Monoclonal antibodies in the treatment of colorectal cancer

Monoclonal antibodies have been developed to target specific proteins involved in the development and progression of cancer. These reagents have the advantage of exquiste specificity, and as currently engineered, low toxicity. The impact monoclonal antibody therapy has recently been demonstrated in colorectal cancer, in which two pathways critical to carcinogenesis have been targeted. The targets are the epidermal growth factor receptor signaling pathway and angiogenesis. Antibodies directed to proteins in both pathways have shown significant activity especially in combination with chemotherapy, and studies in the adjuvant setting are in progress. We review the use of monoclonal antibodies in the treatment of colorectal cancer with particular attention to edrecolomab (Mab 17-1A), bevacizumab (Avastin), cetuximab (IMC-C225), ABX-EGF and EMD 72000. Additional compounds are in earlier stages of development, and the future of this approach in solid tumours is promising.     

Immunogenicity and safety in infants of a DTwPHib full liquid vaccine

Aim: Combining paediatric vaccines is a rational solution to reduce the number of injections during a single clinical visit, to maintain parents' compliance and to extend vaccine coverage. Different diphtheria, tetanus and whole cell pertussis (DTwP)-containing combination vaccines are licensed and used world-wide. This study assessed the immunogenicity and safety in infants of a combined diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b-CRM₁₉₇ conjugate full liquid vaccine. Methods: The safety and efficacy of a combined ready-to-use liquid vaccine containing diphtheria and tetanus toxoids, cell suspension of Bordetella pertussis and H. influenzae type b-CRM₁₉₇ conjugate vaccine (DTwPHib) were assessed in infants eligible for the local Expanded Programme on Immunization (EPI) in Valencia, Spain. The comparative group received separate injections of reference vaccines DTwP + Hib. Results: Local and systemic reactions and adverse events were generally mild and similar in the two groups. DTwPHib elicited anti-PRP antibody titres ≥0.15 μg ml^-1 in 97% and DTwP + Hib in 94% of infants. Furthermore, 89% of DTwPHib and 78% of DTwP + Hib recipients attained anti-PRP antibody titres ≥1.0 μg ml^-1, signifying long-term protection. The anti-PRP geometric mean titre was significantly higher in the combined DTwPHib vaccine group (6.65 vs 3.57 μg ml^-1). In both groups, 99% of infants achieved protective (≥0.01 IU ml^-1) anti-diphtheria antibody levels and all children achieved protective (≥0.1 IU ml^-1) anti-tetanus antibody levels. DTwPHib caused a ≥2-fold increase in anti-pertactin antibody titres in 91% and a ≥4-fold increase in 82% of recipients. The corresponding proportions in the DTwP + Hib group were 95% and 90%. DTwPHib induced a ≥2-fold increase in anti-Aggl2 and 3 antibody levels in 79% and a ≥4-fold increase in 73% of recipients. The corresponding proportions among DTwP + Hib infants were 85 and 82%. Conclusion: Overall, the combined liquid vaccine DTwPHib is a safe and effective immunogenic vaccine for EPI use in infants.     

Effect of mibefradil on CYP3A4 in vivo

Mibefradil, a calcium channel blocker, was removed from the market because of adverse drug interactions with coadministered CYP3A4 substrates. This study examined the effect of mibefradil on the activity of hepatic and intestinal CYP3A4 in vivo, employing the erythromycin breath test (EBT) and oral midazolam pharmacokinetics. This was a two-period, single-blind, placebo-controlled crossover study in which 8 male volunteers were randomized to the order of receiving placebo and a single 100-mg oral dose of mibefradil. Oral midazolam was coadministered with intravenous [14C N-methyl] erythromycin 1 hour after mibefradil/placebo administration. The EBT was performed 20 minutes following erythromycin administration. Blood and urine were collected during the 36 hours following probe drug administration for analysis of midazolam pharmacokinetics. Coadministration of mibefradil increased the Cmax of midazolam 3-fold, the AUC 8- to 9-fold, and the t1/2 4-fold. Mibefradil coadministration decreased the amount of exhaled 14CO2 in 6 of 8 subjects, with a mean decrease of 25%. It was concluded that a single oral dose of mibefradil significantly inhibits CYP3A4 in intestine and liver. These data support that adverse drug interactions involving mibefradil reflect inhibition of CYP3A4 in intestine and liver. Also, they suggest that the EBT, while a valid probe of in vivo hepatic CYP3A4 activity, is a single time point measurement and may be less sensitive than oral midazolam pharmacokinetics in detecting CYP3A4 inhibition.     

Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice

Consumption of typical quantities of grapefruit juice (GFJ) increases the oral bioavailability of several CYP3A4 substrates without affecting their elimination, consistent with selective inhibition of intestinal but not hepatic CYP3A4. However, increases in the AUCs of CYP3A4 substrates recently associated with the consumption of large amounts of GFJ were similar to those observed with potent inhibitors of hepatic CYP3A4. The current study compared the effects of consuming large quantities and more typical amounts of GFJ on the activity of hepatic and intestinal cytochrome P450 3A4 in vivo, employing the erythromycin breath test (EBT) and oral midazolam pharmacokinetics. This was a two-phase, randomized, placebo-controlled crossover study, with each phase conducted with a separate panel of subjects. In Phase I, 8 male volunteers were randomized to the order of receiving one glass (240 mL) of water (placebo) or double-strength (DS) GFJ tid for 2 days and then 90, 60, and 30 minutes prior to administration of probe drugs on the 3rd day. In Phase II, 16 male volunteers were randomized to the order of receiving one glass of (1) single-strength (SS) GFJ, (2) DS GFJ, and (3) water (placebo). All treatments were administered in a fasted state. There was at least a 7-day washout period between treatments. Probe drugs, administered 30 minutes or 1 hour following each treatment in Phase I or II, respectively, consisted of oral midazolam (2 mg) coadministered with IV [14G N-methyl] erythromycin (0.03 mg). The EBT was performed 20 minutes following erythromycin administration. Blood was collected during the 24 hours following probe drug administration for the analysis of midazolam pharmacokinetics. In Phase I, consumption of one glass of DS GFJ tid for 3 days increased the Cmax of midazolam 3-fold, the AUC 6-fold, and the t1/2 2-fold and decreased the amount of exhaled 14CO2 in all 8 subjects, with a mean decrease in EBT of 18%. In Phase II, consumption of one glass of DS GFJ significantly increased the AUC and Cmax of midazolam approximately 2-fold without a significant effect on the t1/2 of midazolam or the EBT. The effects of consuming one glass of SS GFJ on midazolam pharmacokinetics and the EBT were not significantly different from those of one glass of DS GFJ. It was concluded that consumption of one glass of DS GFJ tid for 3 days significantly increased the AUC, Cmax, and t1/2 of midazolam and reduced EBT values, reflecting inhibition of both hepatic and intestinal CYP3A4. In contrast, consumption of one glass of SS or DS GFJ increased midazolam AUC and Cmax, with little effect on the midazolam t1/2 and EBT values, reflecting preferential inhibition of intestinal CYP3A4. Alterations of midazolam AUC and Cmax induced by nine glasses of DS GFJ were significantly greater than those produced by one glass of SS or DS GFJ. These data suggest that GFJ inhibits intestinal and hepatic CYP3A4 in an exposure-dependent fashion and that patients taking medications that are CYP3A4 substrates are at risk for developing drug-related adverse events if they consume large amounts of grapefruit juice.     

PEGylation of the antimicrobial peptide nisin A: problems and perspectives

Nisin is a natural antimicrobial peptide produced by Lactococcus lactis and widely employed as food preservative. Its low solubility in neutral aqueous solutions, its instability at physiological pH and its rapid breakdown by proteolytic enzymes has limited its use for processed foods (processed cheese, milk and derivatives, canned vegetables). The conjugation to poly(ethylene glycol) (PEG) could improve its solubility and protect it towards enzymes present in non optimally processed food. We report the synthesis of a PEG-nisin conjugate, and the microbiology assays against some bacterial cell lines.     

Prognostic value of estrogen receptor status can be improved by combined evaluation of p53, Bcl2 and PgR expression: an immunohistochemical study on breast carcinoma with long-term follow-up

Steroid receptor analysis is the only widely accepted prognostic/predictive marker in breast cancer (BC) treatment. In the present study we evaluated the prognostic role of ER/PgR with p53 and Bcl2, in a series of 277 BC (153 pN1/2, 122 pNO, 2 pNx) with a long-term follow-up (67 months for DFS, 75 months for OS). Our results, besides confirming the usefulness of ER immunohistochemical expression as a prognostic marker, showed that PgR expression alone had a borderline/not significant prognostic value in the whole series (p=0.08 for DFS and p=0.09 for OS), while showed to be prognostic in N+ cases (p=0.02 for DFS and p=0.03 for OS). PgR prognostic value, however, was not independent at the multivariate analysis. By combining ER with PgR, p53 and Bcl2, we showed that ER/p53 and ER/Bcl2 phenotypes had a better discriminant role than ER/PgR phenotype. The ER+/p53+ phenotype was at higher risk of relapse/death as compared with ER+/p53- phenotype. Conversely ER-/p53+ phenotype showed the most unfavourable prognosis. Similar results could be observed concerning ER/Bcl2 phenotypes. Our study showed that the combined evaluation of ER/PgR weakly enhanced the prognostic/predictive power of ER status alone. On the contrary, the combined evaluation of ER/p53 and ER/Bcl2, improved this prognostic/predictive capability and allowed the separation of ER positive and ER negative cases into subgroups with different prognosis.     

The association between the Mediterranean diet and magnetic resonance parameters for knee osteoarthritis: data from the Osteoarthritis Initiative

The Mediterranean diet appears to be beneficial for osteoarthritis (OA), but the few data available regarding the association between the diet and the condition are limited to X-ray and clinical findings. The current study aimed to investigate the association between adherence to the Mediterranean diet and knee cartilage morphology, assessed using magnetic resonance (MRI) in a cohort of North American participants. Seven hundred eighty-three participants in the Osteoarthritis Initiative (59.8% females; mean age 62.3 years) in possession of a MRI assessment (a coronal 3D FLASH with Water Excitation MR sequence of the right knee) were enrolled in our cross-sectional study. Adherence to the Mediterranean diet was evaluated using a validated Mediterranean diet score (aMED). The strength of the association between aMED and knee MRI parameters was gauged using an adjusted linear regression analysis, expressed as standardized betas with 95% confidence intervals (CIs). Using an adjusted linear regression analysis, each increase of one standard deviation (SD) in the aMED corresponded to a significant increase in the central medial femoral cartilage volume (beta?=?0.12; 95%CI 0.09 to 0.15), in the mean central medial femoral cartilage thickness (beta?=?0.13; 95%CI 0.01 to 0.17), in the cartilage thickness of the mean central medial tibiofemoral compartment (beta?=?0.12; 95%CI 0.09 to 0.15), and in the cartilage volume of the medial tibiofemoral compartment (beta?=?0.09; 95%CI 0.06 to 0.12). Higher adherence to a Mediterranean diet was found to be associated with a significant improvement in knee cartilage as assessed by MRI, even after adjusting for potential confounding factors.     

Sequential changes in antibody levels to the ENV and GAG Antigens in human immunodeficiency virus infected subjects

Sera from 51 HTLV-III (human immunodeficiency virus, HIV)-antibody positive subjects consisting of 21 asymptomatic individuals and 15 ARC and 15 AIDS patients were analyzed for their serological profiles toward the viral antigens. One of the asymptomatic subjects only showed a p24 reactivity in the immunoblot, but antibodies to the env antigens were clearly identified by immunoprecipitation of viral antigens (RIP) followed by SDS-polyacrylamide gel electrophoresis. RIP patterns of different subjects and even different bleeds from the same subjects showed a varying reactivity to the gag antigens whereas the reactivity towards the env antigens appeared to be generally stable. RIP analysis of sequential sera of virus-infected individuals indicated a pattern consistent with an initial steady rise of antibody reactivities to the gag antigens relative to the reactivities to the envelope antigens. These reactivities reached a plateau and then slowly declined. While all sera tested had antibodies to the envelope antigens gp160, gp120 and gp4l, 86% of the asymptomatic subjects, 67% of the ARC patients and only 33% of the AIDS patients had antibodies to the gag proteins p24 and pr53gag.Corresponding author.