Methotrexate Simvastatin Combination for Osteosarcoma Treatment
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Solution Overview
Problem
High doses of methotrexate used in osteosarcoma treatment often result in severe adverse side effects, including myelosuppression, mucositis, and neurotoxicity, which can lead to premature interruption of chemotherapy and long-term neurological damage, particularly in children.
Innovation Solution
Combining methotrexate with simvastatin produces a synergistic effect, allowing for reduced methotrexate doses while maintaining treatment efficacy, thereby minimizing side effects and preventing recurrence in osteosarcoma patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If high doses of methotrexate are administered to treat osteosarcoma, then treatment efficacy is improved, but severe adverse side effects occur
Solution Approach 1:
The patent changes the dosage parameter of methotrexate from high doses to reduced doses, and introduces a new parameter (simvastatin) to maintain treatment efficacy at lower methotrexate levels. This resolves the contradiction by finding optimal dosage parameters that balance efficacy and toxicity
Solution Approach 2:
The patent creates a composite chemotherapy regimen combining methotrexate with simvastatin. This composite approach allows the two drugs to work synergistically, maintaining anti-tumor efficacy while reducing the toxic burden compared to high-dose methotrexate alone
2Productivity
If high doses of methotrexate are used, then anti-tumour effect is strengthened, but neurotoxicity and other severe side effects increase
Solution Approach 1:
The patent modifies the dosage parameters by reducing methotrexate to 1-3 g/m² (from typical high doses of 3-12 g/m²) and adding simvastatin at 20-80 mg/m². This parameter optimization maintains anti-tumor productivity while minimizing neurotoxicity and other severe side effects
Solution Approach 2:
Simvastatin acts as an intermediary agent that enhances the anti-tumor effect of methotrexate, allowing lower methotrexate doses to achieve the same therapeutic effect. This intermediary role of simvastatin reduces the direct toxic burden on neurological systems
3Object-affected harmful factors
If methotrexate dose is reduced, then side effects decrease, but treatment efficacy may be compromised
Solution Approach 1:
The patent merges methotrexate with simvastatin in a combination regimen. This combination allows the reduced-dose methotrexate to maintain efficacy through synergistic interaction with simvastatin, preventing the compromise of treatment reliability that would normally occur with dose reduction
Solution Approach 2:
The patent optimizes the dosage parameters of both drugs: methotrexate at 1-3 g/m² and simvastatin at 20-80 mg/m². This parameter optimization ensures that side effects are reduced while treatment efficacy is maintained or improved through the synergistic combination
Data Source
Figure 1A~1B
Figure 2
Figure 3A~3B
AI summary
The invention relates to the use of an inhibitor of the dihydrofolate reductase enzyme selected from the group that consists of methotrexate, trimetrexate and pemetrexed; or a pharmaceutically acceptable salt thereof, for the preparation of a drug for the treatment or prevention of recurrences of a disease selected from the group that consists of cancer, psoriasis, psoriatic arthritis, juvenile polyarticular arthritis, rheumatoid arthritis, Crohn's disease, polymyositis, dermatomyositis and sarcoidosis, wherein said treatment or prevention includes administering to a patient, simultaneously, separately or sequentially, a lipophilic statin and the inhibitor of the dihydrofolate reductase enzyme. The invention also relates to a pharmaceutical composition which includes the inhibitor of the dihydrofolate reductase enzyme and the lipophilic statin together with pharmaceutically acceptable carriers and/or vehicles.