Alterations in the dentate gyrus of the offspring of rats treated with alprazolam during gestation.

Benzodiazepine (BZD) abuse is a global problem, including pregnant women. For this population, the drug of choice is usually alprazolam, which acts as a GABAergic agonist and may compromise the development of integrative areas of the nervous system, such as the dentate gyrus (DG) of the hippocampus. In this context, we studied the changes in the DG of the offspring of rats treated with alprazolam during gestation: control, treatment 1 (T1: 1.25 mg/animal), and an overdose group (T2: 30 mg/animal). Alprazolam was administered orally ten days before mating and during the gestational period. After birth, newborns were counted, sexed, and the body mass of each pup was measured. The newborns' brains were extracted and processed for morphological study of the DG or for total protein extraction of the hippocampus. The results showed that alprazolam can affect the cell number and area, and increased euchromatin in both granular and molecular layers of the DG, especially in the overdose group. Also, alprazolam upregulated the NF-κB and reduced GFAP and caspase-3. Based on our findings, we conclude that the DG is a plausible region of influence by BZDs during embryogenesis. An overdose during gestation may cause structural changes in the DG.

Static magnetic field blocked alprazolam-induced behavior of Wistar rats in the elevated plus-maze test.

Studies have shown that psychotropic drugs change rat behavior in the elevated plus-maze test (EPM). This study investigated whether static magnetic fields could alter alprazolam-induced rat behavior in the EPM. 66 male Wistar rats (270-300 g weight) were assigned to one of the following groups: Sham Magnetic + Saline (SMS), North Pole + Saline (NPS), South Pole + Saline (SPS), Sham magnetic + alprazolam (SMA), NP + alprazolam (NPA), and SP + alprazolam (SPA). After five days of static magnetic stimulation (3200 Gauss), they received alprazolam or saline (1 mg/kg), and their behavior was evaluated. Two-way ANOVA and Holm-Sidak post-hock were used, with a significant P value of <0.05. The SMA and NPA groups showed an increased number of entries and time in the open arms compared with the SMS group. SPA showed a decrease in these measures when compared to SMA [F(2,61) = 6.43 and F(2,61) = 3.72, respectively]. The SMA and NPA groups showed increased head dipping and end-arm activity compared with the SMS group. SPA showed a decrease in these measures when compared to SMA [F(2,61) = 3.37 and [F(2,61) = 4.72, respectively]. These results show that the south magnetic pole of a static magnetic field blocked the alprazolam effect in the space-time variables of the open arms and ethological anxiolytic-like behavior in the EPM.

Estudio comparativo de la calidad biofarmacéutica de Alprazolam 0, 5 mg comercializadas en el mercado peruano / Comparative study of the biopharmaceutical quality of Alprazolam 0. 5 mg commercialized in the Peruvian market

El Alprazolam pertenece a las benzodiazepinas. Sus efectos se atribuyen a que actúa sobre receptores de membrana específicos, lo cual facilita la acción inhibitoria presináptica y postsináptica del ácido γ-aminobutírico (GABA), especialmente en la formación reticular ascendente. Se utiliza para el tratamiento de los estados de ansiedad, crisis de angustia, ataques de pánico y estrés intenso. Este estudio se realizó para analizar los parámetros comparativos de control de calidad in vitro mediante la evaluación de la variación de peso, friabilidad, dureza, tiempo de desintegración, perfil y eficiencia de disolución entre el medicamento innovador (Xanax®) y multifuentes que son comercializados en el mercado peruano. Para realizarlo, se seleccionaron tabletas de Alprazolam 0,5 mg multifuente de diferentes laboratorios comparándolos con el medicamento innovador y se evaluaron las características fisicoquímicas y biofarmacéuticas. Los ensayos farmacopeicos se evaluaron según lo establecido en la USP 42. Los resultados de las pruebas fisicoquímicas indicaron que las muestras analizadas no tenían diferencia significativa y estaban dentro de lo establecido en la farmacopea, así mismo el perfil y eficiencia de disolución permitieron establecer que el comportamiento biofarmacéutico de las mismas era muy similar para ambos tipos de molécula. Se estableció que las tabletas multifuentes de Alprazolam 0,5 mg de esta investigación son bioequivalentes con el innovador, por lo que permite proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico

Alprazolam belongs to benzodiazepines. Its effects are attributed to the fact that it acts on specific membrane receptors, which facilitates the presynaptic and postsynaptic inhibitory action of γ-aminobutyric acid (GABA), especially in the ascending reticular formation. It is used to treat anxiety states, panic attacks, and intense stress. This study was carried out to analyze comparative parameters of in vitro quality control by evaluating the variation in weight, friability, hardness, disintegration time, profile and dissolution efficiency between the innovative drug (Xanax®) and multi-sources tablets that are marketed in the Peruvian market. To perform this, Alprazolam 0.5 mg multi-source tablets were selected from different laboratories comparing them with the innovative medicine and the physicochemical and biopharmaceutical characteristics were evaluated. Pharmacopoeial trials were evaluated as established in USP 42. The results of physicochemical tests indicated that analyzed samples did not have a significant difference and were within the established in the pharmacopoeia, as well as the profile and dissolution efficiency allowed to establish that their biopharmaceutical behavior was very similar for both types of molecules. It was established that Alprazolam 0.5 mg multi-source tablets from this research are bioequivalent with innovator, which makes it possible to propose to scientific community determination of biopharmaceutical equivalency as a support element in decision-making process for purchasing services pharmacist

GABAA/benzodiazepine receptors in the dorsal periaqueductal gray mediate the panicolytic but not the anxiolytic effect of alprazolam in rats.

Although the etiology of panic disorder (PD) remains elusive, accumulating evidence suggests a key role for the dorsal periaqueductal gray matter (dPAG). There is also evidence that this midbrain area is critically involved in mediation of the panicolytic effect of antidepressants, which with high potency benzodiazepines (e.g. alprazolam and clonazepam) are first line treatment for PD. Whether the dPAG is also implicated in the antipanic effect of the latter drugs is, however, still unknown. We here investigated the consequences of blocking GABAA or benzodiazepine receptors within the dPAG, with bicuculline (5 pmol) and flumazenil (80 nmol), respectively, on the panicolytic and anxiolytic effects of alprazolam (4 mg/kg). Microinjection of these antagonists fully blocked the anti-escape effect, considered as a panicolytic-like action, caused by a single systemic injection of alprazolam in male Wistar rats submitted to the elevated T-maze. These antagonists, however, did not affect the anxiolytic effect of the benzodiazepine on inhibitory avoidance acquisition and punished responding, measured in the elevated T-maze and Vogel conflict tests, respectively. Altogether, our findings show the involvement of GABAA/benzodiazepine receptors of the dPAG in the panicolytic, but not the anxiolytic effect caused by alprazolam. They also implicate the dPAG as the fulcrum of the effects of different classes of clinically effective antipanic drugs.

Alprazolam una alternativa terapéutica en Urgencia Hipertensiva / Alprazolam A Therapeutic Alternative in Hypertensive Urgency

Objetivo: Comparar la terapia combinada de captopril mas alprazolam versus captopril mas placebo en el manejo de urgencia hipertensiva (UH). Método: Es un ensayo clínico, uncéntrico, doble ciego, semialeatorizado, en edades comprendidas entre 45 y 80 años con UH que cumplían los criterios del JNC VII, atendidos en el servicio de emergencia entre Agosto 2017 ­ Febrero del 2018, distribuidos en grupo A (Control, n=41) y grupo B (experimental, n= 55) los cuales recibieron captopril mas placebo y alprazolam y captopril respectivamente. Resultados: Hubo predominio del género femenino en ambos grupos, y también el grado de ansiedad leve fue la más frecuente. En el grupo experimental hubo un descenso significativo a los 30, 60 y 90 minutos de la PAM de - 19%, -24 y -27% con una P 0.0000, en PAS a los 30 minutos era de -17%, 60 minutos de -22% y 90 minutos -26%, y en la PAD en los intervalos de tiempo antes citado fue -21%, -26% y -28%. Con una reducción igual o mayor a 25% de la presión arterial media en el grupo B, luego de 90 min de tratamiento. Según el RR aquellos que recibieron el tratamiento experimental tuvieron cerca de 7,5 veces más probabilidades de disminuir la presión arterial de forma efectiva a los 90 min, el NNT indica que es necesario tratar únicamente a 2 pacientes para que uno se beneficie. Conclusión: Acorde con estos resultados podemos discernir que el uso del alprazolam puede ser una alternativa terapéutica en la urgencia hipertensiva.

Objective: To compare the combination therapy of captopril plus alprazolam versus captopril plus placebo in the management of hypertensive emergency (UH). Method:It is a clinical trial, uncentric, double blind, semi-randomized, in ages between 45 and 80 years withUH that met the criteria of JNC VII, attended in the emergency service between August 2017 -February 2018, distributed in group A (Control, n = 41) and group B (experimental, n = 55) who received captopril plus placebo and alprazolam and captopril respectively. Results: There was a predominance of the female gender in both groups, and also the degree of mild anxiety was the most frequent. In the experimental group there was a significant decrease at 30, 60 and 90 minutes of the MAP of -19%, -24 and -27% with a P 0.0000, in PAS at 30 minutes it was -17%, 60 minutes of -22% and 90 minutes -26%, and in the PAD in the aforementioned time intervals it was -21%, -26% and -28%. With a reduction equal to or greater than 25% of the average blood pressure in group B, after 90 min of treatment. According to the RR those who received the experimental treatment were about 7.5 times more likely to lower blood pressure effectively at 90 min, the NNT indicates that it is necessary to treat only 2 patients for one to benefit. Conclusion:According to these results we can discern that the use of alprazolam can be a therapeutic alternative in the hypertensive emergency

Risks and benefits of medications for panic disorder: a comparison of SSRIs and benzodiazepines.

INTRODUCTION: Panic disorder (PD) is a prevalent and disabling anxiety disorder that can be treated effectively. Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are among the most frequently prescribed drugs for PD. In this article, the authors review the current evidence on efficacy, adverse events, and limitations of these two treatment options. AREAS COVERED: MEDLINE/Pubmed and Web of Science databases were searched for open or placebo-controlled trials on SSRIs and/or benzodiazepines in PD treatment. EXPERT OPINION: The literature search yielded 4,957 articles related to the theme. Of these, 24 articles were included in this review. Despite their usefulness in PD, SSRIs are associated with a delay of several weeks in onset of therapeutic effect and have the potential to exacerbate anxiety and panic early in the treatment course. Benzodiazepines present rapid onset of action, but can cause tolerance and dependence. Despite strong evidence of the effectiveness of SSRIs and benzodiazepines in the treatment of PD, few trials have performed head-to-head comparisons of these two drug classes. Future studies on the pharmacological treatment of PD should make direct comparisons of risks, benefits, and limitations of each group. This could help improve the evidence-based pharmacotherapy of PD.

Emerging various environmental threats to brain and overview of surveillance system with zebrafish model.

Pathologies related to neurotoxicity represent an important percentage of the diseases that determine the global burden of diseases. Neurotoxicity may be related to the increasing levels of potentially neurotoxic agents that pollute the environment, which generates concern, since agents that affect children may increase the incidence of neurodevelopmental disorders, affecting the quality of life of future citizens. Many environmental contaminants have been detected, and many of them derive from several human activities, including the mining, agriculture, manufacturing, pharmaceutical, beverage and food industries. These problems are more acute in third world countries, where environmental regulations are lax or non-existent. An additional major emerging problem is drug contamination. Periodic monitoring should be performed to identify potential neurotoxic substances using biological tests capable of identifying the risk. In this sense the fish embryo test (FET), which is performed on zebrafish embryos, is a useful, reliable and economical alternative that can be implemented in developing countries.

Efecto de la pre-medicación con alprazolam por vía oral sobre la presión arterial en pacientes hipertensos en cirugías electivas: un ensayo clínico / Effect of premedication with alprazolam orallyadministered on blood pressure in hypertensive patientsin elective surgeries: a clinical trial

Los ansiolíticos como el alprazolam podrían colaborar en mantener la presión arterial en pacientes hipertensos que deberán someterse a cirugía. El objetivo fue evaluar eficacia de la pre-medicación con alprazolam vía oral para mantener estables cifras de presión arterial en hipertensos programados para cirugías. Ensayo clínico aleatorizado, controlado y a doble ciego. Los pacientes fueron asignados al grupo que recibió alprazolam como premedicación (Grupo A) o al grupo control (Grupo P) que no lo recibió. Se registraron la variación de la presión arterial media (PAM), frecuencia cardíaca (FC) y frecuencia respiratoria (FR) entre el día previo y el día de la cirugía. En el Grupo A se encontró un aumento promedio de la PAM de 0,27 mmHg y en el grupo P de 7,52 mmHg (p= 0,0035). La variación promedio de la FC fue de 2,13 latidos por minuto en el Grupo A y de 5,38 latidos por minuto en el Grupo P (p= 0,0008); y de la frecuencia respiratoria fue de -2,29 respiraciones por minuto en el Grupo A y de -1,18 respiraciones por minuto en el Grupo P (p=0,206).Se halló un aumento significativo de la PAM y la FC en el Grupo P con respecto al Grupo A, no así de la FR. La administración del alprazolam como pre-medicación operatoria evita aumentos significativos de la presión arterial y de la frecuencia cardíaca en los pacientes hipertensos.

Anxiolytics such as alprazolam may help to maintain blood pressure in hypertensive patients who undergo surgery. The aim was to evaluate efficacy of pre-medication with alprazolam orally administered to maintain stable blood pressure in hypertensives programmed for surgeries. Randomized, controlled, double-blind clinical trial. Patients were assigned to the group that received alprazolam as premedication (Group A) or to the control group (Group P) which did not receive it. The variation of the mean arterial pressure(MAP), heart rate (HR) and respiratory rate (RR) were recorded between the day before andthe day of the surgery. In Group A, we found an average increase in MAP of 0.27 mmHgand in the Group P 7.52 mmHg (p = 0.0035). The mean HR variation was 2.13 beats perminute in Group A and 5.38 beats per minute in Group P (p = 0.0008). The mean RR variantion was -2.29 breaths per minute in Group A and -1.18 breaths per minute in Group P (p = 0.206). There was a significant increase in the MAP and HR in Group P compared toGroup A, but not in the RR. The administration of alprazolam as an operative premedication avoids significant increases in blood pressure and heart rate in hypertensive patients.

Comparação de cromatografia líquida de alta eficiência e titulação em meio não aquoso para quantificação de alprazolam em cápsulas manipuladas / Comparison of high performance liquid chromatography and non-aqueous titration for the quantitation of alprazolam in compounded capsules

O objetivo pretendido com o presente trabalho foi avaliar a adequabilidade e viabilidade de dois métodos analíticos para quantificação de alprazolam em cápsulas manipuladas: cromatografia líquida de alta eficiência (CLAE) e titulação em meio não aquoso. A quantificação de alprazolam por CLAE fase normal foi realizada em coluna de sílica (30 x 4,6 mm) e fase móvel composta por acetonitrila, clorofórmio, butanol, água e ácido acético glacial (85:8:5:2:0,05). No método titulométrico, as amostras foram dissolvidas em mistura de ácido acético glacial e anidrido acético (3:2) e tituladas com ácido perclórico 0,1 M até o segundo ponto de inflexão. O teor médio de alprazolam obtido por CLAE foi 94,61%, demonstrando a adequabilidade do método proposto. Já as análises por titulação apresentaram teores equivalentes a 128,87% e 91,49% do valor rotulado, devido a interferências detectadas pela presença de excipientes da formulação. A adaptação e o desenvolvimento de métodos analíticos simples e viáveis são de extrema importância para avaliar e garantir a qualidade de medicamentos manipulados, de acordo com as exigências da legislação vigente.

The aim of this study was to assess the suitability and viability of two analytical methods for the quantitation of alprazolam in compounded capsules: high performance liquid chromatography (HPLC) and non-aqueous titration. Quantitation by normal phase HPLC was performed with a silica column (30 x 4.6 mm) and a mobile phase composed of acetonitrile, chloroform, butyl alcohol, water and glacial acetic acid (85:8:5:2:0.05). In the titration method, samples were dissolved in a mixture of glacial acetic acid and acetic anhydride (3:2) and titrated potentiometrically with 0.1 M perchloric acid until the second inflection point. The mean content of alprazolam obtained by HPLC was 94.61% of the label value, showing the suitability of the proposed method. On the other hand, the titration analysis returned contents equivalent to 128.87% and 91.49% of the label value, owing to interference caused by the presence of formulation excipients. The adaptation and development of simple and viable analytical methods are extremely important, in order to assay and ensure the quality of compounded formulations, according to the requirements of the current legislation.

Error in pharmaceutical compounding of alprazolam capsules / Erro na manipulação de cápsulas de alprazolam

The increase of pharmaceutical drugs formulations consumption by Brazilian population demanded a greater action from the official laboratory to verify the conformity of these products, as the majority of them are composed by anxiolytics. This study reports a serious manipulation error in preparing alprazolam capsules formulation, where the chlordiazepoxide was placed instead of alprazolam, being both drugs belonged to therapeutic class of the benzodiazepines. A warning on the importance of manipulation process control of drugs is presented.

O aumento do consumo de medicamentos manipulados pela população brasileira demandou uma maior ação por parte do laboratório oficial na avaliação da conformidade desses produtos que, em grande parte, são constituídos por fármacos com propriedades ansiolíticas. No presente trabalho, é relatado um grave erro de manipulação em cápsulas de alprazolam, o qual foi trocado pelo clordiazepóxido, ambos pertencentes à classe terapêutica das benzodiazepinas. Alerta-se para a importância do controle de qualidade do processo de manipulação de fármacos.