Randomized trial of oral naproxen or local injection of betamethasone in lateral epicondylitis of the humerus

A randomized pilot study, comparing oral naproxen and a single betamethasone injection, was carried out in 21 patients suffering from lateral epicondylitis of the humerus ("tennis elbow"). The naproxen dosage was 250 mg per day for two weeks. Six milligrams of betamethasone in a long-acting form was given as a local injection. To achieve "blindness," the patients receiving naproxen were also given an injection of saline into the area of maximal tenderness at the epicondyle, while the patients getting the betamethasone-injection were given oral placebo tablets. At a clinical control after two weeks, five of the ten patients receiving naproxen and five of the 11 patients receiving betamethasone injection were improved. Thus, no apparent difference in effect could be noted at an evaluation after two weeks' treatment. No significant side effects were noted with any of the treatments.     

Stereoselective inhibition of monoamine oxidase and semicarbazide-sensitive amine oxidase by 4-dimethylamino-2,α-dimethylphenethylamine (FLA 336)

Summary The in vitro inhibition by amiflamine [FLA 336(+)] and related compounds of the activity of rat monoamine oxidase (MAO)-A and-B, rat semicarbazide sensitive amine oxidase (SSAO) and human platelet poor plasma benzylamine oxidase was studied. Amiflamine was an MAO-A selective inhibitor, but also inhibits SSAO with both a reversible (competitive, K _i=200 mol/l) and a small time-dependent component which was irreversible in nature. The optical isomer FLA 336(–) was ten times less potent towards MAO-A. However, this compound was much more potent an inhibitor of SSAO (competitive, K _i=4.6 mol/l). The amiflamine metabolites FLA 788(+) and FLA 668(+) inhibited SSAO, but only at concentrations considerably higher than required for MAO-A inhibition. Ex vivo experiments indicated that there was no significant irreversible inhibition of rat heart and lung SSAO after both single and repeated administration of amiflamine at doses up to 20 times higher than required for inhibition of MAO-A within central serotoninergic neurones.     

On mechanisms of sex differences in chemical carcinogenesis: effects of implantation of ectopic pituitary grafts on the early stages of liver carcinogenesis in the rat

The resistant hepatocyte model was used to investigate the influenceof pituitary factors on the early events of chemical carcinogenesisin rat liver. Diethylnitrosamine (DEN), 200 mg/kg body weight,was used as an initiator of enzyme altered foci. Two weeks afterinitiation the rats were placed on a 0.02% (w/w) 2-acetylaminofluorene(2-AAF) diet for two weeks. Partial hepatectomy (70%) was performedthree weeks after initiation. The rats were killed four to sixweeks after DEN initiation. Sex differences in area/foci aswell as in area ratio (mm² foci/cm² liver section) were foundin liver sections from sexually mature male and female rats( > ) of both the Sprague-Dawley and Wistar strains. Ectopicpituitary grafts (PG: s) implanted under the kidney capsuleof male Wistar rats one week before DEN initiation and removedby unilateral nephrectomy one week after initiation did notinfluence the number or area of enzyme altered foci as comparedwith sham operated male rats. On the other hand, PG:s implantedone week before 2-AAF selection in male Wistar rats and allowedto remain until the rats were killed two weeks after the 2-AAFselection period, decreased the area ratio to a level closeto that of sham operated female rats, whereas no effect on thenumber of enzyme altered foci was found. The results suggestthat the hypothalamo-pitu-itary axis may be involved in theregulation of early stages of liver carcinogenesis.     

Treatment feasibility of a digital tool for brief self-help behavioural therapy for insomnia (FastAsleep)

Cognitive behavioural therapy for insomnia is efficacious and recommended for insomnia, but availability is scarce. Cognitive behavioural therapy for insomnia self-help interventions could increase availability, especially if unguided. Optimizing cognitive behavioural therapy for insomnia methods and system user-friendliness, we developed a short, digital, self-help programme—FastAsleep—based on the behavioural components of sleep restriction and stimulus control. This study investigated its feasibility and preliminary effects. Thirty media-recruited participants with moderate to severe insomnia were assessed via telephone before using FastAsleep for 4 weeks, and were interviewed afterwards. Self-ratings with web questionnaires were conducted at screening, pre-, mid- and post-treatment, and at 3-month follow-up. Primary outcomes were feasibility (credibility, adherence, system user-friendliness and adverse effects), and secondary outcomes were changes in symptom severity (insomnia, depression and anxiety). Adherence was generally high, participants' feasibility ratings were favourable, and adverse effects matched previously reported levels for cognitive behavioural therapy for insomnia. Symptoms of insomnia decreased after the treatment period (Hedge's g = 1.79, 95% confidence interval = 1.20–2.39), as did symptoms of depression and anxiety. FastAsleep can be considered feasible and promising for alleviating insomnia symptoms among patients fit for self-care. Future controlled trials are needed to establish the efficacy of FastAsleep and its suitability in a stepped care model.     

Insulin concentrations and insulin sensitivity after short-term amiloride in healthy subjects

We have evaluated the short-term effects of amiloride on insulin action in vivo, since amiloride is known to impair insulin action in vitro.Seven healthy subjects were treated according to a randomized, double-blind, cross-over protocol. The treatment periods were 3 days each with amiloride 15 mg daily and placebo. Insulin action on glucose turnover was assessed directly after each treatment period with the hyper-insulinaemic euglycaemic glucose clamp technique.At the two insulin concentrations studied ( 30 mU·l^–1 and 200 mU·l^–1), the glucose infusion rate required to maintain constant euglycaemia did not differ after either amiloride or placebo. The rates of glucose production and utilization were also similar, whereas the so-called insulin sensitivity index at the lower insulin concentration was significantly reduced (by about 15 %) after amiloride. Moreover, amiloride produced significantly higher fasting insulin and C-peptide concentrations, whereas fasting glucose and NEFA concentrations were unaltered.In conclusion, these data suggest that short-term amiloride slightly impairs insulin sensitivity with respect to glucose uptake. However, overall glucose homoeostasis does not appear to be affected, probably due to a compensatory rise in plasma insulin.     

Interspecies differences in the kinetic properties of deoxycytidine kinase elucidate the poor utility of a phase I pharmacologically directed dose-escalation concept for 2-chloro-2′-deoxyadenosine

2-Chloro-2-deoxyadenosine (CdA, Cladribine), is a purine antimetabolite currently under investigation in phase II clinical trials for the treatment of lymphoid malignancies. Significant differences in CdA toxicity between mice and humans were observed during phase I clinical evaluation. For the elucidation of interspecies differences in drug toxicity the pharmacokinetics of CdA after subcutaneous injection and the kinetic properties of the CdA-phosphorylating enzyme, deoxycytidine kinase (dCK), were compared in mice and humans. The ratio of the dose lethal to 10% of mice (LD₁₀) to the maximum tolerated dose (MTD) in humans was 50 and the ratio of the area under the curve obtained at approximately one-half the LD₁₀ (AUC_{approx. one-half the LD 10})/AUC_MTD was 49. A significant interspecies difference was observed in the kinetic properties of dCK, the main CdA-activating enzyme. With CdA as a substrate, the Michaelis constant (K _m) of dCK in crude extracts of mouse thymus was 10 times higher than that in human thymus. An approximately 9-fold interspecies difference in maximum velocity (V_max)/K _m indicated a higher efficiency of dCK for CdA in humans than in mice. The peak plasma concentration was 210 times higher and exceeded theK _m in mice. Initial and terminal half-lives were approximately 7 times shorter in mice and trough levels were similar in mice and humans. Thus, the differences in AUCs at equitoxic doses are largely explained by differences in the target enzyme properties and the pharmacokinetic pattern. The observed lower tolerance for CdA in humans as compared with mice confirms the view that antimetabolites may not be good candidates for pharmacokinetically guided dose-escalation schemes unless detailed information on interspecies variability in drug bioactivation is available.     

Developmental damage, increased lipid peroxidation, diminished cyclooxygenase-2 gene expression, and lowered prostaglandin E2 levels in rat embryos exposed to a diabetic environment

Previous experimental studies suggest that diabetic embryopathy is associated with an excess of radical oxygen species (ROS), as well as with a disturbance of prostaglandin (PG) metabolism. We aimed to investigate the relationship between these pathways and used hyperglycemia in vitro (embryo culture for 24-48 h) and maternal diabetes in vivo to affect embryonic development. Subsequently, we assessed lipid peroxidation and gene expression of cyclooxygenase (COX)-1 and -2 and measured the concentration of prostaglandin E2 (PGE2) in embryos and membranes. Both hyperglycemia in vitro and maternal diabetes in vivo caused embryonic dysmorphogenesis and increased embryonic levels of 8-epi-PGF2alpha, an indicator of lipid peroxidation. Addition of N-acetylcysteine (NAC) to the culture medium normalized the morphology and 8-epi-PGF2alpha concentration of the embryos exposed to high glucose. Neither hyperglycemia nor diabetes altered COX-1 expression, but embryonic COX-2 expression was diminished on gestational day 10. The PGE2 concentration of day 10 embryos and membranes was decreased after exposure to high glucose in vitro or diabetes in vivo. In vitro addition of NAC to high glucose cultures largely rectified morphology and restored PGE2 concentration, but without normalizing the COX-2 expression in embryos and membranes. Hyperglycemia/diabetes-induced downregulation of embryonic COX-2 gene expression may be a primary event in diabetic embryopathy, leading to lowered PGE2 levels and dysmorphogenesis. Antioxidant treatment does not prevent the decrease in COX-2 mRNA levels but restores PGE2 concentrations, suggesting that diabetes-induced oxidative stress aggravates the loss of COX-2 activity. This may explain in part the antiteratogenic effect of antioxidant treatment.     

Somatostatin receptor scintigraphy during treatment with lanreotide in patients with neuroendocrine tumors

To investigate possible changes in somatostatin receptor expression during treatment with high dose lanreotide, eight patients with neuroendocrine tumors were investigated by [¹¹¹In-DTPA-D-Phe¹]-octreotide scintigraphy before and during treatment. The spleen-to-background ratio decreased in all patients, whereas tumor-to-background ratio revealed a heterogeneous pattern with an average increase of 50% (−79% to +1,087%). This finding indicates that lanreotide treatment may influence the binding of radioactively labeled somatostatin to the spleen, while changes in the binding to functioning somatostatin receptors in tumor cells are more complex and not clearly related to treatment.