Neutralization of Acidic Tumor Microenvironment (TME) with Daily Oral Dosing of Sodium Potassium Citrate (K/Na Citrate) Increases Therapeutic Effect of Anti-cancer Agent in Pancreatic Cancer Xenograft Mice Model.

Extracellular pH (pHe) of tumor cells is characteristic of tumor microenvironment (TME). Acidic TME impairs the responses of tumors to some anti-cancer chemotherapies. In this study, we showed that daily oral dosing of sodium potassium citrate (K/Na citrate) increased blood HCO3- concentrations, corresponding to increase of HCO3- concentrations and pHs in urine, and neutralized the tumor pHe. Neutralization of acidic TME by alkaline substance like HCO3-, an active metabolite of K/Na citrate, well potentiated the therapeutic effect of anticancer agent TS-1®, an orally active 5-fuluoro-uracil derivative, in Panc-1 pancreatic cancer-xenograft murine model. Neutralization of acidic TME by using an alkaline K/Na citrate is a smart approach for enhancement of the therapeutic effects of anticancer agents for pancreatic cancer in the end stage.

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.

Helicobacter pylori: past, current and future treatment strategies with gastroretentive drug delivery systems.

Helicobacter pylori have been subject to intense investigation since its discovery from gastric biopsy in 1982. This gastropathogen has been regarded as serious public health problem due to its association with dyspepsia, gastritis, gastroduodenal ulcers, mucus-associated lymphoid tissue lymphoma and gastric carcinoma. In vivo eradication of established H. pylori infections is difficult due to several factors such as gastric niche, coccoid form due to sub-minimum inhibitory concentration of antimicrobials, bacterial load, primary antibiotic resistance, patient compliance and stability of therapeutics in gastric acid secretion. Considering these factors, a logical way to improve the outcome of the treatment is to develop dosage forms which are able to deliver the anti-helicobacter agents in the gastric niche for both local and systemic actions, simultaneously taking care of stability of therapeutics in acidic environment. Such dosage forms, which are popularly known as gastro retentive drug delivery systems (GRDDS), have the immense potential to effectively counter the problem of high bacterial load; prevent induction of coccoid bacteria thereby improving treatment outcome and compliance. This review describes efficacy of various therapeutic agents, treatment strategies and status of different GRDDS until now.

Review article: the clinical pharmacology of proton pump inhibitors.

Proton pump inhibitors inhibit the gastric H+/K+-ATPase via covalent binding to cysteine residues of the proton pump. All proton pump inhibitors must undergo acid accumulation in the parietal cell through protonation, followed by activation mediated by a second protonation at the active secretory canaliculus of the parietal cell. The relative ease with which these steps occur with different proton pump inhibitors underlies differences in their rates of activation, which in turn influence the location of covalent binding and the stability of inhibition. Slow activation is associated with binding to a cysteine residue involved in proton transport that is located deep in the membrane. However, this is inaccessible to the endogenous reducing agents responsible for restoring H+/K+-ATPase activity, favouring a longer duration of gastric acid inhibition. Pantoprazole and tenatoprazole, a novel proton pump inhibitor which has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, are activated more slowly than other proton pump inhibitors but their inhibition is resistant to reversal. In addition, tenatoprazole has a greatly extended plasma half-life in comparison with all other proton pump inhibitors. The chemical and pharmacological characteristics of tenatoprazole give it theoretical advantages over benzimidazole-based proton pump inhibitors that should translate into improved acid control, particularly during the night.

Impact of oral bases on aluminum absorption.

Control of hyperphosphatemia in renal failure is often difficult to achieve. Although calcium-containing phosphate binders have become the preferred phosphate binders, many patients require the addition of an aluminum-containing phosphate binder (APB). Enhanced aluminum absorption has been noted when APBs are administered with citrate-containing products such as citrate/citric acid solution (CCA). Alternative phosphate binders such as calcium acetate may also increase aluminum absorption. This study investigated the effect of CCAs on aluminum absorption when aluminum antacids (APBs) were administered concurrently and 2 hours apart. The effects of the alternative alkalinizing agent sodium bicarbonate and the alternate phosphate binding agent calcium acetate on aluminum absorption were also studied. During five 2-day phases, ten normal volunteers randomly received three times daily with standardized meals aluminum hydroxide alone and concurrently with NaHCO3, calcium acetate, CCA, or with CCA 2 hours postprandially. Twenty-four hour urines were collected on the second day of each phase and aluminum excretion was determined using inductively coupled plasma emission spectroscopy. Urine aluminum excretion was statistically significantly (P <.005) elevated in subjects receiving Al(OH)3 and CCA both with meals, 269.3 +/- 146.3 microg/d, and 2 hours after meals, 303.3 +/- 142.9 microg/d, compared with 79.2 +/- 52.0 microg/d during treatment with Al(OH)3 alone. Administration of CCA 2 hours after APB does not permit the safe use of these agents concurrently. Concomitant administration of sodium bicarbonate and calcium acetate with APBs appears to be safe, as aluminum absorption was not affected.

Interactions of cimetidine and ranitidine with aluminum-containing antacids and a clay-containing gastric-protective drug in an "artificial stomach-duodenum" model.

Interactions of cimetidine and ranitidine with aluminum-containing antacids and clay-containing gastric-protective drugs were analyzed in vitro by using an artificial stomach-duodenum model. The model reproduced near-physiologic conditions, taking into account gastric and duodenal flux variations and interactions between gastric mucosa and drugs added to the gastric content. Clay bound cimetidine in acid medium, but the drug was released when the pH increased, resulting in cimetidine amounts in the duodenal site close to those in controls. In contrast, clay bound ranitidine in acid medium and did not release it in the duodenal site. Aluminum-containing antacids did not significantly modify the amount of cimetidine or ranitidine available for absorption. Several factors play a role in the interactions of cimetidine and ranitidine with aluminum-containing antacids and clay-containing gastric-protective drugs: the structure of the antisecretory drugs, gastroduodenal pH, interactions of the antacid and clay with the gastric mucosa, and release of aluminum that could adsorb the drugs or prevent their adsorption by the mucosa. These phenomena are intricate and difficult to analyze without using a physicochemical approach.

Terapias alternativas; la Montmorillonita-bentonita como antiacido

La farmacopea de las culturas nativas bolivianas contienen productos con actividad farmacologica, como es el caso de la Montmorillonita-bentonita (Phasa), arcilla que a traves de analisis quimicos se ha demostrado que contiene silicatos, hidroxido y carbonatos, principalmente de aluminio y calcio analoga a los tradicionales antiacidos del arsenal terapeutico facultativo.

Calcium citrate markedly enhances aluminum absorption from aluminum hydroxide.

The effect of calcium citrate on intestinal aluminum absorption, assessed by the increment in urinary aluminum excretion, was evaluated in eight normal men. Baseline urinary aluminum excretion was determined for 2 days; thereafter, subjects ingested aluminum hydroxide for 3 days. In a cross-over study, subjects were given either calcium citrate, 950 mg four times a day, or placebo during the 3 days of aluminum hydroxide ingestion (2.4 g/d). Plasma aluminum levels were measured on the second control day and the third day of aluminum hydroxide ingestion. Baseline urinary aluminum excretion was 0.02 +/- 0.004 (6.5 +/- 1.1 micrograms/g creatinine) and 0.03 +/- 0.005 mumol/mmol creatinine (7.4 +/- 1.3 micrograms/g creatinine). These values increased during aluminum hydroxide therapy, but values were much greater when calcium citrate was ingested with aluminum hydroxide. On 3 consecutive days, urinary aluminum excretion levels were 11.1 +/- 3.23, 8.8 +/- 2.9, and 5.3 +/- 0.7 times greater during the administration of calcium citrate with aluminum hydroxide than with aluminum hydroxide alone. Plasma aluminum levels did not differ in the two treatment groups. Thus, calcium citrate markedly enhances the absorption of aluminum from aluminum hydroxide and the two must not be prescribed together in patients with renal failure.

Aluminum speciation studies in biological fluids. Part 3. Quantitative investigation of aluminum-phosphate complexes and assessment of their potential significance in vivo.

Following the discovery that specific health disorders affecting patients with renal disease were due to their excessive body accumulation of aluminum, it was established that aluminum toxicity was mainly due to the ingestion of aluminum-containing phosphate binders. Suspicion of toxicity was thus cast on aluminum-containing antacids, and subsequent tests held on healthy subjects did reveal that aluminum hydroxide gels were also potential oral sources of aluminum, especially in the presence of citric acid. Nevertheless, authors of these tests concluded that there was only marginal absorption of aluminum phosphate. In contrast with these clinical conclusions, it has recently been contended on theoretical grounds that aluminum phosphate represents a serious health hazard. To help elucidate this issue, this paper first deals with a quantitative investigation of aluminum-phosphate equilibria under physiological conditions. Then appropriate computer simulations based on corresponding results are used to assess the actual extent to which phosphate can influence aluminum bioavailability. These simulations confirm that aluminum phosphate is not expected to induce absorption of high amounts of aluminum when administered by itself. Nevertheless, this result may no longer apply in the presence of food, whose various acidic components are likely to modify the involved chemical equilibria. Moreover, it is shown that rising blood plasma phosphate levels should tend to increase aluminum tissue penetration and hence favor its potential toxicity.

Benefit vs. risk of oral aluminum forms: antacid and phosphate binding vs. absorption.

Oral consumption of aluminum (Al) compounds to neutralize stomach acid and bind phosphate can result in Al absorption and potential Al accumulation and toxicity. Selecting an effective antacid/phosphate binder would optimize the benefit/risk of therapy. It has been suggested that Al solubilization would predict oral Al bioavailability, and therefore risk. The acid neutralizing and phosphate binding capacity of eight representative Al forms was determined. The results were compared to the oral bioavailability, solubility and octanol/water partitioning coefficient of each compound. The results fail to confirm Al solubilization as an indicator of Al absorption, and presumably, Al toxicity. Acid neutralizing and phosphate binding capacities did not correlate with bioavailability, solubility or the partitioning coefficient. Determination of acid neutralization and phosphate binding in vitro and Al absorption and/or toxicity in vivo may be more predictive measures to establish the benefit/risk ratio of Al-containing products.

[Influence of pH in the adsorption capacity of bile salts and lysolecithins in vitro by antacids containing clay and/or aluminum]. / Influence du pH dans la capacité d'adsorption des sels biliaires et des lysolécithines in vitro par les antiacides contenant de l'argile et/ou de l'aluminium.

In vitro binding properties of eight clay and/or aluminium-containing antacids for bile salts and lysolecithin were measured in comparison with cholestyramine binding capacity, taking into account the final medium pH. Dihydroxy-bile salt adsorption was greater when the initial pH was 1.8 and the intensity varied according to the drugs. Trihydroxybile salts were less bound and the binding was less related to the medium pH. Lysolecithins were bound by clay-containing antacids with the same intensity as cholestyramine, while the binding capacity of aluminium-containing antacids was weaker and related to the final pH. There were close relationships between binding capacities and the final pH so that bile salts are bound by antacids with a great intensity in acid medium and released by alkalinisation in contrary to the binding capacity of cholestyramine. Lysolecithins should be also bound more intensively in acid medium by aluminium-containing antacids. Binding capacities of the antacids were related to their composition, their antacid effect and to the final pH.

[A method of cisplatin administration with the aid of high-dose bismuth subnitrate, and their pharmacokinetics].

Twelve Patients with malignant neoplasms were treated in twenty-five courses with high-dose Cisplatin and high-dose Bismuth Subnitrate. The pharmacokinetics of Bismuth Subnitrate and Cisplatin were studied in several courses. Bismuth Subnitrate was administered orally at a dose of 150 mg/kg/day for 10 days, and an average dose of 108 mg/m2 of cisplatin was administered intravenously on the 6th day after Bismuth Subnitrate administration. The concentration of Bismuth in blood and urine showed a similar increase, reaching a plateau 5 days after, and peaking 12 days after starting administration. It is estimated that 10-day administration of high-dose Bismuth Subnitrate was appropriate to maintain an adequate concentration of Bismuth for preinduction of Metallothionein in organs. The pharmacokinetics of cisplatin in plasma indicated as follows. a) In terms of the nephrotoxic factors, the Cmax of platinum did not increase dose-dependently, and total clearance of platinum was constant under the same time of injection; b) As for the antitumor effect, AUC of ultrafilterable (free) platinum increased dose-dependently. From the standpoint of pharmacology, high-dose Bismuth Subnitrate was believed to reduce the nephrotoxicity of cisplatin without reducing its antitumor effect.

Differences in plasma and tissue aluminum concentrations due to different aluminum-containing drugs in patients with renal insufficiency and with normal renal function.

The gastrointestinal absorption of aluminum from orally administered aluminum-containing drugs is well documented. Retention of the absorbed aluminum leads to elevated levels of this metal in the tissue of patients with renal failure. We studied two groups of dialysis patients who had received equal amounts of the different aluminum-containing phosphate-binders Aludrox and Antiphosphat. It has recently been shown that Antiphosphat releases only a few aluminum ions in an environment of low pH. Consistent with this finding, we found the aluminum levels to be significantly higher in the plasma, bone, and hair of patients who had received Aludrox as phosphate binder. Subjects with normal renal function excreted most of the ingested and absorbed aluminum. No data are available concerning the tissue load of the element in these subjects. We studied two groups of patients with normal renal function who had received antacid drugs prior to neurosurgery on a brain tumor. The first group of patients were treated with an aluminum-rich antacid (Maalox 70); the other group received an aluminum-poor drug (magaldrate) for 10 days prior to the operation. Analysis of the brain-tissue removed revealed twofold higher aluminum levels in the patients who had received Maalox 70. These results indicate that administration of aluminum-containing drugs leads to a tissue load of aluminum in patients with an impaired renal function as well as in those with a normal function. The extent of the aluminum load depends on the aluminum content and the liberation rate of the drug.