A Review on the New and Old Anticoagulants.

Anticoagulants serve as the primary strategy for the prevention and treatment of both arterial and venous thromboembolism. Anticoagulants disrupt coagulation by interfering at various points in the coagulation cascade. This class of medications does not lyse clots that already exist; rather, it prevents thrombus formation and prevents or slows the extension of an existing clot. For decades, the standard therapy for patients requiring oral anticoagulation was warfarin. However, due to some of the shortcomings of warfarin, including the need for continuous routine monitoring, longtime onset and offset of anticoagulation effect, major food and drug interactions, and high incidence of bleeding, newer agents, termed direct oral anticoagulants, or DOACs were developed. This article will provide a review of clinically important information regarding the most commonly used anticoagulants and their reversal agents.

Schedules of Controlled Substances: Placement of Butyryl Fentanyl and U­47700 Into Schedule I. Final order.

With the issuance of this final order, the Administrator of the Drug Enforcement Administration maintains the placement of the substances butyryl fentanyl (N-(1-phenethylpiperidin-4-yl)-N-phenylbutanamide) and U­47700 (3,4-dichloro-N-[2- (dimethylamino)cyclohexyl]-Nmethylbenzamide), including their isomers, esters, ethers, salts, and salts of isomers, esters and ethers, in schedule I of the Controlled Substances Act. This scheduling action discharges the United States obligations under the Single Convention on Narcotic Drugs (1961). This action continues to impose the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, import, export, engage in research or conduct instructional activities with, or possess), or propose to handle, butyryl fentanyl and U­ 47700.

Schedules of Controlled Substances: Placement of AH-7921 Into Schedule I. Final order.

With the issuance of this final order, the Administrator of the Drug Enforcement Administration places the substance AH-7921 (Systematic IUPAC Name: 3,4-dichloro-N-[(1dimethylamino)cyclohexylmethyl]benzamide), including its isomers, esters, ethers, salts, and salts of isomers, esters and ethers, into schedule I of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act and is required in order for the United States to discharge its obligations under the Single Convention on Narcotic Drugs, 1961. This action imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, import, export, engage in research or conduct instructional activities with, or possess), or propose to handle, AH-7921.

The Effects of Class-Specific Histone Deacetylase Inhibitors on the Development of Limbs During Organogenesis.

Histone deacetylases (HDACs) play a major role in chromatin remodeling, gene regulation, and cellular signaling. While the role of each class of HDAC during normal development is unclear, several HDAC inhibitors are embryotoxic; the mechanisms leading to the teratogenicity of HDAC inhibitors are not known. Here, we investigated the effects of class-specific HDAC inhibitors on the development of organogenesis-stage murine limbs. Timed-pregnant COL2A1-ECFP, COL10A1-mCherry, and COL1A1-YFP CD1 reporter mice were euthanized on gestation day 12; embryonic forelimbs were excised and cultured in vitro for 1, 3, and 6 days in the presence or absence of MS275 (a class I HDAC inhibitor), MC1568 (a class III HDAC inhibitor), Sirtinol (a class II HDAC inhibitor), or valproic acid, our positive control. Fluorescently tagged COL2A1, COL10A1, and COL1A1 served as markers of the differentiation of proliferative chondrocytes, hypertrophic chondrocytes, and osteoblasts, respectively. MS275 and valproic acid caused a reduction in expression of all three markers, suggesting effects on both chondrogenesis and osteogenesis. MC1568 had no effect on chondrocyte markers and mildly inhibited COL1A1 expression at 6 days. Sirtinol had no effect on COL2A1 expression or chondrocyte differentiation 1 day following exposure; however, it caused a drastic regression in limb cartilage and reduced the expression of all three differentiation markers to nearly undetectable levels at 6 days. MS275 and Sirtinol caused a 2.2- and 2.7-fold increase, respectively, in cleaved-caspase 3, a marker of apoptosis, suggesting embryotoxicity. These data demonstrate that inhibition of class I or III HDACs causes severe developmental toxicity and is highly teratogenic.

Effect of temperature on the reversal in the retention order of the enantiomers of mosapride on Chiral-AGP.

The retention order of the enantiomers of mosapride could be controlled by column temperature and mobile phase pH. In the presented paper, temperature studies have been used to study the thermodynamics of the reversal in retention order. A linear relationship was obtained plotting the logarithm of the capacity factor versus the inverted column temperature. However, at higher mobile phase pHs, the logarithm of the separation factor versus the inverted column temperature showed a non-linear behaviour and at the highest mobile phase pH used (pH=7.4), an optimum in the separation factor was observed. The plots showed that the thermodynamics for the two enantiomers of mosapride differ in the studied mobile phase pH interval. Thermodynamic values, enthalpy and entropy were calculated and showed that at a low mobile phase pH, the enantiomeric resolution was caused by differences in enthalpy between the two enantiomers. However, at a higher mobile phase pH, the chiral discrimination was a result of entropy effects. High correlation was obtained between experimental and predicted separation factors at different mobile phase pHs.

Pharmacological classification of benzamides.

The problem of classifying benzamides is, in general, the same as classifying neuroleptics. A pharmacological classification of neuroleptics can be established on the basis of the following criteria: specificity of action on dopaminergic receptors; penetration into the CNS; dopaminergic profile in the CNS; relative binding with respect to subclasses of DA; preferential antagonism of certain effects of apomorphine; preferential affinity for dopaminergic structures; activating effects on DA systems at low doses; different clinical effects: antiemetic, psychiatric (antihallucinatory and disinhibitory), neurologic. A relationship between biochemical, behavioural and clinical effects is proposed: antihallucinatory effect: decrease of dopaminergic function; disinhibitory effect: increase of dopaminergic function. We emphasize the problem of doses used because the different effects occurred for a given drug at different doses. This hypothesis suggests that positive symptomatology of schizophrenia is related to hyperdopaminergic activity, negative symptomatology is related to hypodopaminergic activity. Classification of benzamides: metoclopramide: peripheral dopaminolytic activity antiemesis without psychiatric or neuroleptic effects with low doses. sulpiride, tiapride, DAN 2163: peripheral effects + preferential blockade of D3 and D4 receptors, central DA activation with low doses, disinhibitory effects. With high doses, decrease of specificity for subclasses of DA receptors, central DA inhibition, antihallucinatory effects but little extrapyramidal symptomatology and sedation. sultopride: central DA inhibition, antihallucinatory effects, sedative and neurological effects.