Toxicology

Application Summary: Rilmazafone has been involved in fatal intoxications . It was identified in two separate deaths where the suspected use of pagoclone was involved .

Methods of Application or Experimental Procedures: During the investigation of these deaths, high resolution mass spectrometry was used for screening, and rilmazafone metabolites were presumptively identified . Due to the lack of reference material for the active metabolites, the metabolites were synthesized in-house .

Results or Outcomes: In one case, femoral blood concentrations of 7.9, 65, and 170 ng/g of the metabolites rilmazolam, N-desmethyl rilmazolam, and di-desmethyl rilmazolam, respectively, were detected . The intake of rilmazafone was determined as the cause of death .

Insomnia Treatment

Application Summary: Rilmazafone is a pro-drug that can be prescribed in Japan to treat insomnia . The regular clinical daily dose is 1–2 mg .

Methods of Application or Experimental Procedures: As a pro-drug, rilmazafone is converted in the body to the benzodiazepine rilmazolam . This is the analyte expected to appear in toxicology specimens .

Rilmazafone, also known by its trade name Rhythmy, is a water-soluble prodrug developed in Japan. Its chemical structure is characterized by the formula C21H20Cl2N6O3, with a molecular weight of 475.33 g/mol. Unlike traditional benzodiazepines, Rilmazafone does not contain a fused benzene and diazepine ring, which classifies it differently in various regulatory frameworks. It is primarily metabolized in the body to produce several active benzodiazepine metabolites, notably rilmazolam, which exhibit sedative and hypnotic properties. The compound has been shown to induce sleep without significantly affecting skeletal muscle function, making it an attractive option for treating insomnia and related sleep disorders   .

Rilmazafone itself doesn’t directly interact with GABA receptors in the brain, unlike traditional benzodiazepines. After metabolizing into T-BZD metabolites like rilmazolam, these active components bind to the GABA receptors, promoting the calming effects associated with sleep [, ].

While Rilmazafone itself might not be directly psychoactive, its metabolites can produce effects similar to benzodiazepines. Case studies report involvement in fatal intoxications, highlighting the importance of proper use and potential for misuse [].

Safety Concerns:

• Potential for abuse and dependence: Similar to other benzodiazepines [].
• Overdose: Can be fatal, as reported in case studies [].

Rilmazafone undergoes metabolic conversion primarily via aminopeptidase enzymes in the small intestine. This conversion leads to the formation of rilmazolam, which possesses a triazolo benzodiazepine structure. The metabolic pathway involves hydrolysis and subsequent modifications that yield active metabolites capable of binding to benzodiazepine receptors, although Rilmazafone itself does not interact with these receptors directly   .

Rilmazafone exhibits notable sedative effects, as evidenced by preclinical studies demonstrating its efficacy in inducing and maintaining sleep. Its pharmacokinetics reveal an elimination half-life of approximately 10.5 hours, with excretion primarily via urine. Clinical evaluations indicate that Rilmazafone has less residual impact on psychomotor performance compared to other hypnotics like zolpidem and triazolam, making it a favorable option for elderly patients   .

The synthesis of Rilmazafone can be achieved through several methods:

• Starting Material: 2-amino-2-(2-(4-chloro-2-(2-chlorobenzoyl)phenyl)hydrazono)-N,N-dimethylacetamide.
• Reagents: Various reagents are employed to facilitate the transformation into the final product.
• Routes: At least five distinct synthetic routes have been documented, each yielding Rilmazafone through different reaction pathways involving condensation and cyclization reactions .

Rilmazafone is primarily utilized in the treatment of insomnia and other sleep disorders due to its sedative properties. Its unique mechanism of action allows for effective sleep induction with reduced side effects related to motor function impairment. Additionally, it has been explored for use as a premedicant in surgical settings  .

Studies have indicated that Rilmazafone may interact with various drugs metabolized by cytochrome P450 enzymes. Notably, its metabolites can induce hepatic drug-metabolizing enzymes, which may lead to altered pharmacokinetics for co-administered medications. Monitoring for potential drug interactions is essential when considering Rilmazafone in therapeutic regimens  .

Rilmazafone shares similarities with several other compounds in terms of structure and pharmacological effects:

Rilmazafone’s uniqueness lies in its classification as a prodrug without direct psychoactive effects until metabolized. This differentiates it from traditional benzodiazepines and allows for a potentially safer profile in specific patient populations   .

Nail pitting and splinter hemorrhage possibly induced by zolpidem

Takaya Komori, Atsushi Otsuka, Maria Cho, Tetsuya Honda, Kenji Kabashima
PMID: 30507006   DOI: 10.1111/1346-8138.14715

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Residual effects of zolpidem, triazolam, rilmazafone and placebo in healthy elderly subjects: a randomized double-blind study

Sachiko Ito Uemura, Takashi Kanbayashi, Masahiko Wakasa, Masahiro Satake, Wakako Ito, Kazumi Shimizu, Takanobu Shioya, Tetsuo Shimizu, Seiji Nishino
PMID: 26498242   DOI: 10.1016/j.sleep.2015.05.021

Abstract

With current hypnotic agents, next-day residual effects are a common problem. The purpose of the present study was to evaluate the residual effects of the commercially available hypnotics – zolpidem, triazolam, and rilmazafone – on the physical and cognitive functions of healthy elderly people in the early morning and the day following drug administration. In this study, the next-day residual effects of zolpidem, triazolam, and rilmazafone, following bedtime dosing in elderly subjects, were evaluated. Women (n = 11) and men (n = 2) aged 60-70 years received a single dose (at 23:00) of one of these, zolpidem 5 mg, triazolam 0.125 mg, rilmazafone 1 mg and placebo in a randomized, double-blind, crossover design. Measures of objective parameters and psychomotor performances (Timed up and Go test, Functional Reach Test, body sway test, critical flicker fusion test, simple discrimination reaction test, short-term memory test) and subjective ratings were obtained at 04:00, 07:00, and the next time of the day. All hypnotics were generally well tolerated; there were no serious adverse side effects and no subjects discontinued the evaluations. Compared to placebo, zolpidem and rilmazafone had good results on the Functional Reach Test. Although subjective assessments tended to be poor in the early morning, rilmazafone significantly improved the body sway test in the other hypnotics. A single dose of zolpidem 5 mg and triazolam 0.125 mg did not have any next-day residual effects on healthy elderly subjects. Residual effects appeared to be related to the compound’s half-life and the dose used. Rilmazafone 1 mg exhibited steadiness in static and dynamic balance and seemed to be more favorable for the elderly with early morning awakening.

Hypnotic and sleep quality-enhancing properties of kavain in sleep-disturbed rats

Ryuki Tsutsui, Kazuaki Shinomiya, Yasuhiro Takeda, Yoshihito Obara, Yoshihisa Kitamura, Chiaki Kamei
PMID: 19881224   DOI: 10.1254/jphs.09167fp

Abstract

The present study was performed to investigate the effects of kavain on the sleep-wake cycle in comparison with that of rilmazafone and diphenhydramine using sleep-disturbed rats. Electrodes for the electroencephalogram (EEG) and electromyogram (EMG) were implanted into Wistar rats. Total awake time, non-rapid eye movement (non-REM) sleep and rapid eye movement (REM) sleep were measured for 6 h. Kavain and rilmazafone showed a significant shortening in sleep latency, decreased awake time, and increased non-REM sleep time. On the other hand, significant shortening of the sleep latency was observed following the administration of diphenhydramine, while no effects were observed on the awake and non-REM sleep time. Moreover, kavain showed a significant increase in delta activity during non-REM sleep in sleep-disturbed rats, whereas a significant decrease in delta power during non-REM sleep was observed with rilmazafone. These results clearly indicate that kavain is a compound with not only hypnotic effects, but also sleep quality-enhancement effects.

Effects of melatonin and rilmazafone on nocturia in the elderly

K Sugaya, S Nishijima, M Miyazato, K Kadekawa, Y Ogawa
PMID: 17900408   DOI: 10.1177/147323000703500513

Abstract

We compared the effects of melatonin, an antioxidant and sleep inducer in humans, and rilmazafone hydrochloride, a hypnotic, in elderly patients with nocturia. Patients received either melatonin (2 mg/day; n = 20) or rilmazafone (2 mg/day; n = 22) for 4 weeks. There were no significant differences in the mean age, the quality of life (QoL) score and the serum melatonin levels between the two groups at baseline. After 4 weeks’ treatment, the number of nocturnal urinations was significantly decreased and the QoL score was significantly improved in both groups. There was no significant difference between the patient-reported effectiveness ratings between the two groups. The serum melatonin level was significantly increased in the melatonin-treated group, but it remained unchanged in the rilmazafone-treated group. Melatonin and rilmazafone were equally effective for nocturia in the elderly. We recommend that the problems of sleep disturbance should be considered when choosing a therapy for nocturia.

Comparative hepatic transport of desglycylated and cyclic metabolites of rilmazafone in rats: analysis by multiple indicator dilution method

N Muranushi, S Miyauchi, H Suzuki, Y Sugiyama, M Hanano, H Kinoshita, T Oguma, H Yamada
PMID: 8499579   DOI: 10.1002/bdd.2510140402

Abstract

Rilmazafone (RZ) is an orally active sleep inducer which can be activated to its cyclic form (M1) via the labile desglycylated metabolite (DG). In this scheme, RZ is exclusively metabolized to DG and M1 by aminopeptidases in the small intestine. The concentration of M1 in the systemic plasma after oral administration of RZ has been reported to be higher than that observed after administration of M1, due to the lower hepatic extraction of DG than M1 (Koike et al., Drug Metab. Dispos., 16, 609 (1988)). In the present study, the disposition of DG and M1 in rat liver was investigated, using the multiple indicator dilution method. The hepatic availabilities (F) of DG and M1, assessed from the recovery into the hepatic vein, were 0.16 and 0.07, respectively, which was consistent with the previous in vivo finding that the first-pass elimination of M1 was greater than that of DG. The kinetic analysis based on the distributed model showed that the influx (k’1) and efflux (k’2) rate constants for M1 were larger than those for DG, whereas no significant difference in the sequestration rate constant (k’3) was observed between the two ligands. Based on the concept proposed by Miyauchi et al. (J. Pharmacokinet. Biopharm., 15, 25 (1987)), it was suggested that the determinant factor of the hepatic intrinsic clearance was the influx clearance for both ligands, because the values of k’2 for each ligand were much smaller than the respective k’3 values. It was concluded that the higher plasma concentration of M1 after oral administration of RZ than that observed after administration of M1 is due to the fact that the hepatic uptake of DG is lower than that of M1.

[Pharmacology of a 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), a new sleep-inducer (III). Behavioral study on interactions of 450191-S and other drugs in mice]

N Ibii, M Horiuchi, K Yamamoto
PMID: 6149177   DOI:

Abstract

Interactions between 450191-S and other representative drugs which might be clinically used with 450191-S were behaviorally investigated in mice, and compared with the cases of nitrazepam, estazolam and triazolam. The potencies of 450191-S and nitrazepam in preventing pentetrazol convulsions were markedly decreased by aminopyrine, whereas that of estazolam was remarkably increased by phenytoin. Administration of nitrazepam with other drugs, except aminopyrine, or of estazolam together with haloperidol exhibited an anticonvulsive pattern different from the case of dosing with either drug alone. Only the effect of triazolam was not influenced by any drugs used. The potency of haloperidol against apomorphine-induced climbing behavior was significantly reduced by nitrazepam, and the pattern of the haloperidol effect was changed by treatment together with 450191-S or estazolam. However, triazolam had no influence on the effect of haloperidol. The antagonistic activity of imipramine to reserpine-induced hypothermia was slightly decreased by 450191-S, estazolam and triazolam, but little affected by nitrazepam. In the protection from maximal electroshock convulsions (MEC), the potency of phenytoin was significantly decreased by 450191-S and triazolam. Moreover, the anti-MES pattern of phenytoin was altered by nitrazepam. Estazolam exerted no significant influence on the effect of phenytoin. Analgesic activities of morphine and/or aminopyrine were potentiated by pretreatment with sleep-inducers, but not 450191-S. Thus, judging from the potency and stability of the anti-pentetrazol effect, 450191-S seems to be inferior to triazolam, but superior to nitrazepam and estazolam. Also, 450191-S may be differentiated from other sleep-inducers by the fact that only 450191-S did not potentiate the analgesic activities of morphine and aminopyrine.

Potentiation of ethanol in spatial memory deficits induced by some benzodiazepines

Atsushi Takiguchi, Takayoshi Masuoka, Yasuko Yamamoto, Azusa Mikami, Chiaki Kamei
PMID: 16891765   DOI: 10.1254/jphs.fpj06008x

Abstract

Triazolam caused no significant increase in the total error at 0.05 and 0.1 mg/kg. However, at 0.2 mg/kg, it caused a significant increase in total error. Almost the same findings were observed with brotizolam and rilmazafone. That is, at 0.2 and 0.5 mg/kg of brotizolam, 0.5 and 1.0 mg/kg of rilmazafone caused no significant increase in the total error. However, brotizolam at 1.0 mg/kg and rilmazafone at 2.0 mg/kg caused a significant increase in total error. Triazolam (0.05 mg/kg) and ethanol (1.0 g/kg) showed no significant effect on the numbers of errors when used alone separately, but the simultaneous use of triazolam and ethanol caused a significant increase in total error. Almost the same findings were observed with the coadministration of brotizolam (0.2 mg/kg) or rilmazafone (0.5 mg/kg) with ethanol. These results clearly indicate that all the short-acting benzodiazepines used in the study showed potentiation by ethanol in spatial memory deficits in mice.

[Pharmacological studies on drug dependence. (III): Intravenous self-administration of some CNS-affecting drugs and a new sleep-inducer, 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), in rats]

K Yoshimura, M Horiuchi, Y Inoue, K Yamamoto
PMID: 6538866   DOI:

Abstract

The present study examined comparative self-administration of some typical CNS-affecting drugs with a new sleep-inducer, 450191-S, in rats, Most animals self-administered both methamphetamine and cocaine in an extremely stable and invariable fashion with cycles of alternating responding and non-responding periods during the day and at night. Response frequency increased in proportion to a fixed-ratio value. An initial increase in response rate followed by cessation of the responding was observed during extinction. Sixty-five percent of the rats tested self-administered morphine in a relatively variable and less stable fashion. Total daily morphine intake was directly related to the unit dose. Eighty-three percent of the rats self-administered pentazocine. Fifty and sixty-four percent of the rats maintained self-administration of phenobarbital and diazepam, respectively, with higher intake at night than during the day. Responding persisted at a low rate for several days during extinction. Abrupt withdrawal of 450191-S caused the same slight weight loss and moderate decrease in food intake as those seen with diazepam and nitrazepam, and cross-physical dependence between 450191-S and diazepam was found. Self-administration of 450191-S at 0.5-2.5 mg/kg/infusion was observed with 2 out of 11 rats, which was much less than that found with diazepam. These results suggest that 450191-S possesses little, if any, drug dependence liability of the tranquilizer type.

[Pharmacology of a new sleep inducer, 1H-1,2,4-triazolyl benzophenone derivative, 450191-S (II). Sleep-inducing activity and effect on the motor system]

K Yamamoto, A Matsushita, T Sawada, Y Naito, K Yoshimura, H Takesue, S Utsumi, K Kawasaki, S Hirono, H Koshida
PMID: 6149175   DOI:

Abstract

The sleep-inducing activity and effect on the motor system of the 1H-1,2,4-triazolyl benzophenone derivative 450191-S were examined behaviorally, electroencephalographically and electro-physiologically with various species of animals and were compared with those of diazepam, nitrazepam, estazolam and triazolam. In the rhesus monkey, rabbit and rat with chronically indwelling brain electrodes, 0.6 to 3 mg/kg, p.o. of 450191-S caused a shorter latency of sleep onset, an increase of and a stable continuity of slow wave deep sleep (SWDS) with higher amplitude, and the appearance of clear spindle bursts in the slow wave light sleeping (SWLS) state with little muscle relaxation. Animals treated with nitrazepam and/or estazolam showed a smaller increase in SWDS and its unstable continuity with remarkable disturbance of gait. The doses needed to induce sleep in the rhesus monkey were 0.6 to 1 mg/kg p.o. for 450191-S, 3 mg/kg for nitrazepam, 1 mg/kg for estazolam and 0.3 mg/kg for triazolam. The cat treated with 450191-S showed the phenomena caused by benzodiazepines (BDZ), i.e., behavioral excitation and decrease of frequencies in the hippocampal theta waves. The suppressive effects of 450191-S on the EEG arousal reaction and/or blood pressure elevation induced by hypothalamic stimulation in the rabbit suggested that the inhibitory effects acted on the posterior hypothalamus to the limbic system. The inhibitory effect of 450191-S on the amygdaloid kindling in the rat was as potent as those of diazepam and nitrazepam. Successive daily oral administration of both 3 mg/kg of 450191-S and/or 3 to 6 mg/kg of nitrazepam for 15 days in the rabbit caused slight decrease of SWDS and increase of fast wave (REM) sleep (FWS). During the withdrawal period of both compounds, a slight but insignificant increase in the waking state was noticed for 1 to 2 days, but not a rebound increase of FWS. Intravenously administered 450191-S showed the same action as BDZ on the spinal reflex and the dorsal root potential of the rat; it particularly acted on the crossed extensor reflex in the same manner as the commercial BDZ sleep inducers.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacological studies of a new sleep-inducer, 1H-1,2,4-triazolyl benzophenone derivative (450191-S) (V). General pharmacological activities]

K Yamamoto, M Ueda, A Kurosawa, K Hirose, M Doteuchi, M Nakamura, S Ozaki, S Matsumura, S Matsuda, H Satoh
PMID: 6149178   DOI:

Abstract

General pharmacological activities of 450191-S were studied in various species of animals and compared with those of reference benzodiazepines (BDZ). 450191-S at doses of 10 mg/kg slightly decreased (-5 degrees C) the rectal temperature of rabbits. 450191-S decreased respiratory and heart rates in anesthetized cats, but the effects were less than those of diazepam or triazolam. 450191-S increased respiratory and heart rates in conscious dogs, but had no effect on the blood pressure, electrocardiogram and autonomic nervous system in cats and dogs. The drug displayed a slight spasmolytic activity in the small intestine of guinea pigs and a slight inhibitory effect on isolated non-pregnant and pregnant uteri of rats. These effects were less than those of diazepam or nitrazepam. Below doses of 25 mg/kg, 450191-S did not affect urinary volume and electrolyte excretions in rats. It also decreased brain norepinephrine (NE) turnover rates in rats, but decreased NE and dopamine turnover rates in mice. These effects of 450191-S were less than those of nitrazepam. 450191-S was found to be minimally irritating to the ocular mucosa in rabbits and did not irritate the stomach and small intestine in rats. These effects were also compared with those of active metabolites of 450191-S, M-1, M-2, M-A, M-3 and M-4, and the superiority of the mother compound over its metabolites was clarified.