Midazolam is primarily metabolized in the liver and gut by CYP3A4 to its pharmacologic active metabolite, _alpha-hydroxymidazolam_ (also known as 1-hydroxy-midazolam), and 4-hydroxymidazolam (which makes up 5% or less of the biotransformation products). This metabolite likely contributes to the pharmacological effects of midazolam. Midazolam also undergoes N-glucuronidation via UGT1A4 after the process of hepatic oxidation by cytochrome enzymes.
... Midazolam has a rapid onset of action following intravenous, intramuscular, oral, nasal, and rectal administration. Only 50% of an orally administered dose reaches the systemic circulation due to extensive first-pass metabolism. Midazolam is metabolized by the cytochrome P450 enzyme system to several metabolites including an active metabolite, alpha-hydroxymidazolam. Cytochrome P450 inhibitors such as cimetidine can profoundly reduce the metabolism of midazolam...
Midazolam is a short-acting benzodiazepine routinely used in intensive-care medicine. Conjugates of its main metabolite, alpha-hydroxymidazolam, have been shown to accumulate in renal failure but have not previously been related to the prolonged sedative effects commonly observed in critically ill patients. /This study reports on/ five patients with severe renal failure who had prolonged sedation after administration of midazolam. In all five patients, the comatose state was immediately reversed by the benzodiazepine-receptor antagonist flumazenil. Serum concentration monitoring showed high concentrations of conjugated alpha-hydroxymidazolam when concentrations of the unconjugated metabolite and the parent drug were below the therapeutic range. In-vitro binding studies showed that the affinity of binding to the cerebral benzodiazepine receptor of glucuronidated alpha-hydroxymidazolam was only about ten times weaker (affinity constant 16 nmol/L) than that of midazolam (1.4 nmol/L) or unconjugated alpha-hydroxymidazolam (2.2 nmol/L). Conjugated metabolites of midazolam have substantial pharmacological activity. Physicians should be aware that these metabolites can accumulate in patients with renal failure.
The kinetics and dynamics of midazolam were investigated in 20 female patients undergoing lower abdominal surgery. The relation between the plasma concentrations of midazolam and pharmacokinetic end points was evaluated after an intravenous infusion regimen in 10 patients given an epidural anesthetic. The remaining 10 patients were anesthetized with a totally intravenous anesthetic technique with midazolam and alfentanil. The effect was assessed by means of a rating scale divided into degree of sedation and amnesia. A good correlation was found between plasma level of midazolam and pharmacodynamic response. The relation between the quantal response data and the plasma concentration was represented by an s-shaped concentration-effect curve. Despite similar kinetics of midazolam in the two groups, the postoperative drowsiness was more pronounced in the group receiving total intravenous anesthesia. The concomitant administration of alfentanil shifted the concentration-effect curve regarding sedation to the left.
Midazolam is metabolized extensively in the liver and intestine by cytochrome P-450 CYP3A4. The drug rapidly undergoes hydroxylation via hepatic microsomal enzymes to form 1-hyroxymethylmidazolam (alpha-hydroxymidazolam), the principal metabolite, and 4-hydroxymidazolam; a small portion of 1-hydroxymethylmidzaolam is further hydroxylated to 1-hydroxymethyl-4-hydroxymidazolam (alpha,4-dihydroxymidazolam). These metabolites undergo rapid conjugation with glucuronic acid in the liver. Although the elimination half-life of the principal metabolite, 1-hydroxymethylmidazolam, is not clearly established, it is estimated to be about 60-80 min. The 1-hydroxymethyl and 4-hydroxy metabolites are reportedly pharmacologically active, but their potencies at equivalent molar concentrations appear to be substantially less than that of midazolam. The 1-hydroxymethyl-4-hydroxy metabolite appears to have little, if any, pharmacologic activity.
IDENTIFICATION AND USE: Midazolam is a white to light yellow crystalline insoluble in water. The hydrochloride salt of midazolam, which is formed in situ, is soluble in aqueous solutions. It is a benzodiazepine, commonly used in the emergency department to provide sedation prior to procedures such as laceration repair and reduction of dislocations. Midazolam is also effective in the treatment of generalized seizures, status epilepticus, and behavioral emergencies, and as an induction agent for rapid sequence endotracheal intubation. Midazolam is often employed as probe to measure cytochrome P450 3A4 activity. HUMAN EXPOSURE AND TOXICITY: Changes in vital signs (respiratory rate, blood pressure, pulse rate) are the most frequent adverse effects associated with parenteral midazolam administration. Overdosage of midazolam hydrochloride is likely to produce symptoms that are mainly extensions of the usual pharmacologic effects of benzodiazepines, such as sedation, somnolence, confusion, impaired coordination, diminished reflexes, coma, and alterations in vital signs. Adverse ocular effects occur in less than 1% of patients receiving parenteral midazolam, principally in those receiving the drug iv, and include blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbances, and focusing difficulty. Midazolam is metabolized by the cytochrome P450 enzyme system to several metabolites and Cytochrome P450 inhibitors, such as cimetidine, can profoundly reduce the metabolism of midazolam. Midazolam has been associated with respiratory depression and cardiac arrest when used in combination with an opioid, particularly in the elderly, although all ages are at risk for respiratory depression. Many of the adverse effects associated with midazolam can be reversed rapidly by the administration of flumazenil, a competitive benzodiazepine receptor antagonist. ANIMAL STUDIES: Subchronic oral studies over 13 weeks in doses of 5, 15 and 45 mg/kg/day in the dog and 50, 100 and 200 mg/kg/day in the rat have demonstrated minimal toxicity for midazolam, as for other benzodiazepines. High doses produced increased liver weight in the rat and the expected increases in alkaline phosphatase in the dog (species-specific reaction). Detailed blood and urine analyses as well as histological examination of organs produced no indication of changes relevant for man. Subchronic parenteral studies (i.v. and i.m. for five weeks) using up to 6 mg/kg/day in dogs and rats showed the compound to be not only systemically, but also locally, well tolerated. In albino rabbits of New Zealand, midazolam administered at single dose by the intrathecal route may have neurotoxic effects on the neurons and myelinated axons at 24 hr and 6 days following administration. In baboons, chronic self-injection of 1.0 and 0.25 mg/kg midazolam did produce physical dependence as reflected in classic benzodiazepine spontaneous and flumazenil-precipitated withdrawal syndromes, including tremor, vomiting and, in one instance, seizure. Reproduction toxicology studies have shown that midazolam is neither embryotoxic nor teratogenic and that it has no effect on the fertility and post-natal development of animals. Midazolam was shown to have no mutagenic activity in Salmonella typhimurium (5 bacterial strains), Chinese hamster lung cells (V79) or in the micronucleus test in mice. However, in another study using low passage-number cultured Chinese hamster cells, midazolam treatment produced dose-dependent reductions in the number of diploid cells, with midazolam inducing significant levels of hyperdiploidy and midazolam induced low levels of chromosome aberrations, indicating potential genotoxicity.
It is thought that the actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the brain. Benzodiazepines increase the activity of GABA, thereby producing a calming effect, relaxing skeletal muscles, and inducing sleep. Benzodiazepines act as agonists at the benzodiazepine receptors, which form a component of the benzodiazepine-GABA receptor-chloride ionophore complex. Most anxiolytics appear to act through at least one component of this complex to enhance the inhibitory action of GABA.
Midazolam, like other benzodiazepines, is rarely associated with serum ALT or alkaline phosphatase elevations. Clinically apparent liver injury from midazolam has not been reported and must be extremely rare, if it occurs at all. Isolated single cases of clinically apparent liver injury have been reported with other benzodiazepines including alprazolam, chlordiazepoxide, clonazepam, diazepam, flurazepam, lorazepam, and triazolam. The clinical pattern of acute liver injury from benzodiazepines is typically cholestatic, but hepatocellular patterns of injury have been reported with clorazepate and clotiazepam. The injury is usually mild to moderate in severity with a time to onset of 1 to 6 months and rapid recovery once the benzodiazepine is stopped. Fever and rash are uncommon as is autoantibody formation.
**Oral Absorption**: Rapidly absorbed after oral administration. The absolute bioavailability, if given intramuscularly (IM), is greater than 90%. Due to first pass metabolism, only 40-50% of the administered oral dose reaches the circulation. The absolute bioavailability of the midazolam syrup in pediatric patients is about 36%. **Intramuscular Absorption**: The mean peak concentration (Cmax) and time to peak (Tmax) following the IM dose was 90 ng/mL (20% CV) and 0.5 hour (50% CV). **Rectal administration**: After rectal administration midazolam is absorbed rapidly. Maximum plasma concentration is reached within 30 minutes. The absolute bioavailability is approximately 50%. **Intranasal Administration**: Midazolam is absorbed rapidly after intranasal administration. Mean peak plasma concentrations are reached within 10.2 to 12.6 minutes. The bioavailability is between 55 and 57%.
The _α-hydroxymidazolam_ glucuronide conjugate of midazolam is excreted in urine. No significant amount of parent drug or metabolites is found in urine before beta-glucuronidase and sulfatase deconjugation, suggesting that the urinary metabolites are excreted mainly as conjugates. The amount of midazolam excreted unchanged in the urine when given intravenously is less than 0.5%. 45% to 57% of the dose was excreted in the urine as 1-hydroxymethyl midazolam conjugate. Plasma clearance of midazolam is higher in patients that remain in supine position, because of a 40-60 percent increase in hepatic blood flow during supination. Pregnancy may also increase the metabolism of midazolam.
Female gender, old age, and obesity may increase the volume of distribution. Midazolam may also cross the placenta and has been detected in human milk and cerebrospinal fluid. **Intravenous administration** 1.24 to 2.02 L/kg [pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam] 1 to 3.1 L/kg [midazolam intravenously administered, healthy adults]. **Intramuscular administration** The mean apparent volume of distribution of midazolam after a single IM dose of 10 mg midazolam in healthy adults was 2117 (±845.1) mL/kg.
Following iv administration of midazolam hydrochloride in animals, the drug is widely distributed, with highest concentrations occurring in liver, kidneys, lungs, fat, and heart. The drug crosses the blood-brain barrier and distributes into cerebrospinal fluid in humans and animals. In animals, equilibration of midazolam between plasma and cerebrospinal fluid occurs within a few minutes following iv administration, and cerebrospinal fluid:plasma ratios of the drug are highly correlated with unbound midazolam once equilibrium is reached. Distribution of the drug into human lumbar cerebrospinal fluid may be slow and erratic. Distribution may be altered in geriatric patients.
[EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
申请人：GALLEON PHARMACEUTICALS INC
公开号：WO2009151744A1
公开（公告）日：2009-12-17
The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
Heterobicyclic compounds of Formula (I):
or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.
Formula (I)的杂环化合物：
或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
The invention provides inhibitors of a sterol C14-demethylase, a new series of 4- aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) developed using structure-based drug design as well as structure -property relationship (SPR) analyses. The screening hit starting point, LP 10 (KD < 42 nM; EC50 of 0.65 μΜ), has been optimized to give the potential leads that have low nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts. Many of the optimized compounds have improved microsome stability, and most are selective against the T. cruzi CYP51 relative to human CYPs 1A2, 2D6 and 3A4 (<50% inhibition at 1 μΜ). A rationale for the improvement of microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of several compounds of the invention with the T. brucei CYP51 (TbCYP51) ortholog has been characterized by x-ray structure analysis. Orally active compounds and their cyclodextrin complexes have been shown to be effective against Chagas-infected mice.
