Rectal Gel Research Articles

Implications of Seizure-Cluster Treatment on Healthcare Utilization: Use of Approved Rescue Medications.

People with epilepsy may experience seizure clusters despite a stable regimen of antiseizure medications. Such clusters have the potential to last ≥24 hours, typically occur in the community setting, and may progress to medical emergencies, such as status epilepticus, if untreated. Thus, long-acting rescue therapy for seizure clusters is needed that can be administered by nonmedical individuals outside a hospital. Benzodiazepines are the foundation of rescue therapy for seizure clusters. The approved outpatient treatments (ie, diazepam, midazolam) have differing profiles that may affect multiple aspects of health-care utilization. The current labeling of these medications allows for a second dose if needed to control the cluster. Although no head-to-head studies directly comparing rescue treatments have been conducted, differences between studies with generally similar designs may provide context for the potential importance of second doses of rescue therapy on health-care utilization. For this analysis, large, long-term, open-label studies of approved seizure-cluster treatments designed for use by nonmedical caregivers were reviewed, and the percentage of seizure clusters for which a second dose was used or that were not controlled at 6, 12, and 24 hours was examined. Available data on hospitalizations were also collected. The 3 identified studies meeting the inclusion criteria were for use of diazepam rectal gel, intranasal midazolam, and diazepam nasal spray. Across these studies, the use of a second dose ranged from <40% at 6 hours to <13% at 24 hours. Hospitalizations and serious treatment-emergent adverse events were reported variably across these studies. These results demonstrate the importance of second doses of rescue therapy for seizure clusters for optimizing health-care utilization. Need for second doses should be included as one component. In turn, when second doses are needed, they have the potential to curtail emergency department use and hospitalization and to prevent further seizure clusters.

Impact of endorectal filling on interobserver variability of MRI based rectal primary tumor delineation

BackgroundOnline adaptive MR-guided radiotherapy allows for the reduction of safety margins in dose escalated treatment of rectal tumors. With the use of smaller margins, precise tumor delineation becomes more critical. In the present study we investigated the impact of rectal ultrasound gel filling on interobserver variability in delineation of primary rectal tumor volumes. MethodsSix patients with locally advanced rectal cancer were scanned on a 1.5 T MRI-Linac without (MRI_e) and with application of 100 cc of ultrasound gel transanally (MRI_f). Eight international radiation oncologists expert in the treatment of gastrointestinal cancers delineated the gross tumor volume (GTV) on both MRI scans. MRI_f scans were provided to the participating centers after MRI_e scans had been returned. Interobserver variability was analyzed by either comparing the observers’ delineations with a reference delineation (approach 1) and by building all possible pairs between observers (approach 2). Dice Similarity Index (DICE) and 95 % Hausdorff-Distance (95 %HD) were calculated. ResultsRectal ultrasound gel filling was well tolerated by all patients. Overall, interobserver agreement was superior in MRI_f scans based on median DICE (0.81 vs 0.74, p < 0.005 for approach 1 and 0.76 vs 0.64, p < 0.0001 for approach 2) and 95 %HD (6.9 mm vs 4.2 mm for approach 1, p = 0.04 and 8.9 mm vs 6.1 mm, p = 0.04 for approach 2). Delineated median tumor volumes and inter-quartile ranges were 26.99 cc [18.01–50.34 cc] in MRI_e and 44.20 [19.72–61.59 cc] in MRI_f scans respectively, p = 0.012. ConclusionsAlthough limited by the small number of patients, in this study the application of rectal ultrasound gel resulted in higher interobserver agreement in rectal GTV delineation. The endorectal gel filling might be a useful tool for future dose escalation strategies.

Rescue therapies for seizure clusters: Pharmacology and target of treatments.

The primary goal of treatment for seizure clusters is cessation of the cluster to avoid progression to more severe conditions, such as prolonged seizures and status epilepticus. Rescue therapies are key components of treatment plans for patients with seizure clusters. Three rescue therapies are approved in the United States for the treatment of seizure clusters: diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. This review characterizes the pharmacological function of rescue therapies for seizure clusters, as well as describing γ‐aminobutyric acid A (GABAA) receptor functions. GABAA receptors are heteropentamers, consisting primarily of α1‐6, β1‐3, γ2, and δ subunits in the central nervous system. These subunits can traffic to and from the membrane to regulate membrane potential. Benzodiazepines, such as diazepam and midazolam, are positive allosteric modulators of GABAA receptors, the activation of which leads to an increase in intracellular chloride, hyperpolarization of the cell membrane, and a reduction in excitation. GABAA receptor subunit mutations, dysregulation of trafficking, and degradation are associated with epilepsy. Although benzodiazepines are effective GABAA receptor modulators, individual formulations have unique profiles in practice. Diazepam rectal gel is an effective rescue therapy for seizure clusters; however, adults and adolescents may have social reservations regarding its administration. Intranasal delivery of midazolam or diazepam is a promising alternative to rectal administration because these formulations offer easy, socially acceptable administration and exhibit a rapid onset. Off‐label benzodiazepines, such as orally disintegrating lorazepam and intranasal use of an intravenous formulation of midazolam via nasal atomizer, are less well characterized regarding bioavailability and tolerability compared with approved agents.

Glycerosomal thermosensitive in situ gel of duloxetine HCl as a novel nanoplatform for rectal delivery: in vitro optimization and in vivo appraisal

Duloxetine HCl (DXH) is a reuptake inhibitor of serotonin and norepinephrine used to treat the major depressive disorder. Following its extensive hepatic metabolism, acid-labile nature, and limited aqueous solubility, DXH has poor oral bioavailability (40%). The rectal route has been suggested as another route of administration to surmount such challenges. The present study aimed to prepare DXH-loaded glycerosomal (DXH-GLYS) in situ gel for rectal administration to increase DXH permeability and improve its bioavailability. Box–Behnken design (BBD) was adopted to prepare and optimize nanoglycerosomes. The impact of Phospholipon 90G (PL90G), Tween 80 concentrations, and glycerol percentage on encapsulation efficiency, nanoglycerosomal size, % cumulative DXH released, and the cumulative DXH permeated per unit area after 24 h were studied by the design. The pharmacokinetic and pharmacodynamic behavior of optimized formulation was investigated in rats. The formulated DXH-GLYS had a vesicle size ranging between 135.9 and 430.6 nm and an entrapment efficiency between 69.11 and 98.12%. The permeation experiment revealed that the optimized DXH-GLYS in situ gel increased DXH permeation by 2.62-fold compared to DXH solution. Pharmacokinetics studies disclosed that the DXH-GLYS in situ rectal gel exhibited 2.24-times increment in DXH bioavailability relative to oral DXH solution. The pharmacodynamic study revealed that the DXH-GLYS rectal treatment significantly improved the behavioral analysis parameters and was more efficacious as an antidepressant than the oral DXH solution. Collectively, these findings demonstrate that GLYS can be considered a potentially valuable rectal nanocarrier that could boost the DXH efficacy.Graphical abstract

Safety of Diazepam Nasal Spray in Children and Adolescents With Epilepsy: Results From a Long-Term Phase 3 Safety Study

BackgroundTo evaluate safety and tolerability of long-term treatment with diazepam nasal spray (Valtoco) for seizure clusters in patients aged six to 17 years. MethodsThe study enrolled patients aged six to 65 years with frequent seizure clusters. Age- and weight-based doses of diazepam nasal spray were administered; second doses were permitted if needed. Safety assessments included treatment-emergent adverse events (TEAEs). ResultsOf 163 treated patients, 45 (27.6%) were aged six to 11 years and 33 (20.2%) were aged 12 to 17 years. Mean doses per month were 2.1 in the 6 to 11 subgroup and 2.4 in the 12 to 17 subgroup. Of 1634 seizure clusters in pediatric patients, 186 (11.4%) required a second dose of diazepam nasal spray within 24 hours of the first dose. Similar proportions of TEAEs and serious TEAEs were reported in 6 to 11 (91.1%, 40.0%) and 12 to 17 subgroups (81.8%, 30.3%), respectively. No serious TEAEs were considered treatment related, and no patients discontinued because of TEAEs. Treatment-related TEAEs were more frequent in the 12 to 17 subgroup; only epistaxis and somnolence occurred in two or more patients overall. TEAE rates were similar across subgroups that received concomitant clobazam (90.0%), received prior diazepam rectal gel (90.9%), and were administered less than two versus greater than or equal to two doses per month (87.2% for both) of diazepam nasal spray. Most survey respondents (88%) were satisfied or very satisfied with treatment. ConclusionsIn this long-term safety analysis in pediatric patients with seizure clusters, repeated doses of diazepam nasal spray demonstrated a safety profile consistent across subgroups. These data support the dosing guidelines for diazepam nasal spray according to age and weight for pediatric patients.

Formulation Design and Ex Vivo Evaluation of Carbopol -Incorporated Mucoadhesive Thermoreversible gels of Sucralfate for Rectal Drug Delivery

Aim: The present research is focused on preparation of Thermoreversible gels and screening ex vivo anti-inflammatory activity using croton oil induced hemorrhoid model.&#x0D; Study Design: The animals were divided into four groups, n=8. After overnight fasting, hemorrhoids were induced by inserting sterile cotton swabs soaked in croton oil preparation into the anus of all group animals except normal control group.&#x0D; Place and Duration of Study: Depart of Pharmacology, Sree Vidyanikethan College of Pharmacy, Tirupati. between October 2021 to December 2021&#x0D; Methodology: Experimental runs for optimization of formulation with the help of 23 factorial designs were designed [1]. Design of Expert program 6.0.6 (Stat-Ease Inc. Minneapolis, MN) was used to create formulations. Formulations were optimized using full factorial de­sign. In situ rectal gel was prepared by the cold meth­od [2]. As shown in Table 1, P188 was dissolved in DDW (de-ionized distilled water) including drug (1% w/v) at room temperature, and it was stored at 4°C for complete solubilization of P188. Carbopol solubilized in DDW, HPMC K4M and other mu­coadhesive polymers were then slowly added to the prepared solution with continuous agitation at 4°C, and were kept for 24 h before their use. The composi­tion of developed gel formulations is summarized in Table 1.&#x0D; Results: Results In the first set of experiment, the application of croton oil to recto anal portion of rats induced significant increase in the Recto anal coefficient and serum level of pro inflammatory cytokines such as IL-6, and TNF \(-a\) it also showed a significant increase in recto anal portion compared to normal control animals. However, the treatment with Sucralfate containing Thermoreversible gels has maintained the RAC and Interleukin -6 levels near to normal control group. These findings were further supported by histopathological examination wherein the animals treated with optimized formulation showed significant reversal in the severity of inflammation, vasodilatation in the recto anal portion, and presence of inflammatory cells.&#x0D; Conclusion: The findings of the present study suggest that the improved experimental model described in the present work has advantages and the model has a provision for quantifying the inflammatory exudates in the induced experimental hemorrhoids. Also, it was found that, the optimized formulation ameliorated the croton oil-induced hemorrhoids in rats.

PROSPECTS FOR THE DEVELOPMENT OF A NEW DOSAGE FORM FOR THE TREATMENT OF ANAL FISSURES

Abstract: Anal fissure is one of the most common diseases of the rectum. In recent years, the number of patients suffering from this pathology for social reasons has sharply increased. The aim of the work is to study the methods of treatment of this disease, in particular the principles of drug therapy. Annotation. The article describes the main modern conservative and radical treatment methods. The analysis of the pharmaceutical market of drugs with indications for the use of anal fissure has been carried out. There are 38 registered drugs on the Russian pharmaceutical market, 73% of them are suppositories, 25% are rectal ointments and 2% are rectal gel. About 50% of the drugs in this group are produced by domestic manufacturers, such as JSC "Nizhpharm”, JSC "Dalkhimpharm", LLC "Altpharm", JSC "FP "Obolenskoye", LLC "Tula Pharmaceutical Factory", etc., and the same amount is produced by foreign companies represented by major global holdings: Bayer AG, Switzerland, Stada AG, Germany, Hemofarm A.D., Serbia, Dr. Kade, Germany, JSC "Gedeon Richter", Hungary, Recordati S.p.A. Ireland, etc. They include anticoagulants, venotonic and venoprotective agents, hemostatics, local anesthetics, anti-inflammatory drugs of the group of non-steroidal anti-inflammatory drugs, glucocorticosteroids, antispasmodics, nonspecific drugs that have an antiseptic and antiseptic effect. On the Russian pharmaceutical market, there are no domestic drugs of industrial production, designed to reduce the hypertonicity of the internal sphincter. One drug based on nifedipine, manufactured in Germany, has been registered, which is not able to fully cover the need to provide drugs for this group. One drug has been registered to solve this problem - relifipin gel containing nifedipine and lidocaine, produced in Germany. Ointments of extemporal production are also used, the most widely used is 0.2% nitroglycerin ointment. Obtaining dosage forms of industrial manufacture based on nitric oxide donors is fraught with difficulties due to their explosiveness. These drugs are not able to fully meet the need for the provision of medicines of this group. Conclusion: It has been shown that a well-chosen medical treatment is necessary for the treatment of diseases of mild and moderate severity, as well as after surgery. The urgency of the development of new combined drugs for the treatment of anal fissures, aimed at eliminating all links of the pathological process in the form of ointments and suppositories, has been substantiated.

Patient acceptability and quality of self-administered intravaginal gel for pelvic MRI

Background: MRI of the pelvis can be limited for infiltrating lesions or those of same signal intensity as surrounding structures. Vaginal distension using aqueous gel counters this by defining the fornices, cervix and anterior rectal wall. This increases the accuracy of diagnosis and staging of various pelvic pathology, however, there is currently neither a universally accepted protocol for using gel nor focus on patient self-administration. Aims: To improve patient expectations regarding pelvic MRI with intravaginal gel, as well as the service we provide should they prefer self-administration and this produces vaginal distension of radiological quality equivalent to doctor-administration. Methods: Illustrated information explaining the benefits of gel and the technique of self-administration was sent to patients scheduled for pelvic MRI between March 2020 and April 2021 at our study centre. This included a questionnaire to assess understanding and preference for self-administration. Vaginal distension achieved on imaging was analysed using TeraRecon and compared between self and doctor-administered cases. Results: 38 of 45 patients opted for self-administration of gel. Those who identified as White British were more likely to self-administer. There was comparable quality of vaginal distension between self and doctor administered cases, with no significant difference between orthogonal measurements and retained gel volume. Conclusion: Self-administration of intravaginal gel for pelvic MRI is acceptable to patients and frees a doctor of this duty. It is a well tolerated technique which produces high quality vaginal distention on imaging. We recommend wider use of intravaginal and even rectal gel in the investigation of complex endometriosis and pelvic tumours.

Preferences regarding emerging HIV prevention technologies among Toronto men who have sex with men: a discrete choice experiment

New forms of HIV pre-exposure prophylaxis (PrEP) include long-acting injectables and topical microbicides, each with unique attributes that may appeal to distinct users. We used a discrete choice experiment to characterize preferences for new PrEP formulations among Toronto men who have sex with men. MSM undergoing anonymous HIV testing completed a discrete choice experiment with 12 choice sets by selecting their preferred option within each set. Each set included “usual methods to prevent HIV” (excluding PrEP) as one alternative and two hypothetical PrEP alternatives, which differed according formulation/dosing, side effects (none/mild), risk of drug resistance (none/low/moderate), and HIV prevention efficacy (50%, 65%, 80% or 99% risk reduction). We used mixed logistic regression to infer preferences for PrEP attributes and calculate the marginal rate of substitution between efficacy and other PrEP attributes. 306 men with median (interquartile range) age = 29 (25, 36) years participated, and reported 6 (3, 10) partners and 0 (0, 2) condomless receptive anal sex acts in the preceding six months. An on-demand pill was the most preferred formulation, followed by a monthly injection, daily pill, and on-demand rectal gel. Drug resistance was an important determinant of preferences if the risk was moderate, but not if it was low. The minimum efficacy required for an on-demand pill to be preferred over no PrEP was 32.6% (95%CI = 21.2–43.9%); for a daily pill, injections, and rectal gel, minimum efficacy was 57.9% (95%CI = 44.1–71.7%), 40.1% (27.0–53.2%), and 71.3% (60.5–82.1%), respectively. Attitudes towards PrEP formulations vary among men who have sex with men, with on-demand pills and monthly injections having the highest average preference scores. Understanding these preferences may help to predict uptake.

A novel approach for radiotherapy dose escalation in rectal cancer using online MR-guidance and rectal ultrasound gel filling – Rationale and first in human

IntroductionDose escalated radiotherapy has previously been investigated as a strategy to increase complete response rates in rectal cancer. However large safety margins are required using cone-beam computed tomography guided radiotherapy leading to high doses to organs at risk or insufficient target volume coverage in order to keep dose constraints. We herein present the first clinical application of a new technique for dose escalation in rectal cancer using online magnetic resonance (MR)-guidance and rectal ultrasound gel filling. MethodsA 73-year-old patient with distal cT3a cN0 cM0 rectal cancer was referred for definitive radiochemotherapy with the goal of organ preservation after multidisciplinary discussion. A dose of 45 Gy in 25 fractions with a stereotactic integrated boost to the primary tumor of 50 Gy with concomitant 5-fluorouracil was prescribed. Furthermore, a boost to the primary tumor with 3 Gy per fraction using the adapt-to-shape workflow on a 1.5 T MR-Linac was planned once weekly. For the boost fractions 100 cc of ultrasound gel was applied rectally in order to improve tumor visibility and distancing of uninvolved rectal mucosa. In order to determine the required planning target volume margin diagnostic scans of ten rectal cancer patients conducted with rectal ultrasound gel filling were studied. ResultsBased on the ten diagnostic scans an average isotropic margin of 4 mm was found to be sufficient to cover 95% of the target volume during an online adaptive workflow. Three boost fractions were applied, mean treatment duration was 22:34 min. Treatment was well tolerated by the patient with no more than PRO-CTCAE grade I° toxicity of any kind. The rectal ultrasound gel filling resulted in superior visibility of the tumor and reduced the dose to the involved mucosa especially in the high dose range compared with a boost plan calculated without any filling. A considerable tumor shrinkage was observed during treatment from 17.43 cc at baseline to 4 cc in week four. ConclusionThis novel method appears to be a simple but effective strategy for dose escalated radiotherapy in rectal cancer. Based on the encouraging observation, a prospective trial is currently under preparation.

Physiologically based pharmacokinetic/pharmacodynamic modeling to evaluate the absorption of midazolam rectal gel

ObjectiveWe aimed to 1) develop physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of a novel midazolam rectal gel in healthy adults, 2) assess the contribution of different physiologically relevant factors in rectal absorption, and 3) to provide supports for future clinical studies of midazolam rectal gel. MethodsWe developed the rectal PBPK model after built the intravenous and the oral PBPK model. Then, the physiological progress of rectal route was described in terms of the drug release, the rectal absorption and the particle first-pass elimination. Next, the validated PBPK model was combined with the sigmoid Emax PD model. This PBPK/PD model was used to identify the dose range and the critical parameters to ensure safety sedation. ResultsBased on the simulations, the recommended maximum dose for adults’ sedation was 15 mg. And the retention time of midazolam rectal gel should be longer than 3 h to reach over 80% pharmacokinetics and pharmacodynamics effects. ConclusionWe successfully developed a PBPK/PD model for the midazolam rectal gel, which accurately described the PK/PD behavior in healthy adults and indicated the transit time of rectum was the most sensitive parameter for absorption. This PBPK/PD model would be expected to support the future clinical studies and pediatric application.

Med Check: Updates to Clozapine REMS, Weekly Treatment for OUD, and More

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Updates to Clozapine REMS, Weekly Treatment for OUD, and MoreTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:2 Sep 2021https://doi.org/10.1176/appi.pn.2021.9.1FDA Updates Clozapine REMSIn July the Food and Drug Administration (FDA) approved modifications to the Clozapine Risk Evaluation and Mitigation Strategy (REMS). Several of these changes affect health professionals who prescribe clozapine.Beginning on November 15, the Clozapine REMS requires a New Patient Status Form to document monitoring for all outpatients. This form must be submitted monthly.All health professionals who prescribe clozapine must be recertified by November 15 to continue prescribing the medication and they must re-enroll their patients who will continue taking the medication. Patients who are not re-enrolled by November 15 will no longer be able to receive clozapine.Information on recertifying and re-enrolling in the Clozapine REMS is posted hereWeekly OUD Treatment Gets Fast Track DesignationLyndra Therapeutics’ investigational weekly treatment for opioid use disorder (OUD), LYN-014, has received a fast track designation from the FDA, the company announced in July. LYN-014 is an oral, ultra-long-acting, extended-release levomethadone capsule. The FDA fast track is a process designed to facilitate the development of drugs that treat serious conditions and fill an unmet medical need and expedite their review.Levomethadone, is an enantiomer of racemic methadone (its molecules are a mirror image of those in racemic methadone). Levomethadone is not approved for use in the United States, although it has been approved for use in Europe since the 1960s for pain management and medication treatment for OUD.In April the FDA granted LYN-014 Investigational New Drug status, which enabled Lyndra to initiate a phase 1 clinical trial in patients whose OUD is currently controlled on daily oral immediate-release methadone.FDA Grants Breakthrough Therapy Designation to Investigational Narcolepsy TreatmentIn July Takeda Pharmaceutical Co. Ltd. announced that the FDA granted Breakthrough Therapy designation to TAK-994, the company’s investigational oral orexin agonist for the treatment of excessive daytime sleepiness in patients with narcolepsy type 1. The FDA’s Breakthrough Therapy designation expedites the development and review of drugs for serious conditions. The criteria for Breakthrough Therapy designation require preliminary clinical evidence that indicate that the drug may demonstrate substantial improvement over available therapy on at least one clinically significant endpoint.According to a statement by Takeda, the FDA’s decision to grant the Breakthrough Therapy designation was based in part on early phase and preliminary clinical data suggesting that the drug demonstrates substantially improved objective and subjective measurements of daytime wakefulness in patients with narcolepsy type 1.FDA to Review Diazepam Buccal FilmThe FDA will review Libervant (diazepam) buccal film for the treatment of acute uncontrolled seizures in patients with refractory epilepsy on stable regimens of antiepileptic drugs, Aquestive Therapeutics announced in July.A phase 1/2 open-label trial of 31 patients with seizure disorders who took antiepileptic drugs found that treatment with Libervant resulted in similar systemic exposures to Diastat diazepam rectal gel, the standard treatment.Aquestive originally submitted a New Drug Application (NDA) for Libervant in February 2020, but in September 2020 the FDA issued a Complete Response Letter stating that the study showed a lower drug exposure level than desired in certain weight groups. The letter also noted a number of protocol deviates in blood draws in one of the studies that was included in the NDA. In response, the company provided additional analysis as part of the NDA submission now under FDA review.Kloxxado Now Available to Treat Opioid OverdoseHikma Pharmaceuticals PLC’s nasal spray Kloxxado (naloxone hydrocloride) for the emergency treatment of opioid overdose is now available, the company announced in August. Kloxxado, which was approved by the FDA in April, delivers 8 mg of naloxone directly into the nasal cavity. The FDA had previously approved 2 mg and 4 mg naloxone nasal spray products.The FDA approved Kloxxado based on previous findings about the safety and effectiveness of Narcan injection (naloxone hydrochloride) for treating opioid overdose. Hikma Pharmaceuticals also submitted its own safety and effectiveness data. ■ ISSUES NewArchived

Impact of hydrogel peri-rectal spacer insertion on seminal vesicles intrafraction motion during 1.5 T-MRI-guided adaptive stereotactic body radiotherapy for localized prostate cancer.

MR-guided daily-adaptive radiotherapy is improving the accuracy in the planning and delivery phases of the treatment. Rectal hydrogel-spacer may help in mitigating organ motion, but few data are currently available. We aimed to assess any potential impact of the device on seminal vesicles motion by measuring translational and rotational shifts between the pre- and post-treatment MRI scans of a total of 50 fractions in the first 10 patients who underwent MR-guided prostate SBRT (35 Gy/5 fx). Of them, five patients received the hydrogel-spacer. The comparative analysis was performed using the Mann-Whitney U-test. Median rotational shifts were: in anteroposterior 0° (range, 0.097°/0.112°; SD = 0.05°) vs 0° (-0.162/0.04°; SD = 0.07°) in the no-spacer subgroup (p = 0.36); lateral shifts were 0° (-0.1°/0.54°; SD = 0.28°) vs -0.85° in the no-spacer cohort (-1.56°/0.124°; SD = 0.054°; p = 0.22). Cranio-caudal shifts were 0° (-0.121°/0.029°; SD = 0.06°) in the spacer-cohort vs 0° (-0.066°/0.087°; SD = 0.69°; p = 0.53). Median translational shifts were: in anteroposterior 0.9 mm (-0.014 mm/0.031 mm; SD = 0.036 mm) in the spacer-group vs 0.030 mm (-0.14 mm/0.03 mm; SD = 0.032 mm; p = 0.8); latero-lateral shifts were -0.042 mm (-0.047 mm/0.07 mm; SD = 0.054 mm), vs -0.023 mm (-0.027 mm/-0.01 mm; SD = 0.023 mm) in the no-spacer group (p = 0.94). In cranio-caudal, statistically significant shifts were reported: 0.082 mm (0.06 mm/0.15 mm; SD = 0.04 mm) vs 0.06 mm (-0.06/0.08 mm; SD = 0.09 mm) in the no-spacer cohort (p = 0.031). A favorable impact of the hydrogel-spacer on seminal vesicles motion was observed only in cranio-caudal translational shifts, although being not clinically significant. Further studies are required to fully investigate the potential contribution of this device on vesicles motion. MR-guided daily adaptive radiotherapy may represent a game changer for prostate stereotactic body radiotherapy, given the possibility to better visualize soft-tissues anatomy and to daily recalculate the treatment plan based on real-time conditions. The use of devices like rectal ballon or rectal gel spacers has gained interest in the last years for the possibility to better spare the rectum during prostate radiotherapy. This is one of the first experiences exploring the role of rectal spacer on seminal vesicles intrafraction motion during MR-guided SBRT for prostate cancer.

Examining the patient and caregiver experience with diazepam nasal spray for seizure clusters: Results from an exit survey of a phase 3, open-label, repeat-dose safety study

BackgroundIdeal rescue treatments for acute treatment of seizure clusters should be easy to administer, so it is important to assess user perceptions of these treatments. Diazepam nasal spray is designed to have a rapid, noninvasive, and socially acceptable route of administration. Patient and caregiver (including care partner) responses to surveys from a phase 3 safety study of diazepam nasal spray are reported. MethodsThe study enrolled patients aged 6–65 years with seizure clusters. Surveys distributed to patients and caregivers at study end, completion, or discontinuation collected data on comfort using diazepam nasal spray outside the home, timing of administration and return to their usual selves, and comfort of use compared with rectal diazepam. Safety was assessed. ResultsOf 175 patients enrolled at the October 31, 2019, interim cutoff, 158 received diazepam nasal spray. Sixty-seven (42.4%) patients and 84 (53.2%) caregivers responded to the surveys (including 35 matched pairs). Most patients (78.8%, 52/66) responded that they were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% of patients returned to their usual selves within an hour of administration. Twenty-seven (40.3%) of these patients reported self-administration, 48% doing so at the first sign of a seizure. Administration of diazepam nasal spray was rated extremely or very easy by 93.8% of caregivers. Safety profile was consistent with diazepam rectal gel; no patient discontinued owing to treatment-emergent adverse events. Nasal discomfort was typically mild and transient. Among patients who had used diazepam rectal gel, most were not at all comfortable using it outside the home (86.7%) or at home (64.5%) compared with diazepam nasal spray, whereas caregivers reported that diazepam rectal gel was not at all easy to use compared with diazepam nasal spray. ConclusionsThis survey from the phase 3 safety study of diazepam nasal spray shows that patients and caregivers were satisfied with, and more comfortable using, diazepam nasal spray than rectal diazepam in public.NCT02721069.

Rectum Protection by Rectal Gel Injection in Cervical Cancer Brachytherapy: A Dosimetric Study via Deformable Surface Dose Accumulation and Machine-Learning-Based Discriminative Modeling.

PurposeThis retrospective study aimed to evaluate the dosimetric effects of a rectal insertion of Kushen Ningjiao on rectal protection using deformable dose accumulation and machine learning–based discriminative modelling.Materials and MethodsSixty-two patients with cervical cancer enrolled in a clinical trial, who received a Kushen Ningjiao injection of 20 g into their rectum for rectal protection via high–dose rate brachytherapy (HDR-BT, 6 Gy/f), were studied. The cumulative equivalent 2-Gy fractional rectal surface dose was deformably summed using an in-house-developed topography-preserved point-matching deformable image registration method. The cumulative three-dimensional (3D) dose was flattened and mapped to a two-dimensional (2D) plane to obtain the rectal surface dose map (RSDM). For analysis, the rectal dose (RD) was further subdivided as follows: whole, anterior, and posterior 3D-RD and 2D-RSDM. The dose–volume parameters (DVPs) were extracted from the 3D-RD, while the dose geometric parameters (DGPs) and textures were extracted from the 2D-RSDM. These features were fed into 192 classification models (built with 8 classifiers and 24 feature selection methods) for discriminating the dose distributions between pre-Kushen Ningjiao and pro-Kushen Ningjiao.ResultsThe rectal insertion of Kushen Ningjiao dialated the rectum in the ambilateral direction, with the rectal column increased from pre-KN 15 cm3 to post-KN 18 cm3 (P < 0.001). The characteristics of DGPs accounted for the largest portions of the top-ranked features. The top-ranked dosimetric features extracted from the posterior rectum were more reliable indicators of the dosimetric effects/changes introduced by the rectal insertion of Kushen Ningjiao. A significant dosimetric impact was found on the dose–volume parameters D1.0cc–D2.5cc extracted on the posterior rectal wall.ConclusionsThe rectal insertion of Kushen Ningjiao incurs significant dosimetric changes on the posterior rectal wall. Whether this effect is eventually translated into clinical gains requires further long-term follow-up and more clinical data for confirmation.

Mucoadhesive In Situ Rectal Gel Loaded with Rifampicin: Strategy to Improve Bioavailability and Alleviate Liver Toxicity.

Although it is a front-line in tuberculosis treatment, rifampicin (RF) exhibits poor oral bioavailability and hepatotoxicity. Rectal mucoadhesive and in situ rectal gels were developed to overcome drug drawbacks. A RF/polyethylene glycol 6000 co-precipitate was first prepared in different ratios. Based on the drug solubility, the selected ratio was investigated for drug/polymer interaction and then incorporated into in situ rectal gels using Pluronic F127 (15%) and Pluronic F68 (10%) as a gel base and mucoadhesive polymers (HPMC, sodium alginate and chitosan). The formulations were assessed for gelation temperature and gel strength. The selected formulation was investigated for in vivo assessments. The results showed that a 1:1 drug/polymer ratio exhibited satisfying solubility with the recorded drug/polymer interaction. Depending on their concentrations, adding mucoadhesive polymers shifted the gelation temperature to lower temperatures and improved the gel strength. The selected formulation (F4) did not exhibit any anal leakage or marked rectal irritation. Using a validated chromatographic analytical method, F4 exhibited higher drug absorption with a 3.38-fold and 1.74-fold higher bioavailability when compared to oral drug suspension and solid suppositories, respectively. Toxicity studies showed unnoticeable hepatic injury in terms of biochemical, histopathological and immunohistochemical examinations. Together, F4 showed a potential of enhanced performance and also offered lower hepatic toxicity, thus offering an encouraging therapeutic alternative.

Overcoming the challenges of developing an intranasal diazepam rescue therapy for the treatment of seizure clusters.

Seizure clusters must be treated quickly and effectively to prevent progression to prolonged seizures and status epilepticus. Rescue therapy for seizure clusters has focused on the use of benzodiazepines. Although intravenous benzodiazepine administration is the primary route in hospitals and emergency departments, seizure clusters typically occur in out‐of‐hospital settings, where a more portable product that can be easily administered by nonmedical caregivers is needed. Thus, other methods of administration have been examined, including rectal, intranasal, intramuscular, and buccal routes. Following US Food and Drug Administration (FDA) approval in 1997, rectal diazepam became the mainstay of out‐of‐hospital treatment for seizure clusters in the United States. However, social acceptability and consistent bioavailability present limitations. Intranasal formulations have potential advantages for rescue therapies, including ease of administration and faster onset of action. A midazolam nasal spray was approved by the FDA in 2019 for patients aged 12 years or older. In early 2020, the FDA approved a diazepam nasal spray for patients aged 6 years or older, which has a different formulation than the midazolam nasal product and enhances aspects of bioavailability. Benzodiazepines, including diazepam, present significant challenges in developing a suitable intranasal formulation. Diazepam nasal spray contains dodecyl maltoside (DDM) as an absorption enhancer and vitamin E to increase solubility in an easy‐to‐use portable device. In a Phase 1 study, absolute bioavailability of the diazepam nasal spray was 97% compared with intravenous diazepam. Subsequently, the nasal spray demonstrated less variability in bioavailability than rectal gel (percentage of geometric coefficient of variation of area under the curve = 42%–66% for diazepam nasal spray compared with 87%–172% for rectal gel). The diazepam nasal spray safety profile is consistent with that expected for rectal diazepam, with low rates of nasal discomfort (≤6%). To further improve the efficacy of rescue therapy, investigation of novel intranasal benzodiazepine formulations is underway.

The stereotactic prostate radiotherapy (SPORT) trial: A randomized feasibility study comparing prostate SABR to prostate and pelvic nodal SABR.

248 Background: Stereotactic Ablative Radiotherapy (SABR) is increasingly used to treat low/intermediate risk localised prostate cancer (PCa). However, data on SABR +/- pelvic nodal irradiation (PNI) in high-risk disease is limited to single institution, single-arm studies. The Stereotactic Prostate Radiotherapy (SPORT) trial examined the feasibility of delivering a randomised trial of SABR ± PNI. The composite primary endpoint to determine feasibility comprised: recruitment rate, technical feasibility, acute toxicity (CTCAE v4.0) and quality of life (QoL)(EPIC). Secondary and exploratory endpoints including late toxicity (RTOG) and QoL and potential biomarkers of toxicity (plasma citrulline and DNA damage in circulating lymphocytes) are also presented. Methods: Men with localised PCa demonstrating one of T3a, Gleason score ≥4+3 or PSA&gt;20 were eligible. T3b and T4 disease were excluded. 30 participants were randomised 1:1 to prostate SABR (P-SABR) or prostate and pelvis SABR (PPN-SABR). The prostate and proximal 1-2cm seminal vesicles received 36.25 Gy in 5 fractions over 29 days (prostate CTV 40Gy). The PPN-SABR arm also received 25 Gy in 5 fractions to the pelvic nodes. All patients had fiducial markers and a rectal spacer gel in-situ. As initial toxicity rates were low, the final 10 men received an additional integrated boost to the dominant intraprostatic lesion of up to 50 Gy, irrespective of randomisation. Results: Feasibility was demonstrated. The target recruitment of 30 men was met (83% high risk). Treatment, including an integrated boost plus PNI, was achievable using strict normal tissue constraints. Acute toxicity and QoL were acceptable (Table: Grade≥2 GU 7%, 27% and GI 0%, 7%; minimal clinically important change (MCIC) in EPIC urinary 40%, 60% and bowel score 33%, 47% in P and PPN arms respectively). At median follow up of 30 months (range 18-42 months), late toxicity and QoL were acceptable (Grade≥2 GU 7%, 20% and GI 0%, 13%; MCIC in EPIC urinary 33%, 67% and bowel score 33%, 67% in P and PPN arms respectively). All toxicity was ≤ grade 2 with the exception of one late grade 3 GU toxicity occurring in the PPN arm. Serum citrulline, a marker of small bowel function, trended towards lower levels in the PPN arm, in keeping with a significantly higher dose delivered to the small bowel in this arm. DNA damage foci in circulating lymphocytes increased at 1 hour after radiation. Foci count and repair correlated to toxicity measures will be presented. Conclusions: A randomised clinical trial comparing P-SABR to PPN-SABR is feasible. There was a suggestion of increased toxicity with PPN-SABR, but this remained acceptable. This data will inform a UK multi-centre phase 2 study. Clinical trial information: NCT03253978 . [Table: see text]

COVID-19: исходы беременности и родов при использовании в лечении препаратов рекомбинантного интерферона α-2b

Objective. To evaluate pregnancy and childbirth outcomes after the combined use of VIFERON® (interferon α-2b with antioxidants) rectal suppositories (3,000,000 IU) and VIFERON® gel for external and local use (36,000 IU/g) in the treatment of new coronavirus infection (COVID-19) in pregnant women against the background of standard complex therapy. Patients and methods. A total of 140 pregnant women diagnosed with COVID-19 were examined and divided into two groups: group 1 consisted of 70 patients who received VIFERON® and standard complex therapy; group 2 – 70 patients who received only standard therapy. Results. Patients from group 1 had a significantly decreased incidence of preterm birth, perinatal loss, and severe birth asphyxia. Most of these pregnant women gave birth at 38-40 weeks of gestation, and no antenatal fetal death was recorded. Conclusion. Inclusion of VIFERON® (rectal suppositories and gel for external and local use) in the complex treatment of COVID-19 in pregnant women contributed to more prompt relief of symptoms and improved pregnancy and childbirth outcomes. Key words: pregnancy, childbirth outcomes, interferon α-2b, antioxidants, new coronavirus infection COVID-19

Эффективность применения препарата рекомбинантного интерферона α-2b в комплексной терапии COVID-19

Objective. To evaluate the efficacy and safety of VIFERON® (recombinant interferon α-2b) rectal suppositories and gel for external and local use in the complex therapy of COVID-19 in adult patients. Patients and methods. 140 patients with COVID-19 were included in a prospective comparative controlled research study. The main group consisted of 71 patients who received standard therapy for coronavirus infection in combination with VIFERON® (rectal suppositories 3.000.000 IU for 1 supp. 3 times a day and gel 36.000 IU/g 5 times a day on the surface of nasal mucosa and palatine tonsils for 14 days); the comparison group – 69 patients who received standard therapy. Results. Patients who received VIFERON® complex therapy demonstrated more rapid clinical improvement by reducing the duration of symptoms of weakness and intoxication compared to the patients who received only standard therapy. The high activity of VIFERON® in elimination rate of SARS-CoV-2 RNA in nasopharyngeal samples was shown. The use of VIFERON® made it possible to achieve a stable concentration of IL-6 in the blood serum during the entire follow-up period. There were no adverse events associated with the administration of VIFERON®. Conclusion. The results obtained indicate the superiority of therapy with the inclusion of VIFERON® over standard therapy. Given the favorable safety profile, the studied regimen can be recommended for the treatment of adult patients, especially from risk groups, where the possibilities of conventional etiotropic therapy are limited due to possible toxicological effects. Key words: VIFERON®, human recombinant interferon α-2b, COVID-19 coronavirus infection