Background and overview
Secnidazole, developed by Symbiomix Therapeutics, was approved by the US FDA on September 15, 2017 under the trade name Solosec. The drug is used to treat bacterial vaginosis (BV) in adult women. Previously, secnidazole was developed by Rhone-Planck and was first listed in Switzerland in 1980, and subsequently in China, France and other countries. It is mainly used to treat urethritis and vaginitis, amebiasis and Giardia lamblia caused by vaginal hair droplets. The plasma half-life of secnidazole is long, and a single oral therapy can be used, one oral dose of secnidazole 2g. Chinese chemical name of secnidazole: 1-(2-hydroxypropyl)-2-methyl-5-nitroimidazole; molecular formula: C7H11N3O3; molecular weight: 185.18; CAS registration number: 3366-95-8. At present, the existing synthesis process of secnidazole is: under the condition of strong acid or strong base, by reacting 2-methyl-5 nitroimidazole with chloropropanol, propylene oxide or propylene oxide sulfate, etc. to obtain secnidazole Nitazole. There are many deficiencies in the above-mentioned process: for example, (1) a large amount of strong corrosive acids, such as toxic formic acid, oleum, etc., need to be used, which causes the subsequent recovery and treatment process to be more complicated; (2) the epoxy resin used Propane has a low boiling point, is volatile, and is not easy to operate; (3) the utilization rate of the reaction raw material 2-methyl-5-nitroimidazole is low; (4) the yield of the prepared secnidazole is low.
Function and use
1) Mechanism of action: Same as other 5-nitroimidazoles, secnidazole passively diffuses into microorganisms and is activated by the reduction of the 5-nitro group, because its electron affinity is greater than that of reduced ferredoxin , thereby hindering the normal flow of electrons. Secnidazole is selectively toxic to anaerobic microorganisms and has low activity against facultative and aerobic microorganisms. It can selectively destroy the DNA of target cells, causing DNA breakage and disintegration of the DNA double helix space structure, resulting in the loss of the function of synthetic protein templates, and its cytotoxicity is proportional to the content of thymine and adenine in the target cell DNA.
2) Antiprotozoal and antibacterial effects in vitro test results show that secnidazole and metronidazole have similar activities against Trichomonas vaginalis and Entamoeba histolytica. For 11 strains of Trichomonas vaginalis in the urogenital tract (1 standard strain, 10 strains were isolated from patients), both have good inhibitory and killing effects. The minimum inhibitory concentrations of secnidazole and metronidazole were 0.7 mg/L and 0.60 mg/L, respectively, and the minimum insecticidal concentrations were 0.63 mg/L and 0.42 mg/L, respectively. In vitro anti-Limboflagellate experiments showed that secnidazole required a 10-fold lower amount than metronidazole to reduce 50% of the trophozoites. Studies have shown that the cure rate of secnidazole treatment of infection caused by amoeba is 95% to 100%, the cure rate of infection caused by Giardia lamblia is 89% to 92%, and the cure rate of Trichomonas infection of the genitourinary system. 92% to 100%. Secnidazole and metronidazole showed similar antibacterial activity. In the study of 16 clinically isolated Bacteroides fragilis, it was found that the antibacterial spectrum and pharmacological effects of secnidazole were similar to those of metronidazole, but lower than that of metronidazole. Tinidazole.
Pharmacokinetics
1) Absorption and distribution Secnidazole is well absorbed orally and has no significant difference with intravenous injection. After oral and intravenous injection, it can be rapidly distributed throughout the body, and it can reach half of the maximum plasma concentration in 10 minutes. However, secnidazole is not widely distributed in the body, the steady-state volume of distribution is small (49.2L), and the plasma concentration in target tissues and organs is high. The protein binding rate is about 15%. Secnidazole crosses the placenta and is excreted into breast milk. A single oral dose of 0.5-2g has a bioavailability of (100±26)%, the maximum plasma concentration (Cmax) after one dose is 35.7-46.3mg/L, and the peak time (Tmax) is 1.42-3 hours. Cmax and area under the concentration-time curve (AUC) were significantly dose-related. After a single oral dose of secnidazole 2 g in healthy people, the mean plasma concentrations ranged from 17.8 to 20.8 mg/L at 24 hours, 8.7 to 9.4 mg/L at 48 hours, and 3.9 to 4.8 mg/L at 72 hours. In healthy married female subjects, the Tmax after a single use of secnidazole vaginal effervescent tablets 250, 500, and 750 mg were 12.2, 14.0, and 18.0 hours, respectively, and the Cmax was 3.58 mg/L, 5.42 mg/L, and 8.00, respectively. mg/L, AUC were 103.52, 190.99, 296.92 mg·h/L, respectively. Compared with the oral preparation, the absorption was slower, the peak concentration was lower, and the absorption amount was less. It shows that effervescent tablets have less systemic effect, less adverse reactions, and more local residues are conducive to local therapeutic effects. Cmax=14.30mg/L, Tmax=11.6 hours, AUC=520.14mg·h/L after multiple use of secnidazole vaginal effervescent tablet 500mg, Cmax and AUC were significantly increased compared with single administration, indicating that the There is a certain accumulation of the drug, and multiple doses should be paid attention to. Studies have found that the absorption of the drug (AUC, Cmax) is basically proportional to the dose, and the peak time (Tmax) is prolonged with the dose. This special situation may be related to the limitation of local vaginal volume and local body fluids.
2) Metabolism and excretion Secnidazole is mainly metabolized in the liver, and 50% of the drug is excreted from the kidney in its original form. The major metabolite is RP35843. Secnidazole does not induce or inhibit hepatic cytochrome P450 enzymes. The t1/2β of secnidazole is 17-29 hours, which is longer than other 5-nitroimidazole compounds, such as metronidazole 7-8 hours, tinidazole 12-13 hours, ornidazole 13 hours. Due to the longer half-life of secnidazole, it can be administered in a single dose, improving patient compliance.
Clinical application
1) 5-nitroimidazoles for amebiasis, including secnidazole, metronidazole, tinidazole and ornidazole, are the most effective and commonly used drugs for the treatment of invasive amebiasis, and are also used in Treatment of parenteral infections. Clinical trials usually judge cure rates according to the World Health Organization-defined criteria for parasitological eradication and clinical recovery. Botero reported that 100 patients with amebiasis with symptoms such as abdominal pain, cramps, diarrhea, dysentery syndrome were treated with a single dose of secnidazole 2g, and clinical examinations were performed after 5 and 21 days, and 3 hours and 72 hours for adverse Response evaluation. The results showed that the cure rate for colitis was 83% after 5 days of administration, 75% after 21 days, and the cure rates for parasites (no protozoan cysts in the excrement) were 88% and 75%, respectively. Adverse reactions occurred in 17% of the cases, mostly mild, including abdominal pain, nausea, dizziness, and metallic taste. In a clinical trial of 38 patients with non-dysentery amebic colitis in Brazil, the cure rate was 97.4%, while the cure rate in the placebo group (12 patients) was only 8.3%.
2) Giardiasis The cure rate of secnidazole for giardiasis is above 90%, which is similar to the clinical results of metronidazole, tinidazole and ornidazole. The advantage of secnidazole over the other three drugs is that it can be cured with a single dose. Brazilian researchers conducted a controlled trial of adult patients with giardiasis (222 cases), given a single dose of 30 mg/kg secnidazole or 250 mg metronidazole twice a day for 5 consecutive days, the results of secnidazole The cure rate was 92% in the azole group and 88.2% in the metronidazole group.
3) Trichomoniasis Trichomoniasis is caused by Trichomonas vaginalis and is one of the most common non-viral sexually transmitted diseases. 5-Nitroimidazoles are the best option for treating these infections. A single dose of secnidazole 2g, the parasite eradication rate of Trichomonas patients in the genitourinary system for 2 to 3 days was 92.6% to 95.6%, and the eradication rate was as high as 100% in 20 days, compared with a single dose of 2g metronidazole (82% to 97%). %) and tinidazole (81%-100%) had similar eradication rates. In another report, 50 patients with Trichomonas vaginalis took a single dose of secnidazole 2g, the cure rate was 94%, and the tolerance was good. Only 8 patients (16%) had mild adverse reactions, such as dizziness and nausea.
4) Bacterial vaginosis Bacterial vaginosis is a common lower vaginal infection, with an estimated incidence of 5% to 45%. In a randomized, double-blind, active-controlled trial, patients with bacterial vaginosis received a single dose of secnidazole 2 g (n=65) or tinidazole 2 g (n=64). Results The clinical recovery rates of secnidazole and tinidazole were 90.8% and 87.5%, respectively, and the microbiological cure rates were 81.5% and 78.5%, respectively. The adverse reactions of other nitroimidazoles are the same. Another clinical trial reported that with a single dose of secnidazole 2g, the clinical cure rate was 83.3%, and the laboratory test cure rate was 80.8%; while metronidazole 800mg/d was administered continuously for 7 days, the cure rates were 74.8% and 68.7%, respectively. %. The test results show that compared with metronidazole, secnidazole has better effect in the treatment of bacterial vaginosis, and single-dose medication is simple and convenient, and has better tolerance and compliance.
Security
The results of acute toxicity test in rats showed that the toxicity of secnidazole was extremely low, and the median lethal dose (LD50) was about 2.5g/kg. In the long-term toxicity test, dogs were continuously administered 400 mg/(kg·d) for 1 month, and the tolerance was good; after 3 months of continuous administration at 200 mg/(kg·d), there were neurological adverse reactions. No teratogenic effects have been found in the administration of secnidazole to pregnant mice, rats or rabbits, but because it can pass through the placenta and be secreted into breast milk, it should not be taken by women in the first 3 months of pregnancy and breastfeeding. No effect of secnidazole on male fertility has been observed. Rabbit vaginal irritation test was performed on secnidazole vaginal effervescent tablets, and no obvious vaginal irritation was found.
Tolerability and adverse reactions
A single oral dose of secnidazole 2 g (or 30 mg/kg) was well tolerated. External single dose of effervescent tablet 125, 250, 500, 750mg was well tolerated; 250mg/d, used for 7 days, was well tolerated; 500mg/d, used for 7 days, slight irritation of the vulva occurred in individual cases. Common adverse reactions of oral administration of secnidazole are as follows: nausea, vomiting, glossitis, anorexia, epigastric pain and metallic odor and other gastrointestinal reactions, with an incidence of about 2% to 10%; headache and dizziness, with an incidence of about 2% ; Some patients have mild abnormal white blood cell counts, but no clinical significance; some patients with amebiasis have significantly increased blood urea nitrogen levels, but still within the normal range; occasionally urticaria, rare eyelid and vulvar edema, skin erythema, Salivation, sweating, dizziness, paresthesias, and ataxia.
usage
Adults: for the treatment of intestinal amebiasis, 2g, taken once a day; for the treatment of liver amebiasis, 1.5g/time, once a day, for 5 days.
Children: For the treatment of intestinal amebiasis, the dose should be reduced with reference to adults; for the treatment of hepatic amebiasis, 30 mg/kg orally, once a day, for 5 days.
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