Age-related macular degeneration (AMD), a progressive condition that is untreatable in up to 90% of patients, is a leading cause of blindness in the elderly worldwide. The two forms of AMD, wet and ...dry, are classified based on the presence or absence of blood vessels that have disruptively invaded the retina, respectively. A detailed understanding of the molecular mechanisms underlying wet AMD has led to several robust FDA-approved therapies. In contrast, there are no approved treatments for dry AMD. In this review, we provide insight into the critical effector pathways mediating each form of the disease. A recurring theme that spans most aspects of AMD pathogenesis is defective immune modulation in the classically immune-privileged ocular haven. Interestingly, the latest advances in AMD research also highlight common molecular disease pathways with other neurodegenerative disorders. Finally, the therapeutic potential of intervening at known mechanistic steps of AMD pathogenesis is discussed.
Age-related macular degeneration (AMD) is a progressive blindness condition that is untreatable in up to 90% of patients. Ambati and Fowler review our molecular understanding of the wet and dry forms of this disorder, placing this work in the context of the latest clinical data and possible therapeutic strategies.
In 1989 the British Journal of Radiology published a review proposing the term biologically effective dose (BED), based on linear quadratic cell survival in radiobiology. It aimed to indicate ...quantitatively the biological effect of any radiotherapy treatment, taking account of changes in dose-per-fraction or dose rate, total dose and (the new factor) overall time. How has it done so far? Acceptable clinical results have been generally reported using BED, and it is in increasing use, although sometimes mistaken for "biologically equivalent dose", from which it differs by large factors, as explained here. The continuously bending nature of the linear quadratic curve has been questioned but BED has worked well for comparing treatments in many modalities, including some with large fractions. Two important improvements occurred in the BED formula. First, in 1999, high linear energy transfer (LET) radiation was included; second, in 2003, when time parameters for acute mucosal tolerance were proposed, optimum overall times could then be "triangulated" to optimise tumour BED and cell kill. This occurs only when both early and late BEDs meet their full constraints simultaneously. New methods of dose delivery (intensity modulated radiation therapy, stereotactic body radiation therapy, protons, tomotherapy, rapid arc and cyberknife) use a few large fractions and obviously oppose well-known fractionation schedules. Careful biological modelling is required to balance the differing trends of fraction size and local dose gradient, as explained in the discussion "How Fractionation Really Works". BED is now used for dose escalation studies, radiochemotherapy, brachytherapy, high-LET particle beams, radionuclide-targeted therapy, and for quantifying any treatments using ionising radiation.
Nicotine and cannabis use during adolescence has the potential to induce long lasting changes on affective and cognitive function. Here, we examined whether adolescent exposure to nicotine, the ...cannabinoid agonist WIN55-212,2 (WIN), or co-exposure to both would alter operant learning, locomotion, and anxiety- and reward-related behaviors in male and female mice during adulthood. Males exposed to a moderate dose of WIN (2 mg/kg) or co-exposed to nicotine and the moderate dose of WIN exhibited decreased anxiety-associated behaviors and increased cognitive flexibility, but did not differ in operant learning or generalized locomotion. In contrast, differences were not found among the females in these measures at the moderate WIN dose or in both sexes with exposure to a low WIN dose (0.2 mg/kg). Furthermore, a sex-dependent dissociative effect was found in natural reward consumption. Males exposed to the moderate dose of WIN or co-exposed to nicotine and the moderate dose of WIN demonstrated increased sucrose consumption. In contrast, females exposed to the moderate dose of WIN exhibited a decrease in sucrose consumption, which was ameliorated with co-administration of nicotine. Together, these novel findings demonstrate that adolescent exposure to cannabinoids in the presence or absence of nicotine results in altered affective and reward-related behaviors during adulthood.
In this review, the state of the art for compounds affecting the endocannabinoid (eCB) system is described with a focus on the treatment of pain. Amongst directly acting CB receptor ligands, clinical ...experience with ∆9‐tetrahydracannabinol and medical cannabis in chronic non‐cancer pain indicates that there are differences between the benefits perceived by patients and the at best modest effect seen in meta‐analyses of randomized controlled trials. The reason for this difference is not known but may involve differences in the type of patients that are recruited, the study conditions that are chosen and the degree to which biases such as reporting bias are operative. Other directly acting CB receptor ligands such as biased agonists and allosteric receptor modulators have not yet reached the clinic. Amongst indirectly acting compounds targeting the enzymes responsible for the synthesis and catabolism of the eCBs anandamide and 2‐arachidonoylglycerol, fatty acid amide hydrolase (FAAH) inhibitors have been investigated clinically but were per se not useful for the treatment of pain, although they may be useful for the treatment of post‐traumatic stress disorder and cannabis use disorder. Dual‐acting compounds targeting this enzyme and other targets such as cyclooxygenase‐2 or transient potential vanilloid receptor 1 may be a way forward for the treatment of pain.
The endocannabinoid (eCB) system is involved in processes as diverse as control of appetite, perception of pain and the limitation of cancer cell growth and invasion. The enzymes responsible for eCB ...breakdown are attractive pharmacological targets, and fatty acid amide hydrolase inhibitors, which potentiate the levels of the eCB anandamide, are now undergoing pharmaceutical development. ‘Drugable’ selective inhibitors of monoacylglycerol lipase, a key enzyme regulating the levels of the other main eCB, 2‐arachidonoylglycerol, were however not identified until very recently. Their availability has resulted in a large expansion of our knowledge concerning the pharmacological consequences of monoacylglycerol lipase inhibition and hence the role(s) played by the enzyme in the body. In this review, the pharmacology of monoacylglycerol lipase will be discussed, together with an analysis of the therapeutic potential of monoacylglycerol lipase inhibitors as analgesics and anticancer agents.
Lower urinary tract (LUT) dysfunction is a common sequela of neurological disease, resulting in symptoms that have a pronounced effect on quality of life. The site and nature of the neurological ...lesion affect the pattern of dysfunction. The risk of developing upper urinary tract damage and renal failure is much lower in patients with slowly progressive non-traumatic neurological disorders than in those with spinal cord injury or spina bifida; this difference in morbidity is taken into account in the development of appropriate management algorithms. Clinical assessment might include tests such as uroflowmetry, post-void residual volume measurement, renal ultrasound, (video-)urodynamics, neurophysiology, and urethrocystoscopy, depending on the indication. Incomplete bladder emptying is most often managed by intermittent catheterisation, and storage dysfunction by antimuscarinic drugs. Intradetrusor injections of onabotulinumtoxinA have transformed the management of neurogenic detrusor overactivity. Neuromodulation offers promise for managing both storage and voiding dysfunction. An individualised, patient-tailored approach is required for the management of LUT dysfunction associated with neurological disorders.
Summary
Background
Adalimumab is used to treat several inflammatory diseases, including plaque psoriasis. GP2017 is a proposed adalimumab biosimilar.
Objectives
To assess the impact of multiple ...switches between GP2017 and reference adalimumab (ref‐ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate‐to‐severe plaque psoriasis.
Methods
This 51‐week double‐blinded, phase III study randomly assigned patients to GP2017 (n = 231) or ref‐ADMB (n = 234) 80 mg subcutaneously at week 0, then 40 mg biweekly from week 1. At week 17, patients were rerandomized to switch (n = 126) or continue (n = 253) treatment. The primary end point was patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with equivalence confirmed if the 95% confidence interval (CI) for the difference in PASI 75 between treatments was ± 18%. The key secondary end point was the change from baseline to week 16 in continuous PASI. Other end points were PASI over time; PASI 50, 75, 90 and100; pharmacokinetics; safety; tolerability and immunogenicity for the switched and continued treatment groups.
Results
Equivalent efficacy between GP2017 and ref‐ADMB was confirmed for the primary (66·8% and 65·0%, respectively; 95% CI −7·46 to 11·15) and key secondary end points (−60·7% and −61·5%, respectively; 95% CI –3·15 to 4·84). PASI improved over time and was similar between treatment groups at week 16, and the switched and continued groups from weeks 17 to 51. There were no relevant safety or immunogenicity differences between GP2017 and ref‐ADMB at week 16, or the switched and continued groups from weeks 17 to 51. No hypersensitivity to adalimumab was reported upon switching.
Conclusions
Following the demonstration of GP2017 biosimilarity to ref‐ADMB, switching up to four times between GP2017 and ref‐ADMB had no detectable impact on efficacy, safety or immunogenicity.
What's already known about this topic?
Adalimumab is indicated for use in rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, Crohn disease, ulcerative colitis and uveitis.
GP2017 is a proposed biosimilar to adalimumab.
Previous analytical studies have shown that GP2017 and reference adalimumab have identical amino acid sequences, indistinguishable secondary and tertiary structures, the same level of post‐translational modifications and similar in vitro functionality.
What does this study add?
This phase III confirmatory efficacy and safety study demonstrated equivalent efficacy and similar safety of GP2017 and reference adalimumab in patients with moderate‐to‐severe plaque psoriasis.
Additionally, switching up to four times between GP2017 and reference adalimumab had no impact on the incidence of adverse events or injection‐site reactions.
The frequency of antidrug antibody development was similar between the switched and continued treatment groups, and there was no impact on efficacy.
Linked Comment: Cline and Feldman. Br J Dermatol 2018; 179:557–558.
Respond to this article
Palmitoylethanolamide (PEA,
-hexadecanoylethanolamide) is an endogenous compound belonging to the family of
-acylethanolamines. PEA has anti-inflammatory and analgesic properties and is very well ...tolerated in humans. In the present article, the basal pharmacology of PEA is reviewed. In terms of its pharmacokinetic properties, most work has been undertaken upon designing formulations for its absorption and upon characterising the enzymes involved in its metabolism, but little is known about its bioavailability, tissue distribution, and excretion pathways. PEA exerts most of its biological effects in the body secondary to the activation of peroxisome proliferator-activated receptor-α (PPAR-α), but PPAR-α-independent pathways involving other receptors (Transient Receptor Potential Vanilloid 1 (TRPV1), GPR55) have also been identified. Given the potential clinical utility of PEA, not least for the treatment of pain where there is a clear need for new well-tolerated drugs, we conclude that the gaps in our knowledge, in particular those relating to the pharmacokinetic properties of the compound, need to be filled.
PDF
