the patients, so that more deep drug research and development cannot be carried out on the change of the PNH pathogenesis related functional genomics.
The present invention has been made in view of the above circumstances.
Disclosure of Invention
The invention discovers that retinoic acid can be a potential drug for PNH treatment through integration analysis aiming at PNH disease genomes and retinoic acid drug genomes, and further proves through cell tests and clinical tests.
It is therefore a first object of the present invention to provide a novel method or medicament for the treatment of PNH and a second object to provide a novel use of tretinoin in the treatment of PNH.
In order to achieve the purpose, the invention provides the following technical scheme:
the invention provides an application of tretinoin in treatment of paroxysmal nocturnal hemoglobinuria PNH.
The invention provides an application of tretinoin in preparation of a medicine for treating paroxysmal nocturnal hemoglobinuria PNH.
In some embodiments, the treatment is alleviation or even cure of clinical symptoms in the refractory PNH patient;
in some embodiments, the treatment further comprises reducing hemolysis, thrombotic complications, and/or restoring bone marrow hematopoiesis in a PNH patient.
The invention also provides an application of tretinoin in preparing a medicament for improving the amount of hemoglobin in a body.
In some embodiments, the retinoic acid content in the above-mentioned use is 1-100 mg;
in some embodiments, the medicament further comprises a pharmaceutically acceptable carrier;
in some embodiments, the medicament is administered by the oral, intravenous, intramuscular, subcutaneous, or aerosol inhalation routes.
The invention also provides a pharmaceutical composition for treating paroxysmal nocturnal hemoglobinuria PNH, which is characterized by comprising tretinoin.
In some embodiments the tretinoin content is 1 to 100 mg;
in some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier;
in some embodiments, the pharmaceutical composition is administered by the oral, intravenous, intramuscular, subcutaneous, or aerosol inhalation routes.
The invention also provides application of the pharmaceutical composition in treating paroxysmal nocturnal hemoglobinuria PNH.
The present invention also provides a method of treating paroxysmal nocturnal hemoglobinuria PNH characterized by administration of tretinoin.
In some embodiments the tretinoin content is 1 to 100 mg;
in some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier;
in some embodiments, the pharmaceutical composition is administered by the oral, intravenous, intramuscular, subcutaneous, or aerosol inhalation routes.
The invention has the beneficial technical effects that:
1) the transcriptome change analysis after the mutation of the retinoic acid and the PIG-A shows that the retinoic acid activates the inhibition of a downstream signal path caused by the PIGA mutation and relieves the hemolytic reaction of a PNH patient caused by autoimmune destruction through the immunoregulation effect by adopting a clinical bioinformatics method. Compared with the current common scheme of clinical PNH, the traditional Chinese medicine composition has good economy and high safety, can effectively reduce complications such as hemolysis, thrombus and the like, recovers the hematopoietic function of bone marrow, and can effectively relieve and even cure clinical symptoms of intractable PNH patients.
2) Tretinoin is an active metabolite or derivative of vitamin A, is a natural small molecular substance which can be synthesized by human bodies, has slight toxic effect compared with the traditional treatment, and can be taken for a long time under the condition of not influencing the life quality of patients.
3) The cost is low, the retinoic acid is low in price, the monthly treatment cost of a patient is 50-100RMB, and the retinoic acid is suitable for popularization and use.
Drawings
FIG. 1 transcriptome changes following retinoic acid and PIG-A mutations, Apoptosis signaling pathway;
FIG. 2B cell reporter signaling pathway (asterisk is marked as molecule of common action between retinoic acid and PNH)
FIG. 3 shows a Hematopoietic cell line (asterisk is marked as retinoic acid and PNH onset co-acting molecule);
figure 4 hemoglobin profiles of patients receiving a tretinoin regimen.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention.
Definition of
Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
As used herein, the terms "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
The Retinoic Acid (RA), also known as retinoic acid, all-trans-retinoic acid (ATRA), vitamin A acid, retinoic acid and the like, is an active metabolite or derivative of vitamin A, and is a natural small molecular substance which can be synthesized by a human body.
The Paroxysmal Nocturnal Hemoglobinuria (PNH) is a non-malignant clonal disease caused by mutation of 1 or several hematopoietic stem cells via acquired somatic PIG-A gene (phospholipid synthesis group A), and the PIG-A mutation causes abnormal synthesis of Glycosyl Phosphatidyl Inositol (GPI), which results in loss of a group of membrane proteins anchored on cell membranes by GPI, including CD16, CD55, CD59, and the like, and is clinically mainly manifested by chronic intravascular hemolysis, hematopoietic failure and repeated thrombosis.
The term "treating" as used herein means reversing, alleviating, inhibiting the progression of, or preventing the progression of, a disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. In some embodiments, the treatment is shown to alleviate symptoms or even cure symptoms.
The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the compound of the present invention or one or more pharmaceutically acceptable carriers, preferably the compound is omeprazole, more preferably also TKIs are included.
By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils; physiological saline and aqueous dextrose and glycerol solutions may also be employed as liquid carriers, particularly for injectable solutions; oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, topical form or by inhalation.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms. Such dosage forms include, but are not limited to, tablets, capsules, troches, hard candies, powders, suppositories, gels, pastes, lotions, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
As used herein, an "effective amount" or "effective dose" refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent. The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.
The following is illustrated by specific examples, which do not indicate specific conditions, and are performed according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by manufacturers, and are all conventional products available on the market.
Example 1 prediction based on Credit analysis
The invention predicts that the retinoic acid has a treatment effect on PNH by using the expression profile of the PNH patient and PigA gene mutation expression profile data and applying a functional genomics method.
The method comprises the following steps:
the expression profile of the PNH patient and PigA gene mutation expression profile data obtained in the earlier stage are applied.
Firstly, an Impute program package is used for carrying out normalization processing and annotation on the expression profile.
And then screening differential genes in the expression profile by using a Limma software package, wherein the screening standard of the differential genes is that FDR is less than 0.05, and | Log2FC | > 1, and obtaining characteristic expression genes of PNH patients and PigA gene mutation.
And then, performing multi-group chemical association analysis on PNH patients and PigA gene mutation characteristic expression genes by using an appearance accurate treatment prediction platform (EpiMed) designed based on the theories of 'system biology' and 'comparative functional genomics', searching for drugs or compounds capable of treating PNH action in known compounds and clinical common drugs, and selecting potential effective drugs in a prediction result according to the | association coefficient | 0.1 and the threshold value P < 0.05.
Finally, retinoic acid is predicted to be a candidate for the treatment of PNH.
As a result: integration analysis aiming at PNH disease genome and retinoic acid drug genome shows that the therapeutic effect of retinoic acid on PNH is mainly related to three signal pathways, namely Apoptosis, B cell receptor signaling pathway and hematotoitic cell link.
As shown in fig. 1, 2 and 3, black squares indicate that down-regulation or up-regulation genes are caused by PNH onset and PigA mutation, and asterisked retinoic acid action molecules are marked, wherein the action site of Apoptosis signal retinoic acid is different from the PNH onset site, and the change of the pathway after PNH onset is reversed mainly by activating downstream signal molecules to exert action on the pathway, while B cell receptor signaling pathway and hematotoitic cell pathway act on key sites of PNH onset and realize treatment action by up-regulating the gene expression level.
And (4) conclusion: bioinformatics analysis preliminarily predicts the signal path and potential sites of retinoic acid to PNH treatment, and provides guidance for follow-up mechanism research and clinical treatment.
Example 2 clinical trials of tretinoin treatment of PNH
After the preliminary cytological test to verify the preliminary effectiveness, the present example carries out clinical verification, specifically:
the administration subjects were: 6 cases of definitively diagnosed PNH patients who failed first line therapy;
the administration scheme is as follows: tretinoin protocol (100 mg/d);
the treatment time is as follows: median treatment time 12 months;
clinical response: CR 5 cases and PR 1 cases, and the total effective rate is 100 percent. The gastrointestinal reaction or intolerance phenomena such as headache, nausea, diarrhea and the like do not occur in the treatment period of the patients. Meanwhile, hemolysis and thrombosis of patients are improved remarkably, and hemoglobin of 6 patients is increased and is separated from blood transfusion (see figure 4).
The above test results show that: the tretinoin has the effect of treating PNH and has slight toxic and side effects. The practical recommended scheme is as follows: tretinoin 1mg-100mg, and can be administered by oral, intravenous, intramuscular injection, subcutaneous or aerosol inhalation.
The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various changes and modifications according to the present invention without departing from the spirit of the present invention, which is defined by the scope of the appended claims.
Claims (10)
1. Use of tretinoin in the preparation of a medicament for the treatment of paroxysmal nocturnal hemoglobinuria PNH.
2. Use of tretinoin according to claim 1 in the manufacture of a medicament for the treatment of paroxysmal nocturnal hemoglobinuria PNH, characterized in that the treatment is a reduction in clinical symptoms or even a cure of refractory PNH patients.
3. The use of any one of claims 1-2, wherein the treatment further comprises reducing hemolysis, thrombotic complications in PNH patients, and restoring bone marrow hematopoiesis.
4. Use of tretinoin in the preparation of a medicament for increasing the amount of hemoglobin in the body.
5. A pharmaceutical composition for the treatment of paroxysmal nocturnal hemoglobinuria PNH, comprising tretinoin.
6. The pharmaceutical composition of claim 5, wherein the tretinoin content is 1-100 mg.
7. The pharmaceutical composition of any one of claims 5-6, further comprising a pharmaceutically acceptable carrier.
8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the pharmaceutical composition is administered by oral, intravenous, intramuscular, subcutaneous or aerosol inhalation routes.
9. Use of a pharmaceutical composition according to any one of claims 5 to 8 for the treatment of paroxysmal nocturnal hemoglobinuria PNH.
10. A method of treating paroxysmal nocturnal hemoglobinuria PNH by administration of tretinoin.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015143190A1 (en) * | 2014-03-21 | 2015-09-24 | Beth Israel Deaconess Medical Center, Inc. | Enhanced atra-related compounds derived from structure-activity relationships and modeling for inhibiting pin1 |
| WO2016145186A1 (en) * | 2015-03-12 | 2016-09-15 | Beth Israel Deaconess Medical Center, Inc. | Enhanced atra-related compounds for the treatment of proliferative diseases, autoimmune diseases, and addiction conditions |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015143190A1 (en) * | 2014-03-21 | 2015-09-24 | Beth Israel Deaconess Medical Center, Inc. | Enhanced atra-related compounds derived from structure-activity relationships and modeling for inhibiting pin1 |
| WO2016145186A1 (en) * | 2015-03-12 | 2016-09-15 | Beth Israel Deaconess Medical Center, Inc. | Enhanced atra-related compounds for the treatment of proliferative diseases, autoimmune diseases, and addiction conditions |
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