Regulatory restrictions on the use of valproate in girls and women of childbearing potential: status update

In 2019, some restrictions for use of valproic acid in women with reproductive potential by regulatory authorities and the original drug manufacturer based on the results of studies in real clinical practice were introduced. During 2019–2021, there were a further clinical data accumulation and labeling changes. The review presents a critical analysis of the changes in prescribing information and product label. There is a long lead time from the moment when safety data become known to the moment when changes are made to the medicinal product label and patient brochures. Some of the changes, including the need for high doses of folic acid to prevent neural tube defects, are debatable. Repealing the provision for mandatory archiving of informed consent forms for valproic acid use in girls and women raises legal risks. Improvements in pregnancy prevention programs and further research on the safety of valproic acid in real-world clinical settings are needed.

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Enseñanza clínica en enfermería: escenario del aprendizaje y sus actores

Revista CuidArte ◽

10.22201/fesi.23958979e.2015.4.7.69108 ◽

2015 ◽

Vol 4 (7) ◽

pp. 44

Author(s):

Norma Ivette Beltran Lugo ◽

Betsy Flores Atilano ◽

Dulce María Guillén Cadena

Keyword(s):

Actual World ◽

Clinical Teaching ◽

Clinical Settings ◽

Clinical Practices ◽

Continuous Formation ◽

Great Responsibility ◽

Health Institutions ◽

Personnel Needs ◽

The Moment ◽

Sobre Todo

<div>La enseñanza se concibe como la tarea más peculiar de la escuela, cuyas funciones educativas deben estructurarse (Pérez Gómez, 1992) en torno a dos funciones. El acto de enseñar no es responsabilidad totalmente del docente universitario, sino que involucra al personal operativo de las instituciones de salud. La enseñanza clínica es el momento donde se tiene contacto con el mundo real y los diferentes ambientes que se generan para la construcción de nuevos hábitos profesionales, el desarrollo de la empatía con la disciplina y hasta el gusto de ser enfermero. La problemática que tenemos actualmente es que a veces el personal de Enfermería da por hecho que los y las estudiantes ya tienen los conocimientos pero sobre todo las habilidades prácticas para ejecutar intervenciones que implican gran responsabilidad, pero cuando la alumna demuestra que no tiene esas habilidades es desplazada y limitada a la observación. El profesorado debe tener una formación continua y también debe salir a hacer prácticas clínicas para que de esta forma no pierda las habilidades y destrezas en la ejecución de diversos procedimientos de Enfermería. Aunque existe el programa de estancias clínicas para profesores, éstos deben ser comprometidos a ejecutarlas independientemente de que laboren en algún otro lugar, ya que de ésta forma se pueden actualizar en las nuevas tecnologías del cuidado y tendrán herramientas muy útiles durante su enseñanza.</div><div><br /></div><div><div>Teaching is conceived as the most peculiar task of the school, which educative functions must be structured (Pérez Gómez, 1992) around two functions. The act of teaching isn’t the universitarian teacher’s responsibility completely, but also the health institutions’ personnel´s. Clinical teaching is the moment when contact is had with the actual world and the different environments created to construct new professional habits, development of empathy and even the joy of being a nurse. The issue we currently have is that sometimes nursing personnel take for granted that students already have all the knowledge, but mostly all the practical abilities to perform interventions that imply great responsibility, but when the student shows the lack those skills, they’re set aside and limited to observation only. Teaching personnel needs to have a continuous formation and they also have to do clinical practices so this way they won´t lose the abilities and dexterities on the execution of different nursing procedures. Even though there’s the clinical settings program for teachers, they have to be committed to execute it, whether they work or not at other place, so this way caring technologies can be updated and they’ll have very useful tools for teaching.</div></div><div><br /></div>

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Management of type 2 diabetes mellitus: insights into prescribing trends

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20170910 ◽

2017 ◽

Vol 5 (4) ◽

pp. 1306 ◽

Cited By ~ 1

Author(s):

Prasanna Kumar K. M. ◽

Shahu Ingole ◽

Tushar Tamboli ◽

Rishi Jain

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Safety Data ◽

Clinical Settings ◽

Efficacy Data ◽

Cross Sectional ◽

Prescribing Trends ◽

Improved Glycaemic Control

Background: Recently, management of type 2 diabetes mellitus (T2DM) has changed with advent of novel agents like DPP4i, SGLT2i and GLP-1 agonist. Of these, DPP4i have emerged as promising agents as monotherapy and as an add-on to metformin for improved glycaemic control. This survey was planned to explore current prescribing trends of physicians of India for the management of T2DM.Methods: This was a prospective, cross sectional, questionnaire-based survey of physicians and endocrinologist across different geographic areas in India. A survey questionnaire consisting of 10 questions related to management of T2DM in real-world clinical settings was prepared, validated in a small group of physicians and then administered to physicians and endocrinologists.Results: Responses from 502 physicians were received. About 60% physicians prefer DPP4i as first add-on to metformin followed by sulfonylurea (SU) (30%). Amongst DPP4i, vildagliptin and sitagliptin were preferred by 48% and 28% physicians respectively as first add-on to metformin. For patients uncontrolled on metformin + SU therapy, 54 % physicians prefer DPP4i as second add-on. Vildagliptin is perceived to have the better efficacy and safety data, as suggested by 40% and 43% physicians respectively. Large number of physicians (48%) were hesitant to prescribe teneligliptin due to insufficient data. SGLT2 inhibitors are preferred as third add-on by 44% physicians.Conclusions: DPP4i are being increasingly preferred by physician as an add-on to metformin. Among DPP4i, the survey revealed that vildagliptin is the most preferred DPP4i as an add-on to metformin possibly owing to its established safety and efficacy data.

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Results of the Treatment for Relapsed Acute Lymphoblastic Leukemia (ALL) in Childhood

Blood ◽

10.1182/blood.v116.21.4339.4339 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4339-4339

Author(s):

Myriam Ruth Guitter ◽

Elizabeth M Alfaro ◽

Jorge Rossi ◽

Marta Gallego ◽

Cristina Alonso ◽

...

Keyword(s):

Bone Marrow ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Childhood All ◽

New Therapeutic Approaches ◽

High Doses ◽

Null Response ◽

The Moment ◽

Se 33

Abstract Abstract 4339 INTRODUCTION: Relapses occur in 25–30% of childhood ALL. We evaluated the outcome of this group of patients (pts) according to the duration of the 1st CR, immunophenotype and site of relapse in our Institution. PATIENTS AND METHODS: From Sept’94 to Aug’09, 245 ALL relapses were diagnosed: 73 cases were not evaluable due to: different treatments received (n: 36), palliative care (n: 26) and insufficient data (n: 11); 172 pts were evaluable (54 F/118 M), with a mean age at the moment of the relapse of 9.8 (range 1.8–20.8) years. Induction therapy combined a pre-phase with 10 days of prednisone and 1 block of high doses of chemotherapy, followed by 5 blocks of similar intensity, CNS or testicular (preventive/therapeutic) radiotherapy, and weekly rotational maintenance, until completing two years from the moment of diagnosis. High-risk relapsed pts who had an available identical donor received HSCT. RESULTS: Immunophenotype was B-cell precursor (Bcp) in 89% of the pts and T-cell in 11 %. The duration of the 1st CR was <18 mo in 41 (24%), 18–36 mo in 79 (46%), >36 mo in 52 (30%) pts. The sites of relapse were bone marrow (BM) in 106 pts (61%), combined bone marrow (cBM) in 27 pts (17%) and isolated extramedullar in 39 pts (22%). The response to induction was: CR 134 pts (78%), death during induction 20 pts (12%) and partial/null response 18 pts (10%). Among the 134 pts who achieved CR, 69 (52%) presented a second relapse at 18,8 (r 0.7–88.8) mo from the 2nd CR, 10 (7%) died in CR and 1 developed a 2nd neoplasm. With a mean follow-up of 49 (r 2–155) mo, 54 pts remain in CR, 37 of them out of therapy. Of the 26 pts who received HSCT, 12 relapsed and 3 died in CR. The EFSp (SE) for the total group of pts was 25 (3)% and LFS probability (SE) 33 (4)%; for Bcp relapses it was 28%, and for T relapses 6% (P=0.0025); for BM+cBM cases it was 21%, and 40% for extramedullar (P=0.0061). However, testicular relapses achieved EFSp of 80%, and 12% for the remaining extramedullar cases (P=0.0004). The EFSp for relapses at <18mo of 1st CR was 5%, between 18–36 mo 25% and >36 m 41% (P=0.0001). CONCLUSIONS: The immunophenotype, the duration of the 1st CR and site of relapse significantly influenced the EFSp. Isolated testicular relapses achieved the best EFSp. HSCT is an eligible option for a small group of pts. New therapeutic approaches must be developed to improve outcome of most of relapsed ALL patients. Disclosures: No relevant conflicts of interest to declare.

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Endemic Emergence of Cephalosporin-Resistant Enterobacter: Relation to Prior Therapy

Infection Control and Hospital Epidemiology ◽

10.1017/s0195941700065632 ◽

1986 ◽

Vol 7 (S2) ◽

pp. 120-123 ◽

Cited By ~ 30

Author(s):

Robert A. Weinstein

Keyword(s):

Cardiac Surgery ◽

Wide Spectrum ◽

Clinical Settings ◽

Third Generation ◽

Prior Therapy ◽

Cephalosporin Resistance ◽

Resistant Strains ◽

High Doses ◽

Third Generation Cephalosporins

The “second” and “third” generation cephalosporins offer striking antimicrobial activity against a wide spectrum of Enterobacteriaceae. Nevertheless, mutants resistant to these drugs have emerged in both laboratory and clinical settings. For example, before the commercial availability of the third-generation agents, we treated three cardiac surgery patients for Enterobacter mediastinitis with aminoglycosides and high doses of cefamandole. In two, initial treatment failed due to emergence of strains that were not only resistant to cefamandole, but also to then experimental third-generation drugs. Despite such reports and in vitro studies of the mechanisms of resistance, the frequency with which broad-spectrum cephalosporin resistance develops in clinical practice is not clear. To help delineate this problem, we have reviewed our hospital's experience with Enterobacter strains resistant to newer cephalosporins (using cefamandole and cefotaxime as prototypes) and the relation of resistant strains to cephalosporin use, with special attention to our cardiac surgery patients.

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Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines

Endocrine Related Cancer ◽

10.1677/erc-07-0096 ◽

2007 ◽

Vol 14 (3) ◽

pp. 839-845 ◽

Cited By ~ 53

Author(s):

Maria G Catalano ◽

Roberta Poli ◽

Mariateresa Pugliese ◽

Nicoletta Fortunati ◽

Giuseppe Boccuzzi

Keyword(s):

Valproic Acid ◽

Thyroid Carcinoma ◽

Cell Lines ◽

Combined Treatment ◽

Anaplastic Thyroid Cancer ◽

Anaplastic Thyroid Carcinoma ◽

Tubulin Acetylation ◽

High Doses ◽

Apoptotic Activity ◽

Thyroid Cancer Cell Lines

The introduction of paclitaxel into multimodal therapy for anaplastic thyroid carcinoma has failed to improve overall survival. Toxicity rules out the high doses required, especially in older patients. The search for strategies to enhance paclitaxel antineoplastic activity and reduce its side effects is thus advisable. The study aimed to determine whether the histone deacetylase (HDAC) inhibitor valproic acid (VPA) improves the anticancer action of paclitaxel and elucidate the mechanisms underlying the effects of combined treatment. We examined the effect of VPA on the sensitivity to paclitaxel of two anaplastic thyroid carcinoma cell lines (CAL-62 and ARO), and the ability of the drug to determine tubulin acetylation and enhance paclitaxel-induced acetylation. The addition of as little as 0.7 mM VPA to paclitaxel enhances both cytostatic and cytotoxic effects of paclitaxel alone. Increased apoptosis explains the enhancement of the cytotoxic effect. The mechanism underlying this effect is through inhibition of HDAC6 activity, which leads to tubulin hyperacetylation. The results suggest a mechanistic link between HDAC6 inhibition, tubulin acetylation, and the VPA-induced enhancement of paclitaxel effects, and provide the rationale for designing future combination therapies.

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New Contraception Update — Annovera, Phexxi, Slynd, and Twirla

Current Obstetrics and Gynecology Reports ◽

10.1007/s13669-021-00321-4 ◽

2022 ◽

Author(s):

Courtney C. Baker ◽

Melissa J. Chen

Keyword(s):

Contraceptive Method ◽

Infection Prevention ◽

Ethinyl Estradiol ◽

Safety Data ◽

Pregnancy Prevention ◽

Hormonal Contraceptive ◽

Urogenital Infection ◽

The Usa ◽

One Year ◽

Combined Hormonal Contraceptive

Abstract Purpose of Review In this review, we discuss the efficacy, safety, and benefits of four new contraceptive products available in the USA, specifically Annovera, Phexxi, Slynd, and Twirla. Recent Findings Annovera is a vaginal ring releasing ethinyl estradiol and segesterone acetate that can be used for up to one year (13 cycles), offering patients an effective, user-controlled option that may improve contraceptive access for those in low-resource settings or those with barriers to retrieving monthly prescriptions; however, given limited efficacy and safety data in people with body mass index (BMI) > 29 kg/m2, clinicians may consider whether Annovera is an appropriate contraceptive method for obese patients if there are other acceptable alternatives. Phexxi prescription-only vaginal gel is a user-controlled, non-hormonal, on-demand contraceptive method that represents a novel addition to the market with its additional uses as a personal lubricant and as a potential microbicide for urogenital infection prevention. Slynd, a drospirenone-only pill, provides more flexibility for delayed or missed pills while maintaining efficacy and a more favorable bleeding profile compared with previously available progestin-only pills. Lastly, Twirla is a transdermal patch releasing ethinyl estradiol and levonorgestrel that offers users an additional option for a user-controlled, combined hormonal contraceptive method without daily dosing; however, prescription is limited to patients with BMI < 30 kg/m2 due to decreased efficacy and VTE events in people with obesity. Summary The addition of these products expands the available options for pregnancy prevention to address unmet contraceptive needs.

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Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data

Thrombosis and Haemostasis ◽

10.1160/th14-06-0514 ◽

2015 ◽

Vol 113 (04) ◽

pp. 759-771 ◽

Cited By ~ 53

Author(s):

Albrecht Gröner ◽

Ye Jian ◽

Pendrak Inna ◽

Cristina Solomon

Keyword(s):

Safety Profile ◽

Safety Data ◽

Virus Transmission ◽

Clinical Settings ◽

Fibrinogen Concentrate ◽

Spontaneous Reports ◽

Transmission Case ◽

Pharmacovigilance Database ◽

Polymerase Chain ◽

Negative Polymerase Chain Reaction

SummaryFibrinogen concentrate use as a haemostatic agent has been increasingly explored. This study evaluates spontaneous reports of potential adverse drug reactions (ADRs) that occurred during postmarketing pharmacovigilance of Haemocomplettan P/RiaSTAP, and reviews published safety data. This descriptive study analysed postmarketing safety reports recorded in the CSL Behring pharmacovigilance database from January 1986 to December 2013. A literature review of clinical studies published during the same period was performed. Commercial data indicated that 2,611,294 g of fibrinogen concentrate were distributed over the pharmacovigilance period, main-contribonding to 652,824 standard doses of 4 g each, across a range of clinical settings and indications. A total of 383 ADRs in 106 cases were reported (approximately 1 per 24,600 g or 6,200 standard doses). Events of special interest included possible hypersensitivity reactions in 20 cases (1 per 130,600 g or 32,600 doses), possible thromboembolic events in 28 cases (1 per 93,300 g or 23,300 doses), and suspected virus transmission in 21 cases (1 per 124,300 g or 31,000 doses). One virus transmission case could not be analysed due to insufficient data; for all other cases, a causal relationship was assessed as unlikely due to negative polymerase chain reaction tests and/or alternative explanations. The published literature revealed a similar safety profile. In conclusion, underreporting of ADRs is a known limitation of pharmacovigilance. However, the present assessment indicates that fibrinogen concentrate is administered across a range of indications, with few ADRs and a low thromboembolic event rate. Overall, fibrinogen concentrate showed a promising safety profile.Institution to which work should be attributed: CSL Behring, Marburg, Germany.

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Disrupting folate metabolism alters the capacity of bacteria in exponential growth to develop persisters to antibiotics

10.1101/335505 ◽

2018 ◽

Author(s):

Jasmine Morgan ◽

Matthew Smith ◽

Mark T. Mc Auley ◽

J. Enrique Salcedo-Sora

Keyword(s):

Gene Expression ◽

Exponential Growth ◽

Folate Metabolism ◽

Exponential Growth Phase ◽

Clinical Settings ◽

Aberrant Expression ◽

Enzyme Gene ◽

Gene Expression Analyses ◽

Folate Biosynthesis ◽

High Doses

AbstractBacteria can survive high doses of antibiotics through stochastic phenotypic diversification.We present initial evidence that folate metabolism could be involved with the formation of persisters. The aberrant expression of the folate enzyme genefauseems to reduce the incidence of persisters to antibiotics. Folate impaired bacteria had a lower generation rate for persisters to both antibiotics ampicillin and ofloxacin. Persister bacteria were detectable from the outset of the exponential growth phase in the complex media. Gene expression analyses showed tentatively distinctive profiles in exponential growth at times when bacteria persisters were observed. Levels of persisters were assessed in bacteria with altered, genetically and pharmacologically, folate metabolism. This work shows that by disrupting folate biosynthesis and usage, bacterial tolerance to antibiotics seems to be diminished. Based on these findings there is a possibility that bacteriostatic antibiotics such as antifolates could have a role to play in clinical settings where the incidence of antibiotic persisters seem to drive recalcitrant infections.

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Clozapine: Since the very beginning?

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.1402 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S752-S753

Author(s):

L. Garcia Ayala ◽

M. Gómez Revuelta ◽

C. Martín Requena ◽

E. Saez de Adana Garcia de Acilu ◽

O. Porta Olivares ◽

...

Keyword(s):

Negative Symptoms ◽

Chronic Schizophrenia ◽

First Episode ◽

Childhood And Adolescence ◽

First Line ◽

Competing Interest ◽

High Doses ◽

Disorganized Speech ◽

The Moment ◽

The Right

IntroductionPsychosis in childhood and adolescence could be defined as having hallucinations, with the hallucinations occurring in the absence of insight. A broader definition includes symptoms such as delirious thoughts, disorganized speech, disorganized behavior, cognitive and mood symptoms and what is called negative symptoms. Several researches have been done focused in the treatment of first episode of psychosis showing clozapine as a keystone in the treatment of psychosis, especially in refractory first episodes.ObjectivesClozapine has unique efficacy in improving treatment-resistant patients with chronic schizophrenia but the moment of instauration remains unclear. There have always been doubts about the right moment to start clozapine, after two or more previous anti-psychotics or as first option.Materials and methodsWe report a 18-year- old woman with family history of severe psychosis. Her mum reasserted patient's symptoms contributing to a longer period of non-treating psychosis (about 10 months). Auditory hallucinations, incongruent mood and incoherent language appeared for the first time at the age of 17. High doses of two consecutive anti-psychotics were tried without remission and finally clozapine was initiated with clinical improvement.DiscussionIn clinical practice, a subgroup of psychotic patients experience, significant ongoing positive symptoms despite of using first line anti-psychotic medication.ConclusionMost recent research; suggest that clozapine may have an important role in the early treatment of first-episode patients, even becoming a first line option to consider.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Three Patients Needing High Doses of Valproic Acid to Get Therapeutic Concentrations

Case Reports in Psychiatry ◽

10.1155/2015/542862 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

James Jackson ◽

Betsy McCollum ◽

Judy Ognibene ◽

Francisco J. Diaz ◽

Jose de Leon

Keyword(s):

Valproic Acid ◽

Tuberous Sclerosis ◽

Plasma Concentrations ◽

High Dose ◽

Strongly Correlated ◽

Divalproex Sodium ◽

Day Case ◽

Metabolic Capacity ◽

Normal Dose ◽

High Doses

Valproic acid (VPA) can autoinduce its own metabolism. Cases requiring VPA doses >4000 mg/day to obtain therapeutic plasma concentrations, such as these 3 cases, have never been published. Case 1 received VPA for seizures and schizophrenia and had >50 VPA concentrations in 4 years. A high dose of 5,250 mg/day of VPA concentrate was prescribed for years but this dose led to an intoxication when switched to the enterocoated divalproex sodium formulation, requiring a normal dose of 2000 mg/day. VPA metabolic capacity was significantly higher (t=-9.6; df = 6.3,p<0.001) during the VPA concentrate therapy, possibly due to autoinduction in that formulation. Case 2 had VPA for schizoaffective psychosis with 10 VPA concentrations during an 8-week admission. To maintain a VPA level≥50 μg/mL, VPA doses increased from 1500 to 4000 mg/day. Case 3 had tuberous sclerosis and epilepsy and was followed up for >4 years with 137 VPA concentrations. To maintain VPA concentrations≥50 μg/mL, VPA doses increased from 3,375 to 10,500 mg/day. In Cases 2 and 3, the duration of admission and the VPA dose were strongly correlated (raround 0.90;p<0.001) with almost no change after controlling for VPA concentrations, indicating progressive autoinduction that increased with time.

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