Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers

Purpose Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. Methods A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. Results Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. Conclusions Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. Trial registration NCT03276858, registered September 8, 2017, retrospectively registered.

Comparison of single dose versus multiple doses of antibiotic prophylaxis for prevention of surgical site infection

Background: Surgical site infection is a common problem following general surgical procedures. Despite major improvement in antibiotics, improved antiseptic measures SSI continues to present a big challenge. In this study we will compare single dose versus multiple dose antibiotic prophylaxis for prevention of SSI in clean and clean contaminated surgical wound.Methods: This is an institution based prospective, comparative study, with total 60 patients as study population. Clinical finding, wound swab culture and routine haematological reports were taken as study variables. Patients receiving single dose antibiotic and multiple dose antibiotic were included in ‘Group A’ and ‘Group B’ respectively. The surgical sites were examined from post-operative days 3 to 8 for signs of infection.Results: In This study, 46.7% patients were female, and 53.3% patients were male. In Group-A, patients having post operative fever, tachycardia and leucocytosis were 16.7%, 13.3% and 20.0% respectively. 6.7% patients had purulent and 10.0% patients had seropurulent discharge from wound. In Group-B, patients having post operative fever, tachycardia, and leucocytosis were 13.3%, 16.7% and 13.3% respectively. 6.7% patients had purulent and seropurulent discharge from wound. There is no statistically significant difference between two groups regarding post operative fever, tachycardia, leucocytosis and wound discharge.Conclusions: There is no significant difference between single dose and multiple dose antibiotic prophylaxis to prevent SSI in patients for elective clean and clean contaminated surgery however single dose is more cost effective.

Population pharmacokinetics of intra-peritoneal gentamicin and the impact of varying dwell times on pharmacodynamic target attainment in patients with acute peritonitis undergoing peritoneal dialysis

While the use of intraperitoneal (i.p.) gentamicin is common in the treatment of peritoneal dialysis (PD)-related infections, the ability of these regimens to attain pharmacodynamic target indices of interest in blood and dialysate has not been widely reported. Pharmacokinetic (PK) data was obtained and analyzed from a multiple-dose PK study of i.p. gentamicin with 24 patients who received the drug at 0.6 mg/kg dose of body weight. The probability of target attainment (PTA) for indices of treatment success (i.p. peak/MIC ratio >10) and toxicity (plasma AUC < 120 mg*h/L) was determined for 0.3 to 1.2 mg/kg i.p. regimens every 24 h for dwell times of 2 to 6 hours and for the duration of 2-week course. In the peritoneum, successful PTA was achieved by all of the simulated regimens up to an MIC of 1 mg/L, and by doses equal to or greater than 0.6 mg/kg up to the MIC of 2 mg/L. At the susceptibility break point of 4 mg/L only the highest dose of 1.2 mg/kg is likely to provide adequate PTA. Probability of achieving exposure below the threshold of 120 mg*h/L in the daily AUC in plasma seems acceptable for all regimens at or below 0.6 mg/kg. Based on the model we developed, a gentamicin dose of 0.6 mg/kg is sufficient to treat organisms with an MIC of ≤2 mg/L without the risk of significant systemic exposure. The 1.2 mg/kg dose necessary to reach the pharmacodynamic target for efficacy at the clinical break point of 4 mg/L is likely to produce early toxic levels of exposure that is expected to be detrimental to the renal system.

Single-dose antibiotic prophylaxis compared with multiple-dose protocol in clean pediatric neurosurgical interventions: a nonrandomized, historically controlled equivalence trial

OBJECTIVE Guidelines recommend antimicrobial prophylaxis (AMP) preoperatively for "clean" spinal and cranial surgeries, while dose and timing remain controversial. The use of multiple-dose AMP for such surgeries is under debate in the pediatric context. In this clinical study, the authors aimed to compare single-dose with multiple-dose prophylactic antibiotic usage in cranial and spinal neurosurgical interventions of pediatric patients. METHODS All neurosurgical patients aged 28 days to 18 years who underwent surgery at a single tertiary center were assessed. Three cohorts (noninstrumented clean spinal, noninstrumented cranial, and instrumented cranial interventions), each of which comprised two 50-patient arms (i.e., single-dose AMP and multiple-dose AMP), were included after propensity score–matched retrospective sampling and power analysis. Records were examined for surgical site infections. Using a previously published meta-analysis as the prior and 80% acceptance of equivalence (margin of OR 0.88–1.13), logistic regression was carried out for the total cohort and each subcohort and adjusted for etiology by consideration of multiple-dose AMP as reference. RESULTS The overall sample included 300 age- and sex-matched patients who were evenly distributed in 3 bi-arm cohorts. There was no statistical intercohort difference based on etiology or type of operation (p < 0.05). Equivalence analysis revealed nondiscriminating results for the total cohort (adjusted OR 0.65, 95% CI 0.27–1.57) and each of the subcohorts (noninstrumented clean spinal, adjusted OR 0.65, 95% CI 0.12–3.44; noninstrumented cranial, adjusted OR 0.52, 95% CI 0.14–2.73; and instrumented cranial, adjusted OR 0.68, 95% CI 0.13–3.31). CONCLUSIONS No significant benefit for multiple-dose compared with single-dose AMPs in any of the pediatric neurosurgery settings could be detected. Since unnecessary antibiotic use should be avoided as much as possible, it seems that usage of single-dose AMP is indicated.

Dose tranexamic acid reduce blood loss associated with simultaneous bilateral distal tibial tubercle-high tibial osteotomy?

Background Simultaneous bilateral distal tibial tubercle high tibial osteotomy (SBDTT-HTO) can result in increased blood loss. The aim of this study is to evaluate the actual hemostatic effect of different tranexamic acid (TXA) treatment regimen in SBDTT-HTO. Methods We conducted a retrospective case–control study including 54 patients who underwent SBDTT-HTO. The single-dose group (n = 18) received 1 g of intravenous TXA 15–30 min before surgery, the two-dose group (n = 18) received an additional 1 g of intravenous TXA 6 h after surgery, and the multiple-dose group (n = 18) received an additional 1 g intravenous TXA per-day until discharge. Blood loss, hemoglobin levels, occurrence of any adverse events,functional analysis, quality of life, and pain assessmentswere compared among the three groups. Results The total blood loss, hidden blood loss, drainage volumes, and haemoglobin level in the multiple-dose group all occupy a significant advantage.(p < 0.05). In addition, better quality of life were observed in patients belonging to the multiple-dose group then single-dose group.(p < 0.05). Conclusions Based on our results, for patients undergoing SBDTT-HTO, sequential intravenous TXA administration can effectively and safely reduce blood loss,maintain postoperative Hb levels,and with the advantage of accelerating recovery.