Sublingual Research Articles

Sufentanil sublingual tablet system for enhanced recovery after total knee arthroplasty: a prospective observational case study

BackgroundPostoperative pain is one of the main factors that delays recovery after prosthetic knee surgery. The use of sufentanil sublingual tablet systems (SSTS) can effectively relieve postoperative pain, but their value in facilitating early mobilization has been little studied so far. Our aim here was to assess whether their use could facilitate recovery after knee arthroplasty in an enhanced recovery program.Case presentationIn a prospective observational single-center study, thirty patients operated on for primary knee arthroplasty in the enhanced recovery pathway were included. Patients who received the SSTS (n=15) were compared with those who received an intravenous morphine patient-controlled analgesia (PCA) (n=15). Our recovery program included in particular the use of an adductor canal block, periarticular infiltration of local anesthetic by the surgeon, removal of the venous cannula from the recovery room if possible, the use of an SSTS when available or an IV morphine PCA otherwise, and early physiotherapy. Recovery parameters including the Timed-Up and Go test, pain scores at rest and on exertion, knee flexions, complications, and lengths of hospital stay were not significantly different between the two groups. However, the postoperative opioid consumption in morphine equivalents was significantly greater in the SL-sufentanil group and these patients had their venous cannula removed earlier than in IV-morphine group.ConclusionIn our center, the use of a SSTS was suitable for treating postoperative pain after knee arthroplasty, but it did not improve early recovery in comparison with a morphine PCA.

The first study to evaluate non-invasive haemodynamic profile changes in reaction to nitroglycerin in patients with HFmrEF in comparison to HFpEF and HFrEF

Abstract Introduction According to 2021 guidelines for management of heart failure (HF) there are 3 types of HF – with reduced (HFrEF; ≤40%), mildly reduced (HFmrEF; 41–49%) and preserved (HFpEF; ≥50%) left ventricle ejection fraction (LVEF). The middle group – HFmrEF – is the least known and requires further research. The aim of the study was to assess clinical and hemodynamic profile of patients with HFmrEF at rest and after sublingual administration of 0.4 mg of nitroglycerin (NTG). Material and methods The hemodynamic profile was assessed on the last day of hospitalization due to acute decompensated heart failure. The control groups for patients with HFmrEF were groups of HFpEF and HFrEF, while there was no control group on healthy subjects. The clinical profile of patients was assessed by data from medical interview, results of laboratory tests and measured echocardiographic parameters, while the hemodynamic profile – at rest and after administration of 0.4mg of NTG – was assessed by electrical cardiometry (EC) using the ICON® device. Results Overall, 15 consecutive patients from each type of HF were included into the study and most of them were men (N=32; 71%). Diabetes was significantly more frequent in the HFpEF group. The HFrEF group had significantly higher left ventricle end-diastolic dimension (LVDD; p=0.0003) and lower right ventricle systolic function (TAPSE; p=0.0026). The analysis of the hemodynamic profile at rest showed significant differences between HFmrEF and HFrEF in systolic time ratio (STR; p=0.0202) and pre-ejection period (PEP; p=0.0487). In comparison to HFrEF group, patients with HFmrEF were significantly different in the change of stroke volume and stroke volume index (SV/SI; p=0.0134/0.0223), cardiac output and cardiac index (CO/CI; p=0.005/0.0079), systemic vascular resistance and its' indexed values (SVR/SVRI; p=0.0339/0.0294), the cardiac power index (CPI; p=0.0489) and corrected flow time (FTC; p=0.0369). The change in the following parameters: SV, SI, CO, CI, FTC, SVR, SVRI and CPI after NTG administration, in the HFmrEF group had and an opposite direction in comparison to patients with HFpEF (p=NS) and HFrEF (p<0.05) (Fig. 1). The principal component analysis showed that the HFmrEF group is less heterogenetic and located within the two others (Fig. 2). Conclusions Clinical profile of patients with HFmrEF based on medical interview, laboratory and echographic findings showed that they are a mid-filed group. Patients with HFmrEF significantly differs from HFrEF in the changes of hemodynamic profile after sublingual NTG administration, considering EC parameters of the blood flow (SV, SI, CO, CI, SVR, SVRI) and heart muscle contractility (CPI, FTC). The reaction to NTG showed that HFmrEF is the intermediate and more homogeneous group that is comprised in the other two groups. The median reaction to NTG in the HFmrEF group was opposite to the reaction in HFpEF and HFrEF patients. Funding Acknowledgement Type of funding sources: None.

Efficacy of ibuprofen versus meloxicam in post-surgical pain control after lower third molar surgery

Post-surgical pain is a direct consequence of the surgical event, being closely related to inflammation after treatment, both manifesting itself in parallel. Nonsteroidal anti-inflammatory drugs have been considered the analgesic therapy of choice. Objective: To compare the analgesic effectiveness of ibuprofen against meloxicam after surgical intervention to remove the lower third molar. Materials and Methods: A total of 30 patients were assigned to the two treatment groups: 15 from to ibuprofen group and 15 to the meloxicam group. The first dose was administered at the end of the surgery and the necessary tablets were given to complete the 3-day drug treatment regimen, as well as 1 sublingual ketorolac tablet as rescue medication. Postoperative pain reduction was evaluated making phone calls to evaluate pain by using the numerical scale of pain at 24, 48, 72 hours and 7 days postoperatively. Results: Meloxicam is more effective over time, showing stable analgesic levels and less pain than the ones in ibuprofen group. However, its maximum effect takes longer, which explains that some patients required rescue medication in the first postoperative hours. Conclusions: Due to its analgesic, anti-inflammatory and antipyretic effect, we can consider meloxicam as a good alternative in postoperative pharmacological treatment. It is suggested the use of some other drug that achieves pharmacological synergy to optimize results or to use meloxicam based on preventive analgesia models.

Experience and response to a randomised controlled trial of extended-release injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone for opioid use disorder: protocol for a mixed-methods evaluation

IntroductionOpioid use disorder (OUD) is a debilitating and persistent disorder. The standard-of-care treatment is daily maintenance dosing of sublingual buprenorphine (BUP-SL) or oral methadone (MET). Monthly, extended-release, subcutaneous injectable buprenorphine...

Safety, effectiveness and tolerability of sublingual ketamine in depression and anxiety: A retrospective study of off-label, at-home use.

Intravenous and intranasal ketamine have been shown to be effective therapeutic options in patients suffering from treatment-resistant depression (TRD). The use of sublingual (SL), rapid dissolve ketamine tablets (RDT) offers a novel approach for delivery for mental health indications. This study assessed the effectiveness and safety of self-administration of off-label, SL, rapid dissolve ketamine tablets (RDT) at-home for depression and anxiety. Intake scores on the Generalized Anxiety Disorder Screener (GAD-7) and Patient Health Questionnaire (PHQ-9) were compared to scores after treatments of three doses of ketamine RDT, and after six doses of ketamine RDT. After three doses of SL ketamine, 47.6% of patients showed a significant decrease in PHQ-9 scores, and 47.6% of patients showed a significant reduction in GAD-7 scores. Reduction rates were higher in those patients who completed a clinically recommended six doses of RDT ketamine. This study demonstrates that SL ketamine is a novel, safe, and effective treatment for TRD and treatment-resistant anxiety. SL ketamine offers an alternative therapeutic approach to IV ketamine when treating those with TRD.

Utility of an integrated health system specialty pharmacy in provision of extended-release buprenorphine for patients with opioid use disorder.

Extended-release (ER) monthly injectable buprenorphine offers an alternative to daily sublingual (SL) dosing for treatment of opioid use disorder (OUD) that may be attractive to several patient populations, including those with barriers to adherence and the frequent follow-up that are necessary for traditional SL buprenorphine. Despite the potential benefits of ER-buprenorphine, there are significant barriers to healthcare provider adoption that may prevent utilization in the populations that would benefit. Our health system began providing clinic-administered ER-buprenorphine as treatment for OUD in May 2018 at a single clinic. Expansion was limited due to difficulties with delayed and inaccurate medication delivery and heavy administrative burden. To facilitate uptake of ER-buprenorphine for patients who could benefit, our integrated health-system specialty pharmacy (HSSP) assumed responsibility for medication distribution and administrative management beginning in October 2019. The HSSP provided accurate medication delivery, alleviated administrative burdens of benefits investigation and Risk Evaluation and Mitigation Strategy compliance, and decreased medication wastage by implementing a medication return process. Subsequently, ER-buprenorphine services were expanded to 4 additional sites, allowing 244 more patients to receive treatment. HSSP support can provide significant benefit to patients and the health system through coordinating ER-buprenorphine dispensing and delivery.

Development and characterization of self-assembling sirolimus-loaded micelles as a sublingual delivery system

The aim of this study was to develop self-assembling micelles of poorly water soluble potent immunosuppressant agent sirolimus (SRL) to enhance the solubility and mucosal permeability as stable aqueous formulations for sublingual administration. D-α-tocopheryl 1000 succinate (TPGS), soy phosphatidylcholine (SPC), and sodium cholate (NaC) were used to prepare the SRL-loaded micelles using the one-step self-assembly method. The mean hydrodynamic diameter of optimal micelles ranged from approximately 13 to 42 nm with low polydispersity index (PDI). The formulations possessed drug loading (DL) and drug encapsulation efficiency (EE) of around 18% and 99%, respectively. SPC caused an increase in mean hydrodynamic diameter and PDI of micelles, but no negative impact on DL and EE values was observed when used at concentrations of ≤25% (w/w) of amphiphiles. However, NaC caused a detrimental effect on the characteristics of micelles in every respect. Ex vivo permeation studies revealed that TPGS-based micelles without SPC were not able to enhance the permeation of SRL compared to the SRL solution through bovine sublingual mucosa. However, the incorporation of SPC into the micelles significantly increased the mucosal permeation of SRL compared to the SRL solution. The optimal formulations maintained their characteristics at 4 °C for at least 90 days. These results support the feasibility of SRL-loaded micelles as a sublingual delivery system.

Rapid Sublingual Delivery of Piroxicam from Electrospun Cyclodextrin Inclusion Complex Nanofibers.

Piroxicam (Px) is a nonsteroidal anti-inflammatory drug (NSAID) used for the treatment of osteoarthritis and rheumatoid arthritis. It is administered orally; however, its poor water solubility causes low loading to the nonconventional drug delivery systems (DDSs), such as electrospun fibers. Furthermore, the rapid dissolution of DDS and fast release of the embedded drugs are crucial for oral delivery of drugs to patients who are unconscious or suffering from dysphagia. In this regard, this study reports the development of rapidly dissolving cyclodextrin (CD)-based inclusion complex (IC) nanofibers by waterborne electrospinning for fast oral delivery of Px. Scanning electron microscopy analysis revealed the formation of bead-free fibers with a mean diameter range of 170–500 nm at various concentrations of Px; increasing the Px loading decreased the fiber diameter. The formation of IC was demonstrated by X-ray diffraction (XRD) analysis by the disappearance of crystalline peaks of Px. Likewise, differential scanning calorimetry (DSC) analysis showed the disappearance of the melting peak of the embedded Px due to IC formation. Both Fourier transform infrared (FTIR) and thermogravimetric analysis (TGA) confirmed the presence of Px within the fibers. 1H NMR experiments demonstrated Px preservation in the fibers after six months. Px-loaded nanofibers were employed for sublingual drug delivery. To mimic the environment of the mouth, the nanofibers were treated with artificial saliva, which revealed the instant dissolution of the nanofibers. Furthermore, dissolution experiments were performed on the tissues wetted with artificial saliva, where the dissolution of the fibers could be extended to a few seconds, demonstrating the suitability of the materials for sublingual oral drug delivery. Overall, this paper, for the first time, reports the rapid oral delivery of Px from polymer-free CD fibers produced by waterborne electrospinning without the requirement of any carrier polymer and toxic solvent.

Cell-penetrating albumin enhances the sublingual delivery of antigens through macropinocytosis

Innovations in oral immunotherapy have greatly advanced the therapeutic control of allergies. However, these therapeutic effects suffer from the fact that the amount of antigen delivered to antigen-presenting cells is limited given the formulations that are currently available. We recently designed a cell-penetrating albumin and found that this modified albumin enters cells via the induction of macropinocytosis. Herein, we report on a novel system for delivering antigens based on cell-penetrating albumin-inducible macropinocytosis that allows larger amounts of antigens to be delivered to antigen-presenting cells. A treatment with cell-penetrating albumin significantly increased the permeability of ovalbumin (45 kDa) or dextran (2000 kDa) on monolayers derived from human oral squamous carcinoma cells. Flow cytometric analyses showed that the cell-penetrating albumin treatment resulted in a significant elevation in the amount of dextran that was delivered to two types of antigen-presenting cells. Finally, mice that had been sensitized by Japanese cedar pollen extract (JCPE) and cell-penetrating albumin showed a decline in the frequency of nose-rubbing against a subsequent intranasal administration of JCPE. These findings suggest that the sublingual administration of cell-penetrating albumin efficiently delivers antigens to antigen-presenting cells via the induction of macropinocytosis, resulting in an enhancement in the therapeutic effect of sublingual immunotherapy.

Streptococcus mutans glutamate binding protein (GlnH) as antigen target for a mucosal anti-caries vaccine.

In recent years, several studies have demonstrated that bacterial ABC transporters present relevant antigen targets for the development of vaccines against bacteria such as Streptococcus pneumoniae and Enterococcus faecalis. In Streptococcus mutans, the glutamate transporter operon (glnH), encoding an ABC transporter, is associated with acid tolerance and represents an important virulence-associated factor for the development of dental caries. In this study, we generated a recombinant form of the S. mutans GlnH protein (rGlnH) in Bacillus subtilis. Mice immunized with this protein antigen elicited strong antigen-specific antibody responses after sublingual administration of a vaccine formulation containing a mucosal adjuvant, a non-toxic derivative of the heat-labile toxin (LTK63) originally produced by enterotoxigenic Escherichia coli (ETEC) strains. Serum anti-rGlnH antibodies reduced adhesion of S. mutans to the oral cavity of naïve mice. Moreover, mice actively immunized with rGlnH were partially protected from oral colonization after exposure to the S. mutans NG8 strain. Our results indicate that S. mutans rGlnH is a potential target antigen capable of inducing specific and protective antibody responses after immunization. Overall, these observations raise the prospect of the development of mucosal anti-caries vaccines.

Suitability of potyviral recombinant virus-like particles bearing a complete food allergen for immunotherapy vaccines.

Virus-like particles (VLPs) have been gaining attention as potential platforms for delivery of cargos in nanomedicine. Although animal viruses are largely selected due to their immunostimulatory capacities, VLPs from plant viruses constitute a promising alternative to be considered. VLPs derived from Turnip mosaic virus (TuMV) have proven to present a tridimensional structure suited to display molecules of interest on their surface, making them interesting tools to be studied in theragnostic strategies. Here, we study their potential in the treatment of food allergy by genetically coupling TuMV-derived VLPs to Pru p 3, one of the most dominant allergens in Mediterranean climates. VLPs-Pru p 3 were generated by cloning a synthetic gene encoding the TuMV coat protein and Pru p 3, separated by a linker, into a transient high-expression vector, followed by agroinfiltration in Nicotiana benthamiana plants. The generated fusion protein self-assembled in planta to form the VLPs, which were purified by exclusion chromatography. Their elongated morphology was confirmed by electron microscopy and their size (~400 nm), and monodispersity was confirmed by dynamic light scattering. Initial in vitro characterization confirmed that they were able to induce proliferation of human immune cells. This proliferative capability was enhanced when coupled with the natural lipid ligand of Pru p 3. The resultant formulation, called VLP-Complex, was also able to be transported by intestinal epithelial cells, without affecting the monolayer integrity. In light of all these results, VLP-Complex was furtherly tested in a mouse model of food allergy. Sublingual administration of VLP-Complex could effectively reduce some serological markers associated with allergic responses in mice, such as anti-Pru p 3 sIgE and sIgG2a. Noteworthy, no associated macroscopic, nephritic, or hepatic toxicity was detected, as assessed by weight, blood urea nitrogen (BUN) and galectin-3 analyses, respectively. Our results highlight the standardized production of allergen-coated TuMV-VLPs in N. benthamiana plants. The resulting formula exerts notable immunomodulatory properties without the need for potentially hazardous adjuvants. Accordingly, no detectable toxicity associated to their administration was detected. As a result, we propose them as good candidates to be furtherly studied in the treatment of immune-based pathologies.

Efficacy and safety of house dust mite sublingual immunotherapy tablets in allergic rhinitis: A systematic review and meta-analysis

BackgroundHouse dust mite (HDM) sublingual immunotherapy (SLIT) tablets have been approved for the treatment of patients with allergic rhinitis (AR). However, the meta-analysis on the efficacy of HDM-SLIT tablets for HDM-induced AR patients remained limited. MethodsFive databases were searched including: PubMed/MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and CINAHL for randomized controlled trials (RCTs) that addressed the efficacy and safetyof HDM-SLIT tablets compared with placebo until January 2022. The primary outcome was a combined symptom and medication score (CSMS) after treatment. ResultsEight eligible RCTs were identified with a total of 3601 patients treated with HDM-SLIT tablets and 2783 patients who received a placebo. The CSMS was significantly lower in the HDM-SLIT tablet group compared with the placebo (standardized mean difference (SMD) −0.28 [95% CI: −0.32 to −0.23]). There was a significant reduction in rhinitis symptom scores, rhinitis medication scores, total combined conjunctivitis scores, and rhinoconjunctivitis quality of life questionnaire scores. The consistent efficacy compared to the placebo has been exhibited over the different kinds and doses of HDM tablets (6 SQ, 12 SQ, 300 IR, and 500 IR) and age groups (>5 years old, adolescents and adults) with low degrees of variability across the studies. There was no significant difference in proportions of participants who were injected with epinephrine between the treatment- and placebo groups. ConclusionsHDM-SLIT tablet is an effective treatment in reducing rhinitis symptoms and medication use in AR patients with favorable safety. They also improve quality of life and conjunctivitis symptoms.

Formulation and the Study of Finished Products used for Anginal Disease

Congestive heart failure is a type of disease which is mainly observed due to the improper supply of blood to the heart. In this disease patient feels severe pain in the chest and may cause serious illness. Sudden treatment is needed in this disease to prevent any fatality. Nitroglycerin is the choice of drug for this disease. This study prepares a dosage form that can deliver the drug at a fast rate like a sublingual tablet of nitroglycerin. Sublingual dosage form was manufactured by direct compression method. For the formulation, multiple excipients like super disintegrants, sweeteners and lubricants were used. The finished dosage form was evaluated for different quality parameters. Optimum formulation was compared with the marketed product and kept on the accelerated stability study. Results were observed as satisfactory and comparable with the marketed product.

Elongated Mental Spine with Two Lingual Foramina in the Mandible of A Kurdish Woman: A Case Report

The mental spines are bony prominences found in the lingual surface of anterior mandible, and usually they are arranged in two groups, superior pair and inferior pair. Mostly they are asymptomatic, but sometimes they may interfere with the prosthodontic treatment or with some surgeries. The lingual foramen can be found in different locations around the mental spines, and they are very important vital organ because they transmit nerves and arteries, which may cause a serious problem during some types of surgeries in this region such as implant placement. Here, we report a case of 55-year-old, Kurdish woman with elongated superior mental spine with bilaterally lingual foramina located distally to lower central incisors, that have been seen during a routine CBCT scan. The length of the spine was 6.4 mm, the height was 5.5 mm and the width was 1.9 mm. So, any dentist wants to perform any type of surgery in sublingual and submental regions should be careful of such anatomical variations.

Buprenorphine and its formulations: a comprehensive review.

Buprenorphine, a novel long-acting analgesic, was developed with the intention of two purposes: analgesia and opioid use disorder. Regarding its pharmacodynamics, it is a partial agonist at mu receptors, an inverse agonist at kappa receptors, and an antagonist at delta receptors. For the purpose of analgesia, three formulations of buprenorphine were developed: IV/IM injectable formulation (Buprenex®), transdermal patch formulation (Butrans®), and buccal film formulation (Belbuca®). Related to opioid dependence, the formulations developed were subcutaneous extended release (Sublocade®), subdermal implant (Probuphine®), and sublingual tablets (Subutex®). Lastly, in order to avoid misuse of buprenorphine for opioid dependence, two combination formulations paired with naloxone were developed: film formulation (Suboxone®) and tablet formulation (Zubsolv®). In this review, we present details of each formulation along with their similarities and differences between each other and clinical considerations.

Extended-release pharmacotherapy for opioid use disorder (EXPO): protocol for an open-label randomised controlled trial of the effectiveness and cost-effectiveness of injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone

BackgroundSublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use disorder (OUD). A sizable proportion of the OUD treatment population is not exposed to sufficient treatment to attain the desired clinical benefit. Two promising therapeutic technologies address this deficit: long-acting injectable buprenorphine and personalised psychosocial interventions (PSI). This study will determine (A) the effectiveness and cost-effectiveness — monthly injectable, extended-release (BUP-XR) in a head-to-head comparison with BUP-SL and MET, and (B) the effectiveness of BUP-XR with adjunctive PSI versus BUP-SL and MET with PSI. Safety, retention, craving, substance use, quality-adjusted life years, social functioning, and subjective recovery from OUD will be also evaluated.MethodsThis is a pragmatic, multi-centre, open-label, parallel-group, superiority RCT, with a qualitative (mixed-methods) evaluation. The study population is adults. The setting is five National Health Service community treatment centres in England and Scotland. At each centre, participants will be randomly allocated (1:1) to BUP-XR or SOC. At the London study co-ordinating centre, there will also be allocation of participants to BUP-XR with PSI or SOC with PSI. With 24 weeks of study treatment, the primary outcome is days of abstinence from non-medical opioids during study weeks 2–24 combined with up to 12 urine drug screen tests for opioids. For 90% power (alpha, 5%; 15% inflation for attrition), 304 participants are needed for the BUP-XR versus SOC comparison. With the same planning parameters, 300 participants are needed for the BUP-XR and PSI versus SOC and PSI comparison. Statistical and health economic analysis plans will be published before data-lock on the Open Science Framework. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials and Consolidated Health Economic Evaluation Reporting Standards.DiscussionThis pragmatic randomised controlled trial is the first evaluation of injectable BUP-XR versus the SOC medications BUP-SL and MET, with personalised PSI. If there is evidence for the superiority of BUP-XR over SOC medication, study findings will have substantial implications for OUD clinical practice and treatment policy in the UK and elsewhere.Trial registrationEU Clinical Trials register 2018-004460-63.

The Effect of Preoperative Sublingual Melatonin on Postoperative Pain Severity in Patients Undergoing Colorectal Surgery: A Triple-Blinded Randomized Trial.

Background: Postoperative pain has detrimental physiologic and psychologic effects on patients’ outcomes, such as increased postoperative morbidity, delayed recovery, and reduced patient satisfaction. This study aimed to determine the effect of preoperative sublingual melatonin on pain severity after colorectal surgery. Methods: We performed a randomized, placebo-controlled, triple-blinded study to test the efficacy of 6 mg of sublingual melatonin or placebo 1 hour preoperative on pain severity and sedation of 60 patients after colorectal surgeries. Pain and sedation were assessed by numerical verbal response (NVR) and the Ramsey sedation score, respectively, at the baseline, 1, 2, 6, 12, and 24 hours after surgery. The repeated measures analysis of variance was used to assess group × time interaction, and the Bonferroni adjustment was used for between-group comparisons. Results: A total of 60 patients with a mean ± SD age of 49.35 years were equally randomized to the study groups. There was no significant difference between groups with respect to the baseline characteristics. The mean score of pain severity of patients in the melatonin group was significantly lower compared with the placebo group at 2, 6, 12, and 24 hours after surgery. The total mean pain score for the first 12 hours (mean difference [MD] [SE], 0.41 [0.12]; 95% CI, 0.17-0.65; [P = 0.012]) and the mean score of pain in 24 hours after surgery were significantly lower in the melatonin group in comparison with the placebo group (MD [SE], 0.44 [0.13]; 95% CI, 0.19-0.69; [P = 0.001]). Compared with the placebo group, the percent of patients who were cooperative, aware, and calm was significantly higher in the melatonin group at the baseline (43.3% vs 53.3%) and at 1 (36.7% vs 60%) and 2 hours (33.3% vs 80%). Conclusion: The use of 6 mg preoperative melatonin sublingual tablet in patients with colorectal surgeries could reduce the severity of postoperative pain, patients’ restlessness and anxiety, and increase patients' cooperation and calmness. Therefore, it seems that sublingual melatonin is an effective drug in controlling postoperative pain.

Prophylactic effect of rectal and sublingual misoprostol on postpartum hemorrhage in mothers with preeclampsia following cesarean section surgery; a double-blind randomized controlled trial

BackgroundPostpartum hemorrhage is one of the three major causes of maternal morbidity and mortality, so delay in the diagnosis and proper management of postpartum hemorrhage is of great importance. The present study aimed to determine the prophylactic effect of misoprostol on postpartum hemorrhage in patients with preeclampsia. MethodsThis was a double-blind randomized controlled clinical trial performed on 128 pregnant women with preeclampsia undergoing cesarean section in Kamali hospital in Karaj. After cesarean delivery, immediately after clamping the umbilicus, the first group was administered 400 μg of rectal misoprostol and the second group was given 400 μg of sublingual misoprostol. The third group (control) was given 30 units of oxytocin during surgery and within 12 h after surgery, respectively. Hemoglobin and hematocrit were measured 24 h later. The estimated bleeding rate by the physician, the need for additional medication to control bleeding, and the amounts of hemoglobin and hematocrit in the first 24 h were compared in the three groups. Finally, the obtained information was entered into SPSS version 21 and analyzed using statistical tests. ResultsThe mean hemoglobin and hematocrit levels 6 and 12 h after cesarean section were significantly lower in the oxytocin group than in the sublingual and rectal misoprostol groups (Hemoglobin level (mg/dl) for oxytocin group 10.39 ± 0.73 and 9.53 ± 1.09 vs. sublingual misoprostol 11.05 ± 0.71 and 10.39 ± 0.84 vs. rectal misoprostol 10.92 ± 0.85 and 10 ± 1.01; hematocrit level for Hemoglobin level (%) for oxytocin group 31.27 ± 2.29 and 28.64 ± 2.93 vs. sublingual misoprostol 33.09 ± 2.20 and 31.05 ± 2.37 vs. rectal misoprostol 32.54 ± 2.7 and 29.92 ± 2.86) (p < 0.005). The mean estimation of visual bleeding in the oxytocin group was higher than the other three groups, followed by the rectal and the sublingual groups, respectively. However, there was no significant difference between the three groups regarding visual bleeding. There was no significant difference in hemoglobin and hematocrit between the two groups of sublingual and rectal misoprostol before and 6 and 12 h after the surgery (P > 0.05). ConclusionIt seems that sublingual or rectal misoprostol administration along with oxytocin is associated with a reduction in postpartum cesarean section bleeding compared to oxytocin administration alone.

Development of a Mucoadhesive Vehicle Based on Lyophilized Liposomes for Drug Delivery through the Sublingual Mucosa.

A pharmaceutical vehicle based on lyophilized liposomes is proposed for the buccal administration of drugs aimed at systemic delivery through the sublingual mucosa. Liposomes made of egg phosphatidylcholine and cholesterol (7/3 molar ratio) were prepared and lyophilized in the presence of different additive mixtures with mucoadhesive and taste-masking properties. Palatability was assayed on healthy volunteers. The lyophilization cycle was optimized, and the lyophilized product was compressed to obtain round and capsule-shaped tables that were evaluated in healthy volunteers. Tablets were also assayed regarding weight and thickness uniformities, swelling index and liposome release. The results proved that lyophilized liposomes in unidirectional round tablets have palatability, small size, comfortability and buccal retention adequate for sublingual administration. In contact with water fluids, the tablets swelled, and rehydrated liposomes were released at a slower rate than permeation efficiency determined using a biomimetic membrane. Permeability efficiency values of 0.72 ± 0.34 µg/cm2/min and 4.18 ± 0.95 µg/cm2/min were obtained for the liposomes with and without additives, respectively. Altogether, the results point to the vehicle proposed as a liposomal formulation suitable for systemic drug delivery through the sublingual mucosa.

S-Ketamine Oral Thin Film-Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine.

Ketamine is administered predominantly via the intravenous route for the various indications, including anesthesia, pain relief and treatment of depression. Here we report on the pharmacokinetics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two oral thin films on separate occasions in a randomized crossover design. The oral thin films were placed sublingually (n = 15) or buccally (n = 5) and left to dissolve for 10 min in the mouth during which the subjects were not allowed to swallow. For 6 subsequent hours, pharmacokinetic blood samples were obtained after which 20 mg S-ketamine was infused intravenously and blood sampling continued for another 2-hours. A population pharmacokinetic analysis was performed in NONMEM pharmacokinetic model of S-ketamine and its metabolites S-norketamine and S-hydroxynorketamine; p < 0.01 were considered significant. S-ketamine bioavailability was 26 ± 1% (estimate ± standard error of the estimate) with a 20% lower bioavailability of the 100 mg oral thin film relative to the 50 mg film, although this difference did not reach the level of significance. Due to the large first pass-effect, 80% of S-ketamine was metabolized into S-norketamine leading to high plasma levels of S-norketamine following the oral thin film application with 56% of S-ketamine finally metabolized into S-hydroxynorketamine. No differences in pharmacokinetics were observed for the sublingual and buccal administration routes. The S-ketamine oral thin film is a safe and practical alternative to intravenous S-ketamine administration that results in relatively high plasma levels of S-ketamine and its two metabolites.