Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of the phenylacetic acid class with anti-inflammatory, analgesic, and antipyretic properties. Contrary to the action of many traditional NSAIDs, diclofenac inhibits cyclooxygenase (COX)-2 enzyme with greater potency than it does COX-1. Similar to other NSAIDs, diclofenac is associated with serious dose-dependent gastrointestinal, cardiovascular, and renal adverse effects. Since its introduction in 1973, a number of different diclofenac-containing drug products have been developed with the goal of improving efficacy, tolerability, and patient convenience. Delayed- and extended-release forms of diclofenac sodium were initially developed with the goal of improving the safety profile of diclofenac and providing convenient, once-daily dosing for the treatment of patients with chronic pain. New drug products consisting of diclofenac potassium salt were associated with faster absorption and rapid onset of pain relief. These include diclofenac potassium immediate-release tablets, diclofenac potassium liquid-filled soft gel capsules, and diclofenac potassium powder for oral solution. The advent of topical formulations of diclofenac enabled local treatment of pain and inflammation while minimizing systemic absorption of diclofenac. SoluMatrix diclofenac, consisting of submicron particles of diclofenac free acid and a proprietary combination of excipients, was developed to provide analgesic efficacy at reduced doses associated with lower systemic absorption. This review illustrates how pharmaceutical technology has been used to modify the pharmacokinetic properties of diclofenac, leading to the creation of novel drug products with improved clinical utility.

A 41-kilodalton macrophage capping protein (MCP) has been isolated which is capable of forming complexes with actin monomers in addition to capping the barbed ends of actin filaments (Southwick & DiNubile, 1986). The protein is calcium activated in a fully reversible manner. Using kinetic assays, we determined a capping constant, defined here as a modified Kd, of 1 nM and a Kd of 3-4 microM for MCP-actin monomer complex formation. MCP weakly nucleates actin polymerization: more than 0.5 microM MCP is necessary to shorten the lag period, and 1 microM MCP at an actin/MCP ratio of 10 reduces the average length of actin filaments to about 200 molecules per filament. We determined that the actin nucleus that survives MCP inactivation contains a minimum number of five actin molecules. These experiments also make a point with respect to the interpretation of the prolongation of the lag period. We directly demonstrate that in the presence of an actin binding protein a prolongation of the lag period can be associated with increased nucleation, contrary to the usual interpretation in the literature that it indicates no or decreased nucleation by the actin binding protein.

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Abstract. Chemoattractant stimulation of polymorphonuclear ieukocytes is associated with a nearly twofold rise in actin filament content. We examined the role of the actin monomer sequestering protein, profilin, in the regulation of PMN actin filament assembly during chemoattractant stimulation using a Triton extraction method. Poly-L-proline-conjugated Sepharose beads were used to assess the relative concentration of actin bound to profilin with high enough affinity to withstand dilution (profilin-actin complex) and DNase I-conjugated beads to measure the relative concentration of actin in the Triton-soluble fraction not bound to profilin. Actin associated with the Triton-insoluble fraction (F-actin) was also measured. In unstimulated PMN, the relative concentration of actin bound to profilin was maximum. After FMLP stimulation, profilin released actin monomers within 10 s, with the profilin-actin complex concentration reaching a nadir by 40 s and remaining low as long as the cells were exposed to chemoattractant (up to 30 min). If FMLP was dissociated from PMN membrane receptors using t-BOC, actin reassociated with profilin within 20 s. Quantitative analysis of these reactions, however, revealed that profilin release of and rebinding to actin could account for only a small percentage of the total change in F-actin content. Determination of the total profilin and actin concentrations in PMN revealed that the molar ratio of profilin to actin was 1 to 5.2. When purified actin was polymerized in PMN Triton extract containing EGTA, removal of profilin from the extract minimally affected (12% reduction) the high apparent critical concentration at which actin began to assemble. Although profilin released actin at the appropriate time to stimulate actin assembly during exposure to chemoattractants, the concentration of profilin in PMN was insufficient to explain the high unpolymerized actin content in unstimulated PMN and the quantity of actin released from profilin too small to account for the large shifts from unpolymerized to polymerized actin associated with maximal chemoattractant stimulation.

We conducted a randomized, placebo-controlled clinical study evaluating famciclovir (500 mg 3 times daily and 1.5 g once daily) for 1 year (6 months post-treatment follow-up) in patients with chronic hepatitis B e antigen (HBeAg)-positive hepatitis B virus (HBV) infection. The study was conducted in 80 centers in North America, Europe, and Australia/ New Zealand. A total of 417 patients with histologically documented chronic hepatitis B (histologic activity index [HAI] 9.5-11.0) received famciclovir (500 mg 3 times daily or 1.5 g once daily) or placebo. Famciclovir 500 mg 3 times daily significantly reduced HBV DNA and median HAI scores versus placebo. By week 8, median HBV DNA decreased from 1,645 to 283 MEq/mL (famciclovir 500 mg 3 times daily) and from 1,147 to 304 MEq/mL (famciclovir 1.5 g once daily), while increasing for placebo (1,617 to 1,685 MEq/mL). Median change in HBV DNA at the end of therapy was ؊76% (famciclovir 500 mg 3 times daily; P < .01) and ؊60% (famciclovir 1.5 g once daily; P ‫؍‬ .25) versus ؊37% for placebo. Median change in HAI was ؊1.5 points (famciclovir 500 mg 3 times daily; P ‫؍‬ .02) and ؊1.0 point (famciclovir 1.5 g once daily; P ‫؍‬ .35) and zero for placebo. Fifty percent of patients receiving famciclovir 500 mg 3 times daily (P ‫؍‬ .07) and 43% receiving 1.5 g once daily (P ‫؍‬ .41) experienced >2 points improvement in HAI versus 37% for placebo. Nine percent of patients treated with famciclovir 500 mg 3 times daily underwent anti-HBeAg seroconversion with undetectable HBV DNA at end of follow-up versus 3% in the placebo group (P ‫؍‬ .05). Famciclovir was well tolerated; the incidence of post-treatment alanine transaminase (ALT) elevations was comparable with placebo. In conclusion, famciclovir 500 mg 3 times daily gave modest suppression of viral replication, but translated into significant histologic improvement in median HAI score at 1 year. (HEPATOLOGY 2000;32:413-417.)Hepatitis B virus (HBV) infection is a major cause of chronic liver disease, with an estimated 350 million carriers worldwide. HBV induces a spectrum of clinical manifestations, ranging from mild, unapparent disease to fulminant hepatitis, severe chronic liver disease, and cirrhosis. The virus has also been clearly implicated in the development of primary hepatocellular carcinoma, causing one million deaths per year. [1][2][3] Interferon alfa is widely licensed for the treatment of chronic hepatitis B e antigen (HBeAg)-positive HBV infection. The drug is administered to patients with well-compensated liver disease who can tolerate the potential side effects, which may require dose reduction or discontinuation of treatment. In addition, interferon requires parenteral administration. Efficacy defined as HBe-seroconversion is limited to approximately 30% of treated patients. 4 Availability of nucleoside analogues with activity against HBV offers promise of improved efficacy, greater convenience (i.e., oral formulation) and applicability to patients with well and poorly compensated HBV infection. Lamivudine, the (...