New use of ganciclovir

Abstract

The present application provides a new use of ganciclovir for treating, alleviating and / or relieving non-allergic rhinitis characterized by eosinophilia. The present application research shows that the use of ganciclovir in the treatment of nasal allergic symptoms in NARES patients is obviously relieved, and the originally poor efficacy of anti-allergic drugs can be re-exerted, effectively and durably improving the nasal symptoms of refractory NARES patients, effectively improving the symptoms of rhinitis.

Description

Technical Field

[0001] This invention relates to the field of medicine, specifically, to novel uses of ganciclovir, and more specifically, to the use of ganciclovir in medicaments for the treatment, relief and / or alleviation of diseases associated with non-allergic rhinitis characterized by eosinophilia, and / or diseases associated with chronic inflammation of the sinus mucosa. Background Technology

[0002] Non-allergic rhinitis with eosinophilic syndrome (NARES), also known as eosinophilic nonallergic rhinitis, is a type of non-allergic rhinitis characterized by eosinophilia, the pathogenesis of which is unknown.

[0003] The main symptoms are similar to those of allergic rhinitis, including sneezing, nasal itching, nasal congestion, and clear nasal discharge, but the symptoms are more severe and often accompanied by a decreased or lost sense of smell. Patients often have difficulty identifying the triggers for their symptoms. Nasal examination also reveals no characteristic changes; the nasal mucosa may appear chronically congested or pale and edematous. Nasal secretion smears may show a large number of eosinophils, with the diagnostic criteria being that the number of eosinophils in nasal secretions exceeds 20% of the total number of granulocytes and monocytes (excluding epithelial cells), and the number of eosinophils in peripheral blood is >5%; allergen testing is negative.

[0004] Increased eosinophils in nasal secretions without evidence of allergic reaction, presenting with symptoms of hyperresponsive rhinitis, can lead to a diagnosis of NARES. Clinically, it needs to be differentiated from vasomotor rhinitis and allergic rhinitis.

[0005] Because eosinophilic non-allergic rhinitis has multiple triggering factors and a complex pathogenesis, a comprehensive approach should be taken in its treatment. Improving working conditions and environment, maintaining a healthy lifestyle, stabilizing emotions, and avoiding excessive fatigue and stress are all important. Medication should be selected according to changes in the condition. Currently, commonly used drug treatments are similar to those for allergic rhinitis: first-line treatments include nasal corticosteroids (nasal hormones), second-generation oral and nasal antihistamines, and oral leukotriene receptor antagonists; second-line treatments include oral corticosteroids, etc.

[0006] Ganciclovir (GCV, chemical formula C9H) 13 N5O4, chemical formula and structure as follows Figure 7 (As shown) is an effective antiviral drug for treating DNA viruses, such as cytomegalovirus and herpesvirus infections. Its main mechanism is that GCV is phosphorylated by viral thymidine kinase and enters the cell, inhibiting DNA polymerase and thus suppressing viral replication. Based on currently known drug mechanisms, it does not have an effect on eosinophilic inflammation. Summary of the Invention

[0007] (a) Technical problems to be solved

[0008] The purpose of this invention is to address the problems of existing technologies in treating diseases associated with non-allergic rhinitis characterized by eosinophilia, and / or diseases associated with chronic inflammation of the sinus mucosa, and to propose a new use of ganciclovir in treating the aforementioned diseases.

[0009] (II) Technical Solution

[0010] According to one aspect of the invention, a novel use of ganciclovir is provided in the use of ganciclovir in a medicament for treating, alleviating and / or relieving diseases associated with non-allergic rhinitis characterized by eosinophilia.

[0011] Furthermore, the diseases associated with non-allergic rhinitis characterized by eosinophilia include non-allergic rhinitis with eosinophilia syndrome.

[0012] Furthermore, the ganciclovir is administered at a daily dose of approximately 500 mg to approximately 1000 mg.

[0013] Furthermore, the ganciclovir is administered orally.

[0014] Furthermore, the ganciclovir is administered twice daily, with a fixed dose of approximately 250 mg to approximately 500 mg each time.

[0015] Furthermore, the ganciclovir is administered continuously for at least one course of treatment, each course lasting at least two weeks.

[0016] According to another aspect of the present invention, an evaluation method is provided based on the use of the above-mentioned ganciclovir in a medicament for treating, alleviating and / or relieving diseases associated with non-allergic rhinitis characterized by eosinophilia, characterized in that AR patients who do not respond well to conventional anti-allergy medications are divided into a classic treatment group and a ganciclovir treatment group, wherein the classic treatment group is given oral antihistamines, and the ganciclovir treatment group is given ganciclovir continuously for two weeks, twice daily, at a fixed dose of about 500 mg each time.

[0017] Furthermore, the severity of all syndromes was assessed using a visual analog scale, ranging from 0 for no symptoms to 100 for the most severe symptom imaginable.

[0018] Nasal congestion, nasal itching, sneezing, and runny nose were scored separately, and the total score for nasal symptoms was the sum of the scores for all nasal symptoms.

[0019] The basic information is expressed as mean ± standard deviation using statistical analysis software. If the data conforms to a normal distribution, paired / unpaired t-tests and ordinary one-way ANOVA are performed; if the data does not conform to a normal distribution, nonparametric test methods are used.

[0020] (III) Beneficial Effects

[0021] (1) This invention demonstrates that ganciclovir treatment significantly alleviates nasal symptoms in patients with NARES, and previously ineffective antihistamines can regain their effectiveness, effectively and persistently improving nasal symptoms in patients with refractory NARES, thus effectively improving rhinitis symptoms. Furthermore, ganciclovir greatly facilitates the clinical treatment of refractory NARES, as it is inexpensive and its safety has been fully confirmed in long-term clinical use. For patients with refractory NARES who do not respond well to conventional oral antihistamines and nasal corticosteroids, ganciclovir treatment can significantly improve symptoms. This invention demonstrates the therapeutic effect of ganciclovir on refractory NARES, confirming that ganciclovir can indeed be used as a treatment for refractory NARES. Attached Figure Description

[0022] Various other advantages and benefits will become apparent to those skilled in the art upon reading the following detailed description of preferred embodiments. The accompanying drawings are for illustrative purposes only and are not intended to limit the invention. Furthermore, the same reference numerals denote the same parts throughout the drawings. In the drawings:

[0023] Figure 1 This diagram illustrates a comparison of VAS scores showing how ganciclovir significantly improved nasal symptoms in patients with refractory NARES according to an embodiment of the present invention.

[0024] Figure 2 This diagram illustrates a comparison of TNSS scores showing that ganciclovir significantly improved nasal symptoms in patients with refractory NARES according to an embodiment of the present invention.

[0025] Figure 3 This diagram illustrates a comparison of nasal congestion symptom scores in patients with refractory NARES, as shown in an embodiment of the present invention.

[0026] Figure 4 This diagram illustrates a score comparison of how ganciclovir significantly improves nasal itching symptoms in patients with refractory NARES according to an embodiment of the present invention.

[0027] Figure 5 This diagram illustrates a score comparison of how ganciclovir significantly improves rhinorrhea symptoms in patients with refractory NARES according to an embodiment of the present invention.

[0028] Figure 6 This illustration shows a score comparison of how ganciclovir significantly improves sneezing symptoms in patients with refractory NARES according to embodiments of the present invention;

[0029] Figure 7 A schematic diagram of the chemical formula of ganciclovir according to an embodiment of the present invention is shown. Detailed Implementation

[0030] Exemplary embodiments of the invention will now be described in more detail with reference to the accompanying drawings. While exemplary embodiments of the invention are shown in the drawings, it should be understood that the invention may be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this invention will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

[0031] The inventors of this application observed in clinical practice that some NARES patients experienced significant relief of their nasal allergy symptoms (without signs of viral infection) when using ganciclovir to treat other diseases. Furthermore, after a period of GCV treatment, previously ineffective antihistamines regained their effectiveness, effectively and persistently improving nasal symptoms in patients with refractory NARES. Through long-term and careful observation, the inventors found that ganciclovir treatment effectively improved the rhinitis symptoms in these NARES patients, and therefore selected a group of patients for further observation and research.

[0032] Example 1:

[0033] Ganciclovir is used in medicines for the treatment, relief and / or remission of diseases associated with non-allergic rhinitis characterized by eosinophilia.

[0034] Preferably, the disease associated with non-allergic rhinitis characterized by eosinophilia includes non-allergic rhinitis with eosinophilia syndrome.

[0035] Preferably, the ganciclovir is administered at a daily dose of about 500 mg to about 1000 mg.

[0036] Preferably, the ganciclovir is administered orally.

[0037] Preferably, the ganciclovir is administered twice daily, with a fixed dose of about 250 mg to about 500 mg each time.

[0038] Preferably, the ganciclovir is administered continuously for at least one course of treatment, each course lasting at least two weeks.

[0039] 1. Research Methods and Research Subjects

[0040] 1.1 Research subjects and grouping

[0041] All patients were recruited from the ENT outpatient clinic. Patients with NARES who reported poor response to conventional anti-allergy medications (nasal corticosteroids, oral antihistamines, nasal antihistamines, and oral leukotriene receptor antagonists) were clinically recruited. Patients were randomly assigned to either the classic treatment group or the ganciclovir treatment group based on their order of consultation using a random number table.

[0042] 1.2 Diagnostic criteria

[0043] The diagnostic criteria for non-allergic rhinitis with eosinophilic syndrome were referred to in the "Guidelines for the Diagnosis and Treatment of Allergic Rhinitis (2022)".

[0044] 1.3 Inclusion Criteria

[0045] Referring to the diagnostic criteria for NARES in the 2022 edition of the "Guidelines for the Diagnosis and Treatment of Allergic Rhinitis," the following conditions must be met simultaneously: ① Accumulated nasal symptoms of sneezing, runny nose, nasal itching, and nasal congestion, with the cumulative duration of these symptoms exceeding 1 hour per day, and concurrent ocular symptoms such as conjunctival congestion, itchy eyes, and tearing, lasting for at least 6 months. ② The severity of nasal symptoms is moderate / severe. ③ Negative results for skin prick test (SPT) and serum specific IgE. ④ The number of eosinophils in nasal secretions exceeds 20% of the total number of granulocytes and monocytes (excluding epithelial cells), and the number of eosinophils in peripheral blood is >5%. ⑤ The patient reports that conventional anti-allergy medications are ineffective.

[0046] 1.4 Exclusion Criteria

[0047] ① Symptoms of viral / bacterial infection, fever, and / or other systemic manifestations within the past 2 weeks; ② Other nasal conditions, such as nasal polyps or nasal tumors; ③ History of nasal surgery within the past 6 months; ④ Allergy to GCV; ⑤ Pregnant women or patients planning to become pregnant; ⑥ Severe neutropenia (absolute neutrophil count less than 0.5 × 10⁻⁶). 9 / L) or severe thrombocytopenia (platelet count less than 2.5×10 10 ⑦ Patients with respiratory diseases such as asthma, or cardiovascular or hematological diseases, or other serious diseases that affect survival, such as malignant tumors or AIDS. ⑧ Patients with poor compliance who do not follow the prescribed treatment or who add other treatment measures on their own, thereby affecting the assessment of efficacy.

[0048] 1.5 Rejection and shedding criteria

[0049] ① Patients who voluntarily withdrew from the study after enrollment. ② Cases lost to follow-up due to missing contact information or other reasons. ③ Patients mistakenly admitted but found to be ineligible after enrollment. ④ Patients whose treatment outcomes could not be effectively assessed due to intermittent medication use or other reasons. ⑤ Subjects who experienced significant adverse drug reactions or events, making it impossible to continue the trial. ⑥ Subjects who did not follow treatment instructions, affecting data collection and efficacy evaluation. ⑦ Subjects using other medications, especially those that significantly impacted study results. ⑧ Subjects who self-medicated with other medications for the same disease.

[0050] 2. Research Methods

[0051] 2.1 Treatment plan:

[0052] The classic treatment regimen consisted of oral antihistamines (loratadine or cetirizine, 10 mg, once daily) and nasal corticosteroids (mometasone furoate or budesonide, 1 spray / well, once daily).

[0053] Ganciclovir treatment regimen: GCV treatment for 2 weeks (oral, 500 mg twice daily).

[0054] 2.2 Clinical symptom scores

[0055] Patients were scored before and after treatment.

[0056] Visual Analogue Scale (VAS score): The severity of all combined symptoms is assessed using the VAS, ranging from 0 (asymptomatic) to 100 (most severe symptom imaginable). ARIA 2008 guidelines classify: "Mild" AR = 0-30, "Moderate" AR = 31-70, "Severe" AR = 71-100.

[0057] Nasal Symptom Score: Nasal congestion, nasal itching, sneezing, and runny nose are scored separately. No symptoms = 0; Mild (mild symptoms, easily tolerable) = 1; Moderate (obvious symptoms, annoying but tolerable) = 2; Severe (unbearable symptoms, affecting daily life or sleep) = 3. The Total Nasal Symptom Score (TNSS) is the sum of all nasal symptom scores, ranging from 0 to 12.

[0058] 2.3 Statistical Analysis

[0059] Statistical analysis was performed using Graphpad Prism 9.0 software. Basic information is expressed as mean ± standard deviation. If the data followed a normal distribution, paired / unpaired t-tests and ordinary one-way ANOVA were performed; if the data did not follow a normal distribution, nonparametric tests were used. A p-value < 0.05 was considered statistically significant, with * indicating p < 0.05, ** indicating p < 0.01, *** indicating p < 0.001, and **** indicating p < 0.0001.

[0060] 2.4 Medical Ethics

[0061] The study was approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.

[0062] 3. Research Results

[0063] 3.1 Based on the inclusion and exclusion criteria, and after corresponding treatment and observation, the basic information of all selected patients is shown in Table 1.

[0064] Table 1

[0065]

[0066]

[0067] 3.2 Ganciclovir significantly improved nasal symptoms in patients with refractory NARES.

[0068] like Figures 1 to 6 The diagrams shown illustrate the significant improvement of nasal symptoms in patients with refractory NARES by ganciclovir. They show the comparison of VAS, TNSS scores, nasal congestion scores, nasal itching scores, rhinorrhea scores, and sneezing scores before and after treatment between the classic treatment group and the ganciclovir treatment group.

[0069] 4. Conclusion

[0070] Ganciclovir offers significant convenience for the clinical treatment of refractory NARES. It is inexpensive, and its safety has been well-established through long-term clinical use. For patients with refractory NARES who do not respond well to conventional oral antihistamines and nasal corticosteroids, ganciclovir treatment can significantly improve symptoms. In conclusion, this application demonstrates the therapeutic efficacy of ganciclovir for refractory NARES, confirming that ganciclovir can indeed be used as a treatment for this condition.

[0071] Appendix: Classic Cases

[0072] Case 1: Cao XX, male, 52 years old

[0073] The patient presented to our ENT department on April 11, 2023, with symptoms primarily of nasal congestion and itching, accompanied by occasional sneezing and runny nose. The patient had a 6-year history of rhinitis, which was easily affected by weather changes. Previously, nasal corticosteroids (budesonide) and leukotriene derivatives (montelukast) effectively controlled symptoms during rhinitis flare-ups, but these medications gradually became ineffective. Later, the patient added antibiotics and even underwent steroid injections, but their nasal symptoms did not improve.

[0074] On April 11, 2023, a nasal secretion smear examination showed a small number of inflammatory cells under the microscope, with 70% eosinophils and 30% neutrophils. Allergen testing showed negative results for allergen-specific skin prick tests and serum allergen-specific IgE. The patient was assessed for severe nasal congestion and itching, mild sneezing and runny nose, with a TNSS score of 8 and a VAS score of 92. GCV treatment (500mg / dose, twice daily) was initiated on April 11, 2023, for 14 days. Symptoms improved after treatment, with a TNSS score of 5 and a VAS score of 65. Subsequent use of previously ineffective antihistamines significantly improved nasal symptoms, with overall symptoms improving by 70% compared to before medication. Self-reported symptoms: mild nasal congestion, runny nose, and sneezing, no nasal itching, with a TNSS score of 3 and a VAS score of 31.

[0075] Case 2: Wang XX, female, 32 years old

[0076] The patient presented to the ENT department of our hospital on July 5, 2022, with symptoms of allergic rhinitis, primarily nasal congestion, nasal itching, sneezing, and runny nose. The patient had a 2.5-year history of rhinitis, and had previously found that nasal spray corticosteroids (budesonide) and oral antihistamines (loratadine) effectively controlled symptoms during flare-ups. However, these medications gradually became ineffective. Later, the patient added traditional Chinese medicine fumigation therapy, but the nasal symptoms did not improve.

[0077] On July 5, 2022, a nasal secretion smear examination showed a small number of inflammatory cells under microscopy, with 100% eosinophils. Allergen testing showed negative results for allergen-specific skin prick tests and serum allergen-specific IgE. The patient was assessed for severe nasal congestion, sneezing, runny nose, and nasal itching, with a TNSS score of 12 and a VAS score of 84. GCV treatment (500mg / dose, twice daily) was initiated on July 5, 2022, for 14 days. Symptoms improved after treatment, but the TNSS score of 4 and VAS score of 40 remained slightly high. Subsequently, the previously ineffective antihistamine was used, resulting in significant improvement in nasal symptoms. Overall, symptoms improved by 90% compared to before medication. Self-reported symptoms: mild nasal congestion, no nasal itching, sneezing, or runny nose, with a TNSS score of 1 and a VAS score of 11.

[0078] Case 3: Peng XX, female, 36 years old

[0079] The patient visited the ENT department of our hospital on October 24, 2022, due to symptoms such as nasal itching, sneezing, and runny nose. The patient had a 2-year history of rhinitis and had previously used nasal spray corticosteroids (budesonide), antihistamines (loratadine), and antibiotics (cephalosporins) to effectively control symptoms during rhinitis flare-ups. However, the medications gradually became ineffective, and the patient's nasal symptoms had not improved.

[0080] On October 24, 2022, a nasal secretion smear examination showed a small number of inflammatory cells under the microscope, with 80% eosinophils and 20% neutrophils. Allergen prick test and serum-specific IgE tests were negative. The patient was assessed for severe nasal itching and runny nose, moderate sneezing, and no nasal congestion. TNSS score: 8, VAS score: 81. GCV treatment (500mg / dose, twice daily) was started on October 24, 2022, for 14 days. Symptoms improved after treatment, but the TNSS score remained slightly high at 6 and the VAS score at 55. The previously ineffective antihistamine was then used, resulting in significant improvement in nasal symptoms. Overall, symptoms improved by 80% compared to before medication. Self-reported symptoms: mild sneezing, no nasal itching, nasal congestion, or runny nose; TNSS score: 1, VAS score: 20.

[0081] It should be noted that this invention demonstrates that ganciclovir treatment significantly alleviates nasal symptoms in patients with NARES, and previously ineffective antihistamines can regain their effectiveness, effectively and persistently improving nasal symptoms in patients with refractory NARES, thus effectively alleviating rhinitis symptoms. Furthermore, ganciclovir greatly facilitates the clinical treatment of refractory NARES, as it is inexpensive and its safety has been well-established in long-term clinical use. For patients with refractory NARES who do not respond well to conventional oral antihistamines and nasal corticosteroids, ganciclovir treatment can significantly improve symptoms. This invention demonstrates the therapeutic efficacy of ganciclovir for refractory NARES, confirming that ganciclovir can indeed be used as a treatment for refractory NARES.

[0082] Numerous specific details are set forth in the specification provided herein. However, it will be understood that embodiments of the invention may be practiced without these specific details. In some instances, well-known methods, structures, and techniques have not been shown in detail so as not to obscure the understanding of this specification.

[0083] Similarly, it should be understood that, in order to simplify the invention and aid in understanding one or more of the various inventive aspects, features of the embodiments of the invention are sometimes grouped together in a single embodiment, figure, or description thereof in the above description of exemplary embodiments of the invention. However, this disclosure should not be construed as reflecting an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as reflected in the following claims, inventive aspects lie in fewer than all features of a single foregoing disclosed embodiment. Therefore, the claims following the detailed description are hereby expressly incorporated into this detailed description, wherein each claim itself is a separate embodiment of the invention.

[0084] Those skilled in the art will understand that the methods in the embodiments can be adaptively modified and configured in one or more embodiments different from this embodiment. Except where at least some of such features and / or processes or units are mutually exclusive, any combination of all features disclosed in this specification (including the accompanying claims, abstract, and drawings) and all processes or units of any method so disclosed may be employed. Unless expressly stated otherwise, each feature disclosed in this specification (including the accompanying claims, abstract, and drawings) may be replaced by an alternative feature that serves the same, equivalent, or similar purpose.

[0085] Furthermore, those skilled in the art will understand that although some embodiments herein include certain features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of the invention and form different embodiments. For example, in the following claims, any of the claimed embodiments can be used in any combination.

[0086] It should be noted that the above embodiments are illustrative of the invention and not restrictive, and those skilled in the art can devise alternative embodiments without departing from the scope of the appended claims. In the claims, any reference signs placed between parentheses should not be construed as limiting the claims. The word "comprising" does not exclude the presence of steps not listed in the claims. The use of the words first, second, and third, etc., does not indicate any order. These words can be interpreted as names. Unless otherwise specified, the steps in the above embodiments should not be construed as limiting the order of execution.

[0087] Finally, it should be noted that the above are only specific embodiments of the present invention. Of course, those skilled in the art can make modifications and variations to the present invention. If these modifications and variations fall within the scope of the claims of the present invention and their equivalents, they should be considered as being within the protection scope of the present invention.

Claims

1. Use of ganciclovir in the preparation of a medicine for the treatment, relief and / or relief of non-allergic rhinitis with eosinophilic syndrome.

2. The application according to claim 1, characterized in that, Ganciclovir is administered at a daily dose of 500 mg to 1000 mg.

3. The application according to claim 1, characterized in that, Ganciclovir is administered orally.

4. The application according to claim 3, characterized in that, Ganciclovir is administered twice daily at a fixed dose of 250 mg to 500 mg each time.

5. The application according to claim 4, characterized in that, The ganciclovir is administered continuously for at least one course of treatment, each course lasting at least two weeks.

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