Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis.

BACKGROUND: POL6014 is a novel, orally inhaled neutrophil elastase (NE) inhibitor in development for cystic fibrosis (CF). METHODS: Two studies, one in healthy volunteers (HVs, doses 20 to 960 mg) and one in subjects with CF (doses 80 to 320 mg) were conducted to evaluate the safety, tolerability and pharmacokinetics (PK) of single ascending doses of inhaled POL6014 with a Pari eFlow® nebuliser. PK was evaluated over a period of 24 h. In addition, NE activity in CF sputum was measured. RESULTS: After single doses, POL6014 was safe and well tolerated up to 480 mg in HVs and at all doses in subjects with CF. POL6014 showed a dose-linear PK profile in both populations with Cmax between 0.2 and 2.5 µM in HVs and between 0.2 and 0.5 µM in subjects with CF. Tmax was reached at approximately 2-3 h. Mean POL6014 levels in CF sputum rapidly reached 1000 µM and were still above 10 µM at 24 h. >1-log reduction of active NE was observed at 3 h after dosing. CONCLUSION: Inhalation of POL6014 can safely lead to high concentrations within the lung and simultaneously low plasma concentrations, allowing for a clear inhibition of NE in the sputum of subjects with CF after single dosing. TRIAL REGISTRATION: European Medicines Agency EudraCT-Nr. 2015-001618-83 and 2016-000493-38.

Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing.

Pridopidine is being developed for the treatment of impaired motor function associated with Huntington's disease and belongs to a new class of compounds known as dopidines, which act as dopaminergic stabilizers. In vitro studies have shown that pridopidine is a substrate for the P450 cytochrome 2D6 enzyme (CYP2D6), and clinical data show that the half-life of pridopidine is different following single dosing versus at steady state. To further investigate the pharmacokinetic profile of pridopidine and to establish whether dose adjustment is needed in poor CYP2D6 metabolizers, a single-centre, open-label, multiple-dose study in healthy volunteers was performed. In total, 24 extensive CYP2D6 metabolizers (EMs) and 12 poor CYP2D6 metabolizers (PMs) were enrolled. Both groups received 45 mg pridopidine twice daily (b.i.d.). Plasma samples were taken during the first day of b.i.d. dosing (Day 1) and at steady state, following 14 days of b.i.d. dosing. At Day 1, total exposure in PMs was almost three times higher than those in EMs (AUC0-∞ = 11,192 and 3,782 h·ng/mL, respectively; PM/EM ratio = 2.96; p < 0.001). However, at steady state, PMs and EMs had comparable exposure due to a reduction in pridopidine elimination in EMs over time. Thus, at steady-state peak (C max) and total (AUC0-24) exposures were only 1.24 and 1.29 times higher, respectively, in PMs than EMs. These results support that pridopidine is a CYP2D6 auto-inhibitor. Pridopidine was well tolerated in both EMs and PMs. The slightly higher exposure level in PMs at steady state does not indicate a need for dose adjustment or genotyping for CYP2D6 metabolizer status.

A randomized study of tiotropium Respimat Soft Mist inhaler vs. ipratropium pMDI in COPD.

The aim of these studies was to compare the efficacy and the safety of tiotropium, delivered via Respimat Soft Mist Inhaler (SMI), a novel multi-dose, propellant-free inhaler, with ipratropium pressurized metered-dose inhaler (pMDI) in chronic obstructive pulmonary disease (COPD) patients. Two identical, 12-week, multi-national, randomized, double-blind, double-dummy, parallel-group, active- and placebo-controlled studies were performed. COPD patients were randomized to treatment with either inhaled tiotropium (5 or 10 microg) via Respimat SMI administered once daily, ipratropium (36 microg) pMDI QID or placebo. The primary endpoint was the mean trough forced expiratory volume in 1s (FEV(1)) response after 12 weeks of treatment. Secondary endpoints included other spirometry measures and rescue medication use. A total of 719 patients were randomized; the majority were male (69%) with a mean pre-bronchodilator FEV(1) (% predicted) of 40.7%. The mean treatment differences between tiotropium 5 and 10 microg and placebo for the primary endpoint (mean trough FEV(1) response at week 12) were 0.118 and 0.149L, respectively (both P<0.0001). Treatment differences between tiotropium 5 and 10 microg and ipratropium were 0.064L (P=0.006) and 0.095L (P<0.0001). The increases in peak FEV(1), FEV(1) AUC((0-6h)) and FVC for both tiotropium doses were statistically superior to placebo (P<0.01) and higher than ipratropium. All active treatments significantly reduced the rescue medication use compared with placebo, but only tiotropium 10 microg was statistically superior to ipratropium (P=0.04). The incidence of adverse events was comparable across groups. In conclusion, tiotropium 5 and 10 microg daily, delivered via Respimat SMI, significantly improved lung function compared with ipratropium pMDI and placebo.

The phosphodiesterase 4 inhibitor roflumilast is effective in the treatment of allergic rhinitis.

BACKGROUND: The beneficial effects of phosphodiesterase 4 (PDE4) inhibitors in allergic asthma have been shown in previous preclinical and clinical studies. Because allergic rhinitis and asthma share several epidemiologic and pathophysiologic factors, PDE4 inhibitors might also be effective in allergic rhinitis. OBJECTIVE: The main objective of this study was to investigate the efficacy of oral roflumilast (500 microg/day) in allergic rhinitis. METHODS: In a randomized, placebo-controlled, double-blinded, crossover study, 25 subjects (16 male, 9 female; median age, 28 years) with histories of allergic rhinitis but asymptomatic at screening received roflumilast (500 microg once daily) and placebo for 9 days each with a washout period of at least 14 days in between treatment periods. In each of the treatment periods, controlled intranasal allergen provocation with pollen extracts was performed daily beginning the third day of treatment, each time approximately 2 hours after study drug administration. Five and 30 minutes after each allergen provocation, rhinal airflow was measured by means of anterior rhinomanometry and the subjective symptoms obstruction, itching, and rhinorrhea were assessed by means of a standardized visual analog scale. RESULTS: Rhinal airflow improved almost consistently during the 9 days of roflumilast treatment, and it was significantly higher at study day 9 on roflumilast in comparison with placebo, a result also found for itching and rhinorrhea. With respect to the subjective obstruction score, a significant difference in comparison with placebo could be demonstrated within 4 days. CONCLUSION: This study shows that a PDE4 inhibitor, roflumilast, effectively controls symptoms of allergic rhinitis. Thus PDE4 inhibitors might be a future treatment option not only in allergic asthma but also in allergic rhinitis or the combination of the 2 diseases.

Effect of vegetable and carotenoid consumption on aberrant crypt multiplicity, a surrogate end-point marker for colorectal cancer in azoxymethane-induced rats.

Epidemiological studies indicate that increased vegetable consumption reduces the risk of colorectal cancer mortality. In the present study we have investigated the effect of consumption of standard diets supplemented with freeze-dried vegetables (peas, spinach, sprouts and broccoli) and carotenoids (all-trans beta-carotene and palm oil carotenoid extract) on surrogate end-point markers for colorectal cancer in an azoxymethane-induced rat model. Mean aberrant crypt multiplicity was reduced (19%) by the pea-supplemented diet only (P < 0.05). The vegetable-induced effect was more apparent in aberrant crypt foci with higher multiplicity. Intervention with diets supplemented with peas, spinach, sprouts and a mix of all vegetables reduced the number of foci with >2 aberrant crypts/focus by 37, 26, 23 and 26%, respectively (P < 0.05). Even more pronounced effects were observed in foci with >3 aberrant crypts/focus, with reductions of approximately 50% in the pea and spinach intervention groups. All-trans beta-carotene and palm oil-derived carotenoids, supplied at similar doses to those expected in the vegetable diets, inhibited ACM only marginally. Aberrant crypt foci formation in groups fed a sprout-supplemented diet prior to or following azoxymethane treatment was similar, indicating that this effect is due to inhibition of promotion rather than initiation of colorectal carcinogenesis. Vegetable and carotenoid consumption did not affect in situ proliferation of colonic crypt cells, as assessed by semi-automated image analysis of bromodeoxyuridine (BrdU)-positive nuclei. BrdU-negative nuclei of colonic crypt cells were reduced slightly in the combined vegetable groups, as compared with the control (P < 0.05). These data: (i) are in line with epidemiological evidence regarding beneficial effects of vegetable consumption on colorectal carcinogenesis; (ii) indicate that consumption of several types of vegetables inhibits early post-initiation events in colorectal carcinogenesis; (iii) suggest that the vegetable-induced effect is more pronounced in advanced lesions; (iv) indicate that the carotenoid content of the vegetables (alpha- and beta-carotene) contributes only marginally to the vegetable-induced effects.

The new topical steroid ciclesonide is effective in the treatment of allergic rhinitis.

A randomized, placebo-controlled, double-blind crossover study was performed to investigate the efficacy of ciclesonide nasal spray in allergic rhinitis at the dose level of 200 micrograms per nostril. Twenty-four subjects (13 males, 11 females; median age: 28 years) with a history of allergic rhinitis but free of symptoms at screening entered the study. Ciclesonide and placebo were given for 7 days each with a washout period of at least 14 days in between. In both treatment periods, controlled intranasal allergen provocation with pollen extracts was performed on the 2 days before start of treatment (days -2 and -1) and on all treatment days (days 1 to 7) about 2 hours after administration of the study medication. At 5 and 30 minutes after each allergen provocation, rhinal airflow was measured by anterior rhinomanometry, and the subjective symptoms of obstruction, itching, and rhinorrhea were assessed by means of a standardized visual analog scale. Rhinal airflow improved significantly from day 5, while the subjective symptom of obstruction improved from day 2. Itching and rhinorrhea also improved significantly. The local and systemic tolerability of ciclesonide nasal spray was excellent. The results of this study clearly indicate that the new topical steroid ciclesonide is effective in the treatment of allergic rhinitis without producing local or systemic side effects.

Equipotent inhibition of gastric acid secretion by equal doses of oral or intravenous pantoprazole.

BACKGROUND: Pantoprazole is a proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 system, and linear pharmacokinetics. The recommended oral dose for treatment of acid-related diseases is 40 mg. METHODS: Using a randomized, crossover study design we compared the ability of 40 mg oral and intravenous pantoprazole to elevate the intragastric pH in healthy volunteers (n = 20, 'per protocol'), during two treatment phases. The duration of each phase was 5 days. Pantoprazole 40 mg was administered once daily either as a tablet or as an intravenous injection. A 24 h pHmetry was used to record the intragastric pH on day 5 of each regimen; this was compared to the baseline curve obtained before each study period. The calculated 90% confidence intervals (90% CI) represent the mean difference in the intragastric pH, attained after intravenous or oral administration. The predefined equivalence range for the 90% CI was +/- 20% for the percentage time at which the gastric pH was at least pH 3 or 4 and +/- 1 unit for the median pH. RESULTS: Pantoprazole was well tolerated during both treatment phases. The mean of the 24 h median pH was 3.3 and 3.1 for the intravenous and oral treatments, respectively; the corresponding differences were 0.2 (90% CI: - 0.03 to 0.44). For the mean percentage time at which the pH was 3 or above, the respective calculated values were 57% and 51%, with a difference between the two administration routes of only 5.7% (90% CI: 1.8 to 9.6). At an intragastric pH of 4 or above, the mean percentage time was 420% and 38% following intravenous and oral treatment, respectively, with a difference between the treatment routes of only 4.4% (90% CI: 0.6 to 8.3). CONCLUSIONS: These results imply that the two formulations of pantoprazole can be assumed to be equipotent. Hence, the intravenous formulation of pantoprazole could be considered as an alternative route of administration.

The association of increasing dietary concentrations of fish oil with hepatotoxic effects and a higher degree of aorta atherosclerosis in the ad lib.-fed rabbit.

The long-term effects of consumption of marine long-chain n-3 polyunsaturated fatty acids (PUFA) on atherosclerosis in the rabbit were examined. Female Dutch rabbits were fed purified diets, containing 40 energy% total fat, for a period of 2.5 years. To study the dose response relationship between fish oil intake and atherosclerosis, four diets were formulated with fish oil levels being 0, 1, 10 and 20 energy%. A fifth and sixth group were fed an alpha-linolenic acid-(C18:3, n-3) and linoleic acid-(C18:2, n-6) rich diet, respectively. Every 6 weeks, blood samples were taken for determination of clinical chemical parameters, triacylglycerol and total cholesterol levels. Feeding 10 and 20 energy% fish oil containing diets, resulted in an increase of liver enzymes (AST, ALT and ALP). Histological evaluation of the liver also revealed adverse effects of fish oil containing diets. Triacylglycerol blood levels were similar in all groups, and remained constant throughout the study. Total cholesterol levels in blood was significantly lower in the animals fed a linoleic acid-rich diet, as compared with the other five groups. An n-3 long-chain PUFA concentration dependent increase in aorta plaque surface area was observed in the fish oil groups. A significant positive relationship was found between the group mean score for severity of liver pathology and the aorta plaque surface area. These results indicate that the long-chain n-3 polyunsaturated fatty acids in fish oil may be hepatotoxic to the herbivorous rabbit, which may interfere with the outcome of atherosclerosis studies. This finding necessitates the exclusion of liver pathology in experimental studies on atherosclerosis in animal models.

Concomitant administration of the alpha-glucosidase inhibitor voglibose (AO-128) does not alter the pharmacokinetics of glibenclamide.

OBJECTIVE: Voglibose is a new and potent inhibitor of alpha-glucosidases used for treatment of diabetes mellitus. It increases gastro-intestinal motility and could thus affect absorption of other concurrently administered antidiabetic drugs. The aim of this study was to investigate whether or not voglibose modifies the pharmacokinetics of glibenclamide, a widely used oral antidiabetic, and the glibenclamide-induced decrease in fasting serum glucose. METHODS: Twelve healthy male subjects were included in this double-blind cross-over study and received a single 1.75-mg dose of glibenclamide on the 8th day of continuous administration of either placebo (reference) or voglibose 5 mg t.i.d. (test). Blood samples were taken to determine the pharmacokinetic characteristics of glibenclamide and the test/reference ratios were evaluated according to bioequivalence criteria. Additional blood samples were taken to measure serum glucose on the same day. RESULTS: The concentration-time course of glibenclamide under concomitant voglibose administration was similar to that under placebo. The equivalence ratio (test/reference) for the pharmacokinetic characteristics AUCnorm was 1.03 (geometric mean; 0.95-1.11, 90% confidence interval) and Cmax.norm 1.01 (0.94-1.08). The parameters were within the accepted range of 0.8-1.25 (AUC) or 0.7-1.43 (Cmax), thus fulfilling equivalence criteria and indicating no effect of voglibose on glibenclamide kinetics. The glibenclamide-induced decrease in fasting serum glucose concentration was similarly independent of placebo or voglibose co-administration. CONCLUSIONS: Voglibose did not interact with glibenclamide on a pharmacokinetic level. Concomitant treatment was well tolerated and has been proven to be safe for further clinical use.

24-hour recording of intragastric pH in clinical trials: preconditions, methodology, and standardization strategies.

At present, intragastric pH recording by stomach probe is the standard method for the assessment of the pharmacodynamic effect of newly developed antisecretory drugs, and it is being used increasingly as a diagnostic method. Intraluminal pH can be measured by a variety of different electrode systems, systematic differences among these systems require international standardization of the method. In clinical trials, some recommendations should be followed to standardize the study conditions to assure that repeated measurements are comparable. Standardization of food and liquid intake and a correct positioning of the stomach probe are of paramount importance in assuring that the data are reliable; but there are other factors that may influence the study results, for example, the daily activities of the study participants and the method of data processing. Furthermore, several technical aspects must be considered to guarantee accurate and reproducible recordings, including the type of pH-sensitive electrode and the method of calibration used. Further efforts should be made to create an international standard for the method to assure more comparable study results.

Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man.

OBJECTIVE: Pantoprazole is a selective proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzymes in man. Due to the clinical importance of an interaction with anticoagulants, this study was carried out to investigate the possible influence of pantoprazole on the pharmacodynamics and pharmacokinetics of phenprocoumon. METHODS: Sixteen healthy male subjects were given individually adjusted doses of phenprocoumon to reduce prothrombin time ratio (Quick method) to about 30-40% of normal within the first 5-9 days and to maintain this level. The individual maintenance doses remained unaltered from day 9 on and were administered until day 15. Additionally, on study days 11-15, pantoprazole 40 mg was given per once daily. As a pharmacodynamic parameter, the prothrombin time ratio was determined on days 9 and 10 (reference value) and on days 14 and 15 (test value), and the ratio test/reference was evaluated according to equivalence criteria. RESULTS: The equivalence ratio (test/reference) for prothrombin time ratio was 1.02 (90% confidence interval 0.95-1.09), thus fulfilling predetermined bioequivalence criteria (0.70-1.43). The pharmacokinetic characteristics AUC0-24h and Cmax of S(-)- and R(+)-phenprocoumon were also investigated using equivalence criteria. Equivalence ratios and confidence limits of AUC0-24h and of Cmax of S(-)-phenprocoumon (0.93, 0.87-1.00 for AUC0-24h; 0.95, 0.88-1.03 for Cmax) and of R(+)-phenprocoumon (0.89, 0.82-0.96; 0.9, 0.83-0.98) were within the accepted range of 0.8-1.25. CONCLUSION: Pantoprazole does not interact with the anticoagulant phenprocoumon on a pharmacodynamic or pharmacokinetic level. Concomitant treatment was well tolerated.

Effects of two dietary fat levels and four dietary linoleic acid levels on mammary tumor development in Balb/c-MMTV mice under ad libitum feeding conditions.

The relationship between dietary fat intake (level and type) and the development of breast cancer in humans is a matter of concern in Western society. A high fat intake is associated with a greater mammary cancer risk in humans and in animal models. Higher intake of polyunsaturated fatty acids in humans shows little or no association with mammary tumor development in epidemiologic surveys. From literature data, it appears that a higher intake of polyunsaturated fatty acids (linoleic acid) is related to an increase in mammary tumorigenesis in animal studies in which chemical carcinogens like dimethylbenz[a]anthracene are used as tumor initiator. Mostly the latency period of these chemically induced models in rather short. In this study, the Bald/c-MMTV (mouse mammary tumor virus) mouse strain was chosen as an animal model: MMTV leads to tumor initiation, and dietary factors influence tumor promotion over a relatively long latency period. The mice were fed diets with two fat concentrations: a high [36% of energy (en%)] or low (16 en%) fat level; fat was isocalorically replaced by carbohydrates (cornstarch). At both dietary fat levels, linoleic acid was given at four levels: 2, 3, 6, and 10 en%. Linoleic acid-rich fat was isocalorically replaced by oleic acid-rich fat. The diets were consumed ad libitum over a lifetime. Animals were euthanized as soon as mammary tumor diameter was > or = 1 cm or when the animals were in a poor clinical condition. The incidence of mammary tumors at 18 months was significantly higher in one group only: 36 en% fat and 2 en% linoleic acid. This group also showed the shortest mean latency period for mammary tumor development. Mean mammary tumor incidence was higher and mean onset time shorter in the four high-fat groups than in the low-fat groups. No (linear) dose-response relationship between dietary linoleic acid concentration and mammary tumor incidence and latency period was observed. This indicates that a higher dietary linoleic acid intake does not increase the incidence or shorten the latency period of breast cancer in the Balb/c-MMTV mouse strain at two different dietary fat levels.

Effect of four lansoprazole dose levels and one dosage regimen of omeprazole on 24-hour intragastric pH in healthy subjects.

Lansoprazole is a potent proton pump inhibitor and blocks gastric acid secretion. The potency of many antibiotics in eradicating Helicobacter pylori may be considerably enhanced by increasing the intragastric pH due to a twice-daily coadministration of proton pump inhibitors. This double-blind crossover study was designed to compare the effect on intragastric pH of four dose regimens of lansoprazole (30 mg o.a.d., 30 mg b.i.d., 45 mg b.i.d., 60 mg b.i.d.) after 5 days of treatment and to investigate whether an increment of lansoprazole dose level leads to a more pronounced effect. Omeprazole 20 mg b.i.d. was administered as a reference drug. The study was carried out in 20 healthy male subjects. Intragastric pH was recorded by a nasogastric probe over 24 h. All dose regimens of lansoprazole were well tolerated and no unexpected drug-related adverse events were observed. The lowest lansoprazole dose level, 30 mg o.a.d. already increased intragastric pH considerably. This effect was even enhanced by increase of the lansoprazole dose as assessed by mean pH as well as percentage of time spent above different pH values. The increase in effect with lansoprazole dose increment from 30 mg b.i.d. to 60 mg b.i.d. was only very small. The time spent at pH values above or equal to 3 after b.i.d. administration was slightly higher with all lansoprazole dose levels compared to omeprazole. The time spent at intragastric pH values above or equal to 5 after b.i.d. oral administration of 30 mg, 45 mg and 60 mg lansoprazole was comparable to that observed after b.i.d. oral administration of 20 mg omeprazole, so that it may be recommended to use lansoprazole 30 mg b.i.d. as a treatment equivalent to omeprazole 20 mg b.i.d. for eradication of Helicobacter pylori in combination with antibiotics.

Furocoumarin-photosensitized hydroxylation of guanosine in RNA and DNA.

Guanosine hydroxylation was used as a marker for assessing photooxidation of DNA and RNA sensitized by monofunctional and bifunctional furocoumarins. DNA or RNA, treated with sensitizer and UVA light, was enzymatically hydrolyzed, dephosphorylated and then analyzed by reversed-phase HPLC with electrochemical detection. Hydroxylated guanosine, i.e. 8-hydroxy-2'-deoxyguanosine (8-OHdG) or 8-hydroxyguanosine (8-OHG), was quantitated. 3-Carbethoxypsoralen (3-CP) was found to be an efficient photosensitizer for oxidation of guanosine in DNA, resulting in conversion of up to 0.4% of guanosine residues to 8-OHdG. In contrast, dramatically lower levels of guanosine hydroxylation were observed in 3-CP-photosensitized RNA. Psoralen was found to be a more efficient photosensitizer than angelicin in both DNA and RNA. Additional studies of oxidation of 3-CP-photosensitized DNA indicated that double-stranded DNA is 10 times more susceptible to photooxidation than single-stranded DNA, implicating 3-CP binding to DNA as an important mechanistic step in photooxidation of guanosine. The effects of D2O and degassing with argon on photooxidation of guanosine in DNA sensitized by 3-CP were inconsistent with a mechanism involving 1O2. In addition, chelation of adventitious metal ions present in preparations of DNA photosensitized by 3-CP had no effect on hydroxylation of guanosine.

Mutational analysis of the p50 subunit of NF-kappa B and inhibition of NF-kappa B activity by trans-dominant p50 mutants.

The NF-kappa B family of DNA-binding proteins regulates the expression of many cellular and viral genes. Each of these proteins has an N-terminal region that is homologous to the c-Rel proto-oncogene product, and this Rel homology region defines both DNA binding and protein dimerization properties of the individual proteins. Most of the NF-kappa B family members have been shown to associate with themselves or with each other to form homodimers or heterodimers, and previous studies have shown that dimerization of NF-kappa B factors is necessary to provide a functional DNA binding domain. We have used site-directed mutagenesis to identify regions in the Rel homology domain of the p50/NF-kappa B protein that are important for DNA binding and protein dimerization. Our studies have identified mutations of p50 that interfere with DNA binding only and those that interfere with protein dimerization. Mutations of p50 which disrupt only DNA binding were still able to associate with other members of the NF-kappa B protein family. We demonstrate that such heterodimeric complexes inhibit transcriptional activation mediated in trans through a cis-acting kappa B motif; therefore, we have identified trans-dominant negative mutants of p50.

Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor alpha by transcriptional and post-transcriptional mechanisms.

The immunoregulatory cytokine interleukin 6 (IL-6) directly upregulates production of human immunodeficiency virus (HIV) in acutely as well as in chronically infected cells of monocytic lineage. In addition, IL-6 synergizes with tumor necrosis factor alpha (TNF-alpha) in the induction of latent HIV expression. Unlike TNF-alpha, upregulation of viral expression induced by IL-6 alone does not occur at the transcriptional level and it is not associated with accumulation of HIV RNA. However, when IL-6 and TNF-alpha synergistically stimulate HIV production, accumulation of HIV RNA and increased transcription are observed, indicating that IL-6 affects HIV expression at multiple (transcriptional and post-transcriptional) levels.

[Coccidiosis in lambs: observations in the preventive use of an amprolium-containing medicated feed]. / Coccidiose bij lammeren: waarnemingen bij het preventieve gebruik van een amprolium bevattend gemedicineerd krachtvoer.

The efficacy of preventive in-feed medication with amprolium (2000 ppm) was studied on a farm where clinical coccidiosis in unweaned lambs at pasture has been a problem for the past seven years. Both treated and untreated control lambs had access to the concentrates through creep feeding. In this clinical trial neither the treated group (15-17 mg of amprolium per kg body weight per day for three weeks) nor the control group showed clinical symptoms of coccidiosis. It seems likely that this is attributable to the feeding of concentrates. Nevertheless, the excretion of oocysts by the animals of the treated group was significantly lower than that of the control group. An outbreak of clinical coccidiosis in another group of lambs on this farm was successfully controlled by single drenching, 50 mg.kg-1, followed by the medicated feed. The pharmaceutical availability of amprolium in the concentrates was 95 +/- 1% immediately after preparation and the stability during storage under field conditions for two months was 100% +/- 2%.

Nutritional evaluation of low-erucic-acid rapeseed oils.

Detailed morphometric studies performed in heart tissue from Swiss mice and Wistar rats show that, in comparison with other edible oils, long-term feeding of the new rapeseed oils, poor in erucic acid, do not significantly affect the incidence of myocardial background lesions, in contrast to high-erucic-acid rapeseed oil. The strong predisposition of the Sprague-Dawley rat, however, to develop myocardial necrosis is re-emphasized. The factors underlying this particularity need further clarification. The data presented and the available evidence from experiments involving pigs, monkeys and poultry show that a reduction of the content of erucic acid in rapeseed lipids, as has been achieved by selective plant breeding, considerably improves the nutritional status of the cruciferous oils.