Background
Perioperative hyperglycemia is a known risk factor for postoperative complications after colorectal surgery. The aim of this study was to investigate whether intraoperative blood glucose ...values are associated with colorectal anastomotic leakage in diabetic and non-diabetic patients undergoing colorectal surgery.
Methods
This is an additional analysis of a previously published prospective, observational cohort study (the LekCheck study). Fourteen hospitals in Europe and Australia collected perioperative data. Consecutive adult patients undergoing colorectal surgery with primary anastomosis between 2016 and 2018 were included. From all patients, preoperative diabetic status was known and intraoperative blood glucose was determined just prior to the creation of the anastomosis. The primary outcome was the occurrence of anastomotic leakage within 30 days postoperatively.
Results
Of 1474 patients (mean age 68 years), 224 patients (15%) had diabetes mellitus, 737 patients (50%) had intraoperative hyperglycemia (≥126 mg/dL, ≥7.0 mmol/L), and 129 patients (8.8%) developed anastomotic leakage. Patients with intraoperative hyperglycemia had higher anastomotic leakage rates compared to patients with a normal blood glucose level (12% versus 5%,
P
<0.001). Anastomotic leakage rate did not significantly differ between diabetic and non-diabetic patients (12% versus 8%,
P
=0.058). Logistic regression analyses showed that higher blood glucose levels were associated with an increasing leakage risk in non-diabetic patients only.
Conclusion
Incidence and severity of intraoperative hyperglycemia are associated with anastomotic leakage in non-diabetic patients. Whether hyperglycemia is an epiphenomenon, a marker for other risk factors or a potential modifiable risk factor per se for anastomotic leakage requires future research.
Aims
To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa in healthy subjects.
Methods
Three trials with an open‐label, ...randomized, two‐way crossover design were conducted in healthy subjects. Ipragliflozin 150 mg, sitagliptin 100 mg, pioglitazone 30 mg or glimepiride 1–2 mg were administered alone or in combination. Primary endpoints were the area under the curve from the time of dosing to infinity (AUCinf) and the maximum observed plasma concentration (Cmax) of each drug.
Results
Multiple doses of ipragliflozin did not change the AUCinf and Cmax of a single dose of sitagliptin, pioglitazone or glimepiride. All geometric mean ratios and 90% CIs for AUCinf and Cmax, with and without ipragliflozin, were within the predefined range of 80–125% (AUCinf: sitagliptin 100.1 96.9–103.5, pioglitazone 101.7 96.6–107.0, glimepiride 105.1 101.3–109.0, and Cmax: sitagliptin 92.4 82.8–103.1, pioglitazone 98.6 87.7–110.8, glimepiride 110.0 101.9–118.8). Similarly, multiple doses of sitagliptin, pioglitazone or glimepiride did not change the pharmacokinetics of a single dose of ipragliflozin (AUCinf: 95.0 93.4–103.1, 100.0 98.1–102.0, 99.1 96.6–101.6; and Cmax: 96.5 90.4–103.1, 93.5 86.3–101.2, 97.3 89.2–106.2). Ipragliflozin either alone or in combination with any of the three glucose‐lowering drugs was well tolerated in healthy subjects.
Conclusion
Ipragliflozin did not affect the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa, suggesting that no dose‐adjustments are likely to be required when ipragliflozin is given in combination with other glucose‐lowering drugs in patients with type 2 diabetes mellitus.
To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in ...patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg+CsA 700 mg on day 1, followed by oral paclitaxel (Taxol) 160 mg+CsA 700 mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol) 160 mg as 3-h infusion on day 15. The median (range) area under the plasma concentration-time curve of paclitaxel was 2.06 (1.15-3.47) microg h ml(-1) and 1.97 (0.58-3.22) microg h ml(-1) after oral administration of SMEOF#3 and Taxol, respectively, and 4.69 (3.90-6.09) microg h ml(-1) after intravenous Taxol. Oral SMEOF#3 resulted in a lower median T(max) of 2.0 (0.5-2.0) h than orally applied Taxol (T(max)=4.0 (0.8-6.1) h, P=0.02). The median apparent bioavailability of paclitaxel was 40 (19-83)% and 55 (9-70)% for the oral SMEOF#3 and oral Taxol formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower T(max) than orally applied Taxol, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel.
To explore the pharmacokinetics (PKs) of paclitaxel and two major metabolites after three single oral administrations of a novel drinking solution and two capsule formulations in combination with ...cyclosporin A (CsA) in patients with advanced cancer. Moreover, the tolerability and safety of the formulations was studied. In addition, single nucleotide polymorphisms in the multidrug resistance (MDR1) gene were determined.
Ten patients were enrolled and randomized to receive CsA 10 mg/kg followed by oral paclitaxel 180 mg given as (1) drinking solution (formulation 1), (2) capsule formulation 2B, and (3) capsule formulation 2C on day 1, 8, or 15.
The median C (max) of paclitaxel was 0.42 (0.23-0.96), 0.48 (0.08-0.59), and 0.39 (0.11-1.03) microg/ml and the area under the plasma concentration-time curve was 2.83 (1.69-5.12), 2.01 (1.57-3.04), and 2.67 (1.05-3.61) mug h/ml following administration of formulations 1, 2B, and 2C, respectively. The novel formulations were tolerated after single oral dose without causing relevant gastrointestinal or haematological toxicity.
The PK and metabolism of paclitaxel were comparable between the oral formulations co-administered with CsA.
To investigate the pharmacokinetics, safety, and tolerability of a new oral formulation of paclitaxel containing the polymer polyvinyl acetate phthalate in patients with advanced solid tumors.
A ...total of six patients received oral paclitaxel as single agent given as a single dose of 100 mg on day 1, oral paclitaxel 100 mg in combination with cyclosporin A (CsA) 10 mg/kg both given as a single dose on day 8, and i.v. paclitaxel (Taxol) 100 mg as a 3-h infusion on day 15.
The AUC (mean +/- standard deviation) values of paclitaxel after oral administration without CsA and with CsA were 476 +/- 254 and 967 +/- 779 ng/ml h, respectively. T (max) was 4.0 +/- 0.9 h after oral paclitaxel without CsA, and 6.0 +/- 3.1 h after oral paclitaxel with CsA. The mean AUC after oral administration as single agent was 13% of the AUC after i.v. administration of paclitaxel, and increased to 26% after co-administration with CsA. No haematological toxicities were observed, and only mild (CTC-grade 1 and 2) non-hematological toxicities occurred after oral intake of paclitaxel with or without CsA.
The AUC of the new polymeric paclitaxel formulation increased a factor 2 in combination with CsA, which confirms that CsA co-administration can also improve exposure to paclitaxel after oral administration of a polymeric formulation. Because of the delayed release of paclitaxel from this formulation, we hypothesize that a split-dose regimen of CsA where it is administered before and after paclitaxel administration will further increase the systemic exposure to paclitaxel up to therapeutic levels. The formulation was well tolerated at the dose of 100 mg without induction of severe toxicities.
To investigate the oncological safety and potential cost savings of selective histopathological examination after appendectomy.
The necessity of routine histopathological examination after ...appendectomy has been questioned, but prospective studies investigating the safety of a selective policy are lacking.
In this multicenter, prospective, cross-sectional study, inspection and palpation of the (meso)appendix was performed by the surgeon in patients with suspected appendicitis. The surgeon's opinion on additional value of histopathological examination was reported before sending all specimens to the pathologist. Main outcomes were the number of hypothetically missed appendiceal neoplasms with clinical consequences benefiting the patient (upper limit two-sided 95% confidence interval below 3:1000 considered oncologically safe) and potential cost savings after selective histopathological examination.
Seven thousand three hundred thirty-nine patients were included. After a selective policy, 4966/7339 (67.7%) specimens would have been refrained from histopathological examination. Appendiceal neoplasms with clinical consequences would have been missed in 22/4966 patients. In 5/22, residual disease was completely resected during additional surgery. Hence, an appendiceal neoplasm with clinical consequences benefiting the patient would have been missed in 1.01:1000 patients (upper limit 95% confidence interval 1.61:1000). In contrast, twice as many patients (10/22) would not have been exposed to potential harm due to re-resections without clear benefit, whereas consequences were neither beneficial nor harmful in the remaining seven. Estimated cost savings established by replacing routine for selective histopathological examination were €725,400 per 10,000 patients.
Selective histopathological examination after appendectomy for suspected appendicitis is oncologically safe and will likely result in a reduction of pathologists' workload, less costs, and fewer re-resections without clear benefit.
Aim
Morbidity in patients with an ostomy is high. A new care pathway, including perioperative home visits by enterostomal therapists, was studied to assess whether more elaborate education and closer ...guidance could reduce stoma‐related complications and improve quality of life (QoL), at acceptable cost.
Method
Patients requiring an ileostomy or colostomy, for any inflammatory or malignant bowel disease, were included in a 15‐centre cluster‐randomized ‘stepped‐wedge’ study. Primary outcomes were stoma‐related complications and QoL, measured using the Stoma‐QOL, 3 months after surgery. Secondary outcomes included costs of care.
Results
The standard pathway (SP) was followed by 113 patients and the new pathway (NP) by 105 patients. Although the overall number of stoma‐related complications was similar in both groups (SP 156, NP 150), the proportion of patients experiencing one or more stoma‐related complications was significantly higher in the NP (72% vs 84%, risk difference 12%; 95% CI: 0.3−23.3%). Although in the NP more patients had stoma‐related complications, QoL scores were significantly better (P < 0.001). In the SP more patients required extra care at home for their ostomy than in the NP (60.6% vs 33.7%, respectively; risk difference 26.9%, 95% CI: 13.5−40.4%). Stoma revision was done more often in the SP (n = 11) than in the NP (n = 2). Total costs in the SP did not differ significantly from the NP.
Conclusion
The NP did not reduce the number of stoma‐related complications but did lead to improved quality of care and life, against similar costs. Based on these results the NP, including perioperative home visits by an enterostomal therapist, can be recommended.
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