Biomechanics

Therapeutic agents used to treat osteoporosis reduce the incidence of vertebral and nonvertebral fractures in osteoporotic women. The antiremodeling agents, such as the bisphosphonates, prevent bone loss by suppressing the remodeling rate, perhaps increasing bone volume slightly, and increasing mineralization of the tissue. The anabolic agents, of which rhPTH(1–34) is the only one approved, accomplish this in a manner that is almost completely the opposite in terms of biological process. rhPTH(1–34) causes net bone gain by stimulating both modeling and remodeling, by increasing bone volume significantly through direct bone apposition to trabecular and endocortical surfaces, and by reducing the mean degree of tissue mineralization (a natural consequence of enhanced remodeling). Each of these treatments maintains or increases bone strength and is similarly effective at preventing fractures. However, because of their different mode of action, each has different consequences for bone matrix quality (defined here by microdamage accumulation and by the properties of mineral and collagen) and the mechanical properties of the tissue. Although bone's composite nature makes it a relatively tough material—more like fiberglass than glass—the accumulation of damage will nevertheless reduce its residual mechanical properties until the damage is repaired through remodeling. Agents that suppress remodeling are associated with both microdamage accumulation and increased mineralization. The biological importance of damage and mineralization to bone's mechanical properties is still a source of debate.     

Effect of Liposomal and Free Bisphosphonates on the IL-1β, IL-6 and TNFα Secretion from RAW 264 Cells in Vitro

Purpose. In order to evaluate the possible antiinflammatory action of bisphosphonates, the effect of the drugs on the secretion of proinflammatory cytokines (IL-l, IL-6 and TNF) from macrophages was studied. Liposomes or high concentration of extracellular calcium was used to enhance the intracellular delivery of bisphosphonates. Methods. RAW 264 cells were used as macrophage model, and they were induced with lipopolysaccharide to produce the cytokines. The cytokine concentrations in the culture supernatants were measured with time-resolved fluoroimmunoassay. Results. As a free drug, clodronate and pamidronate, but not etidronate, inhibited LPS-stimulated secretion of the cytokines from macrophage-like RAW 264 cells. Low concentrations of pamidronate, however, induced the IL-6 secretion, and the cytokine inhibitory action at the higher concentrations of pamidronate was attributed to cytotoxicity of the compound. The cytokine induction or toxic effects were not observed with clodronate or etidronate. When the drugs were encapsulated in negatively charged unilamellar liposomes, the inhibitory potency of both clodronate and etidronate enhanced by a factor of 10-20, while that of pamidronate was not increased. The complex formation of bisphosphonates with extracellular calcium, although enhancing the uptake of the compounds by macrophages, did not considerably increase their cytokine inhibitory potency. Conclusions. Bisphosphonates have inhibitory action on cytokine secretion by macrophages. The non-cytotoxic cytokine inhibition by liposome encapsulated clodronate could be beneficial in local inflammatory diseases, where the inflammation is sustained by the excessive amounts of inflammatory cytokines produced by activated macrophages.     

Osseous metastases: drugs that enhance bone integrity and prevent adverse skeletal events

More than 400,000 cancer patients in the USA contend with bone metastases on an annual basis. These patients often suffer pain, a decline in quality of life, and a shortened survival. As a result, over the past several years, efforts to enhance bone integrity in patients with osseus metastases have become a major research priority. This review discusses the evolving role of bisphosphonates and their side effects, highlights other pharmacological interventions aimed at enhancing bone integrity, and reviews other pragmatic approaches to prevent worsening pain and fractures, as derived from a single institution case series of patients with problematic rib metastases.     

Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET™

One of the most important and challenging goals in drug delivery is overcoming the poor oral absorption of high-value therapeutics that include peptides. Gastrointestinal Permeation Enhancement Technology (GIPET?) attempts to address this question by safely delivering drugs across the small intestine in therapeutically relevant concentrations. GIPET is based primarily on promoting drug absorption through the use of medium-chain fatty acids, medium-chain fatty acid derivatives and microemulsion systems based on medium-chain fatty acid glycerides formulated in enteric-coated tablets or capsules. Importantly, these excipients are generally regarded as safe and the systems are formulated in such a way that there is no change in chemical composition of the active ingredient. More than 300 volunteers have been administered GIPET formulations in 16 Phase I studies of 6 separate drugs comprising both single- and repeat-dosing regimes. Oral bioavailability of alendronate, desmopressin and low-molecular-weight heparin in humans was increased using GIPET formulations compared with unformulated controls. GIPET was well tolerated by human subjects. Using fluxes of markers of epithelial permeability, the effects of GIPET on the human intestine were shown to be rapid, short-lived and reversible in vivo. These data suggest that GIPET formulations have genuine potential as a platform technology for safe and effective oral drug delivery of a wide range of poorly permeable drugs.     

Pharmacotherapeutic options for complex regional pain syndrome

Introduction: Complex regional pain syndromes (CRPS) are rare painful conditions characterized by considerable variability in possible triggering factors, usually traumatic, and in the clinical scenario. The limited knowledge of the pathophysiological mechanisms has led to countless treatment attempts with multiple conservative and surgical options that act by different mechanisms of action.

Areas covered: In this narrative review, the authors discuss key points about CRPS definitions, diagnostic criteria and pitfalls, pathophysiological hypotheses, and treatment strategies with particular reference to pharmacotherapy. The article was based on a literature search using PubMed while the available guidelines for the management of CRPS were also examined.

Expert opinion: According to the quality of evidence, pharmacological interventions for CRPS seem to be more effective all the more so when they act on peripheral mechanisms, particularly on nociceptive pain, and when applied early in the disease, while reliable evidence about central mechanisms of chronic pain in CRPS is lacking. In our opinion, drug therapy should be preferred as early as possible, particularly in warm forms of CRPS to prevent significant functional limitation, psychological distress, and social and economic fallout.