'Biogenerics': the off-patent biotech products

The first patents of biopharmaceuticals derived from recombinant DNA will expire shortly, which raises the possibility of marketing generic products ('biogenerics') with limited documentation, similar to that which occurs with conventional pharmaceuticals. We propose the term off-patent biotechnological products (OPBPs) as an alternative to biogenerics when describing such products. It is questionable whether the majority of OPBPs can be classified as similar to the innovator products, considering the size and complexity of the molecules and the many factors that influence biological activity. There are three classes of OPBPs, each of which needs to meet different regulatory demands when seeking marketing authorization.     

Simulation of the exposure to deoxynivalenol of French consumers of organic and conventional foodstuffs

The aim of this study was to estimate the exposure to deoxynivalenol in wheat of consumers of organic and conventional products using a probabilistic method, and to compare these levels with a toxicological reference so as to provide risk managers with scientific data to be used in the regulatory decision-making process. First, a product consumption frequency questionnaire was completed by consumers of organic products, thus providing data on the consumption of organic products. Data on the consumption of conventional products were obtained from the French "INCA" survey. Data on deoxynivalenol levels in wheat came from a previous study. The results of exposure simulations using the Monte-Carlo sampling method showed that 10% of those consuming organic wheat containing deoxynivalenol may be exposed to this natural toxin at levels above the provisional maximum tolerable daily intake.     

Development of a new class of nonimidazole histamine H(3) receptor ligands with combined inhibitory histamine N-methyltransferase activity

In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H(3) receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H(3) receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H(3) receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H(3) receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH(3), K(i) = 0.09 nM; HMT, IC(50) = 51 nM). This class of compounds showed high antagonist potency and good H(3) receptor selectivity in functional assays in guinea pig on H(1), H(2), and H(3) receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.     

Hereditary renal amyloidosis caused by a new variant lysozyme W64R in a French family

BACKGROUND: The number of proteins with mutations resulting in amyloidosis has continued to increase. Five proteins--transthyretin, fibrinogen alpha-A chain, apolipoprotein AI, lysozyme, apolipoprotein AII, cystatin C and gelsolin--can be associated with hereditary amyloidosis involving the kidney. METHODS: A French family with a history of autosomal dominant hereditary amyloidosis with early sicca syndrome and nephropathy leading to renal failure after the fifth to the seventh decade was studied. Several tissue specimens obtained from the proband and his relatives were examined. Immunohistochemistry was performed on paraffin embedded sections using the indirect immunoperoxidase technique. We searched for mutations in the five exons and flanking introns of the lysozyme gene. RESULTS: Amyloid deposits from the bowel, labial salivary gland and kidney were intensively stained by anti-lysozyme antibody. Sequence analysis of lysozyme exon 2 from the affected individuals revealed a nucleotide substitution predicting a substitution of the amino acid at position 64 in the mature protein from tryptophane, an aromatic residue to the cationic residue arginine (W64R). CONCLUSION: We report a novel mutation (W64R) of the lysozyme that is associated with hereditary amyloidosis and prominent nephropathy. Since the treatment of hereditary amyloidosis greatly varies with the nature of the amyloid protein, thorough characterization of the latter is crucial for the management of the disease.     

A CLA mixture prevents body triglyceride accumulation without affecting energy expenditure in Syrian hamsters

We examined the effects of feeding conjugated linoleic acids (CLA) to adult male hamsters on several components of energy metabolism and body composition. Hamsters (n = 54) were assigned for 6-8 wk to one of three diets: 1) a standard diet (in percentage energy: lipids, 33, carbohydrates, 49, and proteins, 18); 2) to the standard diet augmented with the 9c,11t-isomer of CLA to 1.6% of energy (R group); or 3) the standard diet augmented with the 9c,11t-isomer and the 10t,12c-CLA isomer to 3.2 (1.6 + 1.6) % of energy (CLA mix group). (15)N uniformly labeled milk-protein was included in the diet to measure the incorporation of dietary protein into liver and muscle. Basal metabolic rate, thermogenic response to feeding and energy expenditure during spontaneous activity or during an exercise at approximately 60% of VO(2max) were measured. Carnitine palmitoyltransferase-I (CPT-I), leptin, insulin and triiodothyronine concentrations, as well as the in vivo overall adiposity changes were also determined. After 6 wk, the whole-body triglyceride content determined in vivo by NMR was significantly higher in the R group than in the control and CLA mix groups. The CLA mix group differed from the others in the lack of body triglyceride accumulation between d 21 and d 45 of the study, and the appearance of a slight insulin-resistance (homeostatic model assessment index, P < 0.05). Paradoxically, the lack of effect on whole-body lipid oxidation was associated with a greater CPT-I-specific activity in tissues of both CLA-fed groups (P < 0.05). No other major effects of CLA feeding were detected. In conclusion, CLA supplementation in hamsters did not affect adipose weight or the components of energy expenditure despite a theoretically higher capacity of red muscle to oxidize lipids. Only a CLA mixture prevented whole-body triglyceride accumulation over time.     

The plasma and lipoprotein triglyceride postprandial response to a carbohydrate tolerance test differs in lean and massively obese normolipidemic women

The goal of the present study was to compare the plasma lipid responses of massively obese and lean women to a fat load and a carbohydrate load. For this purpose, 11 lean [body mass index (BMI), 21.6 +/- 2 kg/m(2)] and 8 obese (BMI, 50.8 +/- 7 kg/m(2)) normolipidemic women were given, in random order, either a dietary carbohydrate load (3.43 MJ, 166 g carbohydrates, 38 g proteins) or a dietary fat load (3.35 MJ, 70 g fat, 36 g proteins). Blood samples were collected hourly for 9 h after the test meal for measurements of triglyceride-rich lipoprotein (TRL)-lipid, apolipoprotein (apo)B-48 and apoB-100. Triglycerides (P < 0.0001), TRL triglycerides (P < 0.0001), TRL cholesterol (P < 0.04) and apoB-48 (P < 0.0001) peaked 3 h after the fat meal and returned progressively to baseline values in both obese women and lean controls. These lipid and apolipoprotein changes did not differ between the two groups. In contrast, after the carbohydrate load, the plasma triglyceride (P < 0.0001) and TRL triglyceride (P < 0.0001) increments were significantly greater in obese women than in lean controls. This carbohydrate-induced TRL triglyceride increment was half of that following the isocaloric fat load. The carbohydrate load did not affect apoB-100 and apoB-48 levels. These findings suggest that postprandial triglyceride metabolism is impaired after a carbohydrate load in normolipidemic massively obese women.     

p53 status and response to chemotherapy

Numerous studies deal with "p53 status" in patients' tumors (mutated/wild gene status, protein level and functionality) to predict chemotherapy efficacy. Analyses of various cancers, especially breast cancers, lead to controversy that is apparent due to heterogeneity of their design. Recent data from literature lead now to consider i) the nature of chemotherapeutic agents and the regimen, ii) the cancer tissue type, and iii) the histological response of the primary. Molecular actors of senescence, cytostasis and apoptosis, which are responsible of cytotoxic response of cancer cells, are currently under elucidation.     

Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients

OBJECTIVE: To compare the risk of ovarian failure and the fertility of women treated with intravenous cyclophosphamide (IVCY) according to the underlying inflammatory disease. METHODS: Review of the data of 84 consecutive women: 56 with systemic lupus erythematosus (SLE), 28 with other diseases, mainly Wegener's granulomatosis and systemic vasculitides. RESULTS: The mean age at IVCY initiation was 29 +/- 10 years (range 13-53). The mean dosage was 0.9 +/- 0.14 g per pulse (range 0.5-1), and the mean number of pulses 13 +/- 6.5 (range 3-42). With a mean followup of 5.1 +/- 3.7 years, 23 women developed amenorrhea, with a mean duration of 4 +/- 3.6 months between IVCY initiation and amenorrhea. Amenorrhea was sustained in 19 women (13 with SLE and 6 with other diseases, NS). The mean age at ovarian failure onset was 40 +/- 7.6 years. The risk of ovarian failure correlated with the age at IVCY institution (p < 0.0001), and was independent of underlying inflammatory disease. Eighteen women (13 with SLE and 5 with other diseases) became pregnant during or after CY therapy, with a total of 22 pregnancies. The mean age at IVCY initiation, and the mean number of IVCY (maximum 40 pulses) before pregnancy were similar in women with SLE and those with other diseases. Six pregnancies occurred during IVCY therapy, which ended in induced abortion (n = 3), spontaneous abortion (n = 1), and normal pregnancy after IVCY withdrawal (n = 2) in women who wished to keep their pregnancy despite the risk of teratogenicity. Sixteen pregnancies occurred 2.9 +/- 2.1 years (range 1-9) after IVCY withdrawal. They ended in: 3 induced abortions indicated for severe morphological anomalies (n = 2) and for SLE relapse (n = 1), 3 spontaneous miscarriages, and 10 deliveries of healthy newborns. CONCLUSION: The risk of ovarian failure depends essentially on the age at IVCY initiation. Pregnancy may occur during IVCY therapy, and an efficient contraception is mandatory. After IVCY withdrawal, pregnancy is possible with a favorable outcome in two-thirds of the cases.