Characteristics of the case mix, organisation and delivery in cancer palliative care: a challenge for good-quality research.

OBJECTIVES: Palliative care (PC) services and patients differ across countries. Data on PC delivery paired with medical and self-reported data are seldom reported. Aims were to describe (1) PC organisation and services in participating centres and (2) characteristics of patients in PC programmes. METHODS: This was an international prospective multicentre study with a single web-based survey on PC organisation, services and academics and patients' self-reported symptoms collected at baseline and monthly thereafter, with concurrent registrations of medical data by healthcare providers. Participants were patients ≥18 enrolled in a PC programme. RESULTS: 30 centres in 12 countries participated; 24 hospitals, 4 hospices, 1 nursing home, 1 home-care service. 22 centres (73%) had PC in-house teams and inpatient and outpatient services. 20 centres (67%) had integral chemotherapy/radiotherapy services, and most (28/30) had access to general medical or oncology inpatient units. Physicians or nurses were present 24 hours/7 days in 50% and 60% of centres, respectively. 50 centres (50%) had professorships, and 12 centres (40%) had full-time/part-time research staff. Data were available on 1698 patients: 50% females; median age 66 (range 21-97); median Karnofsky score 70 (10-100); 1409 patients (83%) had metastatic/disseminated disease; tiredness and pain in the past 24 hours were most prominent. During follow-up, 1060 patients (62%) died; 450 (44%) <3 months from inclusion and 701 (68%) within 6 months. ANOVA and χ2 tests showed that hospice/nursing home patients were significantly older, had poorer performance status and had shorter survival compared with hospital-patients (p<.0.001). CONCLUSIONS: There is a wide variation in PC services and patients across Europe. Detailed characterisation is the first step in improving PC services and research. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01362816.

Management of acute uncomplicated diverticulitis without antibiotics: a single-centre cohort study.

AIM: This study aimed to evaluate the implementation of nonantibiotic management of acute uncomplicated diverticulitis at a large university hospital in Norway with regard to management failure, disease recurrence and complications. METHOD: On 1 January 2013 we implemented a new policy for the management of acute uncomplicated diverticulitis without antibiotics. Antibiotic treatment was only provided in the case of defined criteria. All patients admitted from 1 January 2013 to 30 June 2014 with a CT-verified, left-sided, acute uncomplicated diverticulitis were included in the study and evaluated retrospectively, with 12 months' follow-up. RESULTS: Of 244 admissions with acute uncomplicated diverticulitis, 177 (73%) were managed without antibiotics. Among these there were seven (4%) management failures, including five patients in whom a deteriorating clinical picture prompted antibiotic treatment and two readmissions within 1 month due to persisting symptoms. The only complication in this group was one fistula (< 1%). Eight (5%) patients had a recurrence of acute diverticulitis requiring hospital care and two (1%) underwent elective surgery within the first year. Twenty (8%) patients met predefined exemption criteria and received antibiotics from admission, six (30%) of whom developed complications. The recurrence rate in this group was 10% and none had surgery performed. The 47 (20%) policy violators treated with antibiotics from admission had no complications. Their recurrence rate was 11% and one (2%) patient underwent elective surgery. CONCLUSION: This study confirms that nonantibiotic management of acute uncomplicated diverticulitis is safe and feasible. Most complications occurred in a small group of high-risk patients treated with antibiotics.

Fermentation and addition of enzymes to a diet based on high-moisture corn, rapeseed cake, and peas improve digestibility of nonstarch polysaccharides, crude protein, and phosphorus in pigs.

Fluctuating prices of cereals have led to an interest in alternative ingredients for feed. The aim of this study was to evaluate the effect of fermentation and the addition of nonstarch polysaccharide (NSP)-degrading enzymes on the ileal and total tract digestibility of nutrients of a diet based on locally grown crops. Four diets were fed including a nonfermented liquid standard grower diet (Control) and 3 experimental diets based on high-moisture corn, rapeseed cake, and peas fed as nonfermented liquid feed (nFLF), fermented liquid feed (FLF), or FLF supplemented with an enzyme mixture of ß-glucanase + xylanase + pectinase (FLF+Enz). The FLF was prepared by mixing feed and water (1:2.5, wt/wt) and, once daily, replacing 50% of the mixture with an equal amount of fresh feed and water. The diets were fed to 8 ileal cannulated barrows in a double Latin square design. Ileal digesta and feces were collected after an adaption period of 10 d. Results showed microbiologically good-quality fermented diets. The levels of Enterobacteriaceae were 5.1 to 5.4 log cfu/g in FLF and FLF+Enz vs. 6.3 log cfu/g in nFLF in the ileum and 5.1 to 5.2 log cfu/g in FLF and FLF+Enz vs. 6.3 log cfu/g in nFLF in the feces. Apparent total tract digestibility (ATTD) of CP was increased by fermentation (73.2% in FLF vs. 69.0% in nFLF; P = 0.033), and digestibility of P showed a tendency (P = 0.073) toward an increase. Addition of the enzyme mixture resulted in a pronounced reduction of dietary NSP compared with FLF (12.8% total NSP in FLF+Enz vs. 15.9% total NSP in FLF; P< 0.001), which also led to increased apparent ileal digestibility (AID) of total and insoluble NSP (total NSP, 31.1% in FLF+Enz vs. 13.6% in FLF; P = 0.002). The Control did not, in general, show higher digestibility values than the experimental diet. However, in the cases were it did, fermentation and enzyme addition brought the digestibility to the level of the Control. In conclusion, fermentation increased the ATTD of CP and the AID of P, with the same tendency (P ≤ 0.07) for the ATTD. Addition of NSP-degrading enzymes resulted in a pronounced reduction in the concentration of NSP in the feed along with increased AID of NSP. Hence, the experimental diet seems to be a possible alternative to a traditional diet for pigs.

Impact of OATP1B1, MDR1, and CYP3A4 expression in liver and intestine on interpatient pharmacokinetic variability of atorvastatin in obese subjects.

Individual variability in expression and function of organic anion-transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 1 (MDR1), and/or cytochrome P450 3A4 (CYP3A4) may impact the clinical response of many drugs. We investigated the correlation between expression of these proteins and pharmacokinetics of atorvastatin, a substrate of all three, in 21 obese patients with paired biopsies from liver and intestinal segments. The patients were also screened for the SLCO1B1 c.521T→C variant alleles. Approximately 30% (r(2) = 0.28) of the variation in oral clearance (CL/F) of atorvastatin was explained by hepatic OATP1B1 protein expression (P = 0.041). Patients carrying the SLCO1B1 c.521C variant allele (homozygous, n = 4; heterozygous, n = 2) exhibited 45% lower CL/F of atorvastatin than the c.521TT carriers (P = 0.067). No association between hepatic and intestinal expression of MDR1 or CYP3A4 and atorvastatin pharmacokinetics was found (P > 0.149). In conclusion, this study suggests that OATP1B1 phenotype is more important than CYP3A4 and MDR1 phenotypes for the individual pharmacokinetic variability of atorvastatin.

Significant increase in systemic exposure of atorvastatin after biliopancreatic diversion with duodenal switch.

Biliopancreatic diversion with duodenal switch is a combined restrictive and malabsorptive surgical weight loss procedure. Given that this procedure introduces a bypass of the proximal small intestine, it is a suitable model for investigating the influence of the proximal intestine on drug bioavailability. Eight-hour pharmacokinetic profiles were obtained the day before surgery and again after surgery at (median) 6 weeks (range, 4-8 weeks) in 10 morbidly obese patients who were receiving treatment with 20-80 mg atorvastatin each morning. The bioavailability of atorvastatin acid was significantly increased, with a mean twofold higher AUC(0-8) after surgery (range 1.0-4.2, P = 0.001). Time to maximum plasma concentration (C(max)) increased from 1.2 h before surgery to 2.3 h after surgery (P = 0.03). The results emphasize the protective nature of the proximal small intestine against ingested exogenous compounds. Consequently, retitration to the lowest effective dose should be considered after biliopancreatic diversion with duodenal switch in the case of drugs with a high degree of intestinal first pass metabolism and a narrow therapeutic window.

Significantly altered systemic exposure to atorvastatin acid following gastric bypass surgery in morbidly obese patients.

The impact of gastric bypass on atorvastatin pharmacokinetics was investigated in 12 morbidly obese patients being treated with 20-80 mg atorvastatin each morning. Eight-hour pharmacokinetic investigations were performed the day before the surgery and at a median of 5 weeks (range 3-6 weeks) after the surgery. Gastric bypass surgery produced a variable effect on individual systemic exposure to atorvastatin acid (area under the plasma concentration vs. time curve from 0 to 8 h postdose (AUC(0-8))), ranging from a threefold decrease to a twofold increase (median ratio = 1.1, P = 0.99). Patients with the highest systemic exposure to atorvastatin before surgery showed reduced exposure after surgery (n = 3, median ratio = 0.4, range = 0.3-0.5, P < 0.01), whereas those with lower systemic exposure before surgery showed a median 1.2-fold increase in atorvastatin AUC(0-8) (n = 9, range = 0.8-2.3, P = 0.03) after surgery. This study indicates that the presurgical first-pass metabolic capacity influences the effect of gastric bypass on atorvastatin bioavailability. Because individual first-pass metabolic capacity is not readily assessable clinically, retitration up to the lowest effective dose should be performed after the surgery.

Continuous infusion versus daily injections of growth hormone (GH) for 4 weeks in GH-deficient patients.

Endogenous GH secretion is pulsatile. Animal studies indicate that GH administered in a pulsatile manner induces growth and insulin-like growth factor I (IGF-I) generation more effectively than continuous administration. Short term human studies, however, have reported similar metabolic effects with constant and pulsatile GH delivery. This study was carried out to compare the metabolic effects of longer term continuous infusion vs. daily injections of GH. Thirteen GH-deficient patients were studied in a cross-over design. The patients were randomized to receive GH as a continuous sc infusion by means of a portable pump for 1 month and as daily sc injections (at 1900 h) for another month. An average daily GH dosage (+/- SEM) of 3.15 +/- 0.27 IU was administered during both periods. Steady state 24-h profiles of GH, IGF-I, IGF-binding proteins (IGFBPs), insulin, glucose, lipid intermediates, and other metabolites were monitored after each treatment period. At the end of each study period (at 0800 h), an oral glucose tolerance test was performed. The mean (+/- SEM) integrated levels of serum GH (micrograms per L) were higher after GH injection [2.51 +/- 0.54 (injection) vs. 1.77 +/- 0.35 (infusion); P < 0.02]. Continuous infusion induced higher nighttime than daytime GH levels (P = 0.01), indicating a diurnal variation in the absorption or clearance of GH. Serum IGF-I levels (micrograms per L) were slightly higher (P < 0.05, by analysis of variance) after continuous GH infusion [312.5 +/- 50.2 (injection) and 334.6 +/- 46.6 (infusion)]. Similarly, constant GH delivery induced higher IGFBP-3 levels (P < 0.05, by analysis of variance). Serum IGFBP-1 levels were similar on the two occasions. Daily GH injections increased daytime insulin levels (P < 0.05), whereas 24-h levels were similar (P = 0.14). The trend toward increased insulin levels after GH injections was also found during the oral glucose tolerance test (P = 0.07). Blood glucose levels were identical on the two occasions. Nocturnal levels of nonesterified fatty acids were higher (P < 0.05) after GH injection. We conclude that continuous sc infusion of GH induced serum IGF-I and IGFBP-3 levels more effectively than daily sc injections. The constant appearance of GH in the circulation did not impair glucose tolerance, but resulted in a less physiological diurnal pattern of nonesterified fatty acids. Our data do not support the concept that a pulsatile GH pattern is of critical physiological significance.

Development, production and pharmacodynamics of human growth hormone.

With the advent of recombinant DNA technology, it is possible to produce biosynthetic human growth hormone (B-hGH). Novo Nordisk A/S has developed a method for manufacturing B-hGH which is identical to the 22K fraction of pituitary human growth hormone (P-hGH), using a nonpathogenic strain of Escherichia coli as host. B-hGH has been investigated extensively in physical, chemical and biological studies and found to be identical to P-hGH. Pharmacological studies have revealed that B-hGH possesses the same pharmacokinetic and short-term metabolic profiles as P-hGH. Long term clinical studies have shown that B-hGH induces a significant increase in height velocity in children with growth hormone deficiency (GHD) and is characterized by a low antigenicity.

Comparative effects of two different multiple injection regimens on blood glucose control and patient acceptance in type 1 diabetes.

In a randomized cross-over study we compared blood glucose control and patient acceptance of a 12-week basal-prandial regimen with short-acting insulin before meals and isophane (NPH) insulin at bedtime (4 injections) with a scheme with a second injection of isophane (NPH) insulin before breakfast (5 injections). Forty-three Type 1 diabetic patients (age 37 +/- 11 (+/- SD) years, duration of diabetes 15 (range 2-48) years, 26 males and 17 females) completed the study. Mean daily blood glucose was 8.6 +/- 2.4 mmol l-1 at baseline, and 8.1 +/- 2.2 mmol l-1 after the four-injection period and 7.9 +/- 2.0 mmol l-1 with five-injections (NS). HbA1c after 12 weeks was not different with the two treatments (6.6 +/- 1.1 vs 6.5 +/- 0.9%), neither was fasting blood glucose (9.6 +/- 4.2 mmol l-1 with 4 injections, and 9.0 +/- 4.4 mmol l-1 with 5 injections). Daily insulin dose did not differ between regimens (55 vs 56 U day-1). No differences in number or severity of hypoglycaemic events were observed. After the study, 13 patients preferred to continue the 5-injection regimen, and 21 patients preferred 4 injections. Treatment satisfaction with either regimen was equally high. It is concluded that dividing the intermediate-acting insulin into a morning and an evening dose did not lead to an improvement in blood glucose control in these moderately-controlled Type 1 diabetic patients.

[Insuject-X for children. A clinical trial of the NPH insulin pen]. / Insuject-X til børn. Klinisk afprøvning af NPH-insulinpen.

The use of Insuject-X for NPH insulin was tested by 21 children, age less than or equal to 10 years with insulin dependent diabetes mellitus less than or equal to 1 year, on conventional treatment with NPH insulin once or twice daily. After a preliminary period of one month the syringe injection regimen was changed to injections by Insuject-X for a four-month "pen" period. We observed no significant changes in metabolic control. The mean potency of NPH insulin in partly used cartridges was 103.6 +/- 5.6 IU/ml (range 91.0-118.1, n = 39) with no correlation to the residual volume or days of use. Measurements over 110 IU/ml were seen at the end of the study indicating the need of repeated instruction in use of the pen by children. No microbial contamination of the cartridges, nor any local reactions at injection sites were found. We observed more technical problems than in adult studies indicating that children handle the pen more roughly. The accept of Insuject-X was good as a more convenient means of injecting. All of the children preferred to continue using it.

A double-blind, crossover study of a sustained-release tablet of ketoprofen and normal ketoprofen capsules in the treatment of patients with osteoarthritis.

A double-blind, crossover study was carried out to assess the efficacy and tolerance of a sustained-release tablet formulation of ketoprofen given as a single daily 200 mg dose compared with 2 X 50 mg normal formulation capsules of ketoprofen twice daily. Eighty-four patients with osteoarthritis of the hip and/or knee were admitted and received treatment for periods of 3 weeks, preceded by a 1-week placebo wash-out period, with each of the two formulations, in random order. Patients were seen after each study period and clinical objective and subjective assessments made of signs and symptoms of the disease, consumption of rescue analgesic and unwanted effects. Forty-eight of the patients continued, mainly on the sustained-release formulation, in an open long-term tolerance study lasting 3 months. The results were analyzed for 68 patients who completed the double-blind phase and for 33 who completed the open phase of the study. The patients who were withdrawn did so mainly for non-drug related reasons; 19 patients did so because of gastric disorders during the first phase. The incidence of side-effects was low and similar in frequency and nature with both formulations; those that were reported were mild and principally gastro-intestinal. Both active treatment periods afforded similar symptomatic relief and were preferred to placebo by all but 2 patients. No significant differences were found between active treatments, although there was a trend in favour of the sustained-release formulation for most of the parameters studied as there was in patient preference.