Aluminium in plasma and tissues after intramuscular injection of adjuvanted human vaccines in rats.

Aluminium (Al) toxicokinetics after intramuscular (IM) injection of Al-adjuvanted vaccines is unknown. Since animal data are required for modeling and extrapolation, a rat study was conducted measuring Al in plasma and tissues after IM injection of either plain Al-hydroxide (pAH) or Al-phosphate (pAP) adjuvant (Al dose 1.25 mg), single human doses of three Al-adjuvanted vaccines (V1, V2, and V3; Al doses 0.5-0.82 mg), or vehicle (saline). A significant increase in Al plasma levels compared to controls was observed after pAP (AUC(0-80 d), mean ± SD: 2424 ± 496 vs. 1744 ± 508 µg/L*d). Percentage of Al dose released from injected muscle until day 80 was higher after pAP (66.9%) and AP-adjuvanted V3 (85.5%) than after pAH and AH-adjuvanted V1 (0 and 22.3%, resp.). Estimated absolute Al release was highest for pAP (836.8 µg per rat). Al concentration in humerus bone was increased in all groups, again strongest in the pAP group [3.35 ± 0.39 vs. 0.05 ± 0.06 µg/g wet weight (ww)]. Extrapolated amounts in whole skeleton corresponded to 5-12% of the released Al dose. Very low brain Al concentrations were observed in all groups (adjuvant group means 0.14-0.29 µg/g ww; control 0.13 ± 0.04 µg/g ww). The results demonstrate systemically available Al from marketed vaccines in rats being mainly detectable in bone. Al release appears to be faster from AP- than AH-adjuvants. Dose scaling to human adults suggests that increase of Al in plasma and tissues after single vaccinations will be indistinguishable from baseline levels.

[Critical analysis of reference studies on aluminium-based adjuvants toxicokinetics]. / Adjuvants aluminiques des vaccins : analyse critique des études toxicocinétiques de référence.

We reviewed the three reference toxicokinetic studies commonly used to suggest innocuity of aluminum (Al)-based adjuvants. A single experimental study was carried out using isotopic 26Al (Flarend et al., 1997). This study ignored adjuvant cell capture. It was conducted over a short period of time (28 days) and used only two rabbits per adjuvant. At the endpoint, Al retention was 78% for aluminum phosphate and 94% for aluminum hydroxide, both results being incompatible with quick elimination of vaccine-derived Al in urines. Tissue distribution analysis omitted three important retention sites: the injected muscle, the draining lymph node and bone. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to the oral Minimal Risk Level (MRL) extrapolated from animal studies. Keith et al., 2002 used a too high MRL (2mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (2011) only considered absorbed Al, with erroneous calculations of absorption duration. They ignored particulate Al captured by immune cells, which play a role in systemic diffusion and the neuro-inflammatory potential of the adjuvant. MRL they used was both inappropriate (oral Al vs injected adjuvant) and far too high (1mg/kg/d) with regard to experimental studies of Al-induced memory and behavioral changes. Both paucity and serious weaknesses of these studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including post-natal and adult exposures, to ensure innocuity and restore population confidence in Al-containing vaccines.

Prediction of drug interaction between oral adsorbent AST-120 and concomitant drugs based on the in vitro dissolution and in vivo absorption behavior of the drugs.

PURPOSE: AST-120 is used to decrease the abundance of serum uremic toxins in treatment of chronic kidney disease; however, it could also adsorb concomitantly administered drugs. This study aimed to develop a prediction method for drug interaction between AST-120 and concomitantly administered drugs based on in vitro dissolution and in vivo absorption behavior. METHODS: Sixty-eight drugs were selected for the analysis. For each drug, theoretical dissolution (R d) and absorption (R a) rates at estimated dosing intervals (1, 30, 60, 90, 120, and 240 min) were calculated using the Noyes-Whitney formula and compartment analysis, respectively. The optimal thresholds for R d and R a (R dth and R ath) were estimated by comparing the results with those of previous drug interaction studies for six drugs. Four drug interaction risk categories for 68 drugs at each dose interval were defined according to the indices of dissolution and absorption against their thresholds. RESULTS: The in vitro dissolution and in vivo absorption behavior of the selected drugs were well fitted to the Noyes-Whitney formula and one- or two-compartment models. The optimal R dth and R ath that gave the highest value of consistency with the equivalence of drug interaction studies were 90 and 30 %, respectively. As the dosing intervals were lengthened, the number of drugs classified into the low-risk categories increased. CONCLUSION: A new drug interaction prediction method based on the pharmacokinetic parameters of drugs was developed. The new model is useful for estimating the risk of drug interaction in clinical practice when AST-120 is used in combination with other drugs.

Safety Assessment of Alumina and Aluminum Hydroxide as Used in Cosmetics.

This is a safety assessment of alumina and aluminum hydroxide as used in cosmetics. Alumina functions as an abrasive, absorbent, anticaking agent, bulking agent, and opacifying agent. Aluminum hydroxide functions as a buffering agent, corrosion inhibitor, and pH adjuster. The Food and Drug Administration (FDA) evaluated the safe use of alumina in several medical devices and aluminum hydroxide in over-the-counter drugs, which included a review of human and animal safety data. The Cosmetic Ingredient Review (CIR) Expert Panel considered the FDA evaluations as part of the basis for determining the safety of these ingredients as used in cosmetics. Alumina used in cosmetics is essentially the same as that used in medical devices. This safety assessment does not include metallic or elemental aluminum as a cosmetic ingredient. The CIR Expert Panel concluded that alumina and aluminum hydroxide are safe in the present practices of use and concentration described in this safety assessment.

Oral absorption and drug interaction kinetics of moxifloxacin in an animal model of weightlessness.

To investigate the effect of simulated weightlessness on the pharmacokinetics of orally administered moxifloxacin and the antacid Maalox or the antidiarrheal Pepto-Bismol using a tail-suspended (TS) rat model of microgravity. Fasted control and TS, jugular-vein-cannulated, male Sprague-Dawley rats received either a single 5 mg/kg intravenous dose or a single 10 mg/kg oral dose of moxifloxacin alone or with a 0.625 mL/kg oral dose of Maalox or a 1.43 mL/kg oral dose of Pepto-Bismol. Plasma concentrations of moxifloxacin were measured by HPLC. Pharmacokinetic data were analyzed using WinNonlin. Simulated weightlessness had no effect on moxifloxacin disposition after intravenous administration but significantly decreased the extent of moxifloxacin oral absorption. The coadministration of moxifloxacin with Maalox to either control or TS rats caused significant reductions in the rate and extent of moxifloxacin absorption. In contrast, the coadministration of moxifloxacin with Pepto-Bismol to TS rats had no significant effect on either the rate or the extent of moxifloxacin absorption. These interactions showed dose staggering when oral administrations of Pepto-Bismol and moxifloxacin were separated by 60 min in control rats but not in TS rats. Dose staggering was more apparent after the coadministration of Maalox and moxifloxacin in TS rats.

The REACH registration process: A case study of metallic aluminium, aluminium oxide and aluminium hydroxide.

The European Union's REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.

Detection of aluminum in lumbar spinal cord of sheep subcutaneously inoculated with aluminum-hydroxide containing products.

The use of vaccines containing aluminum (Al) adjuvants is widespread in ovine production. Al adjuvants induce an effective immune-response but lead to the formation of post-vaccination granulomas from which Al can disseminate. This work aims to study the accumulation of Al in the central nervous system of sheep subcutaneously inoculated with Al-hydroxide containing products. Lumbar spinal cord and parietal lobe from 21 animals inoculated with 19 doses of Vaccine (n = 7), Adjuvant-only (n = 7) or phosphate-buffered saline as Control (n = 7) were analyzed with transversely heated graphite furnace atomic absorption spectroscopy and lumogallion staining for Al analytical measurements and Al tisular localization respectively. In the lumbar spinal cord, Al median content was higher in both the Adjuvant-only and Vaccine group (p = .001) compared with the Control group. Animals of the Adjuvant-only group showed the higher individual measurements in the lumbar spinal cord (14.36 µg/g and 7.83 µg/g). In the parietal lobe, Al median content tended to be higher in the Adjuvant-only group compared with Control group (p = .074). Except for three replicates of the Adjuvant-only group, Al content was always below 1 µg/g. In the lumbar spinal cord, lumogallion-reactive Al deposits were more abundant in the gray matter than in the white matter in both Vaccine (p = .034) and Adjuvant-only groups (p = .017) and Al deposits were mostly associated with glial-like cells (p = .042). In the parietal lobe, few Al deposits, which were sometimes related to blood vessels, were found. In sheep, Al-hydroxide adjuvants inoculated in the subcutaneous tissue selectively accumulate in the lumbar spinal cord.

Retrospective analysis of 4-week inhalation studies in rats with focus on fate and pulmonary toxicity of two nanosized aluminum oxyhydroxides (boehmite) and pigment-grade iron oxide (magnetite): the key metric of dose is particle mass and not particle surface area.

This paper compares the pulmonary toxicokinetics and toxicodynamics of three different types of poorly soluble dusts examined in repeated rat inhalation bioassays (6h/day, 5 days/week, 4 weeks). In these studies the fate of particles was studied during a 3-6-month postexposure period. This retrospective analysis included two types of aluminum oxyhydroxides (AlOOH, boehmite), high purity calcined, and agglomerated nanosized aluminas of very low solubility with primary isometric particles of 10 or 40nm, and synthetic iron oxide black (Fe(3)O(4) pigment grade). Three metrics of dose (actual mass concentration, surface area concentration, mass-based lung burden) were compared with pulmonary toxicity characterized by bronchoalveolar lavage. The results of this analysis provide strong evidence that pulmonary toxicity (inflammation) corresponds best with the mass-based cumulative lung exposure dose. The inhalation study with a MMAD of approximately 0.5microm yielded a higher pulmonary dose than MMADs in the range of 1-2microm, a range most commonly used in repeated exposure inhalation studies. Hence, a key premise for the dosimetric adjustment across species is that comparable lung tissue doses should cause comparable effects. From that perspective, the determination of mass-based pulmonary lung burdens appears to be amongst the most important and critical nominator of dose and dose-related pulmonary toxicity.

One-pot synthesis and characterization of ovalbumin-conjugated gold nanoparticles: A comparative study of adjuvanticity against the physical mixture of ovalbumin and gold nanoparticles.

Only few adjuvants are licensed for use in humans and there is a need to develop safe and improved vaccine adjuvants. In this study, we report the one-pot synthesis of antigen ovalbumin (OVA)-conjugated gold nanoparticles (OVA@GNPs). A systematical study was performed by comparing OVA@GNPs with the simple mixture of OVA and gold nanoparticles (OVA+GNPs), including their physiochemical properties through spectrometric and electrophoretic analysis, in vitro stability, cytotoxicity and cellular uptake, and in vivo humoral immune responses following subcutaneous and transcutaneous immunization in mice. The results demonstrate a much stronger interaction between protein and GNPs in OVA@GNPs than OVA+GNPs, which makes OVA@GNPs more stable under in vitro conditions than OVA+GNPs with the ability to induce 4 times higher OVA-specific serum IgG titers following subcutaneous immunization. We also show the dose sparing of OVA@GNPs, as the dosage for aluminum adjuvant required to reach to an equivalent OVA-specific antibody titer was almost five times higher than OVA@GNPs. However, we found that the co-administration of small-sized GNPs had a limited ability for the transcutaneous delivery of OVA. These results demonstrate the potential application of one-pot synthesis approach for producing antigen protein-conjugated gold nanoparticles for vaccine delivery.

Intranasal immunization with aluminum salt-adjuvanted dry powder vaccine.

Intranasal vaccination using dry powder vaccine formulation represents an attractive, non-invasive vaccination modality with better storage stability and added protection at the mucosal surfaces. Herein we report that it is feasible to induce specific mucosal and systemic antibody responses by intranasal immunization with a dry powder vaccine adjuvanted with an insoluble aluminum salt. The dry powder vaccine was prepared by thin-film freeze-drying of a model antigen, ovalbumin, adsorbed on aluminum (oxy)hydroxide as an adjuvant. Special emphasis was placed on the characterization of the dry powder vaccine formulation that can be realistically used in humans by a nasal dry powder delivery device. The vaccine powder was found to have "passable" to "good" flow properties, and the vaccine was uniformly distributed in the dry powder. An in vitro nasal deposition study using nasal casts of adult humans showed that around 90% of the powder was deposited in the nasal cavity. Intranasal immunization of rats with the dry powder vaccine elicited a specific serum antibody response as well as specific IgA responses in the nose and lung secretions of the rats. This study demonstrates the generation of systemic and mucosal immune responses by intranasal immunization using a dry powder vaccine adjuvanted with an aluminum salt.

Study of iron homeostasis following partial hepatectomy in rats with chronic aluminum intoxication.

Effects of both chronic aluminum (Al) exposure and partial hepatectomy on iron (Fe) homeostasis were studied. Male Wistar rats were intraperitoneally administered either 27 mg Al/kg body weight (as aluminum hydroxide) or the vehicle saline, three times a week for 3 mo. After this time, half of the rats of each group was sham operated (SH) and the other half was partially hepatectomized (PH). Animals of the four experimental groups (vehicle+SH [SH]; Al+SH; vehicle+PH [PH], and Al+PH) were killed 48 h after the surgical procedure. Serum, hepatic, and intestinal Al levels were found to be increased both for Al+SH and Al+PH. The serum Fe concentration and transferrin saturation percentage were significantly diminished in the rats of the Al+PH group, thus showing interaction between Al administration and PH. The 59Fe mucosal-to-serosal transport, studied in the intestinal loop in situ, was not affected by Al or PH. The malregulation of intestinal Fe absorption in Al exposure and/or PH when the serum Fe concentration was diminished could be the result of the increased lipid peroxidation (thiobarbituric acid-reactive substances [TBARS]) observed in this tissue. Mucosal TBARS were increased by Al exposure (+26%) and PH (+37%) and interaction between Al and PH was observed (+44%). These results show that when liver surgery is performed after prolonged Al exposure, it leads to impairment of Fe homeostasis. We underline the importance of the exposure to Al, a potentially toxic element, in the study of risk assessment in patients who must be submitted to major liver resection.

MgAl- Layered Double Hydroxide Nanoparticles for controlled release of Salicylate.

Layered double hydroxides (LDHs), have been known for many decades as catalyst and ceramic precursors, traps for anionic pollutants, and additives for polymers. Recently, their successful synthesis on the nanometer scale opened up a whole new field for their application in nanomedicine. Here we report the efficacy of Mg1-xAlx (NO3)x (OH)2 LDH nanoparticles as a carrier and for controlled release of one of the non-steroidal anti-inflammatory drugs (NSAID), sodium salicylate. Mg1-xAlx (NO3)x (OH)2.nH2O nanoparticles were synthesized using co-precipitation method from an aqueous solution of Mg(NO3)2.6H2O and Al(NO3)3.9H2O. Salicylate was intercalated in the interlayer space of Mg-Al LDH after suspending nanoparticles in 0.0025(M) HNO3 and 0.75 (M) NaNO3 solution and using anion exchange method under N2 atmosphere. The shift in the basal planes like (003) and (006) to lower 2θ value in the XRD plot of intercalated sample confirmed the increase in basal spacing in LDH because of intercalation of salicylate into the interlayer space of LDH. FTIR spectroscopy of SA-LDH nano hybrid revealed a red shift in the frequency band of carboxylate group in salicylate indicating an electrostatic interaction between cationic LDH sheet and anionic drug. Differential thermal analysis of LDH-SA nanohybrid indicated higher thermal stability of salicylate in the intercalated form into LDH as compared to its free state. DLS studies showed a particle size distribution between 30-60 nm for pristine LDH whereas salicylate intercalated LDH exhibited a particle size distribution between 40-80nm which is ideal for its efficacy as a superior carrier for drugs and biomolecules. The cumulative release kinetic of salicylate from MgAl-LDH-SA hybrids in phosphate buffer saline (PBS) at pH7.4 showed a sustained release of salicylate up to 72h that closely resembled first order release kinetics through a combination of drug diffusion and dissolution of LDH under physiological conditions. Also the cytotoxicity tests performed revealed the less toxic nature of the nanohybrid as compared to the bare SA drug.

Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations.

Aluminium adjuvants remain the most widely used and effective adjuvants in vaccination and immunotherapy. Herein, the particle size distribution (PSD) of aluminium oxyhydroxide and aluminium hydroxyphosphate adjuvants was elucidated in attempt to correlate these properties with the biological responses observed post vaccination. Heightened solubility and potentially the generation of Al(3+) in the lysosomal environment were positively correlated with an increase in cell mortality in vitro, potentially generating a greater inflammatory response at the site of simulated injection. The cellular uptake of aluminium based adjuvants (ABAs) used in clinically approved vaccinations are compared to a commonly used experimental ABA, in an in vitro THP-1 cell model. Using lumogallion as a direct-fluorescent molecular probe for aluminium, complemented with transmission electron microscopy provides further insight into the morphology of internalised particulates, driven by the physicochemical variations of the ABAs investigated. We demonstrate that not all aluminium adjuvants are equal neither in terms of their physical properties nor their biological reactivity and potential toxicities both at the injection site and beyond. High loading of aluminium oxyhydroxide in the cytoplasm of THP-1 cells without immediate cytotoxicity might predispose this form of aluminium adjuvant to its subsequent transport throughout the body including access to the brain.

Assessing the utility of testing aluminum levels in dialysis patients.

Plasma aluminum (Al) is routinely tested in many dialysis patients. Aluminum exposure may lead to acute toxicity and levels in excess of ∼2.2 µmol/L (60 µg/L) should be avoided. Historically, toxicity has been caused by excessive dialyzate Al but modern reverse osmosis (RO) water should be Al free. Nevertheless, many units continue to perform routine Al levels on dialysis patients. This single-center study retrospectively analyzed Al levels in plasma, raw water feed, and RO product between 2010 and 2013 using our database (Nephworks 6) with the aim of determining the utility of these measurements. Two thousand fifty-eight plasma Al tests in 755 patients (61.9% male, mean age 64.7 years) were reviewed showing mean ± SD of 0.41 ± 0.30 µmol/L. One hundred eleven (5.4%) tests from 61 patients had Al levels >0.74 µmol/L and 45 (73.8%) of these patients were or had been prescribed Al hydroxide (Al(OH)(3)) as a phosphate binder. Seven patients had Al concentrations >2.2 µmol/L with no source of Al identified in 1 patient. One hundred sixty-six patients taking Al(OH)(3) (78.7% of all patients on Al(OH)(3)) had levels ≤0.74 µmol/L, the odds ratio of plasma Al > 0.74 µmol/L on Al(OH)3 was 9. The cost of plasma Al assay is $A30.60; thus, costs were $A62,974.80 over the study period. Despite RO feed water Al levels as high as 48 µmol/L, Al output from the RO was almost always undetectable (<0.1 µmol/L) with dialyzate Al levels > 2.2 µmol/L only 3 times since 2010, and never in the last 3 years. Routine unselected testing of plasma Al appears unnecessary and expensive and more selective testing in dialysis patients should be considered.

Al adjuvants can be tracked in viable cells by lumogallion staining.

The mechanism behind the adjuvant effect of aluminum salts is poorly understood notwithstanding that aluminum salts have been used for decades in clinical vaccines. In an aqueous environment and at a nearly neutral pH, the aluminum salts form particulate aggregates, and one plausible explanation of the lack of information regarding the mechanisms could be the absence of an efficient method of tracking phagocytosed aluminum adjuvants and thereby the intracellular location of the adjuvant. In this paper, we want to report upon the use of lumogallion staining enabling the detection of phagocytosed aluminum adjuvants inside viable cells. Including micromolar concentrations of lumogallion in the culture medium resulted in a strong fluorescence signal from cells that had phagocytosed the aluminum adjuvant. The fluorescence appeared as spots in the cytoplasm and by confocal microscopy and co-staining with probes presenting fluorescence in the far-red region of the spectrum, aluminum adjuvants could to a certain extent be identified as localized in acidic vesicles, i.e., lysosomes. Staining and detection of intracellular aluminum adjuvants was achieved not only by diffusion of lumogallion into the cytoplasm, thereby highlighting the presence of the adjuvant, but also by pre-staining the aluminum adjuvant prior to incubation with cells. Pre-staining of aluminum adjuvants resulted in bright fluorescent particulate aggregates that remained fluorescent for weeks and with only a minor reduction of fluorescence upon extensive washing or incubation with cells. Both aluminum oxyhydroxide and aluminum hydroxyphosphate, two of the most commonly used aluminum adjuvants in clinical vaccines, could be pre-stained with lumogallion and were easily tracked intracellularly after incubation with phagocytosing cells. Staining of viable cells using lumogallion will be a useful method in investigations of the mechanisms behind aluminum adjuvants' differentiation of antigen-presenting cells into inflammatory cells. Information will be gained regarding the phagosomal pathways and the events inside the phagosomes, and thereby the ultimate fate of phagocytosed aluminum adjuvants could be resolved.

Absorption studies of the H2-blocker nizatidine.

The absolute and relative bioavailability of nizatidine, an H2-blocker, was studied in healthy male volunteers. The absolute oral bioavailability, relative to that after intravenous administration, was 98% +/- 14%. The bioavailability of single and multiple oral doses of 150 mg nizatidine was unaffected by concurrent food ingestion; nizatidine may be administered either with or without food. The relative bioavailability of nizatidine was compared when given simultaneously with placebo or Gelusil, 30 minutes after propantheline, or 60 minutes before activated charcoal. Gelusil reduced the amount of nizatidine absorbed by about 10%, charcoal reduced it by about 30%, and propantheline did not affect it.

An investigation into the effect of cimetidine pre-treatment on raft formation of an anti-reflux agent.

It is now becoming common practice to co-administer H2-receptor antagonists and anti-reflux agents in the treatment of reflux oesophagitis. The mechanism by which anti-reflux agents achieve flotation requires a small amount of gastric acid to be present in the stomach. This study investigated whether an anti-reflux agent would remain effective after the decrease in acid secretion produced by a typical clinical dosage regimen of cimetidine (400 mg q.d.s., 7 days). Gastric distribution and residence of a meal and an anti-reflux agent were assessed in 12 normal subjects using gamma scintigraphy. The area under the gastric and fundal emptying curves demonstrated that Liquid Gaviscon (sodium alginate compound) had a significantly greater gastric residence than the meal, both during the control period and after cimetidine pretreatment, and that the majority of the Gaviscon was located in the fundus. The distribution of Gaviscon into the fundus was not affected by cimetidine pretreatment. Cimetidine pre-treatment slightly, but not significantly, increased the time for half the meal and the Gaviscon to empty from the stomach. The results suggest that the mechanism of action of Liquid Gaviscon is not compromised by concurrent H2-antagonist therapy.

Interaction of meloxicam with cimetidine, Maalox, or aspirin.

Meloxicam is a new enol carboxamide nonsteroidal antiinflammatory drug (NSAID). Preclinical studies have indicated that it possesses a high antiinflammatory potency and a low ulcerogenic potency. This open, randomized, crossover study was conducted to examine the effects of aspirin, the antacid Maalox (Rhone-Poulenc Rorer, Cologne, Germany), and cimetidine on the pharmacokinetics and bioavailability of a single oral dose of meloxicam 30 mg in healthy male volunteers. Plasma concentrations of meloxicam were determined and subjected to noncompartmental pharmacokinetic analysis. Meloxicam was well tolerated, and concomitant treatment with cimetidine or Maalox had little or no effect on the plasma concentration-time curves, maximum plasma concentration (Cmax), or the area under the plasma concentration-time curve (AUC0-infinity) of meloxicam. Concurrent treatment with aspirin increased plasma concentrations of meloxicam, increasing Cmax by approximately 25% and AUC0-infinity by 10%. These differences were not considered to be clinically relevant, and no adjustments of meloxicam dose should be required with coadministration of aspirin, Maalox, or cimetidine.

Orange juice enhances aluminium absorption from antacid preparation.

Aluminium absorption from four doses of the antacid preparation 'Aludrox' when taken alone, with orange juice or with milk was compared by measuring the change in urinary aluminium following Aludrox dosage in 15 normal adults. There was an approximately 10-fold increase in 24 h urinary aluminium excretion following the Aludrox plus orange juice (232 micrograms) which was significantly higher than that following Aludrox alone (62 micrograms) (P < 0.001), but milk had no effect on aluminium absorption. The results showed that orange juice greatly enhanced aluminium absorption and should not therefore be taken in conjunction with aluminium-containing antacid preparations.