The pharmacological profile and clinical use of mesalazine (5-aminosalicylic acid).

For more than 30 years mesalazine (5-aminosalicylic acid; 5-ASA) has been used for the treatment of chronic inflammatory bowel disease (IBD) especially in ulcerative colitis (UC). During this time various rectal and oral formulations have been developed. The modified drug delivery systems were designed to release sufficient 5-ASA at the sites of inflammation. Such a drug targeting strategy is needed for its topical action and especially because local concentrations in the mucosa will determine the clinical outcome. The absorbed part (20-40% of the dose) of 5-ASA is rapidly and presystemically acetylated (t1/2: 1-2.5 h; CL: 300-690 mL/min). Consequently, the systemic exposure of 5-ASA is low and adverse effects are in the range of placebo treatment. The polypotent 5-ASA has a wide spectrum of pharmacological properties and its exact mode of action is not yet clear. Recent meta-analyses of randomized placebo-controlled clinical trials provide convincing data that 5-ASA is the preferred first-line therapy for the acute treatment of mild-to-moderate UC (NNT:6) and for remission management (NNT:4). There is also some clinical benefit for patients with active Crohn's disease (NNT:7) and in the prevention of postsurgical relapse (NNT:10). There is increasing evidence that 5-ASA also has some therapeutic potential for chemoprevention of colorectal cancer, diverticular disease and irritable bowel syndrome. In all clinical studies, the side effects of 5-ASA were very low (5-10%), mild and comparable to placebo. Thus, its use is very safe and 5-ASA will remain an interesting and valuable agent. It is anticipated that more selective drug targeting, including galenic innovations and an optimized dosaging schedule, could result in some improvement of the wide use of 5-ASA.

The influence of chitosan content in cationic chitosan/PLGA nanoparticles on the delivery efficiency of antisense 2'-O-methyl-RNA directed against telomerase in lung cancer cells.

Tailorable cationic chitosan/PLGA nanoparticles (CPNP) were used for the delivery of an antisense 2'-O-methyl-RNA (2OMR) directed against RNA template of human telomerase. Here, we describe the influence of the chitosan content on binding efficiency, complex stability, uptake in different human lung cell types and finally demonstrate the efficacy of this nanoplex system. CPNPs were prepared by the emulsion-solvent evaporation method using different amounts of chitosan and purified by preparative size exclusion chromatography. The characterization by photon correlation spectroscopy and zeta potential measurements showed a small increase in size and an increase of zeta potential with increasing amounts of chitosan. Binding efficiency and complex stability with 2OMR was high in water and correlated well with the chitosan content of particles but was weak in physiologically relevant media (PBS and RPMI cell culture medium). However, flow cytometry analysis showed that the uptake of 2OMR into A549 lung cancer cells was considerably higher in combination with nanoparticles and dependent on the amount of chitosan when compared to 2OMR alone. Confocal laser scanning microscopy revealed that the uptake into A549 cells is mediated via complexes of 2OMR and chitosan/PLGA nanoparticles despite the weak binding in cell culture medium. The nanoparticles were well tolerated and efficient in inhibiting telomerase activity.

Hepatic expression of galectin-3 and receptor for advanced glycation end products in patients with liver disease.

BACKGROUND: Advanced glycation end products (AGEs) are a heterogeneous group of glycosylated proteins (of which carboxymethyl-lysine (CML) is the most common) which accumulate during ageing processes and play an important role in the pathogenesis of a variety of chronic diseases. Impaired hepatic function might result in elevated levels of AGEs, as the liver represents the major site of AGE metabolism. The actions of AGEs are mediated by various receptors, among which the AGE-receptor complex (including galectin-3 as an essential part) is thought to have a cytoprotective effect, and receptor for advanced glycation end product (RAGE) a cytotoxic effect. AIM: To assess the relationship between CML and expression of galectin-3 and RAGE in different histological structures in biopsy specimens from patients with varying degrees of liver impairment. METHOD: Immunohistochemical staining of 164 biopsies from patients with varying degrees of liver impairment was performed to determine the levels of CML, galectin-3 and RAGE in hepatocytes, Kupffer cells and bile ducts by a semiquantative score. RESULTS: Independent of diagnosis, CML and RAGEs were detected in hepatocytes, whereas galectin-3 was present only in hepatocytes of cirrhotics. By contrast, CML and galectin-3 were highly expressed in Kupffer cells (well correlating levels, highest scores in cholestasis) whereas expression of RAGEs was not significant. All three assessed biochemical markers showed their highest levels of expression/detection in bile ducts. CONCLUSION: These findings indicate an increased susceptibility of hepatocytes to the detrimental effects of AGEs and underline the protective function of Kupffer cells. Furthermore, the biliary system seems to play an important role in the disposition of AGEs.

Ziconotide--a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain--a short review.

Worldwide a large number of patients suffer from severe chronic pain even after treatment with opioids following the 3-step analgesic ladder developed by the WHO. Intraspinal agents, including morphine, have been tried as a fourth step. However, approximately 20% of cases remain refractory. Ziconotide, an intrathecal analgesic with orphan drug status, is a novel alternative for the management of chronic intractable pain. Ziconotide is a synthetic peptide based on the toxin of the fish-hunting marine snail, Conus magus. It is the first therapeutic agent in a new pharmacological class of "topically" active analgesics that selectively target neuron-specific (N-type), voltage-gated calcium channels. Ziconotide produces potent analgesia by interruption of Ca-dependent primary afferent transmission of pain signals in the spinal cord. Ziconotide was significantly more effective than placebo in the treatment of chronic malignant (p < 0.001) and non-malignant pain (p < 0.001). In several clinical studies morphine dosages could be substituted by ziconotide. The drug has a lag-time for the onset and offset of analgesia and adverse effects. Initial doses should therefore be low (2.4 microg/day) and titrated slowly (increasing up to a maximum of 21.6 microg/day in increases of 2.4 microg/day no more than twice weekly). The gradual increase in dose helps to reduce the incidence and severity of adverse events which affect primarily the central nervous system (e.g. dizziness, nausea, confusion). Ziconotide maintains its analgesic efficacy over months and does not cause tolerance, dependence or respiratory depression. Following intrathecal infusion ziconotide is distributed within the cerebral spinal fluid (CSF) where its clearance (0.38 ml/min) corresponds to the rate of turnover of the CSF. Negligible amounts of ziconotide are present in the systemic circulation where it is rapidly degraded by proteolysis. In conclusion, ziconotide is a new and valuable alternative analgesic for the acute and long-term treatment of severe pain, especially in patients refractory to opioids.

Biopharmaceutical characterization of the telomerase inhibitor BRACO19.

PURPOSE: To characterize the telomerase inhibitor and G-quadruplex stabilizing substance 9-[4-(N,N-dimethylamino)phenylamino]-3,6-bis (3-pyrrolodino-propionamido) acridine x 3HCl (BRACO19) in terms of biopharmaceutical properties such as solubility, protein binding, interaction with membrane lipids, cytotoxicity, and permeability across pulmonary epithelial cells. METHODS: Protein binding and interaction with membrane lipids were investigated by two high-performance liquid chromatography methods with immobilized human serum albumin and immobilized phosphatidylcholine, respectively. Cytotoxicity (methyl-thiazolyl-tetrazolium assay) and transport studies were performed with the bronchial cell lines 16HBE14o- and Calu-3, primary human alveolar epithelial cells, and the intestinal cell line Caco-2. Transport experiments were also done in the presence of cyclosporin A (10 microM) and tetraethylammonium chloride (5 mM) and at low temperature (4 degrees C). RESULTS: BRACO19 has good solubility of at least 2 mg/mL in water and in physiological buffers of pH 7.4 and below. Protein binding to human serum albumin was 38%. No interaction with membrane lipids could be found. Cytotoxicity in 16HBE14o-, Calu-3, and human alveolar epithelial cells was in the range of IC50 = 3.5 to 13.5 microM. Caco-2 cells were not affected at concentrations up to 50 microM. No transport of BRACO19 was detected across either cell monolayer in absorptive direction. In secretory direction, permeability was very low, with P (app) values in the range of 0.25 x 10(-7) to 0.98 x 10(-7) cm/s for all epithelial cell cultures tested. The transport was not influenced by cyclosporin A or tetraethylammonium chloride or at 4 degrees C, indicating that no efflux/influx systems or active transport are involved. CONCLUSIONS: From these results, we conclude that the very poor permeability of BRACO19 is its main biopharmaceutical limitation. Further applications will require a suitable formulation to warrant adequate delivery across cellular barriers.

Dyspeptic symptoms associated with Helicobacter pylori infection are influenced by strain and host specific factors.

BACKGROUND: Dyspepsia can be associated with H. pylori infection. AIM: To assess dyspeptic symptoms and potentially influencing factors before and up to 6 months following successful H. pylori eradication therapy. METHODS: Prospective cohort study involving H. pylori positive subjects from ambulatory or hospitalized care. Main outcome measures were symptoms during baseline and follow-up, the proportion of symptom-free patients, and symptom scores. RESULTS: After successful eradication, the summary score of all dyspeptic symptoms decreased and during follow-up, the proportion of symptom-free patients was higher in the group with peptic ulcers (69.4% vs. 40.9%, P < 0.0001) than with functional dyspepsia (FD). Regardless of diagnosis, virulent strains of H. pylori were associated with a higher prevalence of epigastric pain before treatment: absolute risk-difference (ARD) with Oip-A: 18.2%, Odds Ratio (OR) 2.35 [1.3-4.2, 95%-CI], P = 0.01; with Cag-A: 24.6%, OR 2.81 [1.6-5], P = 0.01. Low-dose aspirin in part was a major risk factor in FD for previous weight loss bdfore study entry. Post-treatment, non-ulcer patients were more likely to suffer from distention/bloating. Likewise, alcohol induced persistence of nausea and vomiting in this population. CONCLUSIONS: Dyspeptic symptoms in H. pylori infected patients are more common with virulent strains. Symptoms are more likely to persist despite successful eradication if patients initially harboured virulent strains or concomitant aspirin or alcohol intake are present. In one-third of peptic ulcer patients, symptoms will not be cured 3 months after therapy.

[Drug interactions. Mechanisms and clinical relevance]. / Arzneimittelinteraktionen. Mechanismen und klinische Bedeutung

During the last few years 3 important drugs (terfenadine, mibefradil, cisapride) had to been withdrawn from the market because of serious drug-drug interactions. Polypragmacy, not only in advanced age, is often applied. Consequently the possibility of pharmacokinetic and/or pharmacodynamic drug interactions has always to be taken into account which can cause adverse effects, therapeutic failures, hospital admissions and extra costs. Clinically relevant interactions can be observed especially on the level of drug metabolism and transport. Both pharmacokinetic processes can be induced or inhibited by numerous agents. Taking proton pump inhibitors as an example it could be shown that the various compounds can differ in their interaction potential.

Telomeres in neonates: new insights in fetal hematopoiesis.

Progressive telomere shortening occurs in somatic cells, and with increasing donor age a significant decline in telomere length has been shown in various postnatal tissues. In contrast, little is known about changes in telomere length during human fetal development. Therefore, we measured telomere length in the leukocyte fraction of umbilical cord blood samples from 15 preterm (<37 wk of gestation) and 11 full-term (>37 wk of gestation) neonates using the telomere restriction fragment assay. Whereas no differences in mean (+/- SD) telomere restriction fragment between the groups of preterm neonates (8512 +/- 523 bp) and full-term newborns (8323 +/- 503 bp) could be found, significantly longer telomeres (p = 0.002) were found in very low birth weight preterm neonates when compared with low birth weight preterm neonates. In addition, a rapid and significant decline in mean telomere restriction fragment was observed between 27 and 32 wk of gestation (p = 0.02, r = 0.79) followed by a period of no significant loss of telomere repeats between 33 and 42 wk of gestation. These results are consistent with the known almost maximal proliferation rate of hematopoietic progenitor cells before 32 wk of gestation. The initial decrease in telomere restriction fragment could be caused by ontogeny-related functional alterations of hematopoietic cells or differences in stem cell turnover or the rate of telomere loss per cell division.

Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein.

Proton pump inhibitors are a class of drugs which are widely prescribed for acid-related diseases. They are primarily metabolized by CYP2C19 and CYP3A4. It is unknown so far whether proton pump inhibitors are also substrates of the ATP-dependent efflux transporter P-glycoprotein. Moreover, it is not established whether proton pump inhibitors are also inhibitors of P-glycoprotein function. The aim of our study was therefore to characterize omeprazole, lansoprazole and pantoprazole as P-glycoprotein substrates and inhibitors. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells. Inhibition of P-glycoprotein-mediated transport was determined using the cyclosporine analogue PSC-833 (valspodar) as P-glycoprotein inhibitor. Inhibition of efflux transport by omeprazole, lansoprazole and pantoprazole was assessed using digoxin as P-glycoprotein substrate. At concentrations of 5 microM, basal-to-apical transport of omeprazole, lansoprazole and pantoprazole was greater than apical-to-basal transport in Caco-2 and L-MDRI cells. Addition of PSC-833 (1 microM) showed a clear effect only for lansoprazole, suggesting that other transporters contribute to omeprazole and pantoprazole cellular translocation. Furthermore, all of the tested compounds inhibited digoxin transport with IC50 values of 17.7, 17.9 and 62.8 microM for omeprazole, pantoprazole and lansoprazole, respectively. In summary, our data provide evidence that proton pump inhibitors are substrates and inhibitors of P-glycoprotein. These findings might explain some of the drug interactions with proton pump inhibitors observed in vivo.

Drug metabolism and drug interactions in the elderly.

In the elderly concomitant use of several drugs (polypharmacy) is very common. Thus, the risk for drug interactions might be increased in this population. Since most drugs are hepatically eliminated by various metabolic pathways, liver function has to be considered as an additional factor modifying drug response. This chapter focuses on the hepatic mechanisms of interactions, especially on various inhibitors and inducers of the most important cytochrome P450 isoenzymes involved in drug metabolism. In addition, age-dependent changes in liver function are addressed. Based on pharmacokinetic results with different probe drugs, some inconsistencies in this area are discussed. The most important metabolic drug-drug interactions are independent of the age of the patients. However, since elderly patients consume a greater proportional share of drugs, they represent a population at risk for interactions. Awareness of this clinical problem may help to diminish those risks.

Does pH 6 beta-galactosidase activity indicate cell senescence?

Apparently two forms of beta-galactosidase (beta-GAL) in cells or tissue sections can be detected by enzyme histochemical staining (X-GAL). Using a sensitive and specific HPLC method we have determined the pH dependent activity of beta-GAL in cell lines of lung carcinoma (A549), colon carcinoma (Caco2-TC7), promyelocytic leukemia (HL60), hepatoma (HepG2) and human liver homogenates. The HPLC method has been validated and the influence of pH and substrate concentration was studied. There was a good linear correlation between HPLC and quantitative enzyme histochemistry (pH 4.5: r = 0.985; pH 6.0: r = 0.967). Both, pH 4.5 beta-GAL and pH 6 beta-GAL could be demonstrated in all biological material tested and pH 6 beta-GAL activity was always lower (25-50%) than pH 4.5 activity. In Caco2-TC7 cells both activities increased by a factor of 10 from day 3 to day 17 after seeding. In addition, since the beta-GAL activity decreased with increase in pH both in human liver homogenates (independent of the age of the donor) as well as in tumor cell lysates in a similar fashion we believe that the activity at pH 6 can hardly be considered as an exclusive 'senescence marker'. In addition, the more sensitive HPLC method could demonstrate activity in cells that showed negative reaction with X-GAL.

Age-dependent eradication of Helicobacter pylori with dual therapy.

BACKGROUND: Combined treatment using an acid-inhibiting drug with antibiotics can cure Helicobacter pylori infection. However, eradication rates are highly variable, especially if a proton pump inhibitor is used with amoxycillin. Therefore it is important to define factors/predictors of the clinical outcome. METHODS: In a single-blind study, 60 H. pylori-positive patients prospectively matched for diagnosis (erosive gastritis, duodenal and gastric ulcer), age (above and below 50 years) and smoking habits were randomly treated (each group n = 20) for 2 weeks with amoxycillin (1 mg b.d.) and either omeprazole (20 mg b.d.), lansoprazole (30 mg b.d.) or ranitidine (300 mg b.d.). Intragastric pH and plasma levels of the administered drugs were monitored over a dosing interval of 12 h. RESULTS: The overall eradication rates were 45% (intention-to-treat, ITT, 27/60) or 47% (per protocol 27/58); they did not differ (ITT) between omeprazole (50%), lansoprazole (40%) and ranitidine (45%). Median pH and time at which intragastric pH was above 4 was slightly lower for ranitidine (4.0 +/- 1.7; 51 +/- 25%) than for omeprazole (5.4 +/- 1.1: 77 +/- 25%; P < 0.05) or lansoprazole (4.4 +/- 1.6: 68 +/- 32%). Plasma concentrations of amoxycillin were comparable in all three treatment groups. Post-treatment H. pylori status was not dependent on those levels, or the drug-induced extent or duration of increased intragastric pH. However, H. pylori-eradicated patients were significantly (P < 0.05) older (56 +/- 13 years) than patients still H. pylori-positive (47 +/- 14 years). In addition, in patients older than 50 years (n = 33), eradication was higher (P < 0.01) than in patients (n = 25) below 50 years (65 vs. 24%). Eradication rate was highest (75-83%) in subgroups of patients (> 50 years and history of peptic ulcer or smokers). Neither activity/grade of peptic ulcer or erosive gastritis nor initial diagnosis were predictors for clinical outcome. CONCLUSION: The age of patients must be regarded as a major determinant of H. pylori eradication rate and may represent an important factor contributing to the highly variable clinical results.

Pharmacokinetics of Na2B12H11SH (BSH) in patients with malignant brain tumours as prerequisite for a phase I clinical trial of boron neutron capture.

The disposition of Na2B12H11SH (BSH) in patients with malignant glioma has been investigated, in preparation for a Phase I clinical trial of boron neutron capture therapy. BSH was found to possess a linear disposition over the dosage interval investigated (up to 75 mg/kg). A bi-phasic blood pharmacokinetics was observed. Tumour-to-blood ratios showed variations between patients between 0.08 and 5.1. The data allow the definition of amount of BSH and timing of infusion for a Phase I clinical trial protocol.

Adenylate cyclase of gastric mucosa in patients with chronic renal failure.

It has been shown previously that antisecretory response of famotidine is altered in patients with renal failure. To evaluate the underlying mechanism(s) of this clinical observation we obtained biopsy specimens of fundic mucosa from 3 groups of patients with variable renal function (group 1 normal renal function (n = 16); group 2 chronic renal failure (n = 16), CLCR > or = 5 < 90 ml/min; group 3 hemodialysis therapy (n = 16)) (matched for age, sex, and Helicobacter pylori (Hp) status. In the homogenized samples adenylate cyclase (AC) activity was assessed and the influence of uremia on this second messenger system involved in gastric acid secretion was tested. AC activity was measured as the formation of cAMP, which was determined by RIA. The mean basal AC activity was 150 in group 1, 190 in group 2, and 120 pmol cAMP/mg protein/20 min in group 3. There was a dose-dependent stimulation by histamine (1 microM-1 mM). Emax of cAMP formation ranged between 230 and 403 pmol cAMP/mg protein/20 min and EC50 between 5.9 and 20.1 microM histamine, dependent on Hp status. Histamine-stimulated AC activation was reduced to about 50% by 0.1 mM famotidine. The sensitivity of AC to histamine seems to decrease in patients undergoing hemodialysis. Similarly, the colonization with Hp may result in decreased maximal response of the AC system towards histamine.

Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer.

Female gender is a significant independent favorable prognostic factor in lung cancer. To study the possible role of sex hormones in lung cancer, the expression of sex-steroid receptors and the glucocorticoid receptor was investigated in 29 lung-cancer cell lines stemming from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) by means of immunocytochemistry, ligand-binding assays and RNA expression via polymerase chain reaction. In at least 2 methods of investigation, NSCLC cell lines showed a low expression of estrogen receptor in 6, progesterone receptor in 13 and androgen receptor in 12 out of 17 cases examined; sex-steroid-receptor expression was virtually absent in SCLC cell lines. The glucocorticoid receptor was expressed in all 29 cell lines studied. Additionally, 52 tumor samples from primary lung cancer were investigated for their receptor expression by means of immunohistochemistry. Among patients with primary lung-cancer sex-steroid-receptor expression in tumor biopsies was detected most frequently in female patients (in 69% of 16 cases, vs. 42% of 36 tumors from men) and in patients with adenocarcinoma. Further research will focus on these subgroups. Immunohistology is a feasible method of studying steroid-receptor expression in lung cancer.

Influence of diet and nutritional status on drug metabolism.

Genetic and environmental factors contribute to a wide inter- and intraindividual variability in drug metabolism. Among the environmental factors that may influence drug metabolism, the diet and nutritional status of the individuals are important determinants. As altered drug-metabolising enzyme activities can influence the intensity and duration of drug action, such factors should be considered in pharmacotherapy. For this reason the effects of dietary energy, protein deficiency, nutritional ingredients, special diet forms and nutrition regimens and malnutritional states must be differentiated. In various pharmacokinetic studies different model drugs metabolised either by oxidative phase I pathways [e.g. phenazone (antipyrine), aminopyrine, phenacetin, theophylline, propranolol, nifedipine] or phase II conjugation reactions [e.g. paracetamol (acetaminophen), oxazepam] were used and from the calculated pharmacokinetic data some information on the involved and affected drug-metabolising enzymes [e.g. cytochrome P450 (CYP) subspecies, glucuronosyltransferases] can be generated. It is well known that smoking, charcoal broiled food or cruciferous vegetables induce the metabolism of many xenobiotics, whereas grapefruit juice increases the oral bioavailability of the high clearance drugs nifedipine, nitrendipine or felodipine by inhibiting their presystemic (intestinal) elimination. Energy deficiency, and especially a low intake of protein, will cause a decrease of about 20 to 40% in phenazone and theophylline clearance and elimination of those drugs can be accelerated by a protein-rich diet. In the same way, protein deficiency induced by either vegetarian food or undernourishment will have the opposite pharmacokinetic consequences. On the basis of some more examples from the literature it is emphasised that the variable influence of the above factors should be taken into account in study participant selection and study design when the pharmacokinetics of a drug must be determined in healthy individuals and/or patients.

Inadequate response to H2-receptor antagonists. Absence of parietal cell cAMP-stimulating autoantibodies.

In peptic ulcer patients with adequate (AR; N = 16) and inadequate response (IR; N = 20) to H2-receptor antagonists, the presence of parietal cell cAMP-stimulating autoantibodies was studied. Serum Ig fractions from these patients and 10 control subjects were examined to test whether they could stimulate cAMP production in a gastric cell line model. The human cell line HGT-1 was found to be a sensitive in vitro model for the cAMP stimulation assay as histamine (10 microM) increased by 11-fold the production of cAMP. Neither IgG (4 mg/ml) nor IgG-free Ig fractions (1 mg/ml) isolated from the blood of AR or IR affected cAMP production in the HGT-1 cells. The results obtained with the cAMP stimulation assay were confirmed by indirect immunofluorescence measurements based on frozen sections of rat stomach and kidney. No specific staining of rat parietal cells could be observed with patient sera. In addition, human gastric biopsies of the oxyntic mucosa from the same patients were studied for immunoreactive cell populations to assess organ-specific autoimmune processes. Biopsy specimens from AR and IR showed increased lymphocytic infiltrates, usually associated with gastritis. However, no significant differences in location of various cell populations between AR and IR could be observed. Our findings do not support a recent hypothesis that poor response to treatment with H2-receptor antagonists is due to the presence of autoantibodies.

[5-aminosalicylic acid and chronic inflammatory bowel diseases in children]. / 5-Aminosalicylsäure (5-AS) und chronisch entzündliche Darmerkrankungen bei Kindern.

5-Aminosalicylate (mesalazine; 5-AS) represents a new therapeutic strategy in chronic inflammatory bowel disease. The drug (active metabolite of sulfasalazine) has proven its clinical efficacy and safety in numerous controlled studies in adults. However only limited data are available for the pediatric population. This brief review summarises the published spares information on this promising agent. As pharmacokinetic properties of 5-AS are age-independent and since 5-AS has a wide margin of safety clinical studies and use of this drug should be encouraged also in children.

Lansoprazole does not affect the bioavailability of oral contraceptives.

The effects of the proton pump inhibitor lansoprazole on the bioavailability of a low-dose oral contraceptive (OC), containing 0.03 mg ethinyloestradiol (EE) and 0.15 mg levonorgestrel (LNG), were investigated. Twenty-four healthy females (aged 19-35 years; weight 60.6 +/- 7.1 kg) participated in a multiple-dose, placebo-controlled, randomized two-way cross-over study. All subjects received the OC over 2 full menstrual cycles from day 1 to day 21 separated by a drug-free interval of 7 days. Lansoprazole (60 mg day-1) or placebo was coadministered for 3 weeks each. Plasma concentrations of EE and LNG were determined by GC-MS. The 90% confidence intervals for ratios of Cmax and AUC after log transformation of both EE and LNG ranged between 91 and 111%, indicating that lansoprazole did not affect the bioavailability of EE and LNG.

PIP: The research reported in this paper assessed the effects of the proton pump inhibitor lansoprazole on the bioavailability of a low-dose oral contraceptive (OC) containing 0.03 mg ethinyl estradiol (EE) and 0.15 mg levonorgestrel (LNG). Blood plasma concentrations of lansoprazole, EE, LNG, and several hormones were measured following a two-way, cross-over study design. 24 German women in good health were used in this study. All subjects received physical examinations, complete laboratory work-ups, and were found normal. All women received the OC over two complete menstrual cycles from days 1 to 21, with the remaining 7 days being drug-free. 60 mg per day of lansoprazole or a placebo were given for 21 days with the OC. Plasma was assayed by capillary column gas chromatography with mass spectrometry. Urine was also collected and analyzed. The results showed that the 24 women did not experience any significant change or alteration in plasma EE and LNG levels.