A traditional Chinese medicine preparation for treating Parkinson disease olfactory dysfunction of liver-kidney yin deficiency type and a preparation method thereof

Abstract

This invention proposes a traditional Chinese medicine preparation and its preparation method for treating olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type. Belonging to the field of traditional Chinese medicine preparations, it is made from the following raw materials: 10-15g of Rehmannia glutinosa (processed), 20-30g of Paeonia lactiflora, 10-15g of Spatholobus suberectus, 12-15g of Eclipta prostrata, 10-15g of Ligustrum lucidum, 8-10g of Centipeda minima, 10-15g of Acorus tatarinowii, and 10-15g of Angelica dahurica. The entire formula works synergistically to nourish the liver and kidneys, invigorate blood circulation, and clear the nasal passages, exhibiting good clinical therapeutic effects. This invention assesses the olfactory function of patients with olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type using the T&T olfactory test and other methods, and applies a traditional Chinese medicine nasal spray treatment, systematically exploring the therapeutic efficacy of this external application of traditional Chinese medicine for the aforementioned symptoms. This invention can provide clinical data support for the standardized diagnosis and treatment of olfactory dysfunction in Parkinson's disease and has significant clinical application value for improving patients' quality of life and optimizing the prognostic assessment system.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine preparations, specifically relating to a traditional Chinese medicine preparation for treating olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type and its preparation method. Background Technology

[0002] Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide after Alzheimer's disease, characterized by its progressive progression. The core pathological changes in PD are the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain and the abnormal deposition of Lewy bodies (LB). Its clinical symptom spectrum covers two main categories: first, motor dysfunction characterized by asymmetrical tremors, increased muscle tone in the trunk and limbs, bradykinesia, and postural and balance abnormalities; and second, non-motor symptoms primarily manifested as decreased sense of smell, cognitive decline, REM sleep behavior disorders, constipation, orthostatic hypotension, and urinary incontinence.

[0003] The aforementioned symptoms not only severely impair patients' physical and mental health and their ability to live independently, but also place a heavy burden on patients' families and the social healthcare system. Studies have confirmed that olfactory dysfunction is an early hallmark symptom of Parkinson's disease (PD), with a high incidence rate; over 90% of PD patients exhibit significant olfactory impairment. Research by Braak et al. has confirmed that the pathological changes in Parkinson's disease initially originate in brain regions such as the anterior olfactory nucleus. This finding provides an important pathophysiological explanation for the early occurrence of olfactory dysfunction in PD patients. Therefore, early identification and treatment of olfactory dysfunction in PD patients may slow disease progression and improve their quality of life. Summary of the Invention

[0004] The technical problem to be solved by this invention is to provide a traditional Chinese medicine preparation for treating olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type. Combining the external treatment method of traditional Chinese medicine, the drug's effects are achieved through the percutaneous penetration mechanism, allowing the drug to reach the affected area directly through the skin and muscles. It can nourish the liver and kidney, promote blood circulation and unblock the meridians, and clear the nasal passages. It can achieve good intervention results for patients with olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A traditional Chinese medicine preparation for treating olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type is made from the following traditional Chinese medicine raw materials by weight:

[0007] Prepared Rehmannia Root 10-15 g, White Peony Root 20-30 g, Chicken Blood Vine 10-15 g, Eclipta Prostrata 12-15 g, Ligustrum Lucidum 10-15 g, Centipeda minima 8-10 g, Acorus tatarinowii 10-15 g, Angelica dahurica 10-15 g.

[0008] This formula consists of Rehmannia glutinosa (processed), Paeonia lactiflora, Spatholobus suberectus, Eclipta prostrata, Ligustrum lucidum, Centipeda minima, Acorus tatarinowii, and Angelica dahurica. Rehmannia glutinosa, Eclipta prostrata, and Ligustrum lucidum together nourish the liver and kidneys, moisten dryness, and nourish the nasal mucosa; Paeonia lactiflora nourishes blood, astringes yin, softens the liver, and relieves spasms, while also possessing anti-inflammatory and antioxidant effects; Spatholobus suberectus invigorates blood, replenishes blood, unblocks meridians, improves nasal microcirculation, and clears nasal passages; Centipeda minima, Angelica dahurica, and Acorus tatarinowii are aromatic, open the orifices, dispel wind, clear the nasal passages, and eliminate turbidity and pathogens. The combined effects of these herbs nourish the liver and kidneys, invigorate blood, unblock meridians, and clear nasal passages.

[0009] Dr. Yang Wenming, Chief Physician at the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, proposed that liver and kidney yin deficiency is the core pathogenesis in the occurrence and progression of Parkinson's disease. The liver and kidneys share a common origin; the liver stores blood, and the kidneys store essence. Both essence and blood are derived from the essence of food and water, and the two mutually nourish and restrain each other, exhibiting a relationship of mutual balance. Sufficient kidney yin nourishes liver yin, and sufficient liver yin in turn nourishes kidney yin. Only when liver and kidney yin are in harmony and balanced can pathological states such as liver yang hyperactivity and liver meridian cold stagnation be avoided. If kidney essence is deficient and kidney yin is depleted, it will subsequently affect liver yin, ultimately leading to liver and kidney yin deficiency. At this time, yin fluid fails to restrain yang qi, water fails to nourish wood, and liver wind stirs internally, manifesting typical Parkinson's disease symptoms such as tremor and rigidity. Therefore, in its treatment, it is emphasized that the fundamental principle of traditional Chinese medicine treatment for Parkinson's disease should be to regulate and nourish the liver and kidneys. The disease is based on deficiency of the root cause, and the core of treatment lies in strengthening the root and nourishing the source. By ensuring the source of qi and blood production and the orderly rise, fall, entry and exit of qi, the goal of nourishing the liver and kidneys, calming wind and nourishing yin can be achieved. Furthermore, long-term diagnosis and treatment are necessary to achieve ideal therapeutic effects.

[0010] Nasal sprays are a unique external treatment method in Traditional Chinese Medicine (TCM), delivering medication directly to the affected area through the nasal passages to exert its effects. Based on the Xin'an Medical theory of "Yi and Gui sharing the same origin, strengthening the foundation and nourishing the source," and combined with the core pathogenesis of olfactory dysfunction in Parkinson's disease patients, including liver and kidney yin deficiency and nasal meridian obstruction, Chief Physician Yang Wenming of the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine established the treatment principle of nourishing the liver and kidneys, promoting blood circulation and unblocking the meridians, and clearing the nasal passages. Based on long-term clinical experience, he created a nasal spray formula, which has proven effective in clinical applications.

[0011] As a preferred embodiment of the present invention, the traditional Chinese medicine preparation is made from the following traditional Chinese medicine raw materials by weight:

[0012] Prepared Rehmannia Root 12 g, White Peony Root 20 g, Chicken Blood Vine 15 g, Eclipta Prostrata 15 g, Ligustrum Lucidum 15 g, Centipeda minima 10 g, Acorus tatarinowii 15 g, Angelica dahurica 15 g.

[0013] The T&T olfactometer test is a quantitative assessment of olfactory function based on olfactory pigment dilution. As a standardized tool for quantitative assessment of olfactory function, the T&T olfactometer test, with its multi-olfactory pigment detection system, can effectively distinguish between different functional states such as hyperolfaction, hypoolfaction, and anosmia. Its quantitative results not only support the standardized diagnosis and treatment of olfactory disorders but are also suitable for dynamic monitoring of the efficacy of clinical interventions. The test score of the subject is positively correlated with the severity of the olfactory disorder. Using the T&T olfactometer test to assess patients' olfactory function offers advantages such as standardized operation and reproducible results. It can accurately classify olfactory function through the calculation of olfactory recognition thresholds, and its combined application with subjective scales can comprehensively reflect the subject's olfactory physiological state.

[0014] Clinically, there are three main methods for olfactory testing: (1) self-assessment using questionnaires; (2) direct olfactory testing; and (3) objective evaluation of olfactory function using electrophysiological testing or neuroimaging techniques. Olfactory testing can comprehensively and objectively assess the patient's olfactory function status from multiple levels, including olfactory perception, discrimination, and memory. Simultaneously, changes in the Hyposmia Rating Scale (HRS), Visual Analogue Scales (VAS), and TCM syndrome scores before and after treatment were assessed. This study aimed to explore the effects of a TCM-specific nasal spray on the olfactory function of patients with olfactory dysfunction due to liver and kidney yin deficiency in Parkinson's disease, and to compare and evaluate the clinical efficacy of this TCM preparation.

[0015] This invention has been experimentally verified to be true that:

[0016] 1. Intra-group comparison before and after treatment showed that the T&T olfactory test scores of both groups were significantly lower than before treatment (P<0.01); Inter-group comparison after treatment showed that the T&T olfactory test score of the treatment group was significantly lower than that of the control group (P<0.01).

[0017] 2. Intra-group comparisons before and after treatment revealed that the HRS scores of both groups were significantly better after treatment than before treatment (P<0.01); inter-group comparisons after treatment showed that the efficacy of the control group was significantly worse than that of the treatment group (P<0.01). The VAS and TCM syndrome scores of both groups decreased significantly after treatment (P<0.01), and the decrease in the control group was significantly less than that in the treatment group (P<0.01).

[0018] Therefore, the traditional Chinese medicine preparation proposed in this invention involves pulverizing the prescribed amounts of each herb, mixing them, soaking them in water, and then decocting them to prepare a medicinal liquid. The decoction is performed 2-3 times, with the amount of water added being 5-10 times the total amount of the herbs. The resulting liquids are combined and concentrated, and then the pH is adjusted to 7 to make its osmotic pressure similar to that of human nasal fluid. Finally, after filtering again, the liquid is packaged into a sterilized nasal drop bottle, sealed, and the final product is a nasal drop. This nasal drop can be used to treat olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type, with definite efficacy.

[0019] Meanwhile, this invention targets patients with this disease by using quantitative olfactory detection to assess olfactory function, supplemented by traditional Chinese medicine nasal spray therapy, to explore its therapeutic effect. It aims to provide clinical evidence for the objective evaluation and standardized treatment of olfactory function in this disease, and has important clinical value for improving patients' quality of life and assessing prognosis. Detailed Implementation

[0020] This study explores the effects of a traditional Chinese medicine (TCM) nasal spray on olfactory function in patients with Parkinson's disease of the liver and kidney yin deficiency type, thereby comparing and evaluating the clinical efficacy of this TCM preparation. Details are as follows:

[0021] 1. Materials

[0022] 1.1. General Information

[0023] Based on the diagnostic criteria for olfactory dysfunction in Parkinson's disease (PD) of Western medicine and the diagnostic criteria of traditional Chinese medicine, 60 cases from the inpatient and outpatient departments of the Department of Neurology of the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine were collected from September 2023 to October 2024. All patients were randomly divided into two groups: a treatment group and a control group. (Ethics No.: 2022AH-61).

[0024] 1.2. Diagnostic Criteria

[0025] (1) Diagnostic criteria for Parkinson's disease in Western medicine: Refer to the "Diagnostic criteria for Parkinson's disease in China (2016 edition)".

[0026] (2) Diagnostic criteria for liver and kidney yin deficiency syndrome: Referring to the "Guidelines for the Diagnosis and Treatment of Parkinson's Disease with Integrated Traditional Chinese and Western Medicine" and the "Expert Consensus on the Diagnosis and Treatment of Olfactory Disorders with Integrated Traditional Chinese and Western Medicine (2024)" formulated by the Chinese Association of Integrated Traditional and Western Medicine in 2024, the following criteria were jointly formulated for the liver and kidney yin deficiency syndrome of Parkinson's disease: involuntary tremors and shaking of the head and limbs that are difficult to control, stiffness of the limbs and trunk, decreased sense of smell, slow movement, even falls, reduced activity, or accompanied by slow and unclear speech, excessive salivation and sweating, dull consciousness, abdominal distension and constipation, irritability and insomnia, anxiety and depression, and may be accompanied by five-center heat, tidal fever and night sweats, dizziness and tinnitus, soreness and weakness of the waist and knees, and dry mouth, tongue and throat. The tongue is red with a yellow or little coating or a peeled coating, and the pulse is thready and wiry or thready and rapid.

[0027] 1.3. Case inclusion criteria:

[0028] (1) The clinical diagnosis meets the diagnostic criteria for olfactory dysfunction in Parkinson's disease;

[0029] (2) Age between 40 and 70 years old;

[0030] (3) Hoehn & Yahr are classified as grades 1 to 3;

[0031] (4) According to TCM syndrome differentiation, it belongs to the liver and kidney yin deficiency syndrome;

[0032] (5) Disease duration ≥ 6 months;

[0033] (6) Voluntarily participate in this study, sign the informed consent form, and be able to complete the entire treatment and follow-up in accordance with the study protocol;

[0034] (7) Patients diagnosed with olfactory dysfunction by two attending physicians or above.

[0035] 1.4. Case exclusion criteria:

[0036] (1) Patients with severe liver and kidney dysfunction or a history of other serious systemic diseases;

[0037] (2) Individuals with a clear history of allergy to the intervention drug in this study, or who have an allergic constitution;

[0038] (3) Those with comorbid mental illness or cognitive impairment who are unable to cooperate in completing research-related assessments and treatments;

[0039] (4) Those who are unable to accept the intervention program of this study due to intolerance to the smell of traditional Chinese medicine;

[0040] (5) Olfactory dysfunction caused by other organic lesions, adverse drug reactions, trauma or surgery, etc.;

[0041] (6) Those who are participating in other clinical studies at the same time, or who are taking drugs that may interfere with the determination of the efficacy of this study.

[0042] 1.5. Case dropout and exclusion criteria:

[0043] (1) Those who have poor compliance during treatment, actively request to withdraw and whose attempts to dissuade them are ineffective, or who are out of contact during the follow-up period;

[0044] (2) Those who experience adverse reactions or events during medication, making it impossible to continue treatment and thus terminating the trial;

[0045] (3) Patients who develop other serious illnesses during the treatment phase and are unable to tolerate and continue the established medication regimen;

[0046] (4) Subjects who withdraw from this study due to disease progression or fluctuations requiring adjustment of the original treatment plan during the treatment period;

[0047] (5) Failure to complete the full course of medication in accordance with the research procedure, or the determination of the test results due to other interfering factors.

[0048] 2. Methods

[0049] 2.1. Treatment methods

[0050] Control group: Oral administration of DOPA / carbidopa tablets, 0.25 g / tablet, Roche Pharmaceuticals Shanghai Co., Ltd. (National Drug Approval Number H10930198), 1 / 4 tablet three times a day, for a total of 30 days.

[0051] Treatment group: In addition to the treatment given to the control group, patients received nasal spray of traditional Chinese medicine.

[0052] The Chinese medicine prescription is as follows: Rehmannia glutinosa 12 g, Paeonia lactiflora 20 g, Spatholobus suberectus 15 g, Eclipta prostrata 15 g, Ligustrum lucidum 15 g, Centipeda minima 10 g, Acorus tatarinowii 15 g, Angelica dahurica 15 g.

[0053] The preparation method for nasal drops is as follows: Powder all the Chinese herbs, mix them, add 500 mL of distilled water and soak for 20 minutes, then decoct for 30 minutes; after filtering, add 100 mL of distilled water to the dregs again and decoct for 30 minutes; after filtering again, add 100 mL of distilled water to the dregs again and decoct for 30 minutes. Collect the decoction from the three decoctions, heat and concentrate the decoction to a volume of approximately 200 mL, cool, adjust the pH to 7 using phosphate buffer, filter the filtrate again, and then fill it into sterilized nasal drop bottles, seal the bottles to produce nasal drops, each approximately 10 mL, for a total of 20 bottles.

[0054] The method of use is as follows: The patient tilts their head back to fully expose the nasal cavity, and applies 2 drops (approximately 1 mL) to each nostril each time. After spraying, continue tilting the head back for 1 minute to allow for full absorption. Apply 3 times a day for a total of 30 days.

[0055] 2.2. T&T Olfactory Meter Testing Method

[0056] Five olfactory substances—methylcyclopentenone, phenethyl alcohol, undecanoic acid lactone, isovaleric acid, and trimethylindole—were selected as detection substrates and assigned scores ranging from -2 to 5 based on their concentration gradient from low to high. During testing, the mean of the subjects' recognition thresholds for the five olfactory substances was calculated to quantitatively assess their olfactory function.

[0057] Based on the range of recognition thresholds, olfactory ability can be divided into 6 levels:

[0058] A threshold of <-1.0 indicates hyperolence, suggesting that the subject's sensitivity to odors is abnormally elevated.

[0059] A threshold of -1.0 to 1.0 indicates normal olfaction, meaning the subject's olfactory function is at a physiological level.

[0060] A threshold of 1.1 to 2.5 indicates mild olfactory impairment, meaning that the subject's odor perception sensitivity is reduced and they can only identify medium concentrations of olfactory compounds.

[0061] A threshold of 2.6 to 4.0 indicates moderate olfactory impairment, meaning that the subject's olfactory function is significantly impaired and they can only perceive high concentrations of olfactory compounds.

[0062] A threshold of 4.1 to 5.5 indicates severe olfactory impairment, suggesting that the subject has a severe loss of olfactory function and can only identify extremely high concentrations of olfactory compounds.

[0063] A threshold greater than 5.5 indicates anosmia, meaning the subject has completely lost their sense of smell and is almost unable to perceive any concentration of olfactory substances.

[0064] 2.3. Observation Indicators

[0065] 2.3.1 T&T Olfactory Meter Test Score

[0066] The T&T olfactory test scores of the treatment group and the control group were measured before and after treatment.

[0067] 2.3.2. Other scale indicators

[0068] The changes in the Hyposmia Rating Scale (HRS) scores before and after treatment were observed in both the treatment and control groups; the changes in the Visual Analogue Scale (VAS) scores before and after treatment were observed in both the treatment and control groups; and the changes in the Traditional Chinese Medicine Syndrome Score Scale scores before and after treatment were observed in both the treatment and control groups.

[0069] 2.4. Statistical Methods

[0070] Data analysis was performed using SPSS 26.0 statistical software. Quantitative data were expressed as mean ± standard deviation. For comparisons between two groups, a t-test was used if the data met the requirements of normality and homogeneity of variance; for comparisons among multiple groups, an ANOVA was used. Otherwise, non-parametric tests were used. Categorical data were analyzed using the chi-square test. 2 Statistical significance level: P>0.05 indicates no significant difference, P<0.05 indicates a statistically significant difference, and P<0.01 indicates a significant difference.

[0071] 3. Results

[0072] 3.1. T&T Olfactory Meter Test:

[0073] As shown in Table 1, within-group comparisons, the scores of patients in both groups decreased significantly after treatment (P<0.01); between-group comparisons, the treatment group showed a greater decrease in test scores than the control group (P<0.01).

[0074] Table 1: Comparison of T&T olfactory meter test scores before and after treatment

[0075] Group n Before treatment After treatment Treatment group 30 4.26 ± 0.32 <![CDATA[3.07 ± 0.27 △△** ]]> control group 30 4.57 ± 0.21 <![CDATA[3.84 ± 0.32 △△ ]]>

[0076] Note: Compared with before treatment, △ P<0.05 △△ P<0.01; compared with the control group, * P<0.05 ** P<0.01.

[0077] 3.2. HRS Score:

[0078] As shown in Table 2, the intra-group comparison showed that the HRS scores of both groups were significantly improved after treatment compared with those before treatment (P<0.01); the inter-group comparison after treatment showed that the treatment group had significantly better efficacy than the control group (P<0.01).

[0079] Table 2: Comparison of HRS scores before and after treatment

[0080] Group n Before treatment After treatment Treatment group 30 16.02 ± 1.26 <![CDATA[ 20.91 ± 1.24 △△** ]]> control group 30 16.61 ± 0.97 <![CDATA[18.72 ± 1.63 △△ ]]>

[0081] Note: Compared with before treatment, △ P<0.05 △△ P<0.01; compared with the control group, * P<0.05 ** P<0.01.

[0082] 3.3. VAS score:

[0083] As shown in Table 3, the intragroup analysis showed that the scores of both groups were significantly lower after treatment than before treatment (P<0.01); the intergroup comparison showed that the score reduction in the treatment group was significantly better than that in the control group (P<0.01).

[0084] Table 3: Comparison of VAS scores before and after treatment

[0085] Group n Before treatment After treatment Treatment group 30 3.62 ± 0.67 <![CDATA[ 2.06 ± 0.17 △△** ]]> control group 30 4.26 ± 0.51 <![CDATA[3.01 ± 0.08 △△ ]]>

[0086] Note: Compared with before treatment, △ P<0.05 △△ P<0.01; compared with the control group, * P<0.05 ** P<0.01.

[0087] 3.4. Traditional Chinese Medicine Syndrome Scoring:

[0088] As shown in Table 4, within-group comparisons, the scores of both groups decreased significantly after treatment (P<0.01); between-group comparisons after treatment, the score decrease in the treatment group was better than that in the control group (P<0.01).

[0089] Table 4: Comparison of TCM syndrome scores before and after treatment

[0090] Group n Before treatment After treatment Treatment group 30 21.32 ± 2.07 <![CDATA[15.76 ± 1.77 △△** ]]> control group 30 22.45 ± 2.14 <![CDATA[17.93 ± 2.13 △△ ]]>

[0091] Note: Compared with before treatment, △ P<0.05 △△ P<0.01; compared with the control group, * P<0.05 ** P<0.01.

[0092] In summary, the traditional Chinese medicine preparation of this invention, combined with the characteristic nasal spray therapy of traditional Chinese medicine, can effectively treat olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type. Furthermore, by quantitatively detecting and evaluating the olfactory function of patients with this disease, and exploring the therapeutic effect of the nasal spray, we can provide clinical evidence for the objective evaluation and standardized treatment of olfactory dysfunction in this disease, which is of significant clinical importance for improving patients' quality of life and assessing prognosis.

Claims

1. A traditional Chinese medicine preparation for treating olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type, characterized in that, It is made from the following Chinese medicinal materials by weight: Prepared Rehmannia Root 10-15 g, White Peony Root 20-30 g, Chicken Blood Vine 10-15 g, Eclipta Prostrata 12-15 g, Ligustrum Lucidum 10-15 g, Centipeda minima 8-10 g, Acorus tatarinowii 10-15 g, Angelica dahurica 10-15 g.

2. The traditional Chinese medicine preparation as described in claim 1, characterized in that, It is made from the following Chinese medicinal materials by weight: Prepared Rehmannia Root 12 g, White Peony Root 20 g, Chicken Blood Vine 15 g, Eclipta Prostrata 15 g, Ligustrum Lucidum 15 g, Centipeda minima 10 g, Acorus tatarinowii 15 g, Angelica dahurica 15 g.

3. A method for preparing the traditional Chinese medicine preparation as described in claim 1 or 2, characterized in that, The prescribed amount of each Chinese herb is pulverized, mixed, soaked in water, and then decocted. The resulting liquid is concentrated and then poured into a sterilized nasal drop bottle, which is then sealed with a stopper to produce nasal drops.

4. The method as described in claim 3, characterized in that, The concentrated drug solution is adjusted to pH 7 using phosphate buffer solution, then filtered again and bottled.

5. The method as described in claim 3, characterized in that, The decoction is performed in 2-3 batches, with the amount of water added being 5-10 times the total amount of Chinese herbs.

6. The use of the traditional Chinese medicine preparation as described in claim 1 or 2 in the preparation of a drug for treating olfactory dysfunction in Parkinson's disease of the liver and kidney yin deficiency type.