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1.
Rationale
Modulators of the ρ1 GABAA receptor may be useful in the treatment of visual, sleep, and cognitive disorders. Neuroactive steroids and analogues have been shown to modulate ρ1 receptor function, but the molecular mechanisms are poorly understood.Objectives
We employed electrophysiology and voltage-clamp fluorometry to compare the actions of several neuroactive steroids and analogues on the human ρ1 GABAA receptor.Results
Results confirmed that P294S and T298F mutations affect modulation by steroids. The P294S mutation abolished inhibition by (3α,5β)-3-hydroxypregnan-20-one (3α5βP) while the T298F mutation eliminated inhibition by 17β-estradiol. Voltage-clamp fluorometry demonstrated that steroids differing in the presence of a charged group on C3 or nature of substituent on C17 uniquely modified fluorescence changes elicited by GABA in the extracellular domain. The I307Q mutation reversed the inhibitory effect of 3α5βP but was without effect on modulation by (3α,5β)-3-hydroxypregnan-20-one sulfate or 17β-estradiol. The effect of 3α5βP on the fluorescence change generated at Y241C was dependent on whether the steroid acted as an inhibitor or a potentiator. Further, the effect was limited to uncharged 5β-reduced steroids containing an acetyl group on C17.Conclusions
The data demonstrate that steroids and analogues differ with respect to conformational changes elicited by these drugs as well as sensitivity to the effects of mutations. Steroids and analogues could be provisionally divided into three major groups based on their actions on the ρ1 GABAA receptor: 5β-reduced uncharged steroids, sulfated and carboxylated steroids, and 17β-estradiol. Further division among 5β-reduced uncharged steroids was based on substituent at position C17. 相似文献2.
Christopher D. Schmoutz Scott P Runyon Nicholas E. Goeders 《Psychopharmacology》2014,231(17):3391-3400
Rationale
Several compounds that potentiate GABA-induced inhibitory currents also decrease stress, anxiety and addiction-related behaviors. Because of the well-established connection between stress and addiction, compounds that reduce stress-induced responses might be efficacious in treating addiction. Since endogenous neurosteroids such as allopregnanolone may function in a manner similar to benzodiazepines to reduce HPA axis activation and anxiety following stressful stimuli, we hypothesized that exogenously applied neurosteroids would reduce cocaine reinforcement in two animal models.Methods
Male Wistar rats were trained to self-administer cocaine and food under a concurrent alternating operant schedule of reinforcement. Two separate groups of rats were trained to self-administer cocaine or food pellets and were then exposed to similar cue-induced reinstatement paradigms. Both groups of rats were pretreated with various doses of neurosteroids.Results
Allopregnanolone and 3α-hydroxy-3β-methyl-17β-nitro-5α-androstane (R6305-7, a synthetic neurosteroid) were ineffective in selectively decreasing cocaine relative to food self-administration. On the other hand, both allopregnanolone and R6305-7 significantly decreased the cue-induced reinstatement of extinguished cocaine seeking, confirmed by one-way ANOVA.Conclusions
These results suggest that neurosteroids may be effective in reducing the relapse to cocaine use without affecting ongoing cocaine self-administration. 相似文献3.
Zi-Wei Chen Cunde Wang Kathiresan Krishnan Brad D. Manion Randy Hastings John Bracamontes Amanda Taylor Megan M. Eaton Charles F. Zorumski Joseph H. Steinbach Gustav Akk Steven Mennerick Douglas F. Covey Alex S. Evers 《Psychopharmacology》2014,231(17):3479-3491
Rationale
While neurosteroids are well-described positive allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors, the binding sites that mediate these actions have not been definitively identified.Objectives
This study was conducted to synthesize neurosteroid analogue photolabeling reagents that closely mimic the biological effects of endogenous neurosteroids and have photochemical properties that will facilitate their use as tools for identifying the binding sites for neurosteroids on GABAA receptors.Results
Two neurosteroid analogues containing a trifluromethyl-phenyldiazirine group linked to the steroid C11 position were synthesized. These reagents, CW12 and CW14, are analogues of allopregnanolone (5α-reduced steroid) and pregnanolone (5β-reduced steroid), respectively. Both reagents were shown to have favorable photochemical properties with efficient insertion into the C–H bonds of cyclohexane. They also effectively replicated the actions of allopregnanolone and pregnanolone on GABAA receptor functions: they potentiated GABA-induced currents in Xenopus laevis oocytes transfected with α1β2γ2L subunits, modulated [35S]t-butylbicyclophosphorothionate binding in rat brain membranes, and were effective anesthetics in Xenopus tadpoles. Studies using [3H]CW12 and [3H]CW14 showed that these reagents covalently label GABAA receptors in both rat brain membranes and in a transformed human embryonal kidney (TSA) cells expressing either α1 and β2 subunits or β3 subunits of the GABAA receptor. Photolabeling of rat brain GABAA receptors was shown to be both concentration-dependent and stereospecific.Conclusions
CW12 and CW14 have the appropriate photochemical and pharmacological properties for use as photolabeling reagents to identify specific neurosteroid-binding sites on GABAA receptors. 相似文献4.
Miguel Molina-Hernández N. Patricia Téllez-Alcántara Jorge I. Olivera-López M. Teresa Jaramillo 《Psychopharmacology》2014,231(17):3343-3350
Rationale
There is a significant delay in the clinical response of antidepressant drugs, and antidepressant treatments produce side effects.Objective
We examined the relationship between 17β-estradiol and topiramate in ovariectomized Wistar rats submitted to the forced swimming test (FST).Methods
Topiramate was administered alone or combined with 17β-estradiol to ovariectomized rats submitted to the FST.Results
Topiramate (20 mg/kg, P?0.05; 30 mg/kg, P?0.05) reduced immobility by increasing swimming; these effects were antagonized by finasteride (50 mg/kg). In interaction experiments, topiramate (10 mg/kg) plus 17β-estradiol (5 micrograms per rat; P?0.05) reduced immobility by increasing swimming behavior. Besides, 17β-estradiol (2.5 micrograms per rat) shortened the onset of the antidepressant-like effects of topiramate (P?0.05). In the open field test, topiramate alone or combined with 17β-estradiol (P?0.05) reduced locomotion.Conclusions
Topiramate alone or combined with 17β-estradiol produced antidepressant-like actions; and 17β-estradiol shortened the onset of the antidepressant-like effects of topiramate. 相似文献5.
Renu Chadha Swati Bhandari Sadhika Khullar Sanjay K. Mandal D. V. S. Jain 《Pharmaceutical research》2014,31(9):2479-2489
Purpose
The present work aims at improving the physicochemical properties of hydrochlorothiazide, a poorly water soluble antihypertensive drug by preparing its multi-component crystals with nicotinic acid (HCT-NA) and 2-picolinic acid (HCT-PIC).Methods
The crystals prepared by solution crystallization were investigated by thermoanalytical techniques. The crystal structures of HCT-NA (1) and HCT-PIC (2) were determined by the single crystal X-ray diffraction and were assessed for their aqueous solubility, antihypertensive activity and acute toxicity in rats.Results
Both 1 and 2 crystallized in the orthorhombic space group P212121 and formation of salts were confirmed. The solubility profiles of 1 and 2 in basic media showed a maximum release of 2.5 mg/ml and 1.9 mg/ml, respectively, in comparison to the drug (0.82 mg/ml). The in-vivo antihypertensive activity of 1 in deoxycorticosterone acetate salt induced hypertensive rats showed 1.5 fold improvement. No increase in the signs of toxicity were revealed in rats during the acute toxicity studies even at doses of 2,000 mg/kg by body weight in comparison to the free drug. Histopathological findings supported the safety of these multi-component crystals.Conclusions
The new solid phases exhibit potential to be explored for the oral drug delivery of HCT with improved solubility and therapeutic outcome. 相似文献6.
Derk J. Hogenkamp Minhtam B. Tran Ryan F. Yoshimura Timothy B. Johnstone Richard Kanner Kelvin W. Gee 《Psychopharmacology》2014,231(17):3517-3524
Rationale
In order to improve upon the pharmacological properties of the neuroactive steroid ganaxolone, it was used as the starting point in the design of novel neurosteroids that replace the 17β-acetyl side chain with an isoxazole bioisostere.Objectives
UCI-50027 (3-[3α-hydroxy-3β-methyl-5α-androstan-17β-yl]-5-(hydroxymethyl)isoxazole) was designed as an orally active neuroactive steroid specifically targeted at the gamma-aminobutyric acid(A) receptor (GABAAR).Methods
UCI-50027 was tested in vitro in Xenopus oocytes expressing human GABAARs and in vivo as an anticonvulsant, for ataxic effects and for anxiolytic activity.Results
In vitro, UCI-50027 dose-dependently enhanced the activity of GABA at human α1β2γ2L, α2β1γ2L, and α4β3δ GABAARs. Consistent with its action as a positive allosteric modulator (PAM), it had no direct activity in the absence of GABA. UCI-50027 protected against acute pentylenetetrazol (PTZ)-induced convulsions with an ED50 of 6 mg/kg p.o. In the rotarod (RR) paradigm in mice, the AD50 (the ataxic dose where half of the animals fail the RR test) was found to be 38 mg/kg p.o., giving a therapeutic index (TI = RR AD50/PTZ ED50)~6 versus 2.8 for ganaxolone. In the mouse-elevated plus maze (EPM) model for anxiety, UCI-50027 showed a minimum effective dose (MED) ≤0.3 mg/kg p.o. Thus, the TI (TI = RR AD50/EPM MED) for the compound as an anxiolytic is ≥127 versus 3.3 for ganaxolone.Conclusions
UCI-50027 is an orally active neuroactive steroid with pharmacological activity consistent with a GABAAR PAM that has an improved separation between anticonvulsant/anxiolytic and rotarod effects, potent activity as an anticonvulsant and anxiolytic when compared to ganaxolone. 相似文献7.
Dorota Zolkowska Ashish Dhir Kathiresan Krishnan Douglas F. Covey Michael A. Rogawski 《Psychopharmacology》2014,231(17):3325-3332
Rationale
Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms.Objectives
The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models.Methods
Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ).Results
In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α-A and 5α,3α-A, respectively. Similar relationships were obtained for the 5β-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5β,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5β,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5β,3α-A also persisted longer (~3 h) than for 5β,3α-A (~2 h).Conclusions
The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics. 相似文献8.
Rationale
The neurosteroid 3α,5β-THP (3α-OH-5β-pregnan-20-one, pregnanolone) is a modulator of the GABAA receptor (GABAR), with α4β2δ GABARs the most sensitive. However, the effects of 3α,5β-THP at α4β2δ are polarity-dependent: 3α,5β-THP potentiates depolarizing current, as has been widely reported, but decreases hyperpolarizing current by accelerating desensitization.Objectives
The present study further characterized 3α,5β-THP inhibition of hyperpolarizing current at this receptor and compared effects of other related steroids at α4β2δ GABARs.Methods
α4β2δ GABARs were expressed in HEK-293 cells, and agonist-gated current recorded with whole cell voltage-clamp techniques using a theta tube to rapidly apply agonist before and after application of neurosteroids.Results
The GABA-modulatory steroids (30 nM) 3α,5α-THP (3α-OH-5α-pregnan-20-one, allopregnanolone) and THDOC (3α,21-dihydroxy-5α-pregnan-20-one) inhibited hyperpolarizing GABA (10 μM)-gated current at α4β2δ GABARs similar to 3α,5β-THP, while the inactive 3β,5β-THP isomer had no effect. Greater inhibition was seen for current gated by the high efficacy agonist gaboxadol (THIP, 100 μM) than for GABA (0.1–1000 μM), consistent with an effect of 3α,5β-THP on desensitization. Inhibitory effects of the steroid were not seen under low [Cl?] conditions or in the presence of calphostin C (500 nM), an inhibitor of protein kinase C. Chimeras swapping the IL (intracellular loop) of α4 with α1, when expressed with β2 and δ, produced receptors (α[414]β2δ) which were not inhibited by 3α,5β-THP when GABA-gated current was hyperpolarizing, while α[141]β2δ exhibited steroid-induced polarity-dependent modulation.Conclusions
These findings suggest that numerous neurosteroids exhibit polarity-dependent effects at α4β2δ GABARs, which are dependent upon protein kinase C and the IL of α4. 相似文献9.
Rationale
Drug addiction represents a pathological usurpation of neural processes involved in learning and memory. Retrieval of drug-related memories can result in drug craving and relapse. Recently, the insula was identified as part of the neuronal circuit responsible for the processing of drug memory; however, its precise role remains unclear.Objective
To investigate the involvement of insular muscarinic acetylcholine receptors (mAChRs) in the processing of drug memory.Method
The morphine-induced conditioned place preference (CPP) was used to assess drug memory. All rats were first trained with morphine to establish the CPP. Sub-groups of these rats were used for contextual cue-induced CPP reinstatement. Other sub-groups of rats underwent extinction of the CPP, and 5 m/kg morphine was used for priming-induced CPP reinstatement. Microinjection of mAChR antagonists or agonists into the insula was performed prior to the CPP tests in order to evaluate their effect on CPP expression.Results
Insular microinjections of the nonselective mAChR antagonist, scopolamine, and the M1 antagonist, pirenzepine, significantly inhibited CPP expression in both contextual cue- and priming-induced CPP reinstatement; the M1 agonist, MCN-A-343, and the M4 antagonist, tropicamide, enhanced CPP expression. The M4 agonist, LY2033298, inhibited CPP expression. The M2 antagonist, methoctramine, and M3 antagonist, 4-DAMP, had no effect on CPP expression.Conclusion
Our results demonstrate that insular mAChRs play a role in the processing of drug memory. M1 and M4 mAChRs work paradoxically; M1 activation and M4 inhibition attenuate the expression of drug memory, while M1 inhibition and M4 activation augment the expression of drug memory. 相似文献10.
Fadia El Bitar Johann Meunier Vanessa Villard Marion Alméras Kathiresan Krishnan Douglas F. Covey Tangui Maurice Yvette Akwa 《Psychopharmacology》2014,231(17):3293-3312
Rationale
Pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are pro-amnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer’s disease (AD) patient’s brains, their low concentrations are correlated with high levels of Aβ and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models.Objective
The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Aβ25–35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice.Methods
B104 cells pretreated with the steroids before Aβ25–35 were analysed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Aβ25–35 and the steroids were analysed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured.Results
ent-PREGS and PREGS significantly attenuated the Aβ25–35-induced decrease in cell viability. Both steroids prevented the Aβ25–35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Aβ25–35-induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Aβ25–35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Aβ25–35-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before Aβ25–35 in contrast to the natural steroids.Conclusion
The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD. 相似文献11.
Rationale
Endocannabinoids (eCN) exert biphasic effects on several behaviours; however, they have only been reported to inhibit male sexual behaviour. eCN, the endogenous ligands for CB1 receptors, are released in response to neuronal stimulation and regulate the functioning of the mesocorticolimbic system (MCL), which is activated by male sexual behaviour. We hypothesised that eCN might exert biphasic effects on male rat copulatory behaviour and be released during copulation to satiation as a result of the repeated activation of the MCL system.Objectives
The study was conducted to determine if the eCN anandamide exerts biphasic effects on sexual behaviour expression of sexually experienced and sexually satiated male rats and to establish the possible participation of eCN in the sexual satiation phenomenon.Methods
The eCN anandamide and the CB1 receptor antagonist AM251 were systemically administered to sexually experienced or sexually satiated rats and their effects on copulatory behaviour analysed.Results
Low anandamide doses facilitated sexual behaviour expression in sexually experienced and in sexually satiated rats by acting at CB1 receptors. AM251 blocked the establishment of the sexual inhibition that characterises sexual satiation, but did not reverse it once established.Conclusions
Anandamide exerts dose-based biphasic effects on copulatory behaviour of sexually experienced male rats and facilitates sexual behaviour expression of sexually satiated animals at low doses. eCN participate in the establishment, but not in the maintenance of the sexual inhibitory state that characterises the sexual satiation phenomenon. 相似文献12.
Elizabeth Murray Sietske Brouwer Rob McCutcheon Catherine J. Harmer Philip J. Cowen Ciara McCabe 《Psychopharmacology》2014,231(22):4323-4335
Rationale
Opioid antagonism reduces the consumption of palatable foods in humans but the neural substrates implicated in these effects are less well understood.Objectives
The aim of the present study was to examine the effects of the opioid antagonist, naltrexone, on neural response to rewarding and aversive sight and taste stimuli.Methods
We used functional magnetic resonance imaging (fMRI) to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 20 healthy volunteers who received a single oral dose of naltrexone (50 mg) and placebo in a double-blind, repeated-measures cross-over, design.Results
Relative to placebo, naltrexone decreased reward activation to chocolate in the dorsal anterior cingulate cortex and caudate, and increased aversive-related activation to unpleasant strawberry in the amygdala and anterior insula.Conclusions
These findings suggest that modulation of key brain areas involved in reward processing, cognitive control and habit formation such as the dorsal anterior cingulate cortex (dACC) and caudate might underlie reduction in food intake with opioid antagonism. Furthermore we show for the first time that naltrexone can increase activations related to aversive food stimuli. These results support further investigation of opioid treatments in obesity. 相似文献13.
Tingsheng Lin Yifan Zhang Jinhui Wu Xiaozhi Zhao Huibo Lian Wei Wang Hongqian Guo Yiqiao Hu 《Pharmaceutical research》2014,31(10):2655-2663
Aim
Intravesical instillation is commonly used to decrease the tumor recurrence after transurethral resection. However, most drug solutions would be eliminated from bladder after the first voiding of urine, so its clinical efficacy is limited. To overcome this obstacle, we developed a floating hydrogel system for controlled delivery of antitumor drugs.Methods
The floating hydrogel was made of Adriamycin, thermo-sensitive polymer (Poloxamer 407) and NH4HCO3, which was liquid at low temperature while forming hydrogel at high temperature. Meanwhile, at high temperature, NH4HCO3 decomposed to produce CO2 bubbles, which helped hydrogel float in bladder without urinary obstruction.Results
The mixture containing 45% P407 and 6% NH4HCO3 was selected as the optimal formulation. At 37°C, the mixture formed hydrogel and produced many bubbles which could be observed by B ultrasound. The vitro study showed that the antitumor drug Doxorubicin was released in a controlled manner. After the mixture was instilled into rabbit bladder, it formed hydrogel and floated in the bladder. The bladder stimuli was reduced and antitumor drugs could be released continuously in the bladder.Conclusion
Our results suggested that the floating hydrogel was a feasible intravesical drug delivery system and may have application prospects in intravesical therapy for bladder cancer. 相似文献14.
Jayme R. McReynolds Oliver Vranjkovic Malia Thao David A. Baker Khadijah Makky Yiwei Lim John R. Mantsch 《Psychopharmacology》2014,231(20):3953-3963
Rationale
Understanding the mechanisms responsible for stress-induced relapse is important for guiding treatment strategies aimed at minimizing the contribution of stress to addiction. Evidence suggests that these mechanisms involve interactions between noradrenergic systems and the neuropeptide corticotropin-releasing factor (CRF).Objectives
The interaction between β-adrenergic receptors (ARs) and CRF as it relates to the reinstatement of cocaine-conditioned reward in response to a stressor was examined in mice. We hypothesized that β2-ARs are required for stress-induced activation of CRF pathways responsible for reinstatement.Methods
Stress-induced relapse was examined based on the re-establishment of cocaine-induced conditioned place preference (CPP; 4?×?15 mg/kg cocaine, i.p.) after extinction using forced swim (6 min at 22 °C) or an injection of the β2-AR agonist, clenbuterol (4 mg/kg, i.p.). The CRF-R1 antagonist antalarmin (10 mg/kg, i.p.) or the β2-AR antagonist ICI-118,551 (1 mg/kg, i.p.) were given 30 min prior to reinstating stimuli. Quantitative PCR was conducted in dissected bed nucleus of the stria terminalis (BNST) and amygdala, putative sources of CRF that contribute to reinstatement, to examine the effects of ICI-118,551 on swim-induced increases in CRF messenger RNA (mRNA) in mice with a cocaine history.Results
Pretreatment with ICI-118,551 or antalarmin blocked swim-induced reinstatement of CPP. Reinstatement by clenbuterol was also blocked by antalarmin. ICI-118,551 pretreatment prevented swim-induced increases in CRF mRNA in the BNST. Effects in the amygdala were not observed.Conclusions
These findings indicate that, during stress, norepinephrine, via β2-ARs, either directly or indirectly activates CRF-releasing neurons in the BNST that interface with motivational neurocircuitry to induce reinstatement of cocaine-conditioned reward. 相似文献15.
Miguel A. Rodrigues João M. Tiago Luis Padrela Henrique A. Matos Teresa G. Nunes Lídia Pinheiro António J. Almeida Edmundo Gomes de Azevedo 《Pharmaceutical research》2014,31(11):3136-3149
Purpose
To prepare and thoroughly characterize a new polymorph of the broad-spectrum antibiotic minocycline from its hydrochloride dehydrate salts.Methods
The new minocycline hydrochloride polymorph was prepared by means of the antisolvent effect caused by carbon dioxide. Minocycline recrystallized as a red crystalline hydrochloride salt, starting from solutions or suspensions containing CO2 and ethanol under defined conditions of temperature, pressure and composition.Results
This novel polymorph (β-minocycline) revealed characteristic PXRD and FTIR patterns and a high melting point (of 247?ºC) compared to the initial minocycline hydrochloride hydrates (α-minocycline). Upon dissolution the new polymorph showed full anti-microbial activity. Solid-state NMR and DSC studies evidenced the higher chemical stability and crystalline homogeneity of β-minocycline compared to the commercial chlorohydrate powders. Molecular structures of both minocyclines present relevant differences as shown by multinuclear solid-state NMR.Conclusions
This work describes a new crystalline structure of minocycline and evidences the ability of ethanol-CO2 system in removing water molecules from the crystalline structure of this API, at modest pressure, temperature and relatively short time (2 h), while controlling the crystal habit. This process has therefore the potential to become a consistent alternative towards the control of the solid form of APIs. 相似文献16.
Margaret C. Wardle Daniel A. Fitzgerald Michael Angstadt Christine A. Rabinak Harriet de Wit K. Luan Phan 《Psychopharmacology》2014,231(22):4403-4415
Rationale
Evidence from animal and human studies suggests that opiate drugs decrease emotional responses to negative stimuli and increase responses to positive stimuli. Such emotional effects may motivate misuse of oxycodone (OXY), a widely abused opiate. Yet, we know little about how OXY affects neural circuits underlying emotional processing in humans.Objective
We examined effects of OXY on brain activity during presentation of positive and negative visual emotional stimuli. We predicted that OXY would decrease amygdala activity to negative stimuli and increase ventral striatum (VS) activity to positive stimuli. Secondarily, we examined the effects of OXY on other emotional network regions on an exploratory basis.Methods
In a three-session study, healthy adults (N?=?17) received placebo, 10 and 20 mg OXY under counterbalanced, double-blind conditions. At each session, participants completed subjective and cardiovascular measures and underwent functional MRI (fMRI) scanning while completing two emotional response tasks.Results
Our emotional tasks reliably activated emotional network areas. OXY produced subjective effects but did not alter either behavioral responses to emotional stimuli or activity in our primary areas of interest. OXY did decrease right medial orbitofrontal cortex (MOFC) responses to happy faces.Conclusions
Contrary to our expectations, OXY did not affect behavioral or neural responses to emotional stimuli in our primary areas of interest. Further, the effects of OXY in the MOFC would be more consistent with a decrease in value for happy faces. This may indicate that healthy adults do not receive emotional benefits from opiates, or the pharmacological actions of OXY differ from other opiates. 相似文献17.
Rationale
Varenicline, a partial agonist at α4β2 nicotinic receptors (nAChRs) aids smoking cessation by reducing craving. Successful quitting may be associated with greater inhibitory control but the effectiveness of varenicline in this regard is unknown.Objectives
This study aimed to investigate the effect of varenicline on aspects of inhibitory control in smokers.Methods
A double-blind, placebo-controlled study investigating the effect of varenicline 1 mg (or matched placebo) in satiated and abstinent smokers. Tests included Rapid Visual Information Processing (RVIP), Stop-Signal (SS), Prospective Memory (PM) and the Cambridge Gambling Task (CGT).Results
Smoking enhanced RVIP accuracy and latency to respond. Varenicline did not alter RVIP performance, nor the effect of smoking, suggesting that these effects were unrelated to α4β2 nAChRs. Smoking increased the number of errors during SS and increased the stop latency, indicating that smoking decreased inhibitory control. Varenicline partially mimicked this effect of smoking but also reduced the smoking-induced increase, indicating a role for α4β2 nAChRs. Likewise, smoking increased the number of points bet following a win during CGT and varenicline blocked this effect. There was no effect of smoking or varenicline on PM target detection per se. However, smoking protected the target detection rate in the ongoing task when a concurrent intention was introduced. Varenicline improved response speed in both satiated and abstinent smokers.Conclusions
Some aspects of inhibitory control may be mediated by α4β2-related mechanisms and blockade of smoking-induced disinhibition may contribute towards the action of varenicline as an aid to smoking cessation. 相似文献18.
Introduction
Epidemiological and clinical life cycle studies have indicated that the more favorable illness course and the better response to antipsychotic drugs (APDs) in women with schizophrenia correlate with high levels of estrogen, whereas increased vulnerability to exacerbation and relapse and reduced sensitivity to treatment are associated with low estrogen levels. Accordingly, the estrogen hypothesis of schizophrenia proposes that estrogen has a neuroprotective effect in women vulnerable to schizophrenia.Materials and methods
Latent inhibition (LI), the capacity to ignore stimuli that received nonreinforced preexposure prior to conditioning, is disrupted in acute schizophrenia patients and in rats and humans treated with the psychosis inducing drug amphetamine. Disruption of LI is reversible by typical and atypical APDs. The present study tested whether low levels of estrogen induced by ovariectomy (OVX) would lead to disruption of LI in female rats and whether such disruption would be normalized by estrogen replacement treatment and/or APDs.Results
Results showed that OVX led to LI disruption, which was reversed by 17β-estradiol (150 μg/kg) and the atypical APD clozapine (5 mg/kg), but not by the typical APD haloperidol (0.1, 0.2, 0.3 mg/kg). Haloperidol regained efficacy when administered with 17β-estradiol (50 μg/kg).Discussion
These results provide the first demonstration in rats that low levels of hormones can induce a pro-psychotic state that is resistant to at least typical antipsychotic treatment. This constellation may mimic states seen in schizophrenic women during periods associated with low levels of hormones such as the menopause. 相似文献19.
Prasopchai Tonglairoum Tanasait Ngawhirunpat Theerasak Rojanarata Ruchadaporn Kaomongkolgit Praneet Opanasopit 《Pharmaceutical research》2014,31(8):1893-1906
Purpose
This study investigates fabrication of clotrimazole (CZ)-composited electrospun Polyvinylpyrrolidone/Hydroxypropyl-β-cyclodextrin (PVP/HPβCD) blended nanofiber mats for oral candidiasis applications.Methods
PVP/HPβCD blended nanofiber mats containing clotrimazole were electrospun and characterized using SEM, DSC and XRPD. The solvent system ethanol: water: benzyl alcohol (EtOH:H2O:BzOH) with a 70:20:10 ratio was optimal for the electrospinning process. Various amounts of CZ were loaded into the nanofiber mats. The nanofiber mats was further investigated for drug release, antifungal activity and cytotoxicity.Results
The fiber diameters in the mats were in the nanometer range. The DSC and XRPD revealed a molecular dispersion of amorphous CZ in the nanofiber mats. The loading capacity increased when CZ content was raised. A fast dissolved and released of CZ from the nanofibers mat was achieved. The ability of the CZ-loaded nanofiber mats to kill the Candida depended on the amount of CZ in the mats; moreover, the CZ-loaded nanofibers killed the Candida significantly faster than the CZ powder and lozenges with low cytotoxicity.Conclusions
CZ-loaded nanofiber mats were successfully electrospun. They exhibited rapid antifungal activity in vitro relative to CZ powder and lozenges. Further in vivo studies are needed to investigate for their application in oral candidiasis. 相似文献20.
Dupre KB Eskow KL Steiniger A Klioueva A Negron GE Lormand L Park JY Bishop C 《Psychopharmacology》2008,199(1):99-108