Development and validation of high-performance liquid chromatography-Orbitrap mass spectrometric method for quantification of NDMA in ranitidine drug products and evaluation of antioxidants as inhibitors of classical nitrosation reaction.

RATIONALE: N-Nitroso dimethylamine (NDMA) is a mutagenic impurity detected in several ranitidine products. The amino functional group of ranitidine is a risk factor for classical nitrosation-induced NDMA formation in ranitidine drug products during storage conditions. The United States Food and Drug Administration (US FDA) recommended the use of antioxidants to control NDMA in drug products. Considering the need for sensitive analytics, a liquid chromatography/high-resolution mass spectrometry (LC-HRMS) method was developed and validated to detect NDMA in this pilot study to demonstrate the antioxidants as inhibitors of nitrosation reactions. METHODS: The method, utilizing an EC-C18 column and tuned to atmospheric pressure chemical ionization/selected ion monitoring (APCI/SIM) mode, separated NDMA (m/z: 75.0553; tR: 3.71 min) and ranitidine (m/z: 315.1485; tR: 8.61 min). APCI mode exhibited four times higher sensitivity to NDMA than electrospray ionization (ESI) mode. Classical nitrosation of the dimethyl amino group of ranitidine was studied with sodium nitrite in solid pellets. Antioxidants (alpha-tocopherol, ascorbic acid, and trolox) were evaluated as NDMA attenuators in ranitidine pellets under vulnerable storage conditions. The developed method quantified NDMA levels in samples, extracted with methanol through vortex shaking for 45 min. RESULTS: The method achieved a limit of detection (LOD) and limit of quantitation (LOQ) of 0.01 and 0.05 ng/mL, respectively, with linearity within 1-5000 ng/mL (R1: 0.9995). It demonstrated good intra-day and inter-day precision (% RSD [relative standard deviation]: <2) and accuracy (96.83%-101.72%). Nitrosation of ranitidine induced by nitrite was significant (p < 0.001; R2 = 0.9579) at various sodium nitrite levels. All antioxidants efficiently attenuated NDMA formation during ranitidine nitrosation. Ascorbic acid exhibited the highest NDMA attenuation (96.98%), followed by trolox (90.58%). This study recommends 1% ascorbic acid and trolox as potent NDMA attenuators in ranitidine drug products. CONCLUSIONS: This study compared the effectiveness of antioxidants as NDMA attenuators in ranitidine under storage conditions susceptible to NDMA generation. The study concluded that ascorbic acid and trolox are potent inhibitors of NDMA formation and nitrosation attenuators in ranitidine drug products.

N-Nitrosodimethylamine (NDMA) Formation from Ranitidine Impurities: Possible Root Causes of the Presence of NDMA in Ranitidine Hydrochloride.

N-Nitrosodimethylamine (NDMA) is a probable human carcinogen. This study investigated the root cause of the presence of NDMA in ranitidine hydrochloride. Forced thermal degradation studies of ranitidine hydrochloride and its inherent impurities (Imps. A, B, C, D, E, F, G, H, I, J, and K) listed in the European and United States Pharmacopeias revealed that in addition to ranitidine, Imps. A, C, D, E, H, and I produce NDMA at different rates in a solid or an oily liquid state. The rate of NDMA formation from amorphous Imps. A, C, and E was 100 times higher than that from crystalline ranitidine hydrochloride under forced degradation at 110 °C for 1 h. Surprisingly, crystalline Imp. H, bearing neither the N,N-dialkyl-2-nitroethene-1,1-diamine moiety nor a dimethylamino group, also generated NDMA in the solid state, while Imp. I, as an oily liquid, favorably produced NDMA at moderate temperatures (e.g., 50 °C). Therefore, strict control of the aforementioned specific impurities in ranitidine hydrochloride during manufacturing and storage allows appropriate control of NDMA in ranitidine and its pharmaceutical products. Understanding the pathways of the stability related NDMA formation enables improved control of the pharmaceuticals to mitigate this risk.

Exposure to Ranitidine and Risk of Bladder Cancer: A Nested Case-Control Study.

INTRODUCTION: Ranitidine has been shown to contain the carcinogen N-nitrosodimethylamine and increase urinary N-nitrosodimethylamine in humans. We investigated whether ranitidine use is associated with increased bladder cancer risk. METHODS: A nested case-control study was conducted within the Primary Care Clinical Informatics Unit Research database which contains general practice records from Scotland. Bladder cancer cases, diagnosed between 1999 and 2011, were identified and matched with up to 5 controls (based on age, sex, general practice, and date of registration). Ranitidine, other histamine-2 receptor agonists, and proton pump inhibitors were identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression after adjusting for comorbidities and smoking. RESULTS: There were 3,260 cases and 14,037 controls. There was evidence of an increased risk of bladder cancer in ranitidine users, compared with nonusers (fully adjusted OR = 1.22; 95% CI 1.06-1.40), which was more marked with use for over 3 years of ranitidine (fully adjusted OR = 1.43; 95% CI 1.05-1.94). By contrast, there was little evidence of any association between proton pump inhibitor use and bladder cancer risk based on any use (fully adjusted OR = 0.98; 95% CI 0.88-1.11) or over 3 years of use (fully adjusted OR = 0.98; 95% CI 0.80-1.20). DISCUSSION: In this large population-based study, the use of ranitidine particularly long-term use was associated with an increased risk of bladder cancer. Further studies are necessary to attempt to replicate this finding in other settings.

Temperature-Dependent Formation of N-Nitrosodimethylamine during the Storage of Ranitidine Reagent Powders and Tablets.

The purpose of this study was to elucidate the effect of high-temperature storage on the stability of ranitidine, specifically with respect to the potential formation of N-nitrosodimethylamine (NDMA), which is classified as a probable human carcinogen. Commercially available ranitidine reagent powders and formulations were stored under various conditions, and subjected to LC-MS/MS analysis. When ranitidine tablets from two different brands (designated as tablet A and tablet B) were stored under accelerated condition (40 °C with 75% relative humidity), following the drug stability guidelines issued by the International Conference on Harmonisation (ICH-Q1A), for up to 8 weeks, the amount of NDMA in them substantially increased from 0.19 to 116 ppm and from 2.89 to 18 ppm, respectively. The formation of NDMA that exceeded the acceptable daily intake limit (0.32 ppm) at the temperature used under accelerated storage conditions clearly highlights the risk of NDMA formation in ranitidine formulations when extrapolated to storage under ambient conditions. A forced-degradation study under the stress condition (60 °C for 1 week) strongly suggested that environmental factors such as moisture and oxygen are involved in the formation of NDMA in ranitidine formulations. Storage of ranitidine tablets and reagent powders at the high temperatures also increased the amount of nitrite, which is considered one of the factors influencing NDMA formation. These data indicate the necessity of controlling/monitoring stability-related factors, in addition to controlling impurities during the manufacturing process, in order to mitigate nitrosamine-related health risks of certain pharmaceuticals.

Medicine and Media: The Ranitidine Debate.

Ranitidine has been the topic of recent media reports. Current findings, confirmed by the US Food and Drug Administration, indicate that some ranitidine products contain a substance that may be carcinogenic. Providers and patients require additional information on the risks of continuing therapy vs. the benefits of the medication. This article comments on what is currently known about the evolving situation of elevated N-nitrosodimethylamine levels in ranitidine and the limits of the existing information to assess best practices.

The role of chloramine species in NDMA formation.

N-nitrosodimethylamine (NDMA), a probable human carcinogen disinfection by-product, has been detected in chloraminated drinking water systems. Understanding its formation over time is important to control NDMA levels in distribution systems. The main objectives of this study were to investigate the role of chloramine species (i.e., monochloramine and dichloramine); and the factors such as pH, sulfate, and natural organic matter (NOM) influencing the formation of NDMA. Five NDMA precursors (i.e., dimethylamine (DMA), trimethylamine (TMA), N,N-dimethylisopropylamine (DMiPA), N,N-dimethylbenzylamine (DMBzA), and ranitidine (RNTD)) were carefully selected based on their chemical structures and exposed to varying ratios of monochloramine and dichloramine. All amine precursors reacted relatively fast to form NDMA and reached their maximum NDMA yields within 24 h in the presence of excess levels of chloramines (both mono- and dichloramine) or excess levels of dichloramine conditions (with limited monochloramine). When the formation of dichloramine was suppressed (i.e., only monochloramine existed in the system) over the 5 day contact time, NDMA formation from DMA, TMA, and DMiPA was drastically reduced (∼0%). Under monochloramine abundant conditions, however, DMBzA and RNTD showed 40% and 90% NDMA conversions at the end of 5 day contact time, respectively, with slow formation rates, indicating that while these amine precursors react preferentially with dichloramine to form NDMA, they can also react with monochloramine in the absence of dichloramine. NOM and pH influenced dichloramine levels that affected NDMA yields. NOM had an adverse effect on NDMA formation as it created a competition with NDMA precursors for dichloramine. Sulfate did not increase the NDMA formation from the two selected NDMA precursors. pH played a key role as it influenced both chloramine speciation and protonation state of amine precursors and the highest NDMA formation was observed at the pH range where dichloramine and deprotonated amines coexisted. In selected natural water and wastewater samples, dichloramine led to the formation of more NDMA than monochloramine.

Tripolyphosphate-crosslinked chitosan/poly (ethylene oxide) electrospun nanofibrous mats as a floating gastro-retentive delivery system for ranitidine hydrochloride.

The present study describes the fabrication of Tripolyphosphate (TPP)-crosslinked nanofibrous mats based on chitosan for use as a floating gastro-retentive delivery system. TPP-crosslinked chitosan (CH)/poly (ethylene oxide) (PEO)- ranitidine hydrochloride (RH) electrospun nanofibers (75.27 ±â€¯2.10 nm) were prepared by electrospinning 70% v/v acetic acid solutions, and followed by crosslinking by TPP anions. The mechanical, structural and morphological properties of the prepared nanofibers were evaluated via tensile testing, XRD, FT-IR, TGA, NMR, AFM and SEM experimental techniques. The prepared nanofibrous mats showed a pH sensitive swelling profile with maximum water absorbing at pH 1.2. Results obtained from above experimental techniques indicated that crosslinking process did not significantly altered morphological property of nanofibers but rather decreased their diameter and swelling degree, and increased their mechanical properties, thermal stability and bioadhesive strength. Viscosity measurements showed that the addition of PEO and RH to the chitosan solution, depending to its concentration lead to decrease in the viscosity of its solution. Also, floating test showed that the prepared nanofibrous mats remain floated onto surface of the dissolution medium for more than 48 h. Based on in- vitro drug release data analysis, TPP-crosslinked CH/PEO nanofibrous mats decreased initial burst release and it was exhibited a sustained release profile for the RH from the TPP-crosslinked CH/PEO-RH electrospun nanofibrous mats.

Investigation and Evaluation of an in Situ Interpolymer Complex of Carbopol with Polyvinylpyrrolidone as a Matrix for Gastroretentive Tablets of Ranitidine Hydrochloride.

Carbopol (CP) is a biocompatible bioadhesive polymer used as a matrix for gastroretentive (GR) tablets, however, its rapid hydration shortens its bioadhesion and floating when incorporated in effervescent formulae. The interpolymer complexation of CP with polyvinylpyrrolidone (PVP) significantly reduced the excessive hydration of CP, prolonging floating and maintaining the mucoadhesiveness. In early attempts, a lengthy process was followed to prepare such an interpolymer complex. In this study, an in situ interpolymer complexation between CP and two grades of PVP (K25 and K90) in 0.1 N HCl was investigated and characterized by Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Hence, directly compressed GR tablets of different combinations of PVP and CP with sodium bicarbonate (SB) as an effervescent agent were examined for prolonged gastroretention and sustained release of ranitidine hydrochloride (RHCl) as a model drug. Tablets were evaluated for in vitro buoyancy, bioadhesiveness, swelling, and drug release in 0.1 N HCl. All GR tablets containing PVP-CP combinations achieved more prolonged floating (>24 h) than CP tablets (5.2 h). Their bioadhesiveness, swelling, and drug release were dependent on the PVP molecular weight and its ratio to CP. Drug release profiles of all formulae followed non-Fickian diffusion. Formula containing the PVP K90-CP combination at a respective ratio of 1 : 3 (P90C13) was a promising system, exhibiting good floating and bioadhesive properties as well as sustained drug release. Abdominal X-ray imaging of P90C13 formula, loaded with barium sulfate, in six healthy volunteers showed a mean gastric retention period of 6.8±0.3 h.

Effect of Pithecellobium dulce (Roxb.) Benth. fruit extract on cysteamine induced duodenal ulcer in rats.

The edible fruits of Pithecellobium dulce (Roxb.) Benth. are traditionally used for various gastric complications in India. Here, we investigated the antiulcer activity of hydroalcoholic fruit extract of P. dulce (HAEPD) by applying cysteamine induced duodenal ulcer model in rats. Duodenal ulcer was induced in male albino Wistar rats by oral administration of cysteamine @ 420 mg/kg body wt. as a single dose. The rats were pre-administered orally with HAEPD @ 200 mg/kg body wt. for 30 days prior to ulcer induction. Rats pre-administered with ranitidine @ 30 mg/kg body wt. served as reference drug control. Ulcer score, thiobarbituric acid reactive substances (TBARS), glycoproteins, superoxide dismutase, catalase and glutathione peroxidase and reduced glutathione levels were measured in the duodenum. Rats pre-administered with the HAEPD showed significantly reduced ulcer score comparable to that of ranitidine pretreated rats. The co-administration of HAEPD lowered the TBARS level and also restored the levels of glycoproteins, enzymatic and non-enzymatic antioxidants. Histopathological observations confirmed the presence of inflammation, necrosis and hemorrhagic spots in the duodenum of ulcer control rats which were significantly reduced due to HAEPD treatment. No abnormal alterations were observed in normal rats treated with HAEPD at the dosage studied. The results demonstrated antioxidant and cytoprotective nature of P. dulce, and thereby its significant anti ulcer property.

A new approach to predict human intestinal absorption using porcine intestinal tissue and biorelevant matrices.

A reliable prediction of the oral bioavailability in humans is crucial and of high interest for pharmaceutical and food industry. The predictive value of currently used in silico methods, in vitro cell lines, ex vivo intestinal tissue and/or in vivo animal studies for human intestinal absorption, however, is often insufficient, especially when food-drug interactions are evaluated. Ideally, for this purpose healthy human intestinal tissue is used, but due to its limited availability there is a need for alternatives. The aim of this study was to evaluate the applicability of healthy porcine intestinal tissue mounted in a newly developed InTESTine™ system to predict human intestinal absorption of compounds with different chemical characteristics, and within biorelevant matrices. To that end, first, a representative set of compounds was chosen of which the apparent permeability (Papp) data in both Caco-2 cells and human intestinal tissue mounted in the Ussing chamber system, and absolute human oral bioavailability were reported. Thereafter, Papp values of the subset were determined in both porcine jejunal tissue and our own Caco-2 cells. In addition, the feasibility of this new approach to study regional differences (duodenum, jejunum, and ileum) in permeability of compounds and to study the effects of luminal factors on permeability was also investigated. For the latter, a comparison was made between the compatibility of porcine intestinal tissue, Caco-2 cells, and Caco-2 cells co-cultured with the mucin producing HT29-MTX cells with biorelevant samples as collected from an in vitro dynamic gastrointestinal model (TIM). The results demonstrated that for the paracellularly transported compounds atenolol, cimetidine, mannitol and ranitidine porcine Papp values are within 3-fold difference of human Papp values, whereas the Caco-2 Papp values are beyond 3-fold difference. Overall, the porcine intestinal tissue Papp values are more comparable to human Papp values (9 out of 12 are within 3-fold difference), compared to Caco-2 Papp values (4 out of 12 are within 3-fold difference). In addition, for the selected hydrophilic compounds a significant increase in the permeability was observed from duodenum to ileum. Finally, this study indicated that porcine jejunal tissue segments can be used with undiluted luminal samples to predict human intestinal permeability and the effect of biorelevant matrices on this. In conclusion, viable porcine intestinal tissue mounted in the InTESTine™ system can be applied as a reliable tool for the assessment of intestinal permeability in the absence and presence of biorelevant samples. This would enable an accessible opportunity for a reliable prediction of human intestinal absorption, and the effect of luminal compounds such as digested foods, early in drug development.

Formation mechanism of NDMA from ranitidine, trimethylamine, and other tertiary amines during chloramination: a computational study.

Chloramination of drinking waters has been associated with N-nitrosodimethylamine (NDMA) formation as a disinfection byproduct. NDMA is classified as a probable carcinogen and thus its formation during chloramination has recently become the focus of considerable research interest. In this study, the formation mechanisms of NDMA from ranitidine and trimethylamine (TMA), as models of tertiary amines, during chloramination were investigated by using density functional theory (DFT). A new four-step formation pathway of NDMA was proposed involving nucleophilic substitution by chloramine, oxidation, and dehydration followed by nitrosation. The results suggested that nitrosation reaction is the rate-limiting step and determines the NDMA yield for tertiary amines. When 45 other tertiary amines were examined, the proposed mechanism was found to be more applicable to aromatic tertiary amines, and there may be still some additional factors or pathways that need to be considered for aliphatic tertiary amines. The heterolytic ONN(Me)2-R(+) bond dissociation energy to release NDMA and carbocation R(+) was found to be a criterion for evaluating the reactivity of aromatic tertiary amines. A structure-activity study indicates that tertiary amines with benzyl, aromatic heterocyclic ring, and diene-substituted methenyl adjacent to the DMA moiety are potentially significant NDMA precursors. The findings of this study are helpful for understanding NDMA formation mechanism and predicting NDMA yield of a precursor.

Formation of NDMA from ranitidine and sumatriptan: the role of pH.

N-nitrosodimethylamine (NDMA) is an emerging disinfection by-product (DBP) which can be formed via the chloramination of amine-based precursors. The formation of NDMA is mainly determined by the speciation of chloramines and the precursor amine groups, both of which are highly dependent on pH. The impact of pH on NDMA formation has been studied for the model precursor dimethylamine (DMA) and natural organic matter (NOM), but little is known for amine-based pharmaceuticals which have been newly identified as a group of potential NDMA precursors, especially in waters impacted by treated wastewater effluents. This study investigates the role of pH in the formation of NDMA from two amine-based pharmaceuticals, ranitidine and sumatriptan, under drinking water relevant conditions. The results indicate that pH affects both the ultimate NDMA formation as well as the reaction kinetics. The maximum NDMA formation typically occurs in the pH range of 7-8. At lower pH, the reaction is limited due to the lack of non-protonated amines. At higher pH, although the initial reaction is enhanced by the increasing amount of non-protonated amines, the ultimate NDMA formation is limited because of the lack of dichloramine.

Mathematical modelling of the transport of hydroxypropyl-ß-cyclodextrin inclusion complexes of ranitidine hydrochloride and furosemide loaded chitosan nanoparticles across a Caco-2 cell monolayer.

Chitosan nanoparticles (CS-NPs) have been used to enhance the permeability of furosemide and ranitidine hydrochloride (ranitidine HCl) which were selected as candidates for two different biopharmaceutical drug classes having low permeability across Caco-2 cell monolayers. Drugs loaded CS-NPs were prepared by ionic gelation of CS and pentasodium tripolyphosphate (TPP) which added to the drugs inclusion complexes with hydroxypropyl-ß-cyclodextrin (HP-ßCD). The stability constants for furosemide/HP-ßCD and ranitidine HCl/HP-ßCD were calculated as 335 M(-1) and 410 M(-1), whereas the association efficiencies (AE%) of the drugs/HP-ßCD inclusion complexes with CS-NPs were determined to be 23.0 and 19.5%, respectively. Zetasizer and scanning electron microscopy (SEM) were used to characterise drugs/HP-ßCD-NPs size and morphology. Transport of both nano and non-nano formulations of drugs/HP-ßCD complexes across a Caco-2 cell monolayer was assessed and fitted to mathematical models. Furosemide/HP-ßCD-NPs demonstrated transport kinetics best suited for the Higuchi model, whereas other drug formulations demonstrated power law transportation behaviour. Permeability experiments revealed that furosemide/HP-ßCD and ranitidine HCl/HP-ßCD nano formulations greatly induce the opening of tight junctions and enhance drug transition through Caco-2 monolayers.

Lack of a primary physicochemical determinant in the direct transport of drugs to the brain after nasal administration in rats: potential involvement of transporters in the pathway.

The objectives of this study were to evaluate the relative contribution of the direct pathway in overall brain transport for 17 model drugs with different physicochemical properties after nasal administrations and to identify factors that govern the fraction of the dose transported to the brain via the direct pathway (F(a, direct)). When the model drugs were nasally administered to rats, 5 of the 17 model drugs were delivered to a significant extent to the brain via the direct pathway. Multiple linear regression analyses showed that the correlation between various physicochemical properties and F(a, direct) was not statistically significant, indicative of a lack of primary physicochemical determinants in the direct transport pathway. Transporters such as rOAT3 and rOCT2 were expressed at significant levels in rat olfactory epithelia, and uptakes of standard substrates were significantly decreased in HEK293 cells expressing rOAT3 and rOCT2 in the presence of the five model drugs that were delivered to appreciable extents to the brain via the direct pathway. Therefore, these observations indicate that carrier-mediated transport may play a role in the brain delivery of drugs from the nose via the direct transport pathway.

Novel ion exchange resin-based combination drug-delivery system for treatment of gastro esophageal reflux diseases

The present study involves preparation and characterization of a combination tablet of ranitidine in immediate release form and domperidone in sustained release form, using ion exchange resins. Ranitidine lowers acid secretion, while domperidone release over a prolonged period improves gastric motility thus justifying this combination in gastro esophageal reflux diseases (GERD) and ensuring patient compliance. Drug loading was carried out by batch method & resinates were characterized using FTIR, XRPD. Resinates were formulated as a combination tablet and evaluated for tablet properties & in vitro drug release. Resinates provided sustained release of domperidone and immediate release of ranitidine. IR and X-ray studies indicate complexation of drug and resin along with monomolecular distribution of drugs in amorphous form in the resin matrix. The tablets of resinate combination showed good tablet properties. In-vitro drug release gave desired release profiles and ex-vivo drug absorption studies carried out by placing everted rat intestine in dissolution medium indicated statistically significant similarity in absorption from test and marketed formulation. The novelty of this study is that the retardation in release of domperidone from resinates is achieved by presence of weak resin in the formulation.

O presente estudo envolve a preparação e a caracterização de associação do comprimido de ranitidina de liberação imediata e domperidona de liberação prolongada, utilizando resinas de troca iônica. A ranitidina diminui a secreção ácida, enquanto a liberação prolongada de domperidona melhora a motilidade gástica, justificando, dessa forma, a associação em doenças de refluxo gastroesofágico (DRGE) e garantindo a adesão do paciente. A carga de fármaco foi efetuada pelo método em batelada e os resinatos, caracterizados utilizando-se FTIR e XRPD. Os resinatos foram formulados como comprimido da associação e avaliados com relação às propriedades dos comprimidos e liberação do fármaco in vitro. Os resinatos proporcionaram a liberação prolongada da domperidona e a liberação imediata da ranitidina. IV e estudos de difração de raios X indicaram a complexação do fármaco e da resina junto com a distribuição monomolecular dos fármacos, em estado amorfo, na matriz da resina. Os comprimidos da associação do resinato apresentaram boas propriedades. Obtiveram-se os perfis de liberação in vitro e os estudos de absorção dos fármacos ex vivo realizados com intestino de rato em meio de dissolução indicaram semelhança significativa na absorção entre as formulações teste e comercializada. A inovação do trabalho é que o retardamento da liberação da domperidona dos resinatos é atingido pela presença de resina fraca na formulação.

Towards characterization and identification of solid state pharmaceutical mixtures through second harmonic generation.

In this paper, we report improvements to a previously developed method based on optical nonlinearity for characterizing polymorphism and concentration of pharmaceuticals in powdered and tablet form. An apparatus that measures the nonlinear optical response of a sample through second harmonic generation (SHG) is described. The response of several enalapril maleate-polyvinylpyrrolidone (PVP) tablets was measured, the results of which were used to determine the concentration of the drug. The current limit of detection of the apparatus was found to be approximately 1%-2%. Ranitidine hydrochloride (RN) polymorph forms I and II were also characterized using SHG. It was found that pure samples of forms I and II could be clearly and rapidly distinguished. Mixtures consisting of 50% form I and 50% form II were also distinguishable from the respective pure forms. An investigation was performed into the size dependence of the SHG response for crystalline lactose. It was found that the SHG response was a slowly decreasing monotonic function of particle size. Additional investigation into the angular dependence of the scattered SHG light was also undertaken for crystalline lactose. This new technique based on optical nonlinearity offers promise for application in monitoring of pharmaceutical manufacturing processes.

Treatment of H. pylori infection: a review.

Helicobacter pylori infection has been indicated as the main pathogenic factor in the development of chronic gastritis, peptic ulcer disease, and gastric malignancies. Although the vast majority of infected subjects do not carry but a mild, asymptomatic gastritis, still there are some cases in which the eradication of the infection appears mandatory. This review addresses current anti-Helicobacter regimens and pharmacological resources, and highlights the pros and cons of each of them, according to the most recent and reliable clinical trials. Also, basic recommendations are given, regarding treatment choice in the event of the failure of a first or second line eradicating strategy, and about the implementation of standard regimens with newer antibacterial devices as probiotics.

Determination of compatibility and stability of drugs used in palliative care.

BACKGROUND: Drugs for symptom control in the terminal phase of palliative patients may be used in pump systems. OBJECTIVE: To investigate the compatibility and stability of solutions of morphine hydrochloride, haloperidol, metoclopramide hydrochloride, atropine sulphate, butylhyoscine bromide and ranitidine hydrochloride, which may be used together under such circumstances. METHOD: Solutions of the drugs were exposed to ambient light at a temperature of 20 +/- 5 degrees C and +/- 31 degrees C for 24 h and 7 days and the solutions studied by ultraviolet spectrophotometry. RESULTS: The combination of haloperidol or metoclopramide hydrochloride with different concentrations of morphine hydrochloride seemed to be compatible and stable. The concentration of atropine sulphate or butylhyoscine bromide could not be determined by the study method, but morphine hydrochloride seemed to be stable. The combination of ranitidine hydrochloride and morphine hydrochloride showed a change in colour after 7 days. CONCLUSION: The results suggest that the combination of different concentrations of morphine hydrochloride with haloperidol, metoclopramide hydrochloride, atropine sulphate, butylhyoscine bromide or ranitidine hydrochloride do not affect their stability when stored for 7 days up to 30 degrees C under the influence of ambient light. However, more robust stability-indicating methods are required to confirm these results. The proposed method is more useful for identifying combinations that are clearly incompatible than to identify those that are compatible.