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Abstract Neuroactive steroids (NASs) directly affect neuronal excitability. Despite their role in the nervous system is intimately linked to pain control, knowledge is currently limited. This study investigates the peripheral involvement of NASs in chronic ischemic pain by targeting the cytochrome P450 side-chain cleavage enzyme (P450scc). Using a rat model of hind limb thrombus-induced ischemic pain (TIIP), we observed an increase in P450scc expression in the ischemic hind paw skin. Inhibiting P450scc with intraplantar aminoglutethimide (AMG) administration from post-operative day 0 to 3 significantly reduced the development of mechanical allodynia. However, AMG administration from post-operative day 3 to 6 did not affect established mechanical allodynia. In addition, we explored the role of the peripheral sigma-1 receptor (Sig-1R) by co-administering PRE-084 (PRE), a Sig-1R agonist, with AMG. PRE reversed the analgesic effects of AMG during the induction phase. These findings indicate that inhibiting steroidogenesis with AMG alleviates peripheral ischemic pain during the induction phase via Sig-1Rs.

Neuroactive steroids (NASs) directly affect neuronal excitability. Despite their role in the nervous system is intimately linked to pain control, knowledge is currently limited. This study investigates the peripheral involvement of NASs in chronic ischemic pain by targeting the cytochrome P450 side-chain cleavage enzyme (P450scc). Using a rat model of hind limb thrombus-induced ischemic pain (TIIP), we observed an increase in P450scc expression in the ischemic hind paw skin. Inhibiting P450scc with intraplantar aminoglutethimide (AMG) administration from post-operative day 0 to 3 significantly reduced the development of mechanical allodynia. However, AMG administration from post-operative day 3 to 6 did not affect established mechanical allodynia. In addition, we explored the role of the peripheral sigma-1 receptor (Sig-1R) by co-administering PRE-084 (PRE), a Sig-1R agonist, with AMG. PRE reversed the analgesic effects of AMG during the induction phase. These findings indicate that inhibiting steroidogenesis with AMG alleviates peripheral ischemic pain during the induction phase via Sig-1Rs. [ABSTRACT FROM AUTHOR]

Here, we report the synthesis and experimental characterization of three drug-drug eutectic mixtures of drug aminoglutethimide (AMG) with caffeine (CAF), nicotinamide (NIC) and ethenzamide (ZMD). The eutectic mixtures i.e., AMG-CAF (1:0.4, molar ratio), AMG-NIC (1:1.9, molar ratio) and AMG-ZMD (1:1.4, molar ratio) demonstrate significant melting point depressions ranging from 99.2 to 127.2 °C compared to the melting point of the drug AMG (151 °C) and also show moderately higher aqueous solubilities than that of the AMG. The results presented include the determination of the binary melt phase diagrams and accompanying analytical characterization via X-ray powder diffraction, FT-IR spectroscopy and scanning electron microscopy.

Purpose: The incidence of breast cancer worldwide has been on the rise since the late 1970s, and it has become a common tumor that threatens women's health. Aminoglutethimide (AG) is a common treatment of breast cancer. However, current treatments require frequent dosing that results in unstable plasma concentration and low bioavailability, risking serious adverse reactions. Our goal was to develop a molecularly imprinted polymer (MIP) based delivery system to control the release of AG and demonstrate the availability of this drug delivery system (DDS), which was doped with carbon nanotube with aid of metal-organic gel. Methods: Preparation of MIP was optimized by key factors including composition of formula, ratio of monomers and drug loading concentration. Results: By using multi-walled carbon nanotubes (MWCNT) and metal-organic gels (MOGs), MIP doubled the specific surface area, pore volume tripled and the IF was 1.6 times than the reference. Compared with commercial tablets, the relative bioavailability was 143.3% and a more stable release appeared. Conclusions: The results highlight the influence of MWCNT and MOGs on MIP, which has great potential as a DDS. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCS) are known to modulate cardiovascular response during stress conditions. The present study was aimed to test the hypothesis that permissive and/or stimulating effect of GCs is essential for the maintenance of peripheral vascular resistance and for the adequate response of cardiovascular system to stressor exposure. The effects of acute pharmacological adrenalectomy (PhADX) on humoral and cardiovascular parameters were studied in adult Wistar rats under the basal conditions and during the acute restraint stress. Acute PhADX was performed by the administration of metyrapone and aminoglutethimide (100 mg/kg s.c. of each drug) resulting in a suppression of endogenous glucocorticoid synthesis. Blood pressure (BP), heart rate (HR) and core body temperature were measured using radiotelemetry. BP responses to administration of vasoactive agents were determined in pentobarbital-anesthetized animals. PhADX considerably attenuated stress-induced increase of BP, HR and core body temperature. PhADX did not abolish BP and HR lowering effects of ganglionic blocker pentolinium indicating preserved sympathetic function in PhADX rats. BP response to exogenous norepinephrine administration was attenuated in PhADX rats, suggesting reduced sensitivity of cardiovascular system. Suppression of corticosterone synthesis by PhADX increased basal plasma levels of ACTH, aldosterone and plasma renin activity in unstressed animals but there was no further increase of these hormones following stressor exposure. In conclusion, PhADX attenuated stress-induced rise of blood pressure, heart rate and core body temperature indicating an important permissive and/or stimulating role of glucocorticoids in the maintenance of the adequate response of cardiovascular system and thermoregulation to several stimuli including acute exposure to stressor. [ABSTRACT FROM AUTHOR]

Aromatase inhibitory and cytotoxic activities were determined for apigenin, luteolin and the new diterpene named scutebarbalactone VN, which were obtained by bioassay-guided fractionation and isolation from the methanol extract of the Vietnamese medicinal plant Banchi-lien (Scutellaria barbata D. Don). In the aromatase inhibition assay, an IC50 value of 3.36 mM was found for scutebarbalactone VN, while IC50 values of 7.2 mM and 7.95 mM were found for the positive controls aminoglutethimide and b-estradiol, respectively. In the cytotoxicity assays using a panel of human cancer cell lines, scutebarbalactone VN showed promising anticancer activity with IC50 ranging from 2.15 to 8.3 mM compared with those of the positive control ellipticine ranging from 1.0 to 2.1 mM. Apigenin and luteolin were found to be inactive in both assays.

Aminoglutethimide is a steroidogenesis inhibitor and inhibits a cholesterol side-chain cleavage enzyme (CYP11A1) that converts cholesterol to pregnenolone in mitochondria. We investigated histopathological changes induced by 5-day administration of AG in mice. Cytoplasmic vacuoles of various sizes and single cell necrosis were found in zona fasciculata cells in AG-treated mice. Some vacuoles were positive for adipophilin, whereas others were positive for lysosome-associated membrane protein-2 on immunohistochemical staining, indicating they were enlarged lipid droplets and lysosomes, respectively. Electron microscopy revealed enlarged lysosomes containing damaged mitochondria and lamellar bodies in zona fasciculata cells, and they were considered to reflect the intracellular protein degradation processes, mitophagy and lipophagy. From these results, we showed that AG induces excessive lipid accumulation and mitochondrial damage in zona fasciculata cells, which leads to an accelerated lysosomal degradation in mice. [ABSTRACT FROM AUTHOR]

Translocator protein 18 kDa (TSPO) is predominantly located in the mitochondrial outer membrane, playing an important role in steroidogenesis, inflammation, cell survival and proliferation. Its expression in central nervous system, mainly in glial cells, has been found to be upregulated in neuropathology, and brain injury. In this study, we investigated the anti-oxidative and anti-inflammatory effects of a group of TSPO ligands from the N,N -dialkyl-2-phenylindol-3-ylglyoxylamide class (PIGAs), highlighting the involvement of neurosteroids in their pharmacological effects. To this aim we used a well-known in vitro model of neurosteroidogenesis: the astrocytic C6 glioma cell line, where TSPO expression and localization, as well as cell response to TSPO ligand treatment, have been established. All PIGAs reduced l -buthionine-(S,R)-sulfoximine (BSO)-driven cell cytotoxicity and lipid peroxidation. Moreover, an anti-inflammatory effect was observed due to the reduction of inducible nitric oxide synthase and cyclooxygenase-2 induction in LPS/IFNγ challenged cells. Both effects were blunted by aminoglutethimide (AMG), an inhibitor of pregnenolone synthesis, suggesting neurosteroids' involvement in PIGA protective mechanism. Finally, pregnenolone evaluation in PIGA exposed cells revealed an increase in its synthesis, which was prevented by AMG pre-treatment. These findings indicate that these TSPO ligands reduce oxidative stress and pro-inflammatory enzymes in glial cells through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of inflammatory-based neuropathologies with beneficial effects possibly comparable to steroids, but potentially avoiding the negative side effects of long-term therapies with steroid hormones. [ABSTRACT FROM AUTHOR]

This paper reported the facile fabrication of drug delivery devices for zero-order sustained release by molecular crowding strategy of molecularly imprinting technology. Crowding-assisted molecularly imprinting polymers (MIPs) matrices were prepared by free-radical precipitation polymerization using aminoglutethimide (AG) as a model drug. The crowding effect was achieved by adding polystyrene as a macromolecular co-solute in pre-polymerization mixture. The MIP prepared under the non-MMC condition and the two corresponding non-imprinted particles were tested as controlled vehicles. The release profiles presented zero-order behaviors from two crowding-assisted polymers, the duration of approximately 18 h for the crowding-assisted MIP and 10 h for the crowding-assisted NIP, respectively while AG were all very rapid released from the other two controlled particles (85% occurring in the first hour). The BET surface area and pore volume of the crowding-assisted MIP were about ten times than those of the controlled MIP. The value of imprinting factor is 6.02 for the crowding-assisted MIP and 1.19 for the controlled MIP evaluated by the equilibrium adsorption experiment. Furthermore, the values of effective diffusivity ( D eff ) obtained from crowding-assisted MIP (10 −17 cm 2 /s) was about two orders of magnitude smaller than those from the controlled MIP, although the values of free drug diffusivity ( D ) were all found in the order of 10 −13 cm 2 /s. Compared with the commercial AG tablet, the MMC-assisted MIP gave a markedly high relative bioavailability of 266.3%, whereas the MMC-assisted NIP gave only 57.7%. The results indicated that the MMC condition can modulate the polymer networks approaciate to zero-order release of the drug and maintain the molecular memory pockets, even if under the poor polymerization conditions of MIPs preparation. [ABSTRACT FROM AUTHOR]

The multifunctional alkoxysilane precursor, 2,6-bis(propyl-trimethoxysilylurelene)pyridine (DPS) was designed and synthesized, envisaging a multiple hydrogen-bond interaction in the molecular imprinting of the drug aminoglutethimide (AGT). Imprinted xerogels were obtained in bulk and spherical formats. The spherical format was achieved by pore-filling onto spherical mesoporous silica, as a straightforward technique to generate the spherical format. The bulk gels presented better selectivity for the template against its glutarimide (GLU) analogue (selectivity factor: bulk 13.4; spherical 4.6), and good capacity (bulk 5521 μmol/L; spherical 2679 μmol/L) and imprinting factor parameters (bulk 11.3; spherical 1.4). On the other hand, the microspherical format exhibited better dynamic properties associated to chromatographic efficiency (theoretical plates: bulk 6.8; spherical 75) and mass transfer, due mainly to the existence of a mesoporous network, lacking in the bulk material. The performance of the imprinted xerogels was not as remarkable as that of their acrylic counterparts, previously described. Overall it was demonstrated that the use of designed new “breeds” of organo-alkoxysilanes may be a strategy to achieve satisfactory imprints by the sol–gel processes. DPS may in principle be applied even more effectively to other templates bearing better-matching spatially compatible acceptor–donor–acceptor arrays. [ABSTRACT FROM AUTHOR]

In this study, the cellular effects resulting from the metabolism of aminoglutethimide by myeloperoxidase were investigated. Human promyelocytic leukemia (HL-60) cells were treated with aminoglutethimide (AG), an arylamine drug that has a risk of adverse drug reactions, including drug-induced agranulocytosis. HL-60 cells contain abundant amounts of myeloperoxidase (MPO), a hemoprotein, which catalyzes one-electron oxidation of arylamines using H 2 O 2 as a cofactor. Previous studies have shown that arylamine metabolism by MPO results in protein radical formation. The purpose of this study was to determine if pathways associated with a toxic response could be determined from conditions that produced protein radicals. Conditions for AG-induced protein radical formation (with minimal cytotoxicity) were optimized, and these conditions were used to carry out proteomic studies. We identified 43 proteins that were changed significantly upon AG treatment among which 18 were up-regulated and 25 were down-regulated. The quantitative proteomic data showed that AG peroxidative metabolism led to the down-regulation of critical anti-apoptotic proteins responsible for inhibiting the release of pro-apoptotic factors from the mitochondria as well as cytoskeletal proteins such as nuclear lamina. This overall pro-apoptotic response was confirmed with flow cytometry which demonstrated apoptosis to be the main mode of cell death, and this was attenuated by MPO inhibition. This response correlated with the intensity of AG-induced protein radical formation in HL-60 cells, which may play a role in cell death signaling mechanisms. [ABSTRACT FROM AUTHOR]

Primary aromatic amine drugs are structural alerts in drug development because of their association with a high incidence of idiosyncratic drug reactions (IDRs). If biomarkers could be found that predict IDR risk, it would have a major impact on drug development. Previous attempts to do this through screening of hepatic gene expression profiles in rodents treated with aromatic amine drugs found limited changes. Of the drugs studied, aminoglutethimide (AMG) induced the most changes, and this led to a more comprehensive study of its effects on the liver. Brown Norway rats treated with AMG for up to 14 days showed only a transient elevation of glutamate dehydrogenase. Pathway-specific PCR arrays found few AMG-induced gene changes associated with an immune response and, of these changes, the majority were involved with innate immunity such as Tlr2, Ticam2, CD14, and C3. AMG treatment also led to significant changes in the apoptosis and mitochondrial panel of genes. It was recently found that AMG does induce significant changes in the bone marrow of rats, and agranulocytosis is a common IDR caused by AMG. In contrast, liver injury is not a common IDR associated with AMG. Therefore, the liver may be able to effectively deal with AMG reactive metabolites, and changes observed in this study may be involved in adaptation. Myeloperoxidase is also known to be able to oxidize aromatic amines to reactive metabolites, and these observations suggest that metabolism outside of the liver may be important for the mechanism of aromatic amine-induced IDRs. [ABSTRACT FROM AUTHOR]

Straightforward crushing and sieving bulk polymeric R-aminoglutethimide-imprinted materials were prepared by classical free radical polymerization, whereas nano thin walled grafted imprinted materials were prepared using RAFT mediated control polymerization technique. A stoichiometric non-covalent approach based on a triply hydrogen bonding functional monomer-template 1:1 complex (K=599mol-1L-1) led to chiral selectors far outperforming previously used selectors for resolving this racemate. The recognitive materials produced here (enantioselectivity factors, α~10) also have no match within the previously reported enantioselective imprinted polymers (α 1.2-4.5). We here demonstrate a potentially generic solution to produce good quality grafted MIPs for templates interacting by hydrogen bonding alone, relying on solvent polarity tuning, significantly extending the range of templates compatible with this format. [ABSTRACT FROM AUTHOR]

Molecularly imprinted microspheres ( MIMs) for the anticancer drug aminoglutethimide ( AG) were synthesized by aqueous suspension polymerization. The expected size and diameter of MIMs are controlled easily by changing one of the surfactant types, ratio of organic-to-water phase or stirring rate during polymerization. The obtained MIMs exhibit specific affinity toward AG with imprinting factor of 3.11 evaluated with a chromatographic model. The resultant MIMs were used as the SPE materials for the extraction of AG from human urine. A molecularly imprinted SPE ( MISPE) method coupled with HPLC has been developed for the extraction and detection of AG in urine. Our results showed that most impurities from urine can be removed effectively after a washing step and the AG has been enriched effectively after MISPE operation with the recovery of >90% ( n = 3). The developed MISPE- HPLC method could be used for enrichment and detection of AG in human urine. [ABSTRACT FROM AUTHOR]

Background: Airway neutrophilia has been associated with asthma severity and asthma exacerbations. This study attempted to identify biomarkers, pathogenesis, and therapeutic molecular targets for severe asthma in neutrophils using bioinformatics analysis., Methods: Fifteen healthy controls and 3 patients with neutrophilic severe asthma were screened from the Gene Expression Omnibus (GEO) database. Based on the analysis of differentially expressed genes (DEGs), functional and pathway enrichment analyses, gene set enrichment analysis, protein-protein interaction network construction, and analysis were performed. Moreover, small-molecule drug candidates have also been identified., Results: Three hundred and three upregulated and 59 downregulated genes were identified. Gene ontology function enrichment analyses were primarily related to inflammatory response, immune response, leukocyte migration, neutrophil chemotaxis, mitogen-activated protein kinase cascade, Jun N-terminal kinase cascade, I-kappaB kinase/nuclear factor-κB, and MyD88-dependent toll-like receptor signaling pathway. Pathway enrichment analyses and gene set enrichment analysis were mainly involved in cytokine-cytokine receptor interaction, the TNF signaling pathway, leukocyte transendothelial migration, and the NOD-like receptor signaling pathway. Furthermore, 1 important module and 10 hub genes (CXCL8, TLR2, CXCL1, ICAM1, CXCR4, FPR2, SELL, PTEN, TREM1, and LEP) were identified in the protein-protein interaction network. Moreover, indoprofen, mimosine, STOCK1N-35874, trapidil, iloprost, aminoglutethimide, ajmaline, levobunolol, ethionamide, cefaclor, dimenhydrinate, and bethanechol are potential drugs for the treatment of neutrophil-predominant severe asthma., Conclusion: This study identified potential biomarkers, pathogenesis, and therapeutic molecular targets for neutrophil-predominant severe asthma., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

With the aim of searching for phytochemicals with aromatase inhibitory activity, five new prenylcoumarins, mammeasins K ( 1 ), L ( 2 ), M ( 3 ), N ( 4 ), and O ( 5 ), were isolated from the methanolic extract of Mammea siamensis (Miq.) T. Anders. flowers (fam. Calophyllaceae), originating in Thailand. The stereostructures of 1 - 5 were elucidated based on their spectroscopic properties. Among the new compounds, 1 (IC 50 = 7.6 µM) and 5 (9.1 µM) possessed relatively strong inhibitory activity against aromatase, which is a target of drugs already used in clinical practice for the treatment and prevention of estrogen-dependent breast cancer. The analysis through Lineweaver-Burk plots showed that they competitively inhibit aromatase ( 1 , K i = 3.4 µM and 5 , 2.3 µM). Additionally, the most potent coumarin constituent, mammea B/AB cyclo D ( 31 , K i = 0.84 µM), had a competitive inhibitory activity equivalent to that of aminoglutethimide (0.84 µM), an aromatase inhibitor used in therapeutics.

Virtually all drugs that contain a primary aromatic amine are associated with a high incidence of idiosyncratic drug reactions (IDRs), suggesting that this functional group has biological effects that may be used as biomarkers to predict IDR risk. Most IDRs exhibit evidence of immune involvement and the ability of aromatic amines to form reactive metabolites and redox cycle may be responsible for initiation of an immune response through induction of cell stress, as postulated by the Danger Hypothesis. If true, danger signals could be biomarkers of IDR risk. A previous attempt to test the Danger Hypothesis found that sulfamethoxazole (SMX), the only aromatic amine tested, was also the only drug not associated with an increase of cell stress genes in mice. To ensure that these observations were not species-specific, and to determine biomarkers of IDR risk common to aromatic amines, rats were treated with SMX and two other aromatic amine drugs, dapsone (DDS) and aminoglutethimide (AMG), and hepatic gene expression was determined using microarrays. As in mice, SMX induced minimal gene changes in the rat, and none indicated cell stress, whereas DDS and AMG induced several changes including up-regulation of enzymes such as aldo-keto reductase, glutathione- S-transferase, and aldehyde dehydrogenase, which may represent danger signals. Early insulin-induced hepatic gene ( Eiih) was up-regulated by all three drugs. Some mRNA changes were observed in the Keap-1-Nrf2-ARE pathway; however, the pattern was significantly different for each drug. Overall, the most salient finding was that the changes in the liver were minimal, even though aromatic amines cause a high incidence of IDRs. The liver generates a large number of reactive species; however, the ability of aromatic amines to be bioactivated by cells of the immune system may be why they cause a high incidence of IDRs. [ABSTRACT FROM AUTHOR]

Neurosteroids, modulators of neuronal and glial cell functions, are synthesized in the nervous system from cholesterol. In peripheral steroidogenic tissues, cholesterol is converted to the major steroid precursor pregnenolone by the CYP11A1 enzyme. Although pregnenolone is one of the most abundant neurosteroids in the brain, expression of CYP11A1 is difficult to detect. We found that human glial cells produced pregnenolone, detectable by mass spectrometry and ELISA, despite the absence of observable immunoreactive CYP11A1 protein. Unlike testicular and adrenal cortical cells, pregnenolone production in glial cells was not inhibited by CYP11A1 inhibitors DL-aminoglutethimide and ketoconazole. Furthermore, addition of hydroxycholesterols increased pregnenolone synthesis, suggesting desmolase activity that was not blocked by DL-aminoglutethimide or ketoconazole. We explored three different possibilities for an alternative pathway for glial cell pregnenolone synthesis: (1) regulation by reactive oxygen species, (2) metabolism via a different CYP11A1 isoform, and (3) metabolism via another CYP450 enzyme. First, we found oxidants and antioxidants had no significant effects on pregnenolone synthesis, suggesting it is not regulated by reactive oxygen species. Second, overexpression of CYP11A1 isoform b did not alter synthesis, indicating use of another CYP11A1 isoform is unlikely. Finally, we show nitric oxide and iron chelators deferoxamine and deferiprone significantly inhibited pregnenolone production, indicating involvement of another CYP450 enzyme. Ultimately, knockdown of endoplasmic reticulum cofactor NADPH-cytochrome P450 reductase had no effect, while knockdown of mitochondrial CYP450 cofactor ferredoxin reductase inhibited pregnenolone production. These data suggest that pregnenolone is synthesized by a mitochondrial cytochrome P450 enzyme other than CYP11A1 in human glial cells., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Both in vivo and in vitro studies have shown that neurosteroids promote learning and memory by modulating synaptic functions in the hippocampus. However, we do not know to what degree endogenously synthesized neurosteroids contribute to the hippocampal synaptic functions. Cytochrome P450scc is the enzyme that converts cholesterol to pregnenolone (PREG), which is required for the biosynthesis of all other neurosteroids. To investigate the physiological roles of endogenous neurosteroids in synaptic functions, we electrophysiologically examined the effects of aminoglutethimide (AG), a selective inhibitor of P450scc, on the synaptic transmission and plasticity in the dentate gyrus of rat hippocampal slices. The application of AG (100 μM) decreased the slope of the field excitatory postsynaptic potentials (fEPSPs) in granule cells by 20–30% in 20 min through the modulation of postsynaptic AMPA receptors, while it did not affect the presynaptic properties, including the paired-pulse ratio and the probability of glutamate release from presynaptic terminals. The AG-induced depression was nearly completely rescued by exogenously applied 500 nM PREG or by 1 nM dehydroepiandrosterone sulfate (DHEAS), one of the neurosteroids synthesized from PREG, suggesting that the AG-induced depression was caused by the loss of DHEAS. AG also reduced NMDA receptor activity, and suppressed high-frequency stimulation (HFS)-induced long-term potentiation (LTP). These findings provide novel evidence that the endogenous neurosteroids locally synthesized in the brain are required to maintain the normal excitatory synaptic transmission and plasticity in the dentate gyrus of the rat hippocampus. [Copyright &y& Elsevier]

Complexations of R(+) and RS(+/-)aminoglutethimide (AGT), the drug used in a treatment of breast and prostate cancer with native and modified cyclodextrins (α-CD, β-CD, γ-CD, 2,6-di-O-methyl-β-CD (DM-β-CD), 2,3,6-tri-O-methyl-β-CD (TM-β-CD) and carboxymethyl-β-CD (CM-β-CD)) were studied. The stability constants were determined with UV–Vis spectrophotometric method at pH 9.0. The NMR data obtained for TM-β-CD suggest that the complexation of AGT is possible from both sides of CD molecule. This was confirmed by molecular dynamic simulations. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: A capillary electrophoretic method for the separation of the aminoglutethimide (AGT) enantiomers using methylated-β-cyclodextrin (M-β-CD) as chiral selector is described. Several parameters affecting the separation were studied, including the type and concentration of chiral selector, buffer pH, voltage and temperature. Good chiral separation of the racemic mixture was achieved in less than 9min with resolution factor Rs=2.1, using a fused-silica capillary and a background electrolyte (BGE) of tris–phosphate buffer solution (50mmolL−1, pH 3.0) containing 30mgmL−1 of M-β-CD. The separation was carried out in normal polarity mode at 25°C, 16kV and using hydrostatic injection. Acceptable validation criteria for selectivity, linearity, precision, and accuracy/recovery were included. The proposed method was successfully applied to the assay of AGT enantiomers in pharmaceutical formulations. The computational calculations for the inclusion complexes of the R- and S-AGT–M-β-CD rationalized the reasons for the different migration times between the AGT enantiomers. [Copyright &y& Elsevier]

Here, we report the synthesis and experimental characterization of three drug-drug eutectic mixtures of drug aminoglutethimide (AMG) with caffeine (CAF), nicotinamide (NIC) and ethenzamide (ZMD). The eutectic mixtures i.e., AMG-CAF (1:0.4, molar ratio), AMG-NIC (1:1.9, molar ratio) and AMG-ZMD (1:1.4, molar ratio) demonstrate significant melting point depressions ranging from 99.2 to 127.2 °C compared to the melting point of the drug AMG (151 °C) and also show moderately higher aqueous solubilities than that of the AMG. The results presented include the determination of the binary melt phase diagrams and accompanying analytical characterization via X-ray powder diffraction, FT-IR spectroscopy and scanning electron microscopy. [ABSTRACT FROM AUTHOR]

Aminoglutethimide (AGLD, an inhibitor of adrenal steroid synthesis) up to 5?mg/kg and spironolactone (SPIR, a mineralocorticosteroid antagonist and a weak antiandrogen) up to 50?mg/kg did not affect any seizure parameter in amygdala-kindled rats. AGLD (10?mg/kg) significantly reduced seizure activity in rats of both gender. The combination of AGLD (5?mg/kg) with phenobarbital (PB, applied at its subeffective dose of 15?mg/kg) significantly shortened motor seizure and afterdischarge duration in amygdala-kindled seizures. The combined treatment of AGLD (5?mg/kg) and clonazepam (CLO) at its subeffective dose of 0.01?mg/kg caused significant reduction of the seizure severity, seizure duration and afterdischarge duration. Finally, AGLD (5?mg/kg) proved ineffective upon the action of valproate (VPA) in this model of epilepsy. In contrast to AGLD, SPIR (50?mg/kg) did not affect the action of PB, CLO or VPA against kindled seizures in rats. AGLD did not alter the free plasma levels and brain concentration of PB or CLO, so a pharmacokinetic interaction does not seem probable. Among a variety of chemoconvulsants, bicuculline and N-methyl-D-aspartic acid reversed the effects of AGLD/PB and AGLD/CLO combinations. Aminophylline, kainic acid, strychnine and the glucocorticosteroid (hydrocortisone) were ineffective in this respect. Our data confirm the hypothesis that AGLD-mediated events may play a role in seizure activity and can affect the anticonvulsant activity of some conventional antiepileptic drugs against kindled seizures. Moreover, extrapolation of obtained results to clinical practice may indicate that patients with complex partial seizures may be safely co-medicated with AGLD or SPIR without the risk of worsening of seizure control. [ABSTRACT FROM AUTHOR]

Abstract: Antagonists of steroid receptors may interfere with seizure phenomena. The present study deals with effects of aminoglutethimide and spironolactone on the action of carbamazepine and diphenylhydantoin in amygdala-kindled rats of both genders. Co-administration of the antimineralocorticoid with carbamazepine at their ineffective doses (50 and 15 mg/kg, respectively) led to significant reduction of the seizure and afterdischarge durations. No anticonvulsant effect was observed when spironolactone was combined with diphenylhydantoin. The concomitant treatment of aminoglutethimide and carbamazepine (both drugs at their subprotective doses of 5 and 15 mg/kg, respectively) resulted in antiseizure activity in respect of all measured parameters, including the afterdischarge threshold, seizure severity, seizure duration and afterdischarge duration. The similar combination of aminoglutethimide with diphenylhydantoin (2.5 mg/kg) significantly shortened the seizure and afterdischarge durations. The antiseizure effect of tested combinations was not sex-dependent and not reversed by hydrocortisone pretreatment. Pharmacokinetic events may be involved only in the interaction between spironolactone and carbamazepine. Among various chemoconvulsants, bicuculline reversed the action of aminoglutethimide on carbamazepine and diphenylhydantoin. The effect of aminoglutethimide on diphenylhydantoin was also abolished by N-methyl-d-aspartic acid and aminophylline. In conclusion, our results suggest that doses of carbamazepine and diphenylhydantoin should be modified in epileptic patients concomitantly treated with aminoglutethimide or spironolactone. [Copyright &y& Elsevier]