What Are the Symptoms of Digoxin Poisoning?

The active ingredient of this product is Cinidipine.
Chemical name: (±) -3- (2-methoxyethyl) -5- [3-phenyl-2 (E) -propenyl] -2,6-dimethyl-4- (3-nitro Phenyl) -1,4-dihydro-3,5-pyridine dicarboxylate.
Chemical Structure:

Molecular formula: C ₂₇ H ₂₈ N ₂ O ₇
Molecular weight: 492.53

Jiuyue (Xinidipine Capsule), the indication is for the treatment of patients with hypertension.

Drug Name: Jiuyue

Drug type: Prescription drugs, medicines for medical workers' injuries
Use classification: Calcium antagonists

Jiuyue ingredients

Jiuyue traits

This product is a capsule and its content is light yellow granules or powder.

Jiuyue indication

For the treatment of patients with hypertension.

Jiuyue specifications

5mg.

Jiuyue usage and dosage

For adults, the initial dose is 5 mg (one capsule each time), once a day, and taken after breakfast. According to the clinical response of the patient, the dose can be increased to a maximum of 10 mg (two capsules each time), once a day, and taken after breakfast.

Jiuyue adverse reactions

The adverse reactions of cinidipine in some patients (approximately 6.86%) are shown in the following table:
1. Less than 0.1 to 5% Less than 0.1%.
2. Urinary system frequent urination, uric acid, creatine, uric acid nitrogen rise, urinary sediment positive, urinary protein positive.
4. Nervous system: headache, dizziness, stiff shoulder muscles, drowsiness, insomnia, hand tremor, forgetfulness.
5. Circulatory system: complexion flushing, palpitations, dryness, chest pain on electrocardiogram, chills, extra-contractual contraction, sexual function, abnormality (ST segment reduction, T wave reversal), hypotension energy disorder
6. Digestive system AST, ALT, y-GTP rise and other liver dysfunction, constipation, abdominal distension, frequent, vomiting, abdominal pain, thirst.
7. Blood system white blood cell count, abnormal neutrophil thrombocytopenia, red blood cells, hematocrit, eosinophils and lymphocyte abnormalities, allergies, drug rash, pruritus, other edema, fatigue, elevated serum cholesterol, dry eyes, Congestion, gastrocnemius spasm, taste, abnormalities in serum K and P, abnormal urine glucose, fasting blood glucose, total protein, serum Ca and CRP abnormalities.
8. If the above abnormalities occur, you should consult your doctor in time and take appropriate measures.

Jiuyue taboo

Patients who are allergic to any of the ingredients in this product are prohibited.
Disabled for pregnant women.
Because it can cause symptoms such as low blood pressure, it should be disabled when working at height, driving motor vehicles and operating machinery.

Jiuyue notes

1. Elderly patients should start with a small dose and carefully observe the treatment response of the drug.
2. When combined with digoxin, pay close attention to the toxicity of digoxin.
3. Patients with hepatic insufficiency should take cautiously when taking cenidipine, the concentration of plasma cenidipine will increase.
4. Cinidipine is metabolized in the liver, so it should be noted when combined with the following drugs:
-Drugs that inhibit CYP3A4 isoenzymes, such as: cimetidine, ketoconazole, itraconazole, erythromycin, HIV protease inhibitors and fluoxetine.
-CYP3A4 isoenzyme inducers, such as: phenytoin, carbamazepine and rifampicin.
-Drugs that require CYP3A4 isoenzyme metabolism, such as cyclosporin.
-Drugs that inhibit or induce CYP2C19 isoenzymes.
-Drugs that require CYP2C19 isoenzymes to metabolize, such as S-Mephenytoin and Omeprazole.
5. Grape juice can increase the blood concentration of cinidipine, so the two cannot be used together.
6. Contraceptive measures should be taken during the treatment of women of childbearing age.
7. Use with caution in patients with congestive heart failure.
8. Calcium antagonists are not recommended for:
-Unstable angina.
Myocardial infarction occurred within -1 month.
-Left ventricular outflow tract obstruction.
-Untreated congestive heart failure.
9. Caution should be used by those with a history of serious adverse reactions to calcium antagonists.
10. At the beginning of treatment, increasing the dosage can aggravate the symptoms of sore throat.
11. Use with caution in patients with chronic renal insufficiency.
12. Use with caution when combined with beta-blockers, especially those with left ventricular dysfunction.
13. During fentanyl anesthesia, it is recommended to stop taking nifedipine and other dihydropyridine derivatives 36 hours before surgery.
14. Suddenly discontinuing the administration of calcium antagonists may cause the condition to worsen, so you should gradually reduce the dose when you need to stop the medicine, and fully observe the symptoms before stopping the medicine. Please use other drugs when the dosage is reduced to 5mg. Withdrawal should be done under the guidance of a doctor.

Medication for Jiuyue pregnant and lactating women

Use is prohibited in pregnant women (animal experiments have shown toxicity to the fetus and can cause delayed labor). Because this product can be secreted by breast milk, women should avoid using it during lactation, and stop breastfeeding if it cannot be avoided.

Jiuyue children medication

There is no information on the use of this product in children, and it is not recommended for children to use this product.

Jiuyue medication for the elderly

Elderly patients should not be excessively hypotensive, so low-dose administration (such as 5mg) should be started when used for elderly patients. After full observation, dosing carefully.

Jiuyue drug interactions

Combination medication:
1. Ephedra clinically does not recommend that patients take ephedra-containing drugs while using this product. Ephedrine in ephedra can aggravate high blood pressure symptoms.
2. The interaction between hypericum and hypericum has not been reported clinically. But hypericum is the same metabolic pathway as this product. This product is metabolized by the CYP450 enzyme system, which is a substrate for P-glycoprotein drug transport. Hypericum is able to activate cytochromes P4503A4 and P-glycoprotein in the human body. In vitro tests have shown that extracts of hypericum can inhibit cytochrome P450 isoenzymes including P4503A4. Therefore, calcium antagonist drugs that can be metabolized by cytochrome P4503A4 should be avoided in combination with hypericum.
3. Combining with other antihypertensive drugs This product may have an additive effect when used in combination with other antihypertensive drugs, enhancing the antihypertensive effect, and may cause excessive reduction in blood pressure.
4. Combination with digoxin and digoxin may increase the blood concentration of digoxin and even cause digoxin poisoning symptoms, such as: nausea, vomiting, headache, visual abnormality, arrhythmia, etc. Digoxin dose or termination of administration of calcium antagonists can improve the corresponding symptoms. The possible mechanism is that calcium antagonists can reduce the renal and extrarenal clearance of digoxin.
5. Calcium antagonists combined with cimetidine have been reported to have an increased effect. It may be that cimetidine reduces liver blood flow and inhibits the enzyme metabolism of calcium antagonists in liver microsomes. Reduces gastric acid, which increases absorption of calcium antagonists.
6. Calcium antagonists combined with rifampicin have been reported to have a weakened effect, possibly due to rifampicin inducing liver drug enzymes, thereby promoting the metabolism of calcium antagonists and increasing their clearance.
7. Combination with azo antifungal drugs This product will increase the blood concentration when combined with azo antifungal drugs (such as ketoconazole and itraconazole), which may be because azo antifungal drugs inhibit CYP3A4 And reduce the metabolism of this product.
8. Combined with grape juice, certain ingredients in grape juice can inhibit CYP3A4 and reduce the metabolism of this product, resulting in an increase in the blood concentration of this product.

Jiuyue overdose

According to literature reports, taking this product in excessive doses has the effect of first exciting and then suppressing the central nervous system. Patients will experience extreme decreases in blood pressure and even symptoms of shock, headache, vomiting, and nausea, and booster drugs should be given immediately. Stomach lavage and taking activated charcoal can promote the excretion of unabsorbed drugs from the intestine, and 10% glucose can be given by infusion to promote excretion of the absorbed drugs from the kidneys.

Jiuyue clinical trial

The clinical trial of this product is a multi-center, randomized, double-blind, double-simulation, parallel controlled trial design using cinidipine tablets as a positive control drug to evaluate the efficacy and safety of cinidipine capsules in the treatment of mild to moderate essential hypertension . The study subjects were mainly outpatients or inpatients aged 18 to 65 years, both men and women; patients with a clear diagnosis of mild to moderate essential hypertension, with a sitting diastolic blood pressure of 90 to 109 mmHg after a 2-week mock-elution period. And sitting position systolic blood pressure [180mmHg. During the test, the subjects were randomly divided into two groups (Xinidipine Capsule Group and Xinidipine Tablet Group) at a ratio of 1: 1 after a 2-week mock-agent elution period; they were given Xenidipine capsules ( Specification: 5mg / capsule) 1 capsule / time, 1 time / day, and administration of a blank analogue of cinidipine tablet 1 time / time, 1 time / day; or cinidipine tablet (specification: 5mg / tablet) 1 tablet / Once, 1 time / day, and 1 capsule / time, 1 time / day with cilnidipine blank simulant; taken at 8 am-10am. After 2 weeks of treatment, if the blood pressure does not reach the standard (ie DBP 90mmHg), double the dose of cinidipine capsules or cinidipine tablets and the corresponding blank simulant, and observe the effect after 6 weeks of treatment. The main observation indicators were blood routine (including platelet count), urine routine, blood biochemistry, electrocardiogram, chest radiograph or chest radiograph, and dynamic blood pressure was measured in 60 subjects. Validity results were as follows: A total of 227 patients were randomly enrolled in this trial, including 114 in the test group. There were 113 cases in the control group. A total of 13 cases (5.72%) fell off during the trial; 11 cases (4.85%) did not enter the PPS population. Efficacy analysis of the PPS population: 101 cases in the test group, 20 cases (19.80%) with significant effect, 59 cases (58.42%) with effect, the total effective rate was 78.22%; 102 cases in the control group, with 16 cases (15.69%), effective 66 Case (64.71%), the total effective low was 80.40%, and the difference between the two groups was not statistically significant (P) 0.05). The results of the safety test were: 39 adverse events occurred during the test, the incidence of adverse events was 17.18%, and 20 adverse events occurred in the test group (17.54%), of which 9 were drug-related adverse events (7.89%). A total of 19 adverse events (16.81%) occurred in the control group, of which 10 were drug-related (8.85%). There was no significant difference in the incidence of adverse events and related adverse events between the two groups. The main adverse reactions during the trial were dry mouth, palpitations, dizziness, headache, tinnitus, and weakness in the lower limbs. During the trial, two drug-related adverse reactions occurred, one with elevated UA and the other with decreased WBC. The review has returned to normal. The conclusion of this test is that Xinidipine capsule is a safe and effective drug for the treatment of mild and moderate essential hypertension.

Jiuyue Pharmacology and Toxicology

Pharmacological effects:
This product is a lipophilic dihydropyridine calcium antagonist, which can bind to the dihydropyridine site of the L-type calcium channel on the vascular smooth muscle cell membrane, and inhibit the inflow of Ca2 + through the L-type calcium channel, thereby relaxing and expanding the blood vessels Smooth muscles to lower blood pressure. It can also inhibit the release of norepinephrine and the sympathetic nerve activity of the sympathetic nerve endings by inhibiting the influx of Ca2 + through the N-type calcium channel on the sympathetic nerve cell membrane.
Toxicological effects:
Acute toxicity: The results of acute toxicity test in mice show that the maximum resistance to single-dose cinidipine tablets is 10g / kg.
Subacute toxicity: The results of the subacute toxicity test in rats suggest that the non-toxic dose of cinidipine to rats is 50mg / kg / day for male rats and 6.25mg / kg / day for female rats. The abnormal manifestation is 12.5mg / Serum Cl- decreased in the dose group above kg, abdominal distension occurred in the dose group above 25 mg / kg, ovarian weight increased in the dose group above 50 mg / kg, and liver weight increased in both sexes in the dose group above 100 mg / kg, but these abnormal changes disappeared after discontinuation .
Beagle dog subacute toxicity test results indicate that the non-toxic dose of cinidipine to dogs is 25mg / kg / day, and the abnormal manifestation is that females above 50mg / kg can see transient eyes and oral mucosa pale, vomiting, male animals 50mg The QT interval prolonged in the dose group above kg / kg, and the symptoms recovered after stopping the drug.
Long-term toxicity: The results of long-term toxicity tests in rats suggest that the non-toxic dose of cinidipine to rats is 30 mg / kg / day for male rats and 5 mg / kg / day for female rats. The abnormal performance is 25 mg / kg for female animals. Decreased defecation, abdominal distension, increased water intake and ovarian weight, decreased urine specific gravity, male 10mg / kg dose group, urine Na + and urine Cl- excretion increased, but the above symptoms were small hours after discontinuation.
The results of the long-term toxicity test of Beagle dogs indicate that the non-toxic dose of cinidipine to dogs is 6.25 mg / kg / day, and the abnormal manifestation is in a dose group of 25 mg / kg or more. The animals have gum hypertrophy, paraglomerular hypertrophy, and a dose of 100 mg / kg. In the group, weight gain was suppressed, GTP was increased, and the weight of the adrenal kidney was increased. The above symptoms recovered after drug withdrawal.
Reproductive toxicity: Cinnidipine was administered to rats before and during early pregnancy. The experimental results showed that the number of fetuses that died early in the dose group above 50 mg / kg increased, and there was no abnormal effect on the shape, internal organs and bones of the fetus.
Oral administration of cinidipine during the fetal organ formation period in rats showed that the gestation period was prolonged in female rats at a dose of 100 mg / kg or more, and fetal skeletal mutation in the dose group of 50 mg / kg or more caused the development of bone retardation in chickens with certain teratogenicity. The experimental results of oral administration of cinidipine during fetal formation in rabbits showed that 400 mg / kg had no effect on female rabbits and fetuses.
Oral administration of cinidipine during the perinatal and lactation period in rats. The experimental results showed that the delivery time was prolonged in the 24 mg / kg dose group, the number of unexcluded fetuses in the uterus and the number of newborn fetuses were reduced, which had no effect on the development and differentiation of newborn fetuses .
Mutagenic effects: Bacterial reverse mutation experiments, mammalian culture cell chromosome mutation experiments, and mouse micronucleus experiments have shown that cinidipine has no effect.
Carcinogenicity: Experiments in mice and rats have shown that this product has no carcinogenicity.

Jiuyue Pharmacokinetics

Healthy adult men take single-dose cilnidipine at doses of 5mg, 10mg, and 20mg, respectively. At this time, the peak plasma concentration Cmax (unit: ng / ml) is 9.5 ± 1.6, 13.5 ± 5, 16.9 ± 7.6, and Tmax (unit : Hours) are 2.8 ± 1, 3.7 ± 0.8, 3 ± 1.3, and the half-life t1 / 2 () (unit: hour) are 1 ± 0.2 ~ 1.1 ± 0.6, t1 / 2 () (unit: hour) 5.2 ± 2 ~ 8.1 ± 2.7, AUCO ~ (ng.h / ml) were 59.1 ± 12.7, 108.1 ± 29, 95.5 ± 34.5. After the 4th day of drug administration, the blood concentration began to stabilize, and no drug accumulation was found.
Changes in blood concentration of patients with hypertension after a single oral administration of 10 mg of this product, there is no significant difference between patients with normal renal function and patients with abnormal renal function (blood Cr: 1.5-3.1 mg / dl). Taking 10mg of this product once, and continuously taking it for 7 days, the change of its blood concentration will not be affected by multiple administrations.
In healthy adults, this product is mainly metabolized in the liver by CYP3A4 and CYP2C19. The metabolic pathways are demethylation oxidation of methoxyethyl group, hydrolysis of cinnamyl ester, and oxidation of dihydropyridine.
Healthy adult men take 10mg of this product twice a day for 7 days. In urine, the prototype of the drug was detected, and metabolites accounted for 5.2% of the total dose. In vitro tests found that the human serum protein binding rate was 99.3%.

Jiuyue storage

Shaded and sealed.

Jiuyue Packaging

Aluminum plastic blister; 12 capsules / board / box.

Jiuyue validity period

24 months

Jiuyue Executive Standard

State Food and Drug Administration Standard YBH01712008

Jiuyue approval number

National Medicine Standard H20080066

Jiuyue Production Enterprise

Hunan Jiudian Pharmaceutical Co., Ltd.

Jiuyue approval date

June 05, 2008