SUDEP in adults and children

Sudden unexpected death in epilepsy (SUDEP) represents an important cause of death in patients with epilepsy and it exceeds the expected rate of sudden death in the general population by nearly 24 times. We searched the electronic databases (Cochrane, EMBASE, Scopus, Medline, Pubmed) for studies related to etiology and risk stratification of SUDEP including data on Takotsubo cardiomyopathy (TKC) following seizures resulting in death or near death.: SUDEP is more common among males in the fourth decade of life. Risk for SUDEP is increased by early onset of seizures, low IQ, generalised tonic clonic seizures, nocturnal seizures and seizure frequency. Nonadherance to antiepileptic medications, absence of therapeutic drug level monitoring, presence of neuropathological lesions on imaging and certain subgroups like Dravet syndrome increase its risk. The risk for premature death in patients undergoing temporal lobe resection for drug resistant epilepsy decreased over time but remained above the standard population. Prolonged postictal electroencephalographic suppression was a risk factor for SUDEP in patients with generalised seizures which may indicate a cerebral electrical shutdown. Documented ictal/postictal hypoventilation, laryngeal spasm and cardiac rhythm abnormalities prior to SUDEP may suggest central apnea, neurogenic pulmonary edema, cardiac arrhythmia, or a combination of the above as a cause. Seizure triggered TKC does not seem to play a major role in the pathogenesis of SUDEP.

Novel Drug Delivery Systems and its Future Prospects

Most common methods of delivery include the preferred topical (skin), transmucosal (nasal, buccal, sublingual, vaginal, ocular and rectal) and inhalation routes. The conventional dosage forms provide drug release immediately and it causes fluctuation of drug level in blood depending upon dosage form. Therefore to maintain the drug concentration within therapeutically effective range needs novel drug delivery system. In the past few decades, considerable attention has been focused on the development of novel drug delivery system (NDDS). The NDDS should ideally fulfill two prerequisites. Firstly, it should deliver the drug at a rate directed by the needs of the body, over the period of treatment. Secondly, it should channel the active entity to the site of action. In conventional drug delivery systems, there is little or no control over release of the drug and effective concentration at the target site can be achieved by irregular administration of grossly excessive doses. At present, no available drug delivery system behaves ideally, but sincere attempts have been made to achieve them through various novel approaches in drug delivery.

Isavuconazonium Sulfate Use in Multi-Modal Management of Invasive Mucormycosis in Four Pediatric Allogeneic Hematopoietic Cell Transplant Patients

Prolonged neutropenia increases the risk for lethal invasive fungal infections (IFIs) such as those caused by Rhizopus species. Isavuconazonium sulfate is a new triazole that lacks pediatric dosing recommendations. Clinical courses of 4 pediatric patients with IFIs in the peri-allogeneic hematopoietic cell transplantation (alloHCT) period between 2015 and 2017 were reviewed. The reviews included previously unreported pharmacokinetic and safety data, and the IFIs included Rhizopus. Isavuconazonium sulfate was initiated with a loading dose followed by daily dosing, adjusted to a goal trough concentration of >3 mg/L based on adult literature. This target was achieved at a median of 7 days, demonstrating varying rates of metabolism. Renal insufficiency, electrolyte disturbances, and transaminitis were noted, although attribution was confounded by other alloHCT complications. One patient survived infection-free to hospital discharge and 1 of 3 deceased patients had evidence of an unresolved IFI (case 2). Case 2 was subtherapeutic for 39% of the duration of treatment, compared with others at an average of 29%, suggesting this target trough to be clinically relevant because case 2 demonstrated positive sinus and nasal cultures for Rhizopus on autopsy. We recommend initiation of isavuconazonium 10 mg/kg with a maximum dose of 372 mg. A loading dose of 10 mg/kg is used every 8 hours for 6 doses followed by 10 mg/kg dosing every 24 hours. Monitoring must continue beyond steady state. If early monitoring is not possible, we recommend a first drug level at week 3. If dose increases are required, a partial reload has been more successful instead of increasing daily doses. Further larger studies are needed to demonstrate optimum dosing in pediatric patients.

Successful Treatment of Severe Lamotrigine Intoxication with CytoSorb Hemoadsorption

Severe intoxication with the anti-epileptic drug, lamotrigine can cause cardiovascular collapse, neurotoxicity – expressed as intractable seizures, and even death. As there is currently no known specific antidote, extracorporeal removal therapies such as CytoSorb hemoadsorption might represent a promising therapeutic option. We report on a deeply comatosed 60-year-old woman who was treated in our intensive care unit with severe lamotrigine intoxication. To support removal from the blood, combined treatment with continuous veno-venous hemodialysis and CytoSorb hemoadsorption was started. Pre- and post-adsorber drug level measurements showed the rapid elimination of lamotrigine accompanied by an impressive clinical improvement in the patient. Two days after treatment discontinuation, there were no more clinical signs of intoxication and the patient could be extubated, followed by transfer to the stroke unit in a stable condition the following day. In the absence of a viable antidote, for the efficient short-term removal of lamotrigine, hemoadsorption with the CytoSorb device could represent a feasible treatment option for patients with severe lamotrigine intoxication.

A Case Report on Chronic Digoxin Toxicity

Digitalis glycosides are among the oldest drugs used in cardiology. Nowadays, due to the limited indications for their use (advanced heart failure, usually concomitant with atrial fibrillation), cases of toxicity induced by this class of drugs are rarely observed. Digoxin produces a positive inotropic and bathmotropic effect on the heart, but has a negative chronotropic and dromotropic effect. Cardiac glycosides have a narrow therapeutic window, so digitalis treatment can easily lead to symptoms of overdose. In patients taking digoxin, the drug therapeutic level should be maintained at 1-2 ng/ml; the toxic effects occur at concentrations > 2.8 ng/ml and are mainly related to disturbances of cardiac function and of the circulatory system, as well as gastrointestinal symptoms and CNS disturbances. Here, a 65-years-old patient who was hospitalized following chronic ingestion with acute renal impairment. In spite of rapidly applied gastric irrigation and administration of activated charcoal, the drug level in the patient’s blood was estimated at 8.5 ng/ml. During her stay on the ward, typical symptoms of severe toxicity were observed: from gastric symptoms (severe nausea, vomiting) to conduction disturbances. Type I, moitz type 1 and 2 AV blocks were detected, as well as some supraventricular extrasystoles. These conduction disorders required the use of temporary endocardial pacing. Due to the unavailability of specific antidotes (antidigitalis antibodies) and lack of efficient methods of extracorporeal elimination of the drug, symptomatic treatment comprising the correction of electrolyte disturbances and heart rate control remains the most effective. Bangladesh Heart Journal 2021; 36(2): 139-144

Evaluation of intraperitoneal vancomycin in peritoneal dialysis-associated peritonitis

Background: Intraperitoneal (IP) vancomycin is recommended as one of the treatment options for gram-positive coverage in the management of peritoneal dialysis (PD)-associated peritonitis. There is a lack of literature supporting the optimal dose and approach to vancomycin therapeutic drug-level monitoring. Methods: A retrospective chart review was conducted using the BC Renal Agency PROMIS Database and our hospital records from 1 June 2011 to 1 July 2019. Adult patients with PD-associated peritonitis who received IP vancomycin and had at least one serum vancomycin level drawn were included. All patients received a loading dose of 30 mg/kg, which was repeated every 3–5 days depending on PD modality. Serum vancomycin levels were drawn prior to the second vancomycin dose, then at the discretion of the prescriber. The primary end point was the rate of therapeutic serum vancomycin levels ≥15 mg/L. Results: Twenty-three episodes of PD-associated peritonitis in 20 patients met the eligibility criteria. Only 15/23 serum vancomycin levels were drawn appropriately after the first dose. Sixty per cent of these levels were subtherapeutic at <15 mg/L. All subsequent serum vancomycin levels were above the therapeutic target. Most peritonitis episodes (78%) achieved resolution of infection. Residual kidney function was not significantly correlated with serum vancomycin levels ( p = 0.19). Conclusions: An IP vancomycin regimen of 30 mg/kg every 3–5 days resulted in subtherapeutic serum vancomycin levels in most patients following the loading dose but therapeutic levels thereafter. A large percentage of vancomycin levels were drawn inappropriately due to misalignment of outpatient follow-up visits and timing of blood work.

FORMULATION AND EVALUATION OF DARIFENACIN HYDROBROMIDE TRANSDERMAL PATCH

The aim of present study is to formulate and characterize darifenacin hydrobromide transdermal patch and the effects of non-ionic surfactants span 20 and tween 20 on drug permeation were studied. Transdermal patches were prepared by solvent casting method using PVA, PVP, HPMC E5, HPMC E15 polymers. Propylene glycol and Glycerol were used as plasticizers and Span 20 and Tween 20 were used as permeation enhancers. The prepared patches were evaluated for physicochemical properties like drug content, thickness, weight variation, folding endurance, moisture uptake, watervapour transmission studies. Physicochemical properties have shown better. Drug release studies by in-vitro diffusion, ex-vivo permeation as well as skin irritation. Formulations DPAT2, DPLT3 showed better drug release rate, ux and Q when compared to DPAS2, DPLS2. From the results it was concluded that darifenacin hydrobromide transdermal patch 24 (DPAT2) formulation would reduce the administration frequency, side effects and may avoid uctuations of drug level in the blood in comparison to immediate release formulations which might enhance the patient compliance.

Controlled Drug Delivery Systems: Current Status and Future Directions

The drug delivery system enables the release of the active pharmaceutical ingredient to achieve a desired therapeutic response. Conventional drug delivery systems (tablets, capsules, syrups, ointments, etc.) suffer from poor bioavailability and fluctuations in plasma drug level and are unable to achieve sustained release. Without an efficient delivery mechanism, the whole therapeutic process can be rendered useless. Moreover, the drug has to be delivered at a specified controlled rate and at the target site as precisely as possible to achieve maximum efficacy and safety. Controlled drug delivery systems are developed to combat the problems associated with conventional drug delivery. There has been a tremendous evolution in controlled drug delivery systems from the past two decades ranging from macro scale and nano scale to intelligent targeted delivery. The initial part of this review provides a basic understanding of drug delivery systems with an emphasis on the pharmacokinetics of the drug. It also discusses the conventional drug delivery systems and their limitations. Further, controlled drug delivery systems are discussed in detail with the design considerations, classifications and drawings. In addition, nano-drug delivery, targeted and smart drug delivery using stimuli-responsive and intelligent biomaterials is discussed with recent key findings. The paper concludes with the challenges faced and future directions in controlled drug delivery.

Identification of neutralising pembrolizumab anti-drug antibodies in patients with melanoma

Development of anti-drug antibodies (ADAs) can interfere with therapeutic monoclonal antibodies and may lead to drug neutralisation and clinical disease progression. Measurement of circulating drug levels and development of ADAs in the setting of anti-programmed cell death-1 agent pembrolizumab has not been well-studied. Enzyme-linked immunosorbent assays were used to measure pembrolizumab drug level and ADAs in 41 patients with melanoma at baseline, Time-point 1 (3 weeks) and Time-point 2 (21 weeks). Assay results were related to patient demographics and clinical outcome data at 6 months. The median pembrolizumab drug level at 3 weeks was 237 ng/μL and did not correlate with age, sex or body surface area.17/41 patients had an ADA detected at any timepoint, with the highest prevalence at Timepoint 1 (median concentration = 17 ng/μL). The presence of an ADA did not correlate with clinical progression at 6 months. 3/41 (7%) of patients displayed a falling pembrolizumab drug level and rising ADA titre between Timepoint 1 and 2 suggestive of a neutralising ADA. Pembrolizumab drug levels and ADAs can be readily measured. The rates of total and treatment-emergent ADAs may be higher in “real-word” settings than those previously reported. Larger studies are needed to determine effect of neutralising ADAs on long-term clinical outcome.

Exploring Pharmacy Trainee Experiential Learning in a Full Scope Collaborative Rural Primary Care Practice: A Retrospective Chart Review

Despite reported benefits of pharmacy trainees (e.g., pharmacy students, pharmacy residents) in hospital settings, limited research on the impact of these trainees has been conducted in rural primary care. To explore the potential benefits and impact of pharmacy trainees practicing in a supervised collaborative rural primary care setting, a retrospective chart review was conducted. Drug therapy problems (DTPs) were classified using the Pharmaceutical Care Network Europe (PCNE V9) system. Valuation was measured using a validated tool developed by Overhage and Lukes (1999). Over 16 weeks on a part-time basis, pharmacy trainees (n = 3) identified 366 DTPs during 153 patient encounters. The most common causes for DTPs were related to patient transfers and the need for education. Drug level interventions carried out directly by trainees under supervision accounted for 13.1% of total interventions. Interventions that required prescriber authorization had an acceptance rate of 83.25% higher than previous acceptance rates found in urban primary care settings. About half (51%) of the interventions proposed and made by pharmacy trainees were classified as significant or very significant, suggesting these trainees added significant value to the pharmacy service provided to rural community residents. This study suggests that pharmacy trainees can be effective resources and contribute meaningfully to patient care in a collaborative rural primary care team setting.