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1.
Gen Hosp Psychiatry ; 87: 124-133, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38412585

RESUMO

OBJECTIVE: This network meta-analysis assessed the efficacy, tolerability, and acceptability of second-generation antipsychotics (SGAs) for Parkinson's disease psychosis (PDP). METHODS: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov for randomized controlled trials investigating SGAs for PDP up to October 26, 2023. RESULTS: We included 16 trials (N = 1252) investigating clozapine, melperone, olanzapine, pimavanserin, quetiapine, ulotaront, and placebo. In comparisons between SGAs and placebo, the findings were: i) Standardized mean differences, 95% confidence intervals (SMDs, 95%CIs), for psychotic-symptom reduction revealed the first rank of clozapine (-1.31, -1.73 to -0.89), the second rank of pimavanserin, with significant inferiority of quetiapine (SMD = 0.47, 0.02 to 0.92); ii) Mean differences (MDs, 95%CIs) for abnormal movement, as assessed by the Unified Parkinson's Disease Rating Scale - Part III, indicated that clozapine had the least motor side effects (-0.92, -2.75 to 0.91); iii) Risk ratios (RRs, 95% CIs) for adverse-effect dropout rates were lowest for melperone (1.02, 0.20 to 5.24); and iv) RRs (95% CIs) for all-cause dropout rates were lowest for clozapine (0.73, 0.42 to 1.25). CONCLUSIONS: For patients with PDP, clozapine may substantially reduce psychotic symptoms with minimal abnormal movement, high acceptability, and moderate overall tolerability. Pimavanserin, not quetiapine, could be an alternative.


Assuntos
Antipsicóticos , Clozapina , Doença de Parkinson , Transtornos Psicóticos , Humanos , Antipsicóticos/uso terapêutico , Butirofenonas , Clozapina/uso terapêutico , Discinesias/complicações , Discinesias/tratamento farmacológico , Metanálise em Rede , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Piperidinas , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/etiologia , Fumarato de Quetiapina/uso terapêutico , Ureia/análogos & derivados
3.
Gut ; 73(3): 459-469, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38191268

RESUMO

OBJECTIVE: We evaluated the histamine 1 receptor antagonist ebastine as a potential treatment for patients with non-constipated irritable bowel syndrome (IBS) in a randomised, placebo-controlled phase 2 study. METHODS: Non-constipated patients with IBS fulfilling the Rome III criteria were randomly assigned to 20 mg ebastine or placebo for 12 weeks. Subjects scored global relief of symptoms (GRS) and abdominal pain intensity (API). A subject was considered a weekly responder for GRS if total or obvious relief was reported and a responder for API if the weekly average pain score was reduced by at least 30% vs baseline. The primary endpoints were the proportion of subjects who were weekly responders for at least 6 out of the 12 treatment weeks for both GRS and API ('GRS+API', composite endpoint) and for GRS and API separately. RESULTS: 202 participants (32±11 years, 68% female) were randomly allocated to receive ebastine (n=101) or placebo (n=101). Treatment with ebastine resulted in significantly more responders (12%, 12/92) for GRS+API compared with placebo (4%, 4/87, p=0.047) while the proportion of responders for GRS and API separately was higher for ebastine compared with placebo, although not statistically significant (placebo vs ebastine, GRS: 7% (6/87) vs 15% (14/91), p=0.072; API: 25% (20/85) vs 37% (34/92), p=0.081). CONCLUSIONS: Our study shows that ebastine is superior to placebo and should be further evaluated as novel treatment for patients with non-constipated IBS. TRIAL REGISTRATION NUMBER: The study protocol was approved by the local ethics committee of each study site (EudraCT number: 2013-001199-39; ClinicalTrials.gov identifier: NCT01908465).


Assuntos
Síndrome do Intestino Irritável , Piperidinas , Humanos , Feminino , Masculino , Síndrome do Intestino Irritável/terapia , Histamina/uso terapêutico , Resultado do Tratamento , Butirofenonas/efeitos adversos , Método Duplo-Cego , Dor Abdominal/tratamento farmacológico
4.
J Hist Neurosci ; 33(2): 169-179, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38091571

RESUMO

Haloperidol, the first butyrophenone neuroleptic, was created in Europe by Janssen Pharmaceuticals in 1958 and was introduced swiftly throughout the continent with great enthusiasm. On September 15, 1959, at Janssen's headquarters in Belgium, teams from around Europe praised the effectiveness of haloperidol. In the United States, on the contrary, its introduction was a tremendous failure, plagued by accusations of inefficacy and patent disputes. A clinical trial in Manhattan has been blamed for this commercial failure. The results of the Manhattan trial were seen as radically different from the results obtained in continental Europe. This divide would have considerable impact not only with regard to haloperidol's path on both sides of the Atlantic, but also possibly on the practical experience and theoretical construction of psychiatry. This article tries to reconstruct the story of that trial based mainly on published papers and interviews. Exploring how societal changes and issues of gender and race shaped this process, this investigation attempts to understand and contextualize different possible reasons for this Atlantic rift.


Assuntos
Antipsicóticos , Haloperidol , Humanos , Antipsicóticos/uso terapêutico , Butirofenonas , Ensaios Clínicos como Assunto , Europa (Continente) , Haloperidol/uso terapêutico , Estados Unidos , Masculino , Feminino
5.
BMC Microbiol ; 23(1): 276, 2023 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-37773054

RESUMO

BACKGROUND: Staphylococcus haemolyticus (S. haemolyticus) is the main etiological factor in skin and soft tissue infections (SSTI). S. haemolyticus infections are an important concern worldwide, especially with the associated biofilms and drug resistance. Herein, we investigated the inhibitory effect of Flavaspidic acid BB obtained from plant extractions on clinical S. haemolyticus strains and their biofilms. Moreover, we predicted its ability to bind to the protein-binding site by molecular simulation. Since the combination of Hsp70 and RNase P synthase after molecular simulation with flavaspidic acid BB is relatively stable, enzyme-linked immunosorbent assay (ELISA) was used to investigate Hsp70 and RNase P synthase to verify the potential antimicrobial targets of flavaspidic acid BB. RESULTS: The minimum inhibitory concentrations (MIC) of flavaspidic acid BB on 16 clinical strains of S. haemolyticus was 5 ~ 480 µg/mL, and BB had a slightly higher inhibitory effect on the biofilm than MUP. The inhibitory effect of flavaspidic acid BB on biofilm formation was better with an increase in the concentration of BB. Molecular simulation verified its ability to bind to the protein-binding site. The combination of ELISA kits showed that flavaspidic acid BB promoted the activity of Hsp70 and inhibited the activity of RNase P, revealing that flavaspidic acid BB could effectively inhibit the utilization and re-synthesis of protein and tRNA synthesis, thus inhibiting bacterial growth and biofilm formation to a certain extent. CONCLUSIONS: This study could potentially provide a new prospect for the development of flavaspidic acid BB as an antibacterial agent for resistant strains.


Assuntos
Ribonuclease P , Staphylococcus , Ribonuclease P/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Butirofenonas/farmacologia , Testes de Sensibilidade Microbiana , Biofilmes
7.
J Psychopharmacol ; 36(9): 1007-1015, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36045588

RESUMO

Drugs used to treat psychotic disorders ('antipsychotics') have been widely used in psychiatry since the introduction of chlorpromazine in the mid-1950s. The categorization of these drugs evolved in a piecemeal way, relying initially on grouping by chemical structure (e.g. phenothiazines, butyrophenones), then by epoch of introduction (e.g. first generation ('conventional') vs second generation ('atypical')). As psychopharmacological expertise has advanced, it has become possible to quantify affinities for each drug in this class for relevant receptors including dopamine D2, 5HT2A, 5HT2C, histamine H1 and others. However, until the recent emergence of a new generation of agents known collectively as dopamine D2 receptor partial agonists (e.g. aripiprazole, brexpiprazole and cariprazine), there had been little reference in drug classification to specific pharmacological properties. An overview of data on receptor affinities across multiple drugs and receptor types would permit categorization according to binding affinities and putative pharmacological mechanisms. In this paper, we have attempted to construct a 'subway map' of 32 drugs used for treatment of psychotic disorders. This design allows a visualization of both the historical classifications by structure and epoch of introduction, and of the binding affinities for key receptors based on appraisal of scientific literature. The map represents a step towards categorization by mechanism, allowing prescribers and patients to understand which drugs share common biological features and the extent to which drugs may have similarities and differences in their mechanisms. In addition, this approach may encourage more logical groupings of drugs to be used in systematic reviews and meta-analyses.


Assuntos
Antipsicóticos , Transtornos Psicóticos , Ferrovias , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Butirofenonas/uso terapêutico , Clorpromazina , Dopamina/metabolismo , Agonistas de Dopamina/uso terapêutico , Histamina , Humanos , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/metabolismo , Receptores de Dopamina D2/metabolismo , Revisões Sistemáticas como Assunto
8.
Assay Drug Dev Technol ; 20(6): 258-273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36070596

RESUMO

Ebastine, a histamine H1 antagonist, nonsedating, belonging to BCS class II is used in the treatment of allergic rhinitis and chronic idiopathic urticaria. The current study was intended in augmenting the aqueous solubility and dissolution rate of ebastine, by formulating a microemulsion system using oleic acid, Transcutol® HP, and Tween®80 as oily phase, cosurfactant, and surfactant, respectively, by the phase titration method. A custom mixture design with optimality D was used to design the formulation by using the Design Expert® Software (Version 11; Stat-Ease, Inc., Minneapolis, MN, USA). Optimization of formulation was performed using the numerical optimization technique, where optimization is based upon the desirability. The optimized formulation was evaluated for transmittance, viscosity, globule size, polydispersity index, zeta potential, drug content, morphological studies, and in vitro studies. The optimized formulation displayed percent cumulative drug release, ranging from 82.9% to 90.6% obtained after dissolution studies and the percent cumulative drug release after diffusion studies ranged from 83.3% to 100%. The in vitro release data were subjected to kinetic treatment. The zero-order and first-order plots were linear and showed the highest values for R2, which indicated mixed-order release. The Higuchi plot was linear, indicating diffusion as the mechanism of release. From Peppas plot, it was further confirmed that the release for dissolution studies was anomalous and for diffusion studies it was zero order. Thus, the studies concluded that the microemulsion technique is a very good approach for enhancing the solubility and dissolution rate of the BCS class II drug ebastine.


Assuntos
Ácido Oleico , Polissorbatos , Butirofenonas , Emulsões , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Piperidinas , Solubilidade , Tensoativos
9.
BMC Microbiol ; 22(1): 179, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35840879

RESUMO

BACKGROUND: The increase in drug-resistant opportunistic pathogenic bacteria, especially of antibiotic-resistant Staphylococcus epidermidis (S. epidermidis), has led to difficulties in the treatment of skin and soft tissue infections (SSTI). The major reason for bacterial resistance is the formation of bacterial biofilm. Here, we report a promising combination therapy of flavaspidic acid BB (BB) and mupirocin, which can effectively eradicate the biofilm of S. epidermidis and eliminate its drug resistance. RESULT: The susceptibility test showed that the combination of BB and mupirocin has good antibacterial and antibiofilm activities, and the fractional inhibitory concentration index (FICI) of BB combined with mupirocin was 0.51 ± 0.00 ~ 0.75 ± 0.05, showing synergistic effect. Moreover, the time-kill curve assay results indicated that the combination of drugs can effectively inhibit the planktonic S. epidermidis. After drugs treatment, the drug-combination showed significantly inhibitory effects on the metabolic activity and total biomass in each stage of biofilm formation. The synergistic effect is likely related to the adhesion between bacteria, which is confirmed by field emission scanning electron microscope. And the expression level of aap, sarA and agrA genes were detected by real-time quantitative PCR (qRT-PCR). CONCLUSION: Our study provides the experimental data for the use of BB for the clinical treatment of skin infections and further demonstrate the potential of BB as a novel biofilm inhibitor.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Staphylococcus epidermidis , Antibacterianos/farmacologia , Biofilmes , Butirofenonas , Testes de Sensibilidade Microbiana , Mupirocina/farmacologia
10.
ScientificWorldJournal ; 2022: 9618344, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35645632

RESUMO

Ebastine is a long-acting, nonsedating, second-generation antihistaminic drug that prevents histamine action, mainly in immediate hypersensitivity. This project was aimed to formulate and characterize orodispersible tablets of ebastine, utilizing different proportions of three disintegrants, namely crospovidone, sodium starch glycolate, and coprocessed superdisintegrant. Initially, fifteen trial batches of ebastine orodispersible tablets were outlined using the central composite design of Minitab software. The tablets were formulated by the direct compression method. The compressed tablets were then evaluated for precompression and postcompression physicochemical parameters, such as angle of repose, Carr's index, Hausner's ratio, hardness, thickness, weight variation, drug content, friability, wetting time, disintegration time, dispersion time, and water absorption ratio. The in vitro dissolution test was conducted according to Indian Pharmacopeia 2018, with the help of the rotating paddle method using 0.5% w/v sodium lauryl sulfate buffer in 0.1 N HCl. For the optimized batch (8th batch), all the physicochemical parameters like angle of repose (33.77°), Carr's index (19.34%), Hausner's ratio (1.24), weight variation (202.5 mg), hardness (4.3 kg/cm2), friability (0.44%), thickness (3.16 mm), dissolution (95.78%), and drug content (101.67%) were within the acceptable limit as per Indian Pharmacopeia 2018. The wetting time, disintegration time, dispersion time, and water absorption ratio were reported to be 25.1 seconds, 16.0 seconds, 38.6 seconds, and 91.92%, respectively. Hence, the results suggested that orodispersible tablets of ebastine can be formulated. Furthermore, the mixing of crospovidone, sodium starch glycolate, and coprocessed super disintegrants can result in excellent desirable properties in the orodispersible tablet.


Assuntos
Química Farmacêutica , Povidona , Butirofenonas , Química Farmacêutica/métodos , Piperidinas , Controle de Qualidade , Solubilidade , Comprimidos/química , Água
11.
Drug Metab Dispos ; 50(11): 1434-1441, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35701183

RESUMO

Cytochrome P450s (P450s) have been identified and analyzed in dogs and pigs, species that are often used in preclinical drug studies. Moreover, P450s are clinically important for drug therapy not only in humans, but also in species under veterinary care, including dogs and cats. In the present study, seven P450s homologous to human CYP2J2, namely, dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J35, CYP2J91, and CYP2J93, were newly identified and characterized, along with pig CYP2J34 previously identified. The cDNAs of these CYP2Js contain open reading frames of 502 amino acids, except for CYP2J35 (498 amino acids), and share high sequence identity (77%-80%) with human CYP2J2. Phylogenetic analysis revealed that dog and cat CYP2J2 were closely related, whereas pig CYP2Js formed a cluster. All seven CYP2J genes contain nine coding exons and are located in corresponding genomic regions, with the pig CYP2J genes forming a gene cluster. These CYP2J2 mRNAs were predominantly expressed in the small intestine with additional expression in the kidney and brain for dog CYP2J2 and pig CYP2J91 mRNAs, respectively. All seven CYP2Js metabolized human CYP2J2 substrates terfenadine, ebastine, and astemizole, indicating that they are functional enzymes. Dog CYP2J2 and pig CYP2J34 and CYP2J35 efficiently catalyzed ebastine primary hydroxylation and secondary carebastine formation at low substrate concentrations, just as human CYP2J2 does. Velocity-versus-substate plots exhibited sigmoidal relationships for dog CYP2J2, cat CYP2J2, and pig CYP2J33, indicating allosteric interactions. These results suggest that dog, cat, and pig CYP2Js have similar functional characteristics to human CYP2J2, with slight differences in ebastine and astemizole oxidations. SIGNIFICANCE STATEMENT: Dog CYP2J2; cat CYP2J2; and pig CYP2J33, CYP2J34, CYP2J35, CYP2J91, and CYP2J93, homologous to human CYP2J2, were identified and characterized by sequence, phylogenetic, and genomic structure analyses. Intestinal expression patterns of CYP2J mRNAs were characteristic in dogs, cats, and pigs. Dog, cat, and pig CYP2Js likely play roles as drug-metabolizing enzymes in the small intestine, similar to human CYP2J2.


Assuntos
Gatos , Sistema Enzimático do Citocromo P-450 , Cães , Suínos , Animais , Astemizol , Butirofenonas , Gatos/genética , Citocromo P-450 CYP2J2 , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Cães/genética , Humanos , Filogenia , Piperidinas , Suínos/genética , Terfenadina
12.
Dermatol Ther ; 35(5): e15386, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35179272

RESUMO

The second-generation antihistamines at licensed doses are first-line treatment in urticaria and up-dosing is recommended as second-line treatment. To assess the efficacy and safety of escalated doses of ebastine in patients with chronic urticaria (CU), we designed this study. Recruited patients with CU were treated with increasing doses of ebstine. Treatment started at the daily dose of 10 mg. The symptom is assessed weekly, and if there is no significant improvement, the dose is increased from 10 mg to 20 mg, and if still no significant improvement, up to 40 mg. Pruritus, number, diameter, duration and frequency of wheals, and adverse reactions were assessed. One hundred and forty (76.50%) patients achieved marked effect with ebastine 10 mg/day, 27 (14.75%) patients with ebastine 20 mg/day and 13 (7.10%) patients with ebastine 40 mg/day, while 3(1.64%) patients did not get marked effect. There was no significant difference of effect between factitious urticaria, CSU, cholinergic urticaria and CSU with factitious urticaria in different dose (all p > 0.05). Common adverse reactions of ebstine treatment, included dry mouth, somnolence, tiredness and headache, were mild or moderate. There was no significant difference between the degree score of dry mouth with different doses of ebastine, and the same to somnolence, tiredness and headache (all p > 0.05). Doses escalation of ebastine should be effective in treatment of factitious urticaria, CSU and cholinergic urticaria with poorly treated by standard of double doses. Increasing ebastine dose did not increase the incidence of adverse reactions.


Assuntos
Urticária Crônica , Urticária , Xerostomia , Butirofenonas , Colinérgicos/uso terapêutico , Doença Crônica , Cefaleia/induzido quimicamente , Cefaleia/tratamento farmacológico , Antagonistas dos Receptores Histamínicos H1 , Humanos , Piperidinas , Estudos Prospectivos , Sonolência , Urticária/induzido quimicamente , Urticária/diagnóstico , Urticária/tratamento farmacológico , Xerostomia/induzido quimicamente , Xerostomia/tratamento farmacológico
13.
Drug Deliv ; 29(1): 52-61, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34962186

RESUMO

Urticaria affects all age groups of a population. It is triggered by allergens in foods, insect bites, medications, and environmental conditions. Urticaria is characterized by itching, a burning sensation, wheals and flares, erythema, and localized edema. The aim of this study was to develop a polymeric dosage form of ebastine using Carbopol 940 and mixture of span and tween. The emulsion was prepared, the gelling agent was added and the desired emulgel loaded with active drug was formulated. The formulations were subjected to physical stability, pH, viscosity, spreadability, drug content analysis, thermal analysis, in vitro drug release, and in vivo anti-allergic activity in animal model. The formulated emulgel exhibited good physical stability. The pH of the formulation was in the range of 5.2 ± 0.17 to 5.5 ± 0.20 which is suitable for topical application. Insignificant changes (p > .05) were observed in viscosity and spreadability of stored emulgels. The drug content was in the official limit of Pharmacopeia (i.e. 100 ± 10%). DSC measurements predicted that there is no interaction between the active moiety and excipients in emulgel formulation. The optimized formulation (ES3) released 74.25 ± 1.8% of ebastine after 12 h. The ebastine emulgel showed significant (p < .05; ANOVA) in vivo anti-allergic activity as compared to commercial product Benadryl® in histamine-induced allergy in rabbits. This study concluded that a topical drug delivery of ebastine-loaded emulgel could be well tolerated and safe for the treatment of urticaria/hives.


Assuntos
Resinas Acrílicas/química , Butirofenonas/farmacologia , Géis/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Piperidinas/farmacologia , Urticária/patologia , Administração Cutânea , Animais , Butirofenonas/administração & dosagem , Química Farmacêutica , Modelos Animais de Doenças , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões/química , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Concentração de Íons de Hidrogênio , Masculino , Piperidinas/administração & dosagem , Coelhos , Reologia , Viscosidade
14.
J Med Chem ; 64(18): 13622-13632, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34477381

RESUMO

Increased angiogenesis and vascular endothelial growth factor (VEGF) levels contribute to higher metastasis and mortality in uveal melanoma (UM), an aggressive malignancy of the eye in adults. (±)-MRJF22, a prodrug of the sigma (σ) ligand haloperidol metabolite II conjugated with the histone deacetylase (HDAC) inhibitor valproic acid, has previously demonstrated a promising antiangiogenic activity. Herein, the asymmetric synthesis of (R)-(+)-MRJF22 and (S)-(-)-MRJF22 was performed to investigate their contribution to (±)-MRJF22 antiangiogenic effects in human retinal endothelial cells (HREC) and to assess their therapeutic potential in primary human uveal melanoma (UM) 92-1 cell line. While both enantiomers displayed almost identical capabilities to reduce cell viability than the racemic mixture, (S)-(-)-MRJF22 exhibited the highest antimigratory effects in endothelial and tumor cells. Given the fundamental contribution of cell motility to cancer progression, (S)-(-)-MRJF22 may represent a promising candidate for novel antimetastatic therapy in patients with UM.


Assuntos
Inibidores da Angiogênese/farmacologia , Butirofenonas/farmacologia , Melanoma/tratamento farmacológico , Ácidos Pentanoicos/farmacologia , Piperidinas/farmacologia , Pró-Fármacos/farmacologia , Neoplasias Uveais/tratamento farmacológico , Valeratos/farmacologia , Inibidores da Angiogênese/síntese química , Butirofenonas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ácidos Pentanoicos/síntese química , Piperidinas/líquido cefalorraquidiano , Pró-Fármacos/síntese química , Estereoisomerismo , Valeratos/líquido cefalorraquidiano
15.
PLoS One ; 16(8): e0255829, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34370776

RESUMO

In anaesthetic practice the risk of hypoxia and arterial blood gas disturbances is evident, as most anaesthetic regimens depress the respiratory function. Hypoxia may be extended during recovery, and for this reason we wished to investigate if oxygen supply during a one hour post-operative period reduced the development of hypoxia and respiratory acidosis in rats anaesthetized with fentanyl/fluanisone and midazolam. Twelve Sprague Dawley rats underwent surgery and were divided in two groups, breathing either 100% oxygen or atmospheric air during a post-operative period. The peripheral blood oxygen saturation and arterial acid-base status were analyzed for differences between the two groups. We found that oxygen supply after surgery prevented hypoxia but did not result in a significant difference in the blood acid-base status. All rats developed respiratory acidosis, which could not be reversed by supplemental oxygen supply. We concluded that oxygen supply improved oxygen saturation and avoided hypoxia but did not have an influence on the acid-base status.


Assuntos
Midazolam , Animais , Butirofenonas , Fentanila , Masculino , Ratos
16.
Drug Metab Pers Ther ; 36(3): 233-237, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-34412172

RESUMO

OBJECTIVES: Since melperone abuse with lethal intoxication is common, expert opinions based on therapeutical and lethal concentration ranges can be considered as important. Because there is a lack of information about fatalities caused by melperone mono-intoxications and data on tissue samples with concentration distribution, the aim of this work is the examination of lethal concentration ranges of melperone and drug quantification in different matrices. METHODS: An LC-MS/MS method was applied for analyses performed in blood and tissue samples. Quantification based on standard addition and sample preparation on liquid-liquid extraction with 1-chlorobutane. An appropriate tissue homogenization was performed ahead of extraction with an IKA Ultra-Turrax-Tube-Drive®. A Luna 5 µm C18 (2) 100 Å, 150  × 2 mm analytical column was used for chromatographic separation and the elution was performed with two mobile phases consisted of A (H2O/methanol = 95/5, v/v) and B (H2O/methanol = 3/97, v/v) both with 10 mM ammonium acetate and 0.1% acetic acid. RESULTS: A multi-drug LC-MS/MS analytical method developed was applied successfully for melperone quantification in different post-mortem matrices. No analytical problems could be identified during method development and analyses of real samples. The melperone lethal concentration calculated in femoral blood of the drug mono-intoxication investigated was 10 mg/L. Melperone concentration distribution was presented for the first time. CONCLUSIONS: The lethal reference concentration of melperone in femoral blood of 17.1 mg/L pointed out in different reference lists should be used with caution. Instead, a lower lethal melperone concentration should be considered. The post-mortem concentration distribution of the drug presented could be helpful in the interpretation of cases where no blood samples are available.


Assuntos
Butirofenonas , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Humanos , Extração Líquido-Líquido , Espectrometria de Massas em Tandem/métodos
17.
Forensic Sci Int ; 325: 110888, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34186472

RESUMO

We present a case of fatal poisoning by 4-F-methcathinone (4-FMC; also called flephedrone), 4-methoxy-α-pyrrolidinopentiophenone (4-MeO-α-PVP), 4-fluoro-α-pyrrolidinopentiophenone (4-F-α-PVP), and α-pyrrolidinohepatanophenone (PV8). In this study, we compared the mass spectra of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, PV8, and α-pyrrolidinohexanophenone between LC-ESI-LIT-MS and GC-EI-MS analyses. Subsequently, we applied LC-ESI-LIT-MS for detection and quantification analyses of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in human authentic whole blood samples. More specific mass spectra for the target compounds were obtained with the LC-ESI-LIT-MS qualitative analyses than with the GC-EI-MS analyses, indicating that LC-ESI-LIT-MS was more suitable for the qualitative analysis of cathinones. The LC-ESI-LIT-MS validation data showed moderately good linearity and reproducibility for the compounds in the quantitative analyses at the range of 1-500 ng/mL. The detection limits of four cathinones ranged from 0.1 to 1 ng/mL. The concentrations of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in heart whole blood samples were 365, 449, 145, and 218 ng/mL, respectively. Those of the 4 cathinones in femoral vein whole blood samples were 397, 383, 127, and 167 ng/mL, respectively. We can then assume that the cause of death was acute poisoning by a combination of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8. In this article, we present a detailed LC-ESI-LIT-MS procedure for detection and quantification analyses of 4-FMC, 4-MeO-α-PVP, 4-F-α-PVP, and PV8 in authentic human whole blood samples.


Assuntos
Alcaloides/sangue , Butirofenonas/sangue , Pentanonas/sangue , Propiofenonas/sangue , Psicotrópicos/sangue , Pirrolidinas/sangue , Adulto , Cromatografia Líquida , Toxicologia Forense , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Espectrometria de Massas por Ionização por Electrospray
18.
Neurotox Res ; 39(4): 1360-1371, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34043181

RESUMO

Chronic exposure to cathinone derivatives increases the risk of severe health hazards, whereas little is known about the detailed pathogenic mechanisms triggered by the derivatives. We have recently shown that treatment with α-pyrrolidinononanophenone (α-PNP, a highly lipophilic cathinone derivative possessing a long hydrocarbon main chain) provokes neuronal cell apoptosis and its 4'-fluorinated analog (F-α-PNP) potently augments the apoptotic effect. In this study, we found that neuronal SK-N-SH cell damage elicited by F-α-PNP treatment is augmented most potently by pre-incubation with an AKR1B1 inhibitor tolrestat, among specific inhibitors of four aldo-keto reductase (AKR) family members (1B1, 1C1, 1C2, and 1C3) expressed in the neuronal cells. In addition, forced overexpression of AKR1B1 remarkably lowered the cell sensitivity to F-α-PNP toxicity, clearly indicating that AKR1B1 protects from neurotoxicity of the derivative. Treatment of SK-N-SH cells with F-α-PNP resulted in a dose-dependent up-regulation of AKR1B1 expression and activation of its transcription factor NF-E2-related factor 2. Metabolic analyses using liquid chromatography/mass spectrometry/mass spectrometry revealed that AKR1B1 is hardly involved in the F-α-PNP metabolism. The F-α-PNP treatment resulted in production of reactive oxygen species and lipid peroxidation byproduct 4-hydroxy-2-nonenal (HNE) in the cells. The enhanced HNE level was reduced by overexpression of AKR1B1, which also lessened the cell damage elicited by HNE. These results suggest that the AKR1B1-mediated neuronal cell protection is due to detoxification of HNE formed by F-α-PNP treatment, but not to metabolism of the derivative.


Assuntos
Aldeído Redutase/biossíntese , Butirofenonas/toxicidade , Drogas Desenhadas/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neuroproteção/fisiologia , Pirrolidinas/toxicidade , Aldeído Redutase/antagonistas & inibidores , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Naftalenos/farmacologia , Neurônios/patologia
19.
Physiol Rep ; 9(7): e14810, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33818005

RESUMO

BACKGROUND: Local ischemic preconditioning (IPC) and remote ischemic conditioning (RIC) induced by brief periods of ischemia and reperfusion protect against ischemia-reperfusion injury. METHODS: We studied the sensitivity to IR-injury and the influence of strain, age, supplier, and anesthesia upon the efficacy of IPC and RIC in 7- and 16-weeks-old Sprague-Dawley and Wistar rats from three different suppliers. The influence of sedation with a hypnorm and midazolam mixture (rodent mixture) and pentobarbiturate was compared. RESULTS: IPC attenuated infarct size in both 7-weeks-old Sprague-Dawley (48.4 ± 17.7% vs. 20.3 ± 6.9, p < 0.001) and 7-weeks-old Wistar (55.6 ± 10.9% vs. 26.8 ± 5.0%, p < 0.001) rats. Infarct size was larger in 16-weeks-old Sprague-Dawley rats, however, IPC still lowered infarct size (78.8 ± 9.2% vs. 58.3 ± 12.3%, p < 0.01). RIC reduced infarct sizes in 7-weeks-old Sprague-Dawley (75.3 ± 11.8% vs. 58.6 ± 8.9%, p < 0.05), but not in 7-weeks-old Wistar rats (31.7 ± 17.6% and 24.0 ± 12.6%, p = 0.2). In 16-weeks-old Sprague-Dawley rats, RIC did not induce protection (76.4 ± 5.5% and 73.2 ± 14.7%, p = 0.6). However, RIC induced protection in 16-weeks-old Wistar rats (45.2 ± 8.5% vs. 14.7 ± 10.8%, p < 0.001). RIC did not reduce infarct size in 7-weeks-old Sprague-Dawley rats from Charles River (62.0 ± 13.5% and 69.4 ± 10.4% p = 0.3) or 16-weeks-old Wistar rats from Janvier (50.7 ± 11.3 and 49.2 ± 16.2, p = 0.8). There was no difference between sedation with rodent mixture or pentobarbiturate. CONCLUSION: The cardioprotective effect of IPC is consistent across rat strains independent of age, strain, and supplier. RIC seems to be less reproducible, but still yields protection across different rat strains. However, age, animal supplier, and anesthetics may modulate the sensitivity of IR-injury and the response to RIC.


Assuntos
Analgesia/métodos , Precondicionamento Isquêmico/métodos , Traumatismo por Reperfusão Miocárdica/terapia , Pesquisa Translacional Biomédica/normas , Analgesia/efeitos adversos , Animais , Barbitúricos/administração & dosagem , Butirofenonas/administração & dosagem , Combinação de Medicamentos , Fentanila/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Preparação de Coração Isolado/normas , Masculino , Midazolam/administração & dosagem , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Ratos , Ratos Sprague-Dawley , Ratos Wistar
20.
Arch Toxicol ; 95(4): 1443-1462, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33550444

RESUMO

Synthetic cathinones are among the most popular new psychoactive substances, being abused for their stimulant properties, which are similar to those of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Considering that the liver is a likely target for cathinones-induced toxicity, and for their metabolic activation/detoxification, we aimed to determine the hepatotoxicity of three commonly abused synthetic cathinones: butylone, α-methylamino-butyrophenone (buphedrone) and 3,4-dimethylmethcathinone (3,4-DMMC). We characterized their cytotoxic profile in primary rat hepatocytes (PRH) and in the HepaRG and HepG2 cell lines. PRH was the most sensitive cell model, showing the lowest EC50 values for all three substances (0.158 mM for 3,4-DMMC; 1.21 mM for butylone; 1.57 mM for buphedrone). Co-exposure of PRH to the synthetic cathinones and CYP450 inhibitors (selective and non-selective) proved that hepatic metabolism reduced the toxicity of buphedrone but increased that of butylone and 3,4-DMMC. All compounds were able to increase oxidative stress, disrupting mitochondrial homeostasis and inducing apoptotic and necrotic features, while also increasing the occurrence of acidic vesicular organelles in PRH, compatible with autophagic activation. In conclusion, butylone, buphedrone and 3,4-DMMC have hepatotoxic potential, and their toxicity lies in the interference with a number of homeostatic processes, while being influenced by their metabolic fate.


Assuntos
3,4-Metilenodioxianfetamina/análogos & derivados , Butirofenonas/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Metilaminas/toxicidade , Propiofenonas/toxicidade , 3,4-Metilenodioxianfetamina/administração & dosagem , 3,4-Metilenodioxianfetamina/toxicidade , Animais , Autofagia/efeitos dos fármacos , Butirofenonas/administração & dosagem , Linhagem Celular Tumoral , Doença Hepática Induzida por Substâncias e Drogas/patologia , Drogas Desenhadas/administração & dosagem , Drogas Desenhadas/toxicidade , Relação Dose-Resposta a Droga , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Masculino , Metilaminas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Propiofenonas/administração & dosagem , Ratos , Ratos Wistar
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