Does receptor balance matter? - Comparing the efficacies of the dual amylin and calcitonin receptor agonists cagrilintide and KBP-336 on metabolic parameters in preclinical models.

Cagrilintide is a novel long-acting amylin receptor agonist, which has shown a potent induction of weight loss. Interestingly, cagrilintide is a Dual Amylin and Calcitonin Receptor Agonist (DACRA) derived from an amylin backbone. Another class of long-acting DACRAs exists, namely the KBPs. These are salmon calcitonin-based and have shown preclinical potential; however, how and if they differentiate from amylin-derived molecules remain to be studied. Here, we compare cagrilintide to the DACRA KBP-336 with respect to receptor activation balance in vitro and using metabolic in vivo models. Peptide potencies were assessed using receptor-specific assays in vitro and in vivo. In vivo efficacies on body weight and glucose homeostasis were investigated head-to-head in high-fat diet (HFD) fed obese and T2D (ZDF) rat models. Both peptides activate the amylin and the calcitonin receptor in vitro and in vivo, with KBP-336 being more potent, and showing a CTR bias. KBP-336 and cagrilintide induced a potent and dose-dependent weight loss in HFD rats, with the highest dose of KBP-336 being superior to cagrilintide. In diabetic ZDF rats, DACRA treatment improved fasting blood glucose, HbA1c levels, and insulin action, with KBP-336 being superior to cagrilintide in improving glucose control. In summary, both KBP-336 and cagrilintide are DACRAs, however with KBP-336 being biased towards the CTR resulting in a different receptor activation balance. Interestingly, KBP-336 showed superior long-term efficacy on both weight loss and glucose control, supporting relevance of the receptor balance, and highlighting KBP-336 as a promising agent for the treatment of obesity and T2D.

KBP-066A, a long-acting dual amylin and calcitonin receptor agonist, induces weight loss and improves glycemic control in obese and diabetic rats.

OBJECTIVE: Dual amylin and calcitonin receptor agonists (DACRAs) are novel therapeutic agents that not only improve insulin sensitivity but also work as an adjunct to established T2DM therapies. DACRAs are currently administered once daily, though it is unknown whether DACRAs with increased plasma half-life can be developed as a once-weekly therapy. METHODS: The in vitro potencies of the KBP-066A and KBP-066 (non-acylated) were assessed using reporter assays. Acylation functionality was investigated by a combination of pharmacokinetics and acute food intake in rats. in vivo efficacies were investigated head-to-head in obese (HFD) and T2D (ZDF) models. RESULTS: In in vitro, KBP-066A activated the CTR and AMY-R potently, with no off-target activity. Acylation functionality was confirmed by acute tests, as KBP-066A demonstrated a prolonged PK and PD response compared to KBP-066. Both compounds induced potent and dose-dependent weight loss in the HFD rat model. In ZDF rats, fasting blood glucose/fasting insulin levels (tAUC) were reduced by 39%/50% and 36%/47% for KBP-066 and KBP-066A, respectively. This effect resulted in a 31% and 46% vehicle-corrected reduction in HbA1c at the end of the study for KBP-066 and KBP-066A, respectively. CONCLUSIONS: Here, we present pre-clinical data on an acylated DACRA, KBP-066A. The in vivo efficacy of KBP-066A is significantly improved compared to its non-acylated variant regarding weight loss and glycemic control in obese (HFD) and obese diabetic rats (ZDF). This compendium of pre-clinical studies highlights KBP-066A as a promising, once-weekly therapeutic agent for treating T2DM and obesity.

Pain characteristics and management of inpatients admitted to a comprehensive cancer centre: a cross-sectional study.

AIMS: This prospective, cross-sectional study aimed to assess cancer pain and its management in an inpatient setting at a comprehensive cancer centre in Denmark. METHODS: One hundred and eighty-eight inpatients with cancer were invited to participate (May/June 2011). Demographics, diagnoses, World Health Organization performance status, health-related quality of life, pain and data regarding analgesic treatment were registered. RESULTS: One hundred and thirty-four (71.3%) patients agreed to participate in the study. Most frequent diagnoses were leukaemia (27.6%) and lung cancer (14.2%). A high prevalence of pain was observed, 65.7%. Thirty-two per cent reported moderate to severe pain when it was at its worst, 96% reported no or mild pain when it was at its least. Nearly 22% reported moderate to severe pain when the pain was categorised as average. Breakthrough pain episodes were reported by 30.5%. Adjuvant medication was sparsely used and not always correctly indicated. Out of 88 patients with pain, 62.5% were left untreated according to the Electronic Medication System. Higher health-related quality of life was associated with lower pain intensity. The use of opioids with or without adjuvants was associated with higher pain intensity and higher number of breakthrough pain episodes. CONCLUSIONS: Approximately two thirds of inpatients reported pain and one third had breakthrough pain. A substantial number of patients with pain were left untreated. Opioid-treated patients reported highest pain intensity and number of breakthrough episodes; however, analgesic medication seemed to be underused. Measures to improve pain assessment and management are highly required.

[Course after surgery of subdural hematoma in alcohol abusers]. / Forløbet efter operation for subduralt haematom hos alkoholmisbrugere.

The postoperative course and final outcome after evacuation of subdural haematoma are described in 106 male patients in relation to their alcohol consumption. One-third of the patients were alcohol abusers, drinking at least 60 g of ethanol daily. Despite comparable head trauma, they had a significantly higher incidence of acute subdural haematomas and showed increased postoperative morbidity and mortality compared to the non-alcoholics. The postoperative hospitalization costs were initially higher and the final outcome was significantly worse for the alcohol abusers.

Headache after lumbar iohexol myelography: the influence of a history of headaches and early ambulation.

Whether a history of headache or "early" versus "late" ambulation (no bed rest or bed rest for 24 h) influence the occurrence of headache after lumbar iohexol myelography was studied by blinded interviews in 158 consecutive patients referred for elective lumbar myelography (LM) because of suspected lumbar disc prolapse or spinal stenosis. Headache after LM occurred more often in patients with a history of headache (57%) than in patients without such a history (29%), P < 0.001. Patients with normal myelographic findings complained of headache after LM more often (55%) than patients with abnormal myelograms (31%), P < 0.008. No difference in the incidence of headache after LM was demonstrated in early versus late ambulation.

Total intravenous anaesthesia for direct laryngoscopy: propofol infusion compared to thiopentone combined with midazolam and methohexitone infusion.

Total intravenous anaesthesia for direct laryngoscopy was investigated in 40 patients, randomized into four groups of 10 patients each. First, propofol infusion was compared to thiopentone combined with midazolam. Next, a comparison of propofol infusion with methohexitone infusion was undertaken. The propofol group showed significantly lower peroperative blood pressure compared to the thiopentone/midazolam group. The second propofol group required significantly less alfentanil to stabilize the blood pressure, compared to the methohexitone group. Completeness of recovery, assessed by means of a coin counting test, was faster in the propofol group compared to the thiopentone/midazolam group, while no difference could be demonstrated between the second propofol group and the methohexitone group. It is concluded that propofol seems to be superior to both thiopentone/midazolam and methohexitone with respect to the stability of peroperative blood pressure. Concerning recovery, propofol is superior to thiopentone/midazolam, but offers no advantage over methohexitone.

The influence of alcoholism on outcome after evacuation of subdural haematoma.

The postoperative course and final outcome after evacuation of subdural haematoma are described in 106 male patients in relation to their alcohol consumption. One-third of the patients were alcohol abusers, drinking at least 60 g of ethanol daily. Despite comparable head trauma, they had a significantly higher incidence of acute subdural haematomas and showed increased postoperative morbidity and mortality compared to the non-alcoholics. The postoperative hospitalization costs were initially higher and the final outcome was significantly worse for the alcohol abusers.

Recovery after total intravenous anaesthesia using combined midazolam/alfentanil infusion and reversal with flumazenil.

One of the major problems with total intravenous anaesthesia (TIVA) is postoperative sedation, possibly with respiratory depression. The aim of the present study was to evaluate the recovery characteristics after TIVA using a continuous infusion of a mixture of midazolam and alfentanil with flumazenil reversal before extubation. This method was compared to balanced anaesthesia using midazolam, alfentanil and nitrous oxide without flumazenil reversal. The degree of sedation was measured by reaction time test, Glasgow Coma Scale, cipher copying test and subtraction test. We found significantly faster reaction times postoperatively in the TIVA group (n = 15) compared to the balanced group (n = 13), despite larger doses of both midazolam (median 21 mg versus 9 mg) and alfentanil (median 5.9 mg versus 4.5 mg). The other tests revealed no difference between the groups. One patient became resedated after flumazenil. We conclude that the TIVA technique described here resulted in slightly better recovery characteristics, offering a usable alternative to balanced anaesthesia.