CN107021946B - Compound with cough relieving effect and preparation and application thereof - Google Patents
Compound with cough relieving effect and preparation and application thereof Download PDFInfo
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- CN107021946B CN107021946B CN201710409126.8A CN201710409126A CN107021946B CN 107021946 B CN107021946 B CN 107021946B CN 201710409126 A CN201710409126 A CN 201710409126A CN 107021946 B CN107021946 B CN 107021946B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 206010011224 Cough Diseases 0.000 title description 46
- 230000000694 effects Effects 0.000 title description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 101100175487 Glycine max CG-1 gene Proteins 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 230000002829 reductive effect Effects 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 240000008058 Lilium brownii Species 0.000 claims description 10
- 235000015982 Lilium brownii Nutrition 0.000 claims description 10
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- 206010065563 Eosinophilic bronchitis Diseases 0.000 description 1
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- 208000000616 Hemoptysis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001634096 Lilium martagon Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
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- BBFQZRXNYIEMAW-UHFFFAOYSA-N aristolochic acid I Chemical compound C1=C([N+]([O-])=O)C2=C(C(O)=O)C=C3OCOC3=C2C2=C1C(OC)=CC=C2 BBFQZRXNYIEMAW-UHFFFAOYSA-N 0.000 description 1
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- 208000017574 dry cough Diseases 0.000 description 1
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- 239000002038 ethyl acetate fraction Substances 0.000 description 1
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- 210000004907 gland Anatomy 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
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- 229910052739 hydrogen Chemical group 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
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- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8967—Lilium, e.g. tiger lily or Easter lily
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound with an antitussive effect, as well as a preparation method and application thereof, which are shown as a formula (I). The invention also provides a preparation method and application of the compound. The compound is derived from a compound extracted, separated and purified from Yunnan large lily (Cardiocrinum giganteum var. yunnanense), is mainly distributed in Yunnan Guizhou plateau areas in China, is easy to obtain, is convenient to extract, is simple to operate and low in cost, and has good antitussive activity proved by pharmacodynamic tests, so that a new drug selection is provided for clinic
。
Description
Technical Field
The invention belongs to the field of natural medicinal chemistry, and particularly relates to a compound with an antitussive effect, a preparation method thereof, and application thereof in preparation of a medicine for preventing cough or/and relieving cough.
Background
Cough is a protective reflex action of a human body, pathological secretion in a respiratory tract and foreign matters entering the respiratory tract from the outside can be removed, and the human body is injured due to high sensitivity or function damage of the cough. Cough can be classified into acute cough (less than 3 weeks in disease course), subacute cough (3-8 weeks in disease course) and chronic cough (more than 8 weeks in disease course) according to different time periods. Common causes of acute cough are common cold and acute tracheo-bronchitis; common causes of subacute cough are post-infectious cough, upper airway cough syndrome and cough variant asthma; common symptoms of chronic cough are cough variant asthma, upper airway cough syndrome, eosinophilic bronchitis, and gastroesophageal reflux cough. Professor Zhongnan mountain (epidemiological investigation of cough by 1087 college students in Guangzhou region [ J ].2006,22(2): 123-: the prevalence of acute cough was 7.6% and the prevalence of chronic cough was 3.3%. This result suggests that the general community population is more likely to be exposed to dust and harmful particles in the environment than the students, and the prevalence of cough is higher. However, the prevalence rate of cough gradually increases with age, and the harm of cough is not negligible.
Some antitussives sold on the market are codeine, dextromethorphan, pseudoephedrine hydrochloride and some Chinese patent medicines containing aristolochia debilis. The most common codeine has good antitussive effect, and can be used for treating dry cough disturbing rest. But its adverse effects such as low potassium paralysis, intoxication, dependence syndrome and urinary retention are well known. On 20/2.2013, FDA officially issued a black frame warning at its official website to warn children after tonsil or gland resection of codeine fatal risk FDA. drug Safety Podcast: Safety review update of codeine use in childrenn; the new bound moving and containment on use after transformation and/or oradienoic. Such a safety problem also exists with the cold drug dextromethorphan with antitussive effect, which was published by the american Academy of Pediatrics in 1997 and which states that children should be considered to be contraindicated for the antitussive containing codeine or dextromethorphan, noauthorsted. use of codeine-and dextromethorphan-conjugating Drugs in children. A report of an assessment by the united states centers for disease control and prevention (CDC) is: about 7000 children are sent to hospital first aid each year due to cold and cough medications. Some cough-relieving Chinese patent medicines containing aristolochia debilis are also affected by the disease of aristolochia debilis. In 1999 2001, the british drug safety Committee (CSM), the british drug monitoring center, the united states drug and food administration (FDA), the australian drug administration (TGA), etc. successively declared the indefinite disablement of aristolochic acid-containing herbs and their products.
Phytochemical studies of traditional herbal medicines have shown that other types of compounds also have beneficial antitussive activity and have fewer side effects than the above synthetic compounds. Yunnan big lily (Cardiococcus giganteus var. yunnanense) is a perennial herb of Liliaceae (Liliaceae) great lily, is a variety of the big lily in China, and is mainly distributed in Yunnan, Guizhou and other areas of China. Has antitussive, antiasthmatic, and lung heat clearing away effects, and can be used for treating cough, asthma, hemoptysis, and pulmonary tuberculosis. The fruit of Yunnan big lily is commonly called fructus aristolochiae, and the medicinal use is as the substitute of the fruit of aristolochia debilis in Taiwan. Ming Li, Ka-Ho Ling, Hilary Lam, Pang-Chui Shaw, et al 2010, Cardiocrinum seeds as a replacement for aristolichia fructicola interacting drugs, Journal of Ethnopharmacology,130: 429-. However, the antitussive active ingredients of the seeds of lilium yunnanense are not clear.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a compound with cough-relieving activity, a preparation method thereof and application thereof in preparing a medicament for preventing cough or/and relieving cough.
The invention provides a compound shown as a formula (I),
wherein R is alkyl or hydrogen.
Further, the alkyl group is C1～C5An alkyl group.
Further, the structure of the compound is shown as CGY-1 or CGY-2:
a method of preparing a compound, comprising: it comprises the following steps:
(1) crushing a raw medicinal material, performing ultrasonic extraction for 3-4 times by using a 50-95% ethanol solution, and filtering and removing residues to obtain a raw medicinal material extracting solution;
(2) concentrating the extractive solution under reduced pressure to obtain slurry;
(3) suspending the total extract with water, extracting with petroleum ether, extracting with ethyl acetate, and distilling under reduced pressure to remove ethyl acetate to obtain extract;
(4) dissolving the extract with chromatographic pure solvent, and separating and purifying by HPLC to obtain compound CGY-1 and compound CGY-2.
Further, the raw medicinal material in the preparation method is Yunnan large lily seed.
Further, the final product in the preparation method contains two structures of the formulas CGY-1 and CGY-2.
Further, the ethanol solution in the step (1) in the preparation method is an ethanol solution with an ethanol volume fraction of 50-95%.
Further, in the preparation method, the ultrasonic time in the step (1) is 1-2 hours each time.
Further, in the above preparation method: the chromatographic pure solvent in the step (4) is methanol or acetonitrile.
Further, the mobile phase condition for separation and purification by preparative HPLC described in step (4) of the above preparation method is acetonitrile-water solution, the flow rate is 8ml/min, and the ultraviolet detection wavelength is 254 nm.
The invention also provides application of the compound in preparing a medicine for preventing cough or/and relieving cough.
The invention also provides a medicine for preventing cough or/and relieving cough, which is a common preparation in pharmacy prepared by the compound and pharmaceutically acceptable auxiliary materials or auxiliary components.
The compound is extracted, separated and purified from Yunnan large lily (Cardiocrinum giganteum var. yunnanense), is mainly distributed in Yunnan high altitude areas in China, is easy to obtain, is convenient to extract, is simple to operate, is low in cost, and is proved by drug effect tests to have good antitussive activity, so that a new drug choice is provided for clinic.
According to the present invention, it is possible to make various modifications, substitutions and alterations without departing from the basic technical idea of the present invention as described above, according to the common technical knowledge and conventional means in the field.
Drawings
FIG. 1 is a total LC-MS chromatogram of ethyl acetate fraction of Lilium martagon seeds; wherein the upper graph is a mass spectrum signal, the lower graph is a high performance liquid phase signal, and compounds CGY-1 and CGY-2 are used as index components.
FIG. 2 is a single crystal X-ray diffraction pattern of compound CGY-1.
FIG. 3 is an ESI-MS mass spectrum of compound CGY-1.
FIG. 4 is an ESI-MS mass spectrum of compound CGY-2.
FIG. 5 Effect of CGY-1 and CGY-2 on cough latency in Guinea pigs ((
n is 8, M: a vehicle group; p: the positive drug codeine hydrochloride group is 12 mg/kg; a: CGY-1 low dose group, 100 mg/kg; b CGY-1 high dose group, 200 mg/kg; c: CGY-2 low dose group, 100 mg/kg; d: CGY-2 high dose group, 200 mg/kg.
FIG. 6 Effect of CGY-1 and CGY-2 on the number of coughs in Guinea pigs ((
n is 8, M: a vehicle group; p: the positive drug codeine hydrochloride group is 12 mg/kg; a: CGY-1 low dose group, 100 mg/kg; b: CGY-1 high dose group, 200 mg/kg; c: CGY-2 low dose group, 100 mg/kg; d: CGY-2 high dose group, 200 mg/kg.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
Example 1 preparation of CGY-1 and CGY-2
(1) Preparation of the extract
A. Pulverizing Yunnan Lilium Brownii seed 100g, extracting with 50% ethanol solution at room temperature by KQ-250DE ultrasonic machine for 3 times, each time using 1000ml ethanol, each time for 2 hr, mixing the three extractive solutions, filtering, and removing residue to obtain Yunnan Lilium Brownii seed extractive solution;
B. concentrating the extractive solution under reduced pressure with N-1100V-W rotary evaporator to constant weight to obtain yellow slurry, which is 12g of total extract of Yunnan Bulbus Lilii seed;
C. suspending the total extract of the Yunnan Lilium Brownii seeds with ultrapure water, extracting with 100ml petroleum ether, extracting with 100ml ethyl acetate, and distilling under reduced pressure to remove ethyl acetate to obtain 1g extract;
(2) analyzing the extract obtained in step (1)
Dissolving the extract obtained in the step (1) in methanol to prepare a solution of 1mg/ml, and performing reverse phase preparation by HPLC, wherein the specific preparation conditions are as follows: LP-C18Welch Ultimate reverse phase preparative column (21.2 mm. times.250 mm,5 μm), UV detection wavelength 254nm, flow rate 8ml/min, gradient system: a is water, B is acetonitrile; 0-35 min, 25% (v/v%) → 60% (v/v%) of an acetonitrile solution; 36-50 min, 60% (v/v%) → 100% (v/v%) of acetonitrile; chromatographic peaks were collected at 13.986min, 21.211min, respectively (see FIG. 1). The collected solution was concentrated under reduced pressure (N-1100V-W) using a rotary evaporator to obtain compound CGY-1(95mg) and compound CGY-2(86mg), respectively. The compounds 1-2 can be identified based on the spectral data.
(3) Identification of CGY-1 and CGY-2
CGY-1: yellow columnar crystals (methanol-water); reacting vanillin with concentrated sulfuric acid to obtain yellow product; single crystal X-rayThe line diffraction structure diagram and ESI-MS mass spectrogram are respectively shown in FIG. 2 and FIG. 3, and the molecular formula is C31H22O11，HR-ESI-MS m/z:569.1093[M-H]-(calcd for[M-H]-:569.1084)；UV(MeOH)λmax:209,267,340nm；IR(KBr):νmax3396,1643,1603cm-1。1H NMR(400MHz，DMSO-d6) And13C NMR(75MHz，DMSO-d6) (δ): see table 1.
CGY-2: a light yellow powder; reacting vanillin with concentrated sulfuric acid to obtain yellow product; ESI-MS mass spectrum shown in FIG. 4, and molecular formula C30H20O11，HR-ESI-MS m/z:555.0922[M-H]-(calcd for[M-H]-:555.0927)；UV(MeOH)λmax:209,267,298,340nm；IR(KBr):νmax3403,1643,1615cm-1。1H NMR(400MHz，DMSO-d6) And13CNMR(75MHz，DMSO-d6) (δ): see table 1.
Table 1: of CGY-1 and 21H NMR and13c NMR data (delta, in DMSO-d)6,J in Hz)
Example 2 preparation of CGY-1 and CGY-2
(1) Preparation of the extract
A. Pulverizing Yunnan Lilium Brownii seed 100g, extracting with 95% ethanol solution at room temperature by KQ-250DE ultrasonic machine for 2 times, each time using 1000ml ethanol, each time for 1 hr, mixing the three extractive solutions, filtering, and removing residue to obtain Yunnan Lilium Brownii seed extractive solution;
B. concentrating the extractive solution under reduced pressure with N-1100V-W rotary evaporator to constant weight to obtain yellow slurry, which is 11g of total extract of Yunnan Lilium Brownii seed;
C. suspending the total extract of Lilium Viridium seed with ultrapure water, extracting with 100ml petroleum ether, extracting with 100ml ethyl acetate, and distilling under reduced pressure to remove ethyl acetate to obtain 0.9g extract;
(2) HPLC analysis and HPLC preparation were carried out on the extract obtained in step (1) under the same conditions as in example 1 to obtain compound CGY-1(98mg) and compound CGY-2(90mg), respectively. The two compounds were identified as in example 1.
Example 3 preparation of CGY-1 and CGY-2
(1) Preparation of the extract
A. Pulverizing Yunnan Lilium Brownii seed 100g, extracting with 75% ethanol solution at room temperature by KQ-250DE ultrasonic machine for 3 times, each time using 1000ml ethanol, each time for 1.5 hr, mixing the three extractive solutions, filtering, and removing residue to obtain Yunnan Lilium Brownii seed extractive solution;
B. concentrating the extractive solution under reduced pressure with N-1100V-W rotary evaporator to constant weight to obtain yellow slurry, which is 10.5g of total extract of Yunnan Lilium Brownii seed;
C. suspending the total extract of Lilium Viridium seed with ultrapure water, extracting with 100ml petroleum ether, extracting with 100ml ethyl acetate, and distilling under reduced pressure to remove ethyl acetate to obtain 0.95g extract;
(2) HPLC analysis and HPLC preparation of the extract obtained in step (1) were carried out under the same conditions as in example 1 to obtain compound CGY-1(94mg) and compound CGY-2(89mg), respectively. The two compounds were identified as in example 1.
The beneficial effects of the present invention are demonstrated by specific pharmacodynamic tests below.
Experimental example 1 antitussive test of the Compound of the present invention
Guinea pigs weighing 250-350 g, male and female half, were bred adaptively for 3-5 days, and randomly divided into 6 groups, namely a vehicle group, a codeine phosphate group, a CGY-1 low dose group, a CGY-1 high dose group, a CGY-2 low dose group and a CGY-2 high dose group.
Marking animals, placing the animals in a 24L closed box, spraying 0.5M citric acid into the box through a spray head at a constant speed, spraying for 10min, observing and recording the cough frequency of guinea pigs within 10min, and selecting experimental animals with cough frequency between 18 and 30 times as subsequent cough-relieving experimental objects. After a 5-day recovery period, the selected 48 animals were randomized into 6 groups of 8 animals each with half male and female according to body weight and sex. The low dose and high dose compounds were administered at doses of 100mg/kg and 200mg/kg, respectively; the positive drug codeine phosphate is 12 mg/kg; the vehicle group was given distilled water. The administration volume is 1.0ml/100g body weight, and the 0.5M citric acid spray is used for inducing cough after the gastric lavage administration for 60 minutes, and then the cough latency and the cough frequency of the guinea pigs within 10min are observed and recorded.
After atomization, the experimental animals are anesthetized by 20% urethane according to 1.5g/kg of abdominal administration, abdominal aorta blood sampling is carried out, and serum samples are stored in an ice box; after the animals are sacrificed, dissection is carried out immediately, lung lavage fluid is collected, and BALF samples are placed in an ice box; bronchial and lung tissue samples were collected and preserved in formalin.
Data are expressed as means ± standard error (X ± SEM), statistical analysis of data was performed using SPSS18.0 software, two comparisons, t-test using two sample mean comparisons, and one-way analysis of variance (ANOVA) between groups.
Evaluation results of antitussive activity:
as shown in fig. 5, 100 and 200mg/kg i.g. CGY-1 extended the cough latency by 46.1% and 53.8%, respectively, (P <0.01) during the nebulization challenge in this trial compared to the vehicle group. Whereas CGY-2 at 100 and 200mg/kg i.g. extended the cough latency by 73.1% and 80.8%, respectively (P < 0.01).
As shown in fig. 6, 100 and 200mg/kg i.g. CGY-1 reduced the number of coughs by 41.1% and 44.6%, respectively, compared to the vehicle group in the effect on the number of coughs (P < 0.01). Whereas 100 and 200mg/kg i.g. of CGY-2 reduced the number of coughs by 51.8% and 66.1%, respectively (P < 0.01).
These results indicate that both compounds have antitussive properties, thus expanding the range of application of the seeds of lilium yunnanense. The invention proves the cough relieving effect of the compounds for the first time. As the CGY-1 and the CGY-2 are the main components of the Yunnan big lily, the contents of the CGY-1 and the CGY-2 are high, and the preparation is easy.
The invention is not limited by the embodiments described above, which are given as examples only and can be modified in various ways within the scope of protection defined by the appended claims.
Claims (4)
1. A preparation method of a compound CGY-1 is characterized by comprising the following steps: it comprises the following steps:
(1) crushing a raw medicinal material, performing ultrasonic extraction for 3-4 times by using a 50-95% ethanol solution, and filtering and removing residues to obtain a raw medicinal material extracting solution;
(2) concentrating the extractive solution under reduced pressure to obtain slurry;
(3) suspending the total extract with water, extracting with petroleum ether, extracting with ethyl acetate, and distilling under reduced pressure to remove ethyl acetate to obtain extract;
(4) dissolving the extract with chromatographic pure solvent, and separating and purifying by HPLC to obtain compound CGY-1;
wherein the raw medicinal materials are seeds of lilium brownii in Yunnan province;
the compound CGY-1 has a structural formula of
2. A process for the preparation of a compound according to claim 1, characterized in that: the time of each ultrasonic treatment in the step (1) is 1-2 h.
3. A process for the preparation of a compound according to claim 1, characterized in that: the chromatographic pure solvent in the step (4) is methanol or acetonitrile.
4. A process for the preparation of a compound according to claim 1, characterized in that: the mobile phase condition of HPLC separation and purification in the step (4) is acetonitrile-water solution, the flow rate is 8ml/min, and the ultraviolet detection wavelength is 254 nm.
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| CN101049301A (en) * | 2007-05-14 | 2007-10-10 | 湖北中医学院 | Pharmaceutical preparation of biflavone compound for anti gout |
| CN101361733A (en) * | 2008-09-17 | 2009-02-11 | 暨南大学 | Use of flavone derivates and preparation method thereof |
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| CN101049301A (en) * | 2007-05-14 | 2007-10-10 | 湖北中医学院 | Pharmaceutical preparation of biflavone compound for anti gout |
| CN101361733A (en) * | 2008-09-17 | 2009-02-11 | 暨南大学 | Use of flavone derivates and preparation method thereof |
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| A new biflavonoid from Aristolochiacontorta;li-li yu et al;《Pharmazie》;20051001;第60卷(第10期);第789-791页，化合物1，2. Investigations, results and discussion * |
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