Route Of Administration In Patients Research Articles

Exploring ex vivo peptideolysis of thymopentin and lipid-based nanocarriers towards oral formulations

The oral delivery of medicines is the most popular route of administration for patients. However, thymopentin (TP5) is only available in the market in forms for parenteral administration. In large part, this is because of extensive peptidolytic degradation in the gastrointestinal tract (GIT), which decreases the amount of TP5 available for absorption. This study aims to understand the extent of TP5 peptideolysis and determine effective inhibitors and suitable lipid-based nanocarriers to aid in the development of an effective oral delivery formulation. Enzymatic degradation kinetics of TP5 was investigated in the presence or absence of mucosal and luminal components extracted from various parts of the rat intestine, including the duodenum, jejunum, ileum, and colon. Inhibition of TP5 enzymatic peptidolysis was screened in the presence or absence of EDTA, trypsin and chymotrypsin inhibitors from soybean (SBTCI), and bestatin. TP5 with SBTCI was loaded into lipid-based nanocarriers, including microemulsions, niosomes and solid lipid nanoparticles. These TP5-loaded nanocarriers were investigated through characterization of morphology, particle size, zeta potential, entrapment efficacy (EE%), and ex vivo rat intestinal degradation studies to select a lead formulation for a future oral drug delivery study. The degradation kinetics of TP5 followed pseudo-first-order kinetics, and the biological metabolism of TP5 was displayed in the presence of luminal contents, indicating that TP5 is sensitive to luminal enzymes. Notably, a considerable decrease in TP5 peptidolysis was found in the presence of SBTCI, bestatin, and EDTA. TP5 and SBTCI were loaded into three lipid-based delivery systems, displaying superior protection under ex vivo intestinal luminal contents and mucosal homogenates for 6 h compared with the pure drug solution. These findings suggest that using select inhibitors and lipid-based nanocarriers can decrease peptide degradation and may improve oral bioavailability of TP5 following oral administration.

An Ex Vivo Evaluation of Cenobamate Administered via Enteral Tubes.

BackgroundCenobamate is a new, Food and Drug Administration (FDA)-approved oral antiepileptic drug for treatment of focal seizures in adults. This study examined recovery of cenobamate from suspensions administered through ex vivo enteral feeding tubes.MethodsSuspensions containing 100 and 200 mg of cenobamate were prepared (five duplicates for each dose), passed through five vertically standing tubes, and collected into flasks. The flasks containing the suspensions were rinsed with deionized water, and this content was also injected into the tubes and collected in the flasks. Acetonitrile, isopropyl alcohol, and trifluoroacetic acid were added to the flasks, followed by deionized water to a concentration of 500 (100-mg cenobamate) and 400 (200-mg cenobamate) µg/mL. A 3-mL aliquot from each suspension was placed into a 10-mL flask, diluted to volume, and mixed, resulting in final concentrations of 150 and 120 µg/mL, respectively. All suspensions were analyzed by high-performance liquid chromatography (LC). The % LC recovery of cenobamate was calculated for each suspension, and mean % LC for duplicates.ResultsThe % LC recovery of cenobamate from the 100-mg suspensions ranged from 96.2 to 99.1%, with mean % LC recovery between 96.3 and 98.3%. The % LC recovery of cenobamate from the 200-mg suspensions ranged from 97.1 to 102.6%, with mean % LC recovery between 98.5 and 101.7%.ConclusionThe mean % LC recovery of cenobamate was within the predetermined acceptable range of 90.0–110.0%, suggesting no adhesion or adsorption of cenobamate to enteral feeding tubes. Delivery of cenobamate suspension via enteral feeding tubes may be a viable route of administration for patients who cannot swallow tablets.

Characteristics of Fecal Microbiota Transplantation Use in Inflammatory Bowel Disease Cohort.

BackgroundThere is a growing interest in the role of gut bacteria in a number of diseases and an emerging hypothesis that inflammatory bowel disease (IBD) is triggered by microbial dysbiosis in genetically susceptible individuals. Currently, fecal microbiota transplantation (FMT) is utilized for the treatment of Clostridium difficile colitis. Data on the efficacy of FMT for IBD are mixed, but patients are interested in its use for the treatment of IBD. We sought to describe the use of FMT (self or medical professional administered) in individuals with IBD using IBD Partners, an Internet-based cohort.MethodsPatients enrolled in the IBD Partners cohort were offered the opportunity to complete an optional survey on the use of FMT between January 2017 to September 2018 (n = 5430). A cross-sectional analysis was performed within patients who completed the survey and did not have a pouch or ostomy. Patients’ demographic characteristics, disease activity and phenotype, mode of FMT delivery, and patient-reported efficacy were compared.ResultsAmong 3274 eligible patients, 51 (1.6%) responded that they had an FMT in the past. Of patients undergoing FMT, 22 patients had the FMT for C. difficile while 29 reported that the FMT was for another indication. Most patients receiving FMT for an indication other than C. difficile had ulcerative colitis/indeterminate colitis (25, 86.2%). Colonoscopy (68.2%) and nasogastric tube (18.2%) were the most common routes of administration for patients receiving FMT for C. difficile colitis. Self-administration (72.4%) and enemas (17.2%) were the most common routes of administration in patients receiving FMT for an alternate indication. Patients reporting FMT for an indication other than C. difficile were less likely to have a physician directing their FMT treatment (20.6%) as compared to patients receiving FMT for C. difficile (86.3%). Patient-reported efficacy was lower for FMT given for a non-C. difficile indication.ConclusionsPatients undergoing FMT for an indication other than C. difficile infection were more likely to have ulcerative colitis, self-administer FMT, and were less likely to be receiving FMT under the guidance of a medical professional. FMT was not as effective for symptoms when given for a non-C. difficile indication. Patients should be counseled on potential harms and lack of proven benefit associated with FMT for IBD indications to try to discourage self-administered FMT without proper medical oversite.

P013 Characteristics of Fecal Microbiota Transplantation Use in Inflammatory Bowel Disease cohort

BACKGROUND: There is a growing interest in the role of gut bacteria in a variety of diseases and an emerging hypothesis that inflammatory bowel disease (IBD) is triggered by microbial dysbiosis in genetically susceptible individuals. Currently fecal microbiota transplantation (FMT) is utilized for the treatment of C. difficile colitis. Data on the efficacy of FMT for IBD are mixed, but patients are interested in its use for treatment of IBD. We sought to describe the use of FMT (self or medical professional administered) in individuals with IBD using IBD Partners, an internet-based cohort. METHODS: A total of 3,247 patients enrolled in the IBD Partners cohort were offered the opportunity to complete an optional survey on use of FMT. Bivariate statistics were used to determine factors associated with use of FMT including IBD disease characteristics, indication for FMT, and mode of FMT delivery. RESULTS: Of the 3,247 patients eligible to complete the FMT survey, 51 (1.6%) people responded that they had an FMT in the past. Of patients undergoing FMT, 22 patients had the FMT for C. difficile while 29 reported that the FMT was for another indication. Most patients receiving FMT for an indication other than C. difficile had UC/IC (25, 86.2%). Colonoscopy (68.2%) and nasogastric tube (18.2%) were the most common routes of administration for patients receiving FMT for C. difficile colitis. Self-administration (72.4%) and enemas (17.2%) were the most common routes of administration in patients receiving FMT for an alternate indication. Patients reporting FMT for an indication other than C. difficile were less likely to have a physician directing their FMT treatment (20.6%) as compared to patients receiving FMT for C. difficile (86.3%). Patient reported efficacy was lower for FMT given for a non-C. difficile indication. CONCLUSION(S): Patients undergoing FMT for an indication other than C. difficile infection were more likely to have UC, self-administer FMT, and were less likely to be receiving FMT under the guidance of a medical professional. FMT was not as effective for symptoms when given for a non-C. difficile indication. Patients should be counseled on potential harms and lack of efficacy data associated with FMT for IBD indications to try to discourage self-administered FMT without proper medical oversite.

Appropriate empirical antibiotic use in the emergency department: full compliance matters!

BackgroundLittle is known about determinants of appropriate antibiotic use in the emergency department (ED). We measured appropriateness of antibiotic use for seven quality indicators (QIs) and studied patient-related factors that determine their variation.Patients and methodsA retrospective analysis of 948 patients presumptively diagnosed as having an infection needing empirical antibiotic treatment in the ED was performed. Outcomes of seven previously validated QIs were calculated using computerized algorithms. We used logistic regression analysis to identify patient-related factors of QI performance and evaluated whether more appropriate antibiotic use in the ED results in better patient outcomes (length-of-stay, in-hospital mortality, 30 day readmission).ResultsQI performance ranged from 57.3% for guideline-adherent empirical therapy to 97.3% for appropriate route of administration in patients with sepsis. QI performance was positively associated with patients’ disease severity on admission (presence of fever, tachycardia and hypotension). Overall, the clinical diagnosis and thus the guidelines followed influenced QI performance. The difference in complexity between the guidelines was a possible explanation for the variation in QI performance. A QI performance sum score of 100% was associated with reduced in-hospital mortality. QI performance was not associated with readmission rates.ConclusionsWe gained insights into factors that determine quality of antibiotic prescription in the ED. Adherence to the full bundle of QIs was associated with reduced in-hospital mortality. These findings suggest that future stewardship interventions in the ED should focus on the entire process of antibiotic prescribing in the ED and not on a single metric only.

Combined Intravenous and Intraarticular Tranexamic Acid Does Not Offer Additional Benefit Compared with Intraarticular Use Alone in Bilateral TKA: A Randomized Controlled Trial.

Tranexamic acid (TXA) is efficacious for reducing blood loss and transfusion use in patients who undergo bilateral TKA, and it is administered intravenously alone, intraarticularly alone, or as a combination of these. However, it is unclear whether combined intravenous (IV) and intraarticular TXA offers any additional benefit over intraarticular use alone in patients undergoing bilateral TKA. The purposes of our study was to determine (1) whether combined IV and intraarticular TXA reduces blood loss and blood transfusion use compared with intraarticular use alone and (2) whether the frequency of adverse events is different between these routes of administration in patients who undergo simultaneous or staged bilateral TKA. Between April 2015 and May 2017, one surgeon performed 316 same-day bilateral TKAs and 314 staged bilateral TKAs. Of those, 98% of patients in each same-day TKA (310) and staged bilateral TKA (309) groups were eligible for this randomized trial and all of those patients agreed to participate and were randomized. The study included four groups: simultaneous TKA with intraarticular TXA only (n = 157), simultaneous TKA with IV and intraarticular TXA (n = 153), staged TKA with intraarticular TXA only (n = 156), and staged TKA with IV and intraarticular TXA (n = 155). There were no differences in demographic data among the intraarticular alone and IV plus intraarticular TXA groups of patients who underwent simultaneous or staged bilateral TKA in terms of age, proportion of female patients, BMI, or preoperative hematologic values. The primary outcome variables were total blood loss calculated based on patient blood volume and a drop in the hemoglobin level and administration of blood transfusion. The secondary outcomes of this study were a decrease in the postoperative hemoglobin level; the proportion of patients with a hemoglobin level lower than 7.0, 8.0, or 9.0 g/dL; and the frequencies of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, wound complications, and periprosthetic joint infection. Total blood loss with intraarticular TXA alone in patients undergoing simultaneous bilateral TKA and those undergoing staged procedures was not different from the total blood loss with the combined IV plus intraarticular TXA regimen (1063 mL ± 303 mL versus 1004 mL ± 287 mL, mean difference 59 mL [95% CI -7 to 125]; p = 0.08 and 909 ml ± 283 ml versus 845 ml ± 278 ml; mean difference 64 mL [95% CI 1 to 127]; p = 0.046, respectively). The use of blood transfusions between intraarticular alone and combined IV and intraarticular TXA was also not different among patients undergoing simultaneous (0% [0 of 152] versus 1%; p = 0.149) and staged TKA (1% [1 of 155] versus 0% [0 of 153]; p = 0.98). Furthermore, the frequency of symptomatic thromboembolic events, wound complications, and periprosthetic joint infections was low, without any differences among the groups with the numbers available. Because there was no difference between intraarticular alone and combined intraarticular plus IV regimen of TXA administration, we recommend that IV and intraarticular TXA should not be used in combination. Moreover, other studies have found no differences between intraarticular and IV TXA used alone, and hence to avoid potential complications associated with systemic administration, we recommend that intraarticular alone is sufficient for routine TKA. Level I, therapeutic study.

Ketogenic Diet as a Treatment for Super-Refractory Status Epilepticus in Febrile Infection-Related Epilepsy Syndrome.

Background: Febrile infection-related epilepsy syndrome (FIRES) is a fatal epileptic encephalopathy associated with super-refractory status epilepticus (SRSE). Several treatment strategies have been proposed for this condition although the clinical outcomes are poor. Huge efforts from neurointensivists have been focused on identifying the characteristics of FIRES and treatment to reduce the mortality associated with this condition. However, the role of ketogenic diet (KD) in FIRES is not fully understood.Methods: We performed a retrospective review of patients who met the diagnostic criteria of FIRES, SRSE, and were treated with KD between 2015 and 2018 at the Department of Pediatrics, Xiangya Hospital of Central South University. The following data were recorded: demographic features, clinical presentation, anticonvulsant treatment, timing and duration of KD and follow-up information. Electroencephalography recordings were reviewed and analyzed.Results: Seven patients with FIRES were put on KD (5 via enteral route, and 2 via intravenous line) for SRSE in the PICU. The median age was 8. Four patients were male and 3 were female. Although patients underwent treatment with a median of 4 antiepileptic drugs and 2 anesthetic agents, the status epilepticus (SE) persisted for 7–31 days before KD initiation. After KD initiation, all patients achieved ketosis and SE disappeared within an average of 5 days (IQR 3.5), although there were minor side effects. In 6 patients, a unique pattern was identified in the EEG recording at the peak period. After initiation of KD, the number of seizures reduced, the duration of seizure shortened, the background recovered and sleep architecture normalized in the EEG recordings. The early initiation of KD (at the onset of SE) in the acute phase of patients decreased the mRS score in the subsequent period (p = 0.012, r = 0.866).Conclusions: The characteristic EEG pattern in the acute phase promoted timely diagnosis of FIRES. Our data suggest that KD may be a safe and promising therapy for FIRES with SRSE, and that early initiation of KD produces a favorable prognosis. Therefore, KD should be applied earlier in the course of FIRES. Intravenous KD can be an effective alternative route of administration for patients who may not take KD enterally.

MON-464 Non-Clinical Profiling of ONO-5788, a Novel Oral Small Molecule Somatostatin Receptor Type-2 (SST2) Agonist, to Support Studies in Humans

Somatostatin analogues (SSAs) are indicated for use in acromegaly and gastroenteropancreatic neuroendocrine tumors (GEP NETs). However, SSAs are administered as injections which can be a challenge for patients and healthcare providers. ONO-5788 is a novel low molecular weight orally administered molecule with potent and selective agonistic effects at the human SST2 subtype. ONO-5788 could offer the advantages of a more convenient route of administration for patients with acromegaly and other indications and also a preferential safety profile compared to injections. In order to support clinical evaluation of ONO-5788, a series of non-clinical experiments were undertaken. Findings: In vitro, ONO-5788 and its active metabolite, ONO-ST1-641, has a greater agonistic effect on human SST2 compared to other somatostatin receptor subtypes, with EC50 values of 0.11 and 0.016 nmol/L, respectively. There is no difference in mean EC50 values between human SST2 and rat SST2. ONO-5788 and ONO-ST1-641 significantly inhibits growth hormone-releasing hormone (GHRH)-induced GH secretion from primary cultured rat pituitary cells. In vivo studies in rats confirmed that a single oral dose of ONO-5788 resulted in systemic exposure of ONO-5788 and ONO-ST1-641 that increased in a dose dependent manner. Orally administrated ONO-5788 significantly inhibited both GHRH-induced GH secretion and basal GH secretion at all the doses tested (≥0.1 and ≥0.03 mg/kg, respectively). ONO-5788 and ONO-ST1-641 administrated intravenously significantly inhibited GHRH-induced GH secretion with effect on maximum inhibition of GH secretion similar to octreotide (ONO-5788 98.0%, ONO-ST1-641 98.6%, octreotide 98.7%, respectively). Plasma concentrations of ONO-5788 and ONO-ST1-641 required to supress serum GH level to a clinically meaningful degree in acromegaly patients were estimated to be 21.3 and 1.29 ng/mL. In experiments evaluating the effects on insulin and glucagon secretion in anaesthetised rats, ONO-5788, ONO-ST1-641, octreotide and pasireotide significantly inhibited glucagon secretion, but ONO-5788 and ONO-ST1-641 had no significant impact on insulin secretion at doses up to 10-fold higher than the dose required for either of these compounds to almost maximally inhibit GH secretion. In contrast, pasireotide and octreotide showed a significant inhibition of insulin secretion at equivalent doses of both ONO-5788 and ONO-ST1-641. A standard battery of preclinical safety and toxicology studies provided adequate evidence of safety to support commencement of a Phase I study in healthy volunteers to measure the safety, pharmacokinetics, and pharmacodynamics of ONO-5788. Conclusion: Orally administered ONO-5788 demonstrates potency as a SST2 agonist and has the potential to be a new treatment option for patients with acromegaly and NET.

Evaluation of Underlying Cause of Genitourinary (GU) Adverse Events (AEs) in Patients with Myelodysplastic Syndromes upon Oral Administration of Rigosertib: Safety and Pharmacokinetic Analysis of Rigosertib across Three Clinical Trials

Introduction: Oncogenic mutations of Ras genes have been implicated in number of human cancers whereby the cells grow uncontrollably, and evade death signals (Ledford, Nature, 520, 278, 2015). Rigosertib is a small molecule that inhibits cellular signaling in cancer cells by acting as a Ras mimetic (Athuluri-Divakar SK, Cell 2016). Rigosertib, as a single agent, was evaluated in a Phase III clinical trial in refractory MDS patients where the drug was administered as a 3 day continuous IV infusion every other week (NCT01241500). Rigosertib has also been evaluated in Phase I/II trials via oral route of administration in patients with solid malignancies (NCT01168011); and with myelodysplastic syndromes (NCT01926587). We performed pharmacokinetic and safety analysis of 253 patients across three different trials. The pharmacokinetics and safety profile of orally administered Rigosertib was evaluated in patients with MDS and solid malignancies. The results were compared to data obtained from high risk MDS patients receiving intravenous rigosertib therapy. In this investigation, we present evidence that differential GU toxicity of Rigosertib is probably related to the route of administration and dosing regimen; and independent of the underlying disease state.Methods: Data was analyzed from three clinical studies. Study NCT01241500 was conducted with MDS patients (n = 184) who were administered Rigosertib by continuous IV infusion (1800 mg/day for 72 hours) every 2 weeks. Blood samples were collected at 6, 24, 30, 48, 56 and 72 hours after infusion initiation. In Study NCT01168011, patients with advanced solid tumors (n=33) received oral Rigosertib (560 mg) Q12 hours of a 28-day cycle (3 weeks on, 1 week off). Study NCT01926587, conducted in MDS patients (n=36) with oral administration Rigosertib in combination with parenteral Azacitidine, evaluated the same AM dose but a lower 280 mg PM dose. In both studies, pharmacokinetic assessment was conducted after administration of the AM dose (560 mg) on day 1 of cycle 1. Blood samples were collected predose and 0.5, 1, 1.5, 2, 4, 6 and 8 hours after administration. For Study NCT01168011, urine was collected for 24 hours (0-4, 4-8 and 8-24 hrs) to determine the percent of dose excreted in urine. Rigosertib concentrations in plasma and urine were determined by a validated LC/MS-MS method. Rigosertib pharmacokinetic parameters were estimated using non-compartmental analysis. Treatment emergent adverse events were recorded throughout each study.Results: There was no difference in Rigosertib pharmacokinetic parameters between the two patient populations (Table 1) upon oral administration, and the plasma concentration-time profiles were super imposable (Figure 1). Approximately 2% of the orally administered dose was recovered in the urine. In both studies, the most common AEs observed were GU AEs (dysuria, hematuria). The incidence of grade ≥2 GU toxicity observed with oral dosing was 17 of 33 (52%) and 17 of 36 (47%) in Study NCT01168011 and NCT01926587, respectively. The incidence of GU AEs in both the studies was comparable even though the PM dose was lower (560 mg vs 280mg) in study NCT01926587. Peak plasma concentration and AUC0-∞ were similar in patients with or without urinary symptoms. Compared to oral dosing, the incidences of GU AEs were dramatically lower (10%) following IV infusion despite 8-fold higher and more prolonged systemic exposure (Table 2).Conclusions: This study demonstrates that the urinary adverse events and systemic exposure are similar in patients with either solid malignancies or MDS treated with orally administered rigosertib. The incidence of GU AEs is relatively high in spite of the very low amount (2%) of the administered dose eliminated through the renal route. In contrast, the GU AEs are significantly lower when Rigosertib is administered by IV infusion despite of 8 fold higher exposure. This is probably due to the short half-life of drug and dosing holiday of 12 days between two doses within the cycle. The higher incidence of GU AE upon oral administration is likely related to the dwell time of high concentration of drug in the bladder at night in patients treated daily for 3/4 weeks. This was successfully addressed in the clinical trial, NCT01926587 expansion with risk mitigation strategies, by deploying a novel dosing regimen derived through pharmacokinetic modeling and simulation (Taft, et al; ASH 2018 Abstract Submitted). [Display omitted] DisclosuresManiar:Onconova Therapeutics, Inc: Employment, Equity Ownership. Ren:Onconova Therapeutics, Inc: Employment, Equity Ownership. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Taft:Onconova Therapeutics, Inc: Research Funding.

Clinical management of drug-resistant bacteria in Australian hospitals: An online survey of doctors' opinions.

To gain a better understanding of clinical practice for the treatment of common drug-resistant infections. A web-based anonymous survey was developed to gain a better understanding of clinical practice of patients infected with drug-resistant bloodstream infections (BSI). The survey instrument was a questionnaire requesting doctors to provide their opinion on the most likely choice of an antibiotic, dose and route of administration for patients infected with a drug-resistant Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa or Enterococcus faecium. All of the survey participants (n=28) were hospital-based doctors. Choice of therapy for drug-resistant E. coli and K. pneumoniae was uniform across survey participants. However, optimal treatment of ceftazidime-resistant P. aeruginosa and VRE was less clear. The survey adds to the limited body of evidence in this clinical area and can be a useful tool for health economists in determining the additional cost of treating patients with drug-resistant infections.

Strange Routes of Administration for Substances of Abuse

Strange Routes of Administration for Substances of Abuse

Opioid switch and change of route of administration in palliative care cancer patients treated by morphine: Update of French guidelines.

226 Background: In 2002 guidelines for the treatment of cancer pain (National Federation of French Cancer Centers) were adapted to the availability of drugs in France. In 2015, a group of experts nominated by the 3 French Societies involved in cancer pain (AFSOS, SFAP, SFETD: Supportive Care, Palliative Care and Pain Societies), reviewed these guidelines and established new ratios for morphine switching and/or changing the route of administration in patients whose pain was not adequately controlled. Methods: A review of the literature via Pubmed (key words: morphine, oxycodone, fentanyl, hydromorphone, methadone, tapentadol, pain, cancer, palliative care, opioid rotation, opioid switching, equianalgesic ratios) plus a manual search, led us to retain 43 original works containing good scientific evidence (methodology French Health Authority).Final approval for publishing was obtained from each of the aforementioned three scientific committees of the societies. Results: Experts explained why the theory of opioid rotation using fixed ratios was no longer appropriate for a secure practice. In the light of recent publications enhancing our knowledge on the efficacy of new drug switching ratios and for changing the route of administration of morphine, the group of experts recommended to use reconsidered switching ratios favoring security over efficacy, to minimize overdosing and adverse effects. Consequently, after the new conversion ratio (using slow release opioids) was applied, a second titration should be done by using normal release rescue formulations for breakthrough pain episodes. Conclusions: This work can be apply to an international situation (despite different drug availability amongst countries). A smartphone app is available for rapid and secure dose conversions and will be translated into English. The adequate opioid dose is obtained from a theoretical dose calculation adapted to patient’s personal situation and needs (second titration). Continuous updating of good practice guidelines may provide security and adequacy of prescription for adequate and safe pain relief for our patients, limiting overconsumption and risk of misuse.

Subcutaneous infusion of kisspeptin-54 stimulates gonadotrophin release in women and the response correlates with basal oestradiol levels

BACKGROUND AND OBJECTIVE Kisspeptin stimulates hypothalamic GnRH secretion resulting in gonadotrophin release and has potential as a future therapeutic. Chronic subcutaneous infusion of kisspeptin via a pump (similar to an insulin pump) may provide an alternative route of administration in the future. We investigated for the first time in humans, the gonadotrophin response to subcutaneous (SC) infusions of kisspeptin-54 in healthy women. Women are markedly more responsive to exogenous kisspeptin in the late follicular phase preovulation when oestradiol levels are naturally high. Therefore, we further investigated whether there was a correlation between baseline oestradiol levels and LH response to kisspeptin. DESIGN AND PATIENTS A prospective, single-blinded placebo-controlled study. Healthy women (n = 4) received an 8-h SC infusion of kisspeptin-54 0·1, 0·3 or 1·0 nmol/kg/h or saline in the early follicular phase of 4 separate menstrual cycles. Gonadotrophins and oestradiol were measured every 10 min during the infusions. RESULTS SC infusion of kisspeptin-54 increased LH and FSH. The LH response to SC infusion of kisspeptin-54 (0·3 and 1·0 nmol/kg/h) positively correlated with baseline oestradiol levels (P < 0·001). Further statistical analyses showed that in the 1·0 nmol/kg/h group, a 100pmol/l rise in baseline oestradiol was associated with a 1·0 IU/l increase in LH. CONCLUSIONS Kisspeptin administered via a SC infusion could be a viable future therapeutic route of administration for patients with infertility. Baseline oestradiol levels may be an important determinant of the gonadotrophin response to kisspeptin treatment in women and should be taken into consideration when evaluating gonadotrophin response.

P087: Cellulitis and erysipelas management at an academic emergency department: current practice vs the literature

Introduction: Cellulitis and erysipelas are common presentations for the general practitioner. Antibiotic therapy targeting beta-hemolytic streptococci and Staphylococcus aureus is the mainstay of treatment for children and adults with these infections. Although evidence-based Canadian guidelines for appropriate management exist, inconsistent practices persist. Our objective was to determine the level of adherence to current evidence by emergency physicians at two academic hospitals in Kingston, Ontario. Methods: We conducted a retrospective chart review of 200 randomly selected electronic medical records. Records belonged to patients with a discharge diagnosis of cellulitis or erysipelas who were seen in the emergency departments of Kingston General Hospital or Hotel Dieu Hospital between January 1 and June 30, 2015. We manually collected data describing patient demographics, medical history, and medical management. Results: There were 707 total visits to the emergency departments in the study period for cellulitis or erysipelas. In our random sample, for those diagnosed with cellulitis, 44% received oral cephalexin alone, which was the most common form of therapy for uncomplicated infection. Of all the patients who received any antibiotics, 36% received at least one dose of parenteral antibiotics, despite only 6.7% showing systemic signs of illness. Emergency physicians chose ceftriaxone for 88% of the patients who received parenteral antibiotics. Conclusion: There was wide variation in antibiotic selection and route of administration for patients with cellulitis or erysipelas. Ceftriaxone was chosen for most patients receiving parenteral antibiotics, but it may not have been the most effective antibiotic in some cases. Overuse of antibiotics is common, and we believe medication choice should be justified based on disease severity, spectrum of activity, and regional antibiotic resistance patterns, among other factors. In conclusion, we found that emergency physicians could more closely align management plans with current guidelines to improve management of uncomplicated infection and reduce unnecessary administration of parenteral antibiotics.

Role of Steroid in Adult Patients of Septic Shock - A Critical Analysis

" Sepsis and septic shock is the condition which has been with intensive care units from long before. In fact, it is one of the highly ranked diseases causing mortality in ICU patients. There are currently many evidence based practices in the management of septic shock and use of steroid is one of them. The aim of this article is to critically evaluate the evidences regarding the role of steroids in adult patients of septic shock. This article has also evaluated all the current evidences regarding details of the role of steroids including their formulation, dosage, duration and route of administration in patients of septic shock.KYAMC Journal Vol. 4, No.-2, Jan 2014, Page 409-414

Pilot safety study of intrabronchial instillation of bone marrow-derived mononuclear cells in patients with silicosis

BackgroundSilicosis is an occupational disease for which no effective treatment is currently known. Systemic administration of bone marrow-derived mononuclear cells (BMDMCs) has shown to be safe in lung diseases. However, so far, no studies have analyzed whether bronchoscopic instillation of autologous BMDMCs is a safe route of administration in patients with silicosis.MethodsWe conducted a prospective, non-randomized, single-center longitudinal study in five patients. Inclusion criteria were age 18–50 years, chronic and accelerated silicosis, forced expiratory volume in 1 s <60 % and >40 %, forced vital capacity ≥60 % and arterial oxygen saturation >90 %. The exclusion criteria were smoking, active tuberculosis, neoplasms, autoimmune disorders, heart, liver or renal diseases, or inability to undergo bronchoscopy. BMDMCs were administered through bronchoscopy (2 × 107 cells) into both lungs. Physical examination, laboratory evaluations, quality of life questionnaires, computed tomography of the chest, lung function tests, and perfusion scans were performed before the start of treatment and up to 360 days after BMDMC therapy. Additionally, whole-body and planar scans were evaluated 2 and 24 h after instillation.ResultsNo adverse events were observed during and after BMDMC administration. Lung function, quality of life and radiologic features remained stable throughout follow-up. Furthermore, an early increase of perfusion in the base of both lungs was observed and sustained after BMDMC administration.ConclusionAdministration of BMDMCs through bronchoscopy appears to be feasible and safe in accelerated and chronic silicosis. This pilot study provides a basis for prospective randomized trials to assess the efficacy of this treatment approach.Clinical trials.gov identifierNCT01239862 Date of Registration: November 10, 2010

New delivery device for inhaled drugs for bronchial asthma treatment. Multidose Easyhaler dry powder inhaler

According to current conception of bronchial asthma treatment, the main goals are symptoms control and good life quality. Inhalation is the preferred route of drug administration for patients with airway diseases such as asthma. Inhalation delivers drugs directly to the airways and thereby the effective dose can be small compared with oral therapy (in 20 times), the risk of systemic side effects is reduced, it could be used for poorly soluble drugs which are not absorbed in the gastrointestinal canal. Inhalation is the route of drug administration and can be used for delivery of bronchodilators, mucolytics, steroids, and cromoglicate acid drugs as well.

Subcutaneous Versus Intravenous Bortezomib in Two Different Induction Therapies for Newly Diagnosed Multiple Myeloma – Subgroup Analysis from the GMMG-MM5 Trial

Subcutaneous Versus Intravenous Bortezomib in Two Different Induction Therapies for Newly Diagnosed Multiple Myeloma – Subgroup Analysis from the GMMG-MM5 Trial

P245 Evaluation Of Outcomes Of Oral Ribavirin In The Treatment Of Viral Lower Respiratory Tract Infection In Lung Transplant Patients

Introduction Viral lower respiratory tract infections are common in lung transplant patients and contribute to the development of chronic rejection. Studies have highlighted the improvement in lung function and reduction in relative risk of chronic rejection in patients who are treated with appropriate anti-virals. Our study aimed to investigate the efficacy of three different routes of administration in patients with symptomatic declines in lung function and positive viral cultures. Method Retrospective cohort study of viral respiratory tract infections treated with Ribavirin over a 5 year period was performed. Patients were divided in to 3 groups dependent on route of administration – Oral, Nebulised or Intravenous. Data was collected on patient demographics along with the indication for transplant, time since transplantation, pre and post treatment (6–8 weeks) lung function, viral cultures and details of any confounding factors such as prior rejection or concomitant bacterial infection were recorded. Results 47 patients were identified. 12 patients were excluded due to insufficient clinical data. Of the remaining 34 patients, 11 were treated with Oral medication, 13 with Nebulised and 10 with Intravenous. Conclusion Treatment with Ribavirin results in an improvement in lung function. In this small study it appears that there is no difference in lung function between the different routes of administration. Whilst the efficacy appears comparable oral treatment offers significant advantage to the patients and has benefits for treatment cost and bed occupancy.

Buccal drug delivery: what's new and what does the future hold?

The buccal mucosa is the stratified squamous epithelial tissue inside lining of the cheeks. It is a favorable site of drug absorption since the tissue is non-keratinized, relatively immobile and strongly supplied with blood by a dense capillary-vessel network; moreover, it is highly tolerant to allergens, resistant to potentially harmful agents and has a relatively low enzymatic activity. The tissue consents quick onset of effect, offers an easily accessible and generally well-accepted site for drug delivery, is a useful route of administration in patients in an unconscious state (e.g., when swallowing is impaired), and is suitable for retentive dosage forms of administration. Buccal mucosa allows drug delivery for both locoregional and systemic treatments. Locoregional delivery has a number of applications, including treatment of local conditions, such as mucositis, bacterial and fungal infections, aphthous stomatitis, vesiculobullous diseases, and potentially malignant disorders and oral cancer. On the other hand, the tissue is appropriate for delivering systemically acting drugs. The actives directly enter general circulation through capillary vessels, bypassing the first-pass metabolism in the intestine and liver, avoiding presystemic drug elimination or chemical/enzymatic degradation within the gastrointestinal tract thus leading to high bioavailability. “If low concentrations of drug are required to gain access to the blood, transbuccal drug delivery may be very satisfactory for safe and well-accepted future clinical applications” [1–3]. Controlled delivery of drugs through the buccal mucosa should be considered like a slow intravenous infusion. These characteristics contribute to optimal pharmacokinetic behavior of drugs after administration of smaller doses than in conventional oral formulations [4]. Nevertheless, similar to other mucosal membranes, the buccal mucosa has some disadvantages, including short residence time and small absorption area. The major limitation to buccal drug delivery is the barrier property of the tissue which has inadequate permeability for certain molecules, resulting in low drug bioavailability. Drug absorption is very satisfactory only for those actives that possess adequate physicochemical properties and the ability to permeate across the tissue. Accordingly, the formulative approach alone could be not sufficient for an effective control of drug delivery through the mucosa, and limited rate of absorption should be adjusted by simultaneous chemical and physical enhancement, including supersaturation and eutectic formation [4,5]. Buccal dosage forms reside in a tastesensing organ, and organoleptic aspects of formulation could become crucial limiting factors for drug application. Suitable palatal properties are often required to get optimal acceptability of dosage form or for masking less desirable properties of the active component [6]. Despite offering the possibility of improved systemic drug delivery, buccal administration has been utilized for relatively few pharmaceutical products so far. Conventional dosage forms, such as solutions, are commercially available for Buccal drug delivery: what’s new and what does the future hold?