The first biological therapeutics in rheumatology are approaching patent expiration, encouraging development of 'follow-on' versions, known as 'biosimilars'. Biological agents range from simple replacement hormones to complex monoclonal antibodies and soluble receptors: large, intricate proteins with unique tertiary and quaternary structures that are inherently difficult to replicate. Post-translational modifications, such as glycosylation, may occur from changes in cell lines and/or manufacturing processes, resulting in products that are highly similar, but not identical, to approved 'reference' agents, hence, the term 'biosimilar', rather than 'bioidentical'. Even minor modifications in manufacturing processes, which iteratively occur with reference products due to improvements in efficiency, scale up to meet commercial demands or changes in manufacturing sites, may alter biological function and/or immunogenicity, potentially changing their safety and efficacy profile. As biosimilars are now in randomised controlled trials for treatment of rheumatic diseases, rheumatologists face decisions regarding equipoise and will need to consider their clinical use versus reference products. A clear understanding of the inherent differences between reference antibodies and biosimilars, their clinical implications and the processes governing regulation, approval and clinical use of biosimilars, is paramount. A panel of international experts in the field of rheumatology recently convened to evaluate and discuss these issues.

No abstract

No abstract

Biosimilars are now a reality in rheumatology. Although analytical and non-clinical procedures to establish similarity have evolved significantly, clinical trials demonstrating equivalent efficacy and safety are absolutely required for all biosimilars. The design of such trials, including equivalence and non-inferiority statistical approaches, are discussed. Clinical evidence on biosimilars that have been approved recently or are presently being developed for use in rheumatology is also reviewed and contrasted with that available for biomimics (or intended copies), which are non-innovator biologics that are marketed in several countries but have not undergone review according to a regulatory pathway for biosimilars.

A new experimental model to assess analgesic activity of both analgesic and nonsteroidal antiinflammatory drugs is described. It uses the unilateral intra-articular knee injection of an uric acid suspension in mineral oil to produce acute inflammation, pain, and functional motor impairment. The model, named "pain-induced functional impairment in the rat" (PIFIR) assesses analgesic activity by measuring the capacity to walk with the injured extremity. The procedure determines both the potencies of analgesic drugs and the time course of the effect. Analgesia of selected reference agents was followed for 4 h and the effect versus time curves were constructed. The area under the curve (effect versus time), an expression of the overall activity during the observation period, increased in a dose-dependent manner. The area under the curve, E, , , , Ttmax, and E D , , of reference agents tested are reported. The PIFIR procedure was sensitive to opiate and nonopiate analgetics (nonsteroidal antiinflammatory drugs) and possibly steroidal antiinflammatory drugs. These characteristics make it suitable for screening purposes. D 1993 WiIey-Liss, Inc.

No abstract

Recent behavioral and electrophysiological studies have attributed an important role to dorsal root reflexes (DRRs) in the initiation and development of neurogenic inflammation produced by intradermal capsaicin (CAP). The DRRs can occur in peptidergic fibers, resulting in peripheral release of neuromediators that produce vasodilation, plasma extravasation and subsequently hyperalgesia and allodynia. In this study, we have evaluated the effect of spinal administration of bumetanide (a blocker of the Na+-K+-2Cl- cotransporter, NKCC) on DRR activity, changes in cutaneous blood flow (vasodilation), hindpaw edema, mechanical allodynia, and hyperalgesia induced by intradermal injection of 1% CAP in Sprague-Dawley rats. Vasodilation was monitored using laser Doppler flowmetry, neurogenic edema was evaluated by measurements of hindpaw volume, and secondary mechanical allodynia and hyperalesia were tested using von Frey filaments (10 and 200 mN) applied to the plantar surface of the paw. Changes in the blood flow were blocked significantly by intrathecal bumetanide at 10 and 100 microM in both pre- and posttreatment studies. Spinal bumetanide at 10 and 100 microM blocked neurogenic edema when it was administered before CAP injection, but only bumetanide at 100 microM administered after CAP injection reduced the paw edema significantly. Furthermore, the administration of bumetanide onto the spinal cord reduced the increment in DRR activity produced by CAP. Finally, both secondary mechanical allodynia and hyperalesia were reduced by bumetanide at 1, 10, and 100 microM. Taken together these results suggest that NKCC is involved in the increases in DRR activity, neurogenic inflammation and hyperalgesia and allodynia induced by intradermal CAP.

Factors related to hemodynamic response and vital support measures have a significant influence on the disposition kinetics of amikacin in severely ill patients with sepsis. Consideration of hemodynamic response and vital support measures, in addition to other previously described covariates, can be of great value in the design of initial dosing regimens.