-
CNS Drugs Feb 2024Patients with epilepsy may experience seizure clusters, which are described by the US Food and Drug Administration (FDA) as intermittent, stereotypic episodes of... (Review)
Review
Patients with epilepsy may experience seizure clusters, which are described by the US Food and Drug Administration (FDA) as intermittent, stereotypic episodes of frequent seizure activity that are distinct from a patient's usual seizure pattern. Untreated seizure clusters may increase the risk for status epilepticus, as well as decrease quality of life and increase burden on patients and care partners. Benzodiazepine therapies are the mainstay for acute treatment of seizure clusters and are often administered by nonmedical care partners outside a healthcare facility. Three rescue therapies are currently FDA-approved for this indication, with diazepam rectal gel being the first in 1997, for patients aged ≥ 2 years. Limitations of rectal administration (e.g., positioning and disrobing the patient, which may affect ease of use and social acceptability; interpatient variation in bioavailability) led to the investigation of the potential for nasal administration as an alternative. Midazolam nasal spray (MDS) was approved by the FDA in 2019 for patients aged ≥ 12 years and diazepam nasal spray (DNS) in 2020 for patients aged ≥ 6 years; these two intranasal therapies have differences in their formulations [e.g., organic solvents (MDS) vs. Intravail and vitamin E for absorption and solubility (DNS)], effectiveness (e.g., proportion of seizure clusters requiring only one dose), and safety profiles. In clinical studies, the proportion of seizure clusters for which only one dose of medication was used varied between the three approved rescue therapies with the highest single-dose rate for any time period for DNS; however, although studies for all three preparations enrolled patients with highly intractable epilepsy, inclusion and exclusion criteria varied, so the three cannot be directly compared. Treatments that have been used off-label for seizure clusters in the USA include midazolam for injection as an intranasal spray (indicated for sedation/anxiolysis/amnesia and anesthesia) and tablet forms of clonazepam (indicated for treatment for seizure disorders) and lorazepam (indicated for anxiety). In the European Union, buccal and intranasal midazolam are used for treating the indication of prolonged, acute convulsive seizures and rectal diazepam solution for the indication of epileptic and febrile convulsions; duration of effectiveness for these medications for the treatment of seizure clusters has not been established. This paper examines the literature context for understanding seizure clusters and their treatment and provides effectiveness, safety, and administration details for the three FDA-approved rescue therapies. Additionally, other medications that are used for rescue therapy in the USA and globally are discussed. Finally, the potential benefits of seizure action plans and candidates for their use are addressed. This paper is intended to provide details about the unique characteristics of rescue therapies for seizure clusters to help clarify appropriate treatment for individual patients.
Topics: Humans; Benzodiazepines; Midazolam; Anticonvulsants; Nasal Sprays; Quality of Life; Diazepam; Status Epilepticus; Epilepsy; Epilepsy, Generalized; Administration, Intranasal
PubMed: 38358613
DOI: 10.1007/s40263-023-01060-1 -
World Journal of Emergency Surgery :... Dec 2023Laparoscopy is widely adopted across nearly all surgical subspecialties in the elective setting. Initially finding indication in minor abdominal emergencies, it has...
BACKGROUND
Laparoscopy is widely adopted across nearly all surgical subspecialties in the elective setting. Initially finding indication in minor abdominal emergencies, it has gradually become the standard approach in the majority of elective general surgery procedures. Despite many technological advances and increasing acceptance, the laparoscopic approach remains underutilized in emergency general surgery and in abdominal trauma. Emergency laparotomy continues to carry a high morbidity and mortality. In recent years, there has been a growing interest from emergency and trauma surgeons in adopting minimally invasive surgery approaches in the acute surgical setting. The present position paper, supported by the World Society of Emergency Surgery (WSES), aims to provide a review of the literature to reach a consensus on the indications and benefits of a laparoscopic-first approach in patients requiring emergency abdominal surgery for general surgery emergencies or abdominal trauma.
METHODS
This position paper was developed according to the WSES methodology. A steering committee performed the literature review and drafted the position paper. An international panel of 54 experts then critically revised the manuscript and discussed it in detail, to develop a consensus on a position statement.
RESULTS
A total of 323 studies (systematic review and meta-analysis, randomized clinical trial, retrospective comparative cohort studies, case series) have been selected from an initial pool of 7409 studies. Evidence demonstrates several benefits of the laparoscopic approach in stable patients undergoing emergency abdominal surgery for general surgical emergencies or abdominal trauma. The selection of a stable patient seems to be of paramount importance for a safe adoption of a laparoscopic approach. In hemodynamically stable patients, the laparoscopic approach was found to be safe, feasible and effective as a therapeutic tool or helpful to identify further management steps and needs, resulting in improved outcomes, regardless of conversion. Appropriate patient selection, surgeon experience and rigorous minimally invasive surgical training, remain crucial factors to increase the adoption of laparoscopy in emergency general surgery and abdominal trauma.
CONCLUSIONS
The WSES expert panel suggests laparoscopy as the first approach for stable patients undergoing emergency abdominal surgery for general surgery emergencies and abdominal trauma.
Topics: Humans; Abdomen; Abdominal Injuries; Emergencies; Laparoscopy; Randomized Controlled Trials as Topic; Retrospective Studies; Practice Guidelines as Topic
PubMed: 38066631
DOI: 10.1186/s13017-023-00520-9 -
Journal For Immunotherapy of Cancer Oct 2023Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate...
BACKGROUND & AIMS
Intratumoral lactate accumulation and acidosis impair T-cell function and antitumor immunity. Interestingly, expression of the lactate transporter monocarboxylate transporter (MCT) 4, but not MCT1, turned out to be prognostic for the survival of patients with rectal cancer, indicating that single MCT4 blockade might be a promising strategy to overcome glycolysis-related therapy resistance.
METHODS
To determine whether blockade of MCT4 alone is sufficient to improve the efficacy of immune checkpoint blockade (ICB) therapy, we examined the effects of the selective MCT1 inhibitor AZD3965 and a novel MCT4 inhibitor in a colorectal carcinoma (CRC) tumor spheroid model co-cultured with blood leukocytes in vitro and the MC38 murine CRC model in vivo in combination with an antibody against programmed cell death ligand-1(PD-L1).
RESULTS
Inhibition of MCT4 was sufficient to reduce lactate efflux in three-dimensional (3D) CRC spheroids but not in two-dimensional cell-cultures. Co-administration of the MCT4 inhibitor and ICB augmented immune cell infiltration, T-cell function and decreased CRC spheroid viability in a 3D co-culture model of human CRC spheroids with blood leukocytes. Accordingly, combination of MCT4 and ICB increased intratumoral pH, improved leukocyte infiltration and T-cell activation, delayed tumor growth, and prolonged survival in vivo. MCT1 inhibition exerted no further beneficial impact.
CONCLUSIONS
These findings demonstrate that single MCT4 inhibition represents a novel therapeutic approach to reverse lactic-acid driven immunosuppression and might be suitable to improve ICB efficacy.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Colorectal Neoplasms; Glycolysis; Immune Checkpoint Inhibitors; Lactic Acid; Monocarboxylic Acid Transporters
PubMed: 37880183
DOI: 10.1136/jitc-2023-007349 -
Dermatologie (Heidelberg, Germany) Jul 2023Fertility preservation is of high importance for patients prior to treatment that can impair fertility. The individual risk of becoming infertile after... (Review)
Review
Fertility preservation is of high importance for patients prior to treatment that can impair fertility. The individual risk of becoming infertile after a fertility-reducing therapy depends on the type and duration of therapy, surgical technique, dose and combination of gonadotoxic drugs or radiation applied, and individual predisposition. Cryopreservation of ejaculated sperm is the standard procedure for creating a fertility reserve in men. In cases of azoospermia or inability to obtain semen by masturbation, testicular sperm can be obtained by (micro-)testicular sperm extraction (TESE) and cryopreserved. In case of retrograde ejaculation, sperm collection can be attempted by rectal electrostimulation or after off-label administration of imipramine from postmasturbatory urine. The cryopreserved sperm can be stored permanently in the gaseous phase of liquid nitrogen before being used in fertility therapy. In Germany, approval according to § 20b of the German Medicines Act (AMG) is a mandatory requirement for performing cryopreservation of sperm and testicular tissue; approval according to § 20c of the AMG must be obtained for use. For prepubertal boys, it is possible to cryopreserve dormant spermatogonial stem cells as part of an experimental procedure.
Topics: Humans; Male; Fertility Preservation; Semen; Cryopreservation; Testis; Spermatozoa
PubMed: 37286872
DOI: 10.1007/s00105-023-05167-w -
Future Oncology (London, England) Aug 2023Locally advanced rectal cancer has traditionally been treated with chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, a new strategy, total... (Review)
Review
Locally advanced rectal cancer has traditionally been treated with chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, a new strategy, total neoadjuvant therapy, involves the administration of CRT and neoadjuvant chemotherapy with the aim of eradicating micrometastases earlier and achieving greater control of the disease. The use of total neoadjuvant therapy has shown higher rates of pathological complete response and resectability compared with CRT, including improved survival. Nevertheless, distant relapse is the main cause of morbidity and mortality in locally advanced rectal cancer. To address this, new biomarkers are being developed to predict disease response.
Topics: Humans; Neoadjuvant Therapy; Chemoradiotherapy; Chemotherapy, Adjuvant; Neoplasms, Second Primary; Rectal Neoplasms
PubMed: 37650764
DOI: 10.2217/fon-2023-0481 -
Children (Basel, Switzerland) Sep 2023Patients with spinal abnormalities often struggle with fecal and/or urinary incontinence (up to 87 and 92%, respectively) and require a collaborative approach to bowel... (Review)
Review
BACKGROUND
Patients with spinal abnormalities often struggle with fecal and/or urinary incontinence (up to 87 and 92%, respectively) and require a collaborative approach to bowel management in conjunction.
METHODS
To define existing approaches and propose state-of-the-art bowel management, a literature search was performed using Medline/PubMed, Google Scholar, Cochrane, and EMBASE databases and focusing on the manuscripts published July 2013 and July 2023.
RESULTS
Patients with spinal anomalies have impaired innervation of the rectum and anal canal, decreasing the success rate from laxatives and rectal enemas. Thus, transanal irrigations and antegrade flushes are widely utilized in this group of patients. Based on spinal MRI, the potential for bowel control in these children depends on age, type, and lesion level. On referral for bowel management, a contrast study is performed to assess colonic motility and evacuation of stool, followed by a series of abdominal X-rays to define colonic emptying and adjust the regimen. The options for management include laxatives, rectal enemas, transanal irrigations, antegrade flushes, and the creation of a stoma. Approximately 22-71% of patients achieve social continence dependent on the type and level of the lesion.
CONCLUSION
Patients with spinal anomalies require a thorough assessment for continence potential and stool burden prior to initiation of bowel management. The optimal treatment option is defined according to the patient's age, anatomy, and mobility. The likelihood of independent bowel regimen administration should be discussed with the patients and their caregivers.
PubMed: 37761519
DOI: 10.3390/children10091558 -
International Journal of Pharmaceutics:... Dec 2023Infliximab is a monoclonal antibody that plays an important role in the management and treatment of chronic inflammatory bowel diseases (IBD). Due to its macromolecular...
Infliximab is a monoclonal antibody that plays an important role in the management and treatment of chronic inflammatory bowel diseases (IBD). Due to its macromolecular structure, its delivery through the oral route is challenging, limiting its administration to only via the parenteral route. The rectal route offers an alternative way for administering infliximab, allowing it to be localised at the disease site and circumventing its passage across the alimentary canal and thus, maintaining its integrity and bioactivity. Three-dimensional (3D) printing is an advanced production technology that permits the creation of dose-flexible drug products from digital designs. The current study assessed the feasibility of utilising semi-solid extrusion 3D printing for the fabrication of infliximab-loaded suppositories for the local treatment of IBD. Various printing inks composed of Gelucire® (48/16 or 44/14) mixed with coconut oil and/or purified water were investigated. It was shown that following reconstitution in water, the infliximab solution can be directly incorporated into the printing ink of Gelucire® 48/16 and can withstand the extrusion process, resulting in well-defined suppositories. Since water content and temperature are critical for safeguarding infliximab's potency, the effect of changing the composition of the printing inks and printing parameters on infliximab's biologic efficiency was evaluated by measuring its binding capacity (i.e., the amount of infliximab that actively binds to its antigen to exert an effect). Despite drug loading assays showing that infliximab remains intact following printing, it was found that the incorporation of water in isolation results in only ∼65% binding capacity. However, when oil is added to the mixture, infliximab's binding capacity increases up to ∼85%. These promising results demonstrate that 3D printing has the potential to be exploited as a novel platform for fabricating dosage forms containing biopharmaceuticals, avoiding patients' compliance issues observed with injectables and addressing their unmet needs.
PubMed: 37396625
DOI: 10.1016/j.ijpx.2023.100176 -
Pancreatology : Official Journal of the... Nov 2023There is an unmet clinical need for effective, targeted interventions to prevent post-ERCP pancreatitis (PEP). We previously demonstrated that the serine-threonine...
OBJECTIVE
There is an unmet clinical need for effective, targeted interventions to prevent post-ERCP pancreatitis (PEP). We previously demonstrated that the serine-threonine phosphatase, calcineurin (Cn) is a critical mediator of PEP and that the FDA-approved calcineurin inhibitors, tacrolimus (Tac) or cyclosporine A, prevented PEP. Our recent observations in preclinical PEP models demonstrating that Cn deletion in both pancreatic and hematopoietic compartments is required for maximal pancreas protection, highlighted the need to target both systemic and pancreas-specific Cn signaling. We hypothesized that rectal administration of Tac would effectively mitigate PEP by ensuring systemic and pancreatic bioavailability of Tac. We have tested the efficacy of rectal Tac in a preclinical PEP model and in cerulein-induced experimental pancreatitis.
METHODS
C57BL/6 mice underwent ductal cannulation with saline infusion to simulate pressure-induced PEP or were given seven, hourly, cerulein injections to induce pancreatitis. To test the efficacy of rectal Tac in pancreatitis prevention, a rectal Tac suppository (1 mg/kg) was administered 10 min prior to cannulation or first cerulein injection. Histological and biochemical indicators of pancreatitis were evaluated post-treatment. Pharmacokinetic parameters of Tac in the blood after rectal delivery compared to intravenous and intragastric administration was evaluated.
RESULTS
Rectal Tac was effective in reducing pancreatic injury and inflammation in both PEP and cerulein models. Pharmacokinetic studies revealed that the rectal administration of Tac helped achieve optimal blood levels of Tac over an extended time compared to intravenous or intragastric delivery.
CONCLUSION
Our results underscore the effectiveness and clinical utility of rectal Tac for PEP prophylaxis.
Topics: Animals; Mice; Administration, Rectal; Anti-Inflammatory Agents, Non-Steroidal; Ceruletide; Cholangiopancreatography, Endoscopic Retrograde; Mice, Inbred C57BL; Pancreatitis; Tacrolimus
PubMed: 37778935
DOI: 10.1016/j.pan.2023.09.080 -
European Journal of Obstetrics,... Dec 2023Botulinum toxin (BoNT) administration has been proposed in the gynecologic field for pelvic, vulvar and vaginal disorders. On this regard, we aimed assessing the... (Review)
Review
INTRODUCTION
Botulinum toxin (BoNT) administration has been proposed in the gynecologic field for pelvic, vulvar and vaginal disorders. On this regard, we aimed assessing the therapeutic effectiveness and safety of BoNT usage in the treatment of vaginal, vulvar and pelvic pain disorders.
METHODS
We searched for all the original articles without date restriction until 31.12.2021. We included all the original articles which administered botulinum toxin in the vulva or vagina of women suffering from vaginismus, dyspareunia, and chronic pelvic pain. Only English language studies and those performed in humans were eligible. We excluded all case reports and pilot study from the qualitative analysis, although we accurately evaluated them. 22 original studies were finally included in the systematic review.
RESULTS
Botulinum toxin injection was found to be effective in improving vulvar and vaginal dyspareunia, vaginismus, and chronic pelvic pain. No irreversible side effects were detected. Major side effects reported were transient urinary or fecal incontinence, constipation and rectal pain. The risk of bias assessment proved original articles to be of medium quality. No metanalysis could have been performed since lack of congruency in the definition of pathology and methods of botulinum toxin administration.
CONCLUSION
Data extraction pointed out different endpoints and different methods of analysis. Studies focus on different types of participants and use various techniques and timing. According to the best evidence available, different techniques provide evidence about positive outcomes, with the need for a standardized protocol.
Topics: Female; Humans; Dyspareunia; Vaginismus; Pilot Projects; Botulinum Toxins; Vulva; Pelvic Pain; Chronic Pain; Pelvic Floor; Vagina; Botulinum Toxins, Type A
PubMed: 38353087
DOI: 10.1016/j.ejogrb.2023.10.028