Absorption Of Oral Medications Research Articles

Description of Gastric Acidity (pH) with Simple Method in Lipopolysaccharide Induced Mice

The gastrointestinal acidity/pH can considerably influence the stability and absorption of oral medications. As a result, understanding the circumstances for drug delivery requires knowledge of gastrointestinal pH. Mice injected with lipopolysaccharide (LPS) are used in the most well-studied animal models of sepsis. However, information on gastrointestinal pH in sepsis mice is still insufficient. This study was conducted to identify gastric pH values in mice induced by lipopolysaccharide. The LPS was injected intraperitoneally as well as 0.9% NaCl as control groups. Treated groups (LPS) consisted of four groups and the control group (0.9% NaCl) consisted of four groups. Ten mice were used in each group. Gastric pH measurement was conducted using pH meter Lutron PH-201. Based on this study, the factors that influenced gastric pH in sepsis animal models were the LPS doses and the time after LPS injection. The results of gastric pH measurement in sepsis mice did not show a decrease in the pH compared to the normal conditions. The dose of LPS significantly influences the gastric pH change.

1122. Effect of Aluminum Hydroxide/Magnesium Hydroxide/Simethicone and Omeprazole on the Pharmacokinetics of Tebipenem Pivoxil Hydrobromide (TBP-PI-HBr) in Healthy Adult Subjects

BackgroundTebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug that is converted to tebipenem (TBP), the active moiety being developed for treating complication urinary tract infections. Antacids and proton pump inhibitors are known to change gastric pH after administration, which could affect the absorption of oral medications. This study evaluated the effect of a single dose of aluminum hydroxide/magnesium hydroxide/simethicone and the effect of multiple doses of omeprazole on the PK of TBP, following a single dose of TBP-PI-HBr.MethodsThis was an open-label, 3-period, fixed sequence drug-drug interaction study. On Day 1, Period 1, subjects received a single oral dose of TBP-PI-HBr 600 mg (2 x 300 mg tablets) at Hour 0. On Day 1, Period 2, subjects received a single oral 20 mL dose of aluminum hydroxide 800 mg/magnesium hydroxide 800 mg/simethicone 80 mg suspension per 10 mL (Maalox® Advanced Maximum Strength oral suspension) with a single oral dose of TBP-PI-HBr 600 mg at Hour 0. In Period 3, on Days 1 through 5, subjects received a single oral dose of omeprazole 40 mg (Prilosec®) once daily (QD), at Hour -2. On Day 5, a single oral dose of 600 mg TBP-PI-HBr was administered at Hour 0. Whole blood sampling for TBP PK occurred pre-dose and up to 24 hours post dose. Whole blood samples were assayed for TBP by liquid chromatography-tandem mass spectrometry.ResultsTwenty subject were enrolled and completed the study. Geometric mean ratios for AUC indicated mean TBP exposure (AUC) was approximately 11% lower and mean Cmax was 22% lower for TBP-PI-HBr combined with aluminum hydroxide/magnesium hydroxide/simethicone vs. TBP-PI-HBr alone (Figure). Similarly, geometric mean ratios for AUC indicated mean TBP exposure (AUC) was approximately 11% lower and mean Cmax was 43% lower for TBP-PI-HBr in combination with omeprazole vs. TBP-PI-HBr alone. Because the PK/PD driver for TBP efficacy is AUC dependent, concomitant administration is not expected to impact the efficacy of oral TBP-PI-HBr. Figure 1. Arithmetic mean plasma TBP concentrations following a 600 mg dose of clinical study drug product (A1 and A2) and registrational drug product (B) – PK population.ConclusionAdministration of TBP-PI-HBr combined with aluminum hydroxide/magnesium hydroxide/simethicone or omeprazole QD had no meaningful effect on plasma TBP exposure; Cmax decreased with both agents. Co-administration was generally safe and well tolerated.Disclosures Vipul K. Gupta, Ph.D., Spero Therapeutics (Employee, Shareholder) Gina Patel, PhD, Spero Therapeutics, Inc. (Consultant) Leanne Gasink, MD, Spero Therapeutics, Inc. (Consultant) Floni Bajraktari, MSc, Spero Therapeutics, Inc. (Employee) Yang Lei, PhD, Spero Therapeutics, Inc. (Employee) Akash Jain, PhD, Spero Therapeutics, Inc. (Employee) Praveen Srivastava, MS, BS, Spero Therapeutics, Inc. (Employee) Angela Talley, MD, Spero Therapeutics, Inc. (Employee)

The use of non-oral therapies in Parkinson's disease

It is widely recognised that with the progression of Parkinson's disease, oral treatments that are used in the management of symptom control may become less effective. This can be due to a number of reasons, but a dysfunctional gastrointestinal tract is increasingly thought to play a major role. Features including severe motor and/or non-motor fluctuations may be due to issues related to gastrointestinal dysfunction, including delayed gastric emptying and reduced absorption of oral medication. The Parkinson's specialist will therefore need to consider alternative treatment approaches that could be beneficial for the person living with Parkinson's disease. This article will provide an overview of treatment approaches that do not rely on the gastrointestinal system, and these are referred to as non-oral therapies.

Intestinal Stem Cells to Advance Drug Development, Precision, and Regenerative Medicine: A Paradigm Shift in Translational Research

Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell-derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies. Importantly, because they are derived from individuals with different genotypes, environmental risk factors and drug sensitivity profiles, organoids are a highly relevant screening system for personalized therapy in both human and veterinary medicine. Lastly, and in the context of patient-specific congenital diseases, orthotopic transplantation of engineered organoids could repair and/or replace damaged epithelial tissues reported in various GI diseases, such as inflammatory bowel disease, cystic fibrosis, and tuft enteropathy. Ongoing translational research on organoids derived from dogs with naturally occurring digestive disorders has the potential to improve the predictability of preclinical models used for optimizing the therapeutic management of severe chronic enteropathies in human patients.

Non-oral dopaminergic therapies for Parkinson's disease: current treatments and the future.

Dysfunction of the gastrointestinal tract has now been recognized to affect all stages of Parkinson’s disease (PD). The consequences lead to problems with absorption of oral medication, erratic treatment response, as well as silent aspiration, which is one of the key risk factors in developing pneumonia. The issue is further complicated by other gut abnormalities, such as small intestinal bacterial overgrowth (SIBO) and an altered gut microbiota, which occur in PD with variable frequency. Clinically, these gastrointestinal abnormalities might be associated with symptoms such as nausea, early-morning “off”, and frequent motor and non-motor fluctuations. Therefore, non-oral therapies that avoid the gastrointestinal system seem a rational option to overcome the problems of oral therapies in PD. Hence, several non-oral strategies have now been actively investigated and developed. The transdermal rotigotine patch, infusion therapies with apomorphine, intrajejunal levodopa, and the apomorphine pen strategy are currently in clinical use with a few others in development. In this review, we discuss and summarize the most recent developments in this field with a focus on non-oral dopaminergic strategies (excluding surgical interventions such as deep brain stimulation) in development or to be licensed for management of PD.

Metoclopramide nasal spray is effective in symptoms of gastroparesis in diabetics compared to conventional oral tablet

Delayed gastric emptying symptoms interfere with the absorption of oral medications. Intranasal metoclopramide is being developed as an alternative to oral metoclopramide for patients with diabetic gastroparesis. To compare the efficacy and safety of metoclopramide nasal spray to oral tablets in diabetic patients with symptoms of gastroparesis, this randomized, open-label, parallel design study randomized subjects to 10 or 20 mg nasal spray or 10 mg tablet four times a day for 6 weeks. Efficacy was evaluated using a total symptom score (TSS). Eighty-nine subjects were enrolled. For the intention to treat population, both nasal dose groups (10 and 20 mg) had lower TSS with treatment compared to the oral 10 mg group. The change from baseline in TSS for nasal 20 mg was greater than the oral 10 mg at Week 6 (p = 0.026). For the per-protocol population, there was a significant difference in the TSS between baseline and Week 6 for both the nasal 10 mg (p = 0.026) and the nasal 20 mg (p = 0.008) cohorts compared to the oral 10 mg group. Based on the definition of a responder, 88.9% of subjects who received oral 10 mg, 91.2% who received nasal 10 mg, and 97.1% who received nasal 20 metoclopramide were classified as responders. The side-effect profile of the metoclopramide nasal spray was favorable. More side effects, especially nausea, occurred with the oral tablets. Metoclopramide nasal spray offers better symptom control than metoclopramide oral tablet in diabetic patients with symptoms of gastroparesis.

BK Virus Encephalitis

To describe a case of BK virus encephalitis with attempted direct antiviral therapy, review the reported cases of BK virus in the central nervous system, and report the novel use of intravenous cimetidine in place of oral probenecid to minimize the toxicities of intravenous cidofovir. A 36-year-old male with acute myelomonocytic leukemia and subsequent myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplant. His course was complicated by severe graft-versus-host disease involving his skin and gastrointestinal tract. Five weeks after transplantation, he developed fever and confusion. Magnetic resonance imaging was suggestive of limbic encephalitis and cerebrospinal fluid tested positive for BK virus. Therapy with intravenous cidofovir was thought to be indicated. Although probenecid is commonly used to minimize the toxicities of cidofovir, the patient's severe graft-versus-host disease raised concerns about absorption of oral medications. Based on animal models and pharmacokinetic data, intravenous cimetidine was used in place of oral probenecid. Despite these therapies, the patient's mental status did not improve. He developed progressive organ system failure, and care was ultimately withdrawn. BK virus is increasingly described as a cause of encephalitis. The majority of reported cases have occurred in immunocompromised patients and have generally had a poor outcome. This case describes attempted antiviral therapy using cidofovir, the antiviral agent used most frequently in other syndromes due to BK virus. Intravenous cimetidine is a novel modality used to minimize ocular and renal toxicities frequently seen with cidofovir, and we believe this warrants further investigation. BK virus may be a cause of encephalitis in immunocompromised hosts, and cidofovir represents a possible treatment option. Intravenous cimetidine can be considered to minimize toxicities associated with cidofovir use in patients unable to tolerate or absorb oral probenecid.

New drugs: Liraglutide, dalfampridine, and abobotulinumtoxinA

Antidiabetic agent Liraglutide (Victoza—Novo Nordisk) is an analog of glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 receptor agonist. Its properties are most similar to those of exenatide (Byetta), and both agents are administered subcutaneously. Liraglutide and exenatide reduce blood glucose concentrations via several mechanisms that include increased insulin release in the presence of elevated glucose concentrations, decreased glucagon secretion, and delayed gastric emptying. Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes and may be used as monotherapy or in conjunction with one or more oral antidiabetic drugs, such as metformin, glimepiride, or a thiazolidinedione. However, it is not recommended as first-line therapy for patients inadequately controlled on diet and exercise, whereas the labeling for exenatide does not include this limitation. The effectiveness of liraglutide was demonstrated in studies in which it was used alone or in patients also treated with metformin and/or glimepiride or with metformin and rosiglitazone (Avandia). In the study in which liraglutide monotherapy was compared with glimepiride monotherapy, the new drug provided significantly greater reductions in glycosylated hemoglobin (A1C; –0.8% and –1.1% with daily doses of 1.2 and 1.8 mg liraglutide, respectively, compared with –0.5% with 8 mg daily glimepiride, after 52 weeks). In one study, either liraglutide (1.8 mg once a day) or exenatide (10 μg twice a day) was added to a regimen of metformin and/or glimepiride. After 26 weeks, patients receiving liraglutide achieved a significantly greater reduction in A1C from baseline (–1.2%) compared with 0.79% in patients receiving exenatide. Liraglutide also provided significantly greater reductions in fasting plasma glucose, but patients treated with exenatide experienced a greater reduction in postprandial glucose after breakfast and dinner. As with exenatide, many patients treated with liraglutide lose weight (~3 kg on average); this is an added benefit for these medications, which are often used in patients who are overweight. In contrast, use of glimepiride and other sulfonylureas is often associated with weight gain. The adverse events reported most often in the study in which liraglutide was used as monotherapy included nausea (28%), diarrhea (17%), vomiting (11%), constipation (10%), upper respiratory tract infection (10%), and headache (9%). As with exenatide, pancreatitis has been reported infrequently. Caution should be exercised in patients with a history of pancreatitis, particularly when treatment is initiated and following increases in dosage. If symptoms suspected to be associated with pancreatitis develop, treatment should be discontinued. If pancreatitis is confirmed, liraglutide should not be resumed. Liraglutide has been reported to cause malignant thyroid C-cell tumors in rodents, and this is the subject of a boxed warning in the labeling for the drug. Although whether liraglutide causes such tumors, including medullary thyroid carcinoma (MTC), in humans is unknown, the new drug is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2. The labeling for exenatide does not address this problem, although recent observations suggested the possibility of an increased cancer risk with its use. Many of the patients in the clinical studies were tested for the presence of anti-liraglutide antibodies at the end of treatment. These antibodies were detected in approximately 9% of those tested, but the potential for significant neutralization of the clinical benefit was not assessed. Although experienced infrequently, immunogenicity-related events, including urticaria, were reported more often in patients treated with liraglutide (0.8%) than with other antidiabetic agents. Liraglutide is classified in Pregnancy Category C and should only be used during pregnancy if the anticipated benefit justifies the risk to the fetus. Whether the drug is excreted in human milk is not known, and a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of liraglutide in pediatric patients have not been established. Liraglutide is not likely to cause hypoglycemia. However, serious hypoglycemia may result when it is used concurrently with an insulin secretagogue such as a sulfonylurea. The risk of hypoglycemia may be reduced by decreasing the dosage of the latter agent when treatment with liraglutide is initiated. Because liraglutide delays gastric emptying, a potential exists for altered absorption of oral medications used concurrently. Although interactions of this type were not reported in the clinical studies, the potential for changes in absorption and activity of orally administered drugs should be monitored. Liraglutide is administered subcutaneously in the abdomen, thigh, or upper arm. Following administration, maximum concentrations are attained within 12 hours, and the absolute bioavailabil-

The Effect of Sevelamer on Tacrolimus Target Levels

Herein we report on a 55-year-old male patient who received his second kidney transplant because of recurrent IgA nephropathy in 1999. The graft function had been stable during the first years following the transplantation, with the immunosuppressive therapy consisting of tacrolimus, mycophenolate mofetil, and low-dose steroid. In July 2004, cardiac surgery was performed because of severe coronary artery disease and aortic stenosis. The patient was dependent on dialysis perioperatively. Mycophenolate mofetil was discontinued because of a persistently low creatinine clearance. However, the patient refused to return on a chronic hemodialysis program and was therefore kept on low doses of tacrolimus and steroid. Intermittent dialysis treatments were performed. In August 2004, sevelamer (Renagel, 800 mg tablets by Genzyme) was started because of a high calcium-phosphate product. The oral medication was otherwise retained unchanged. Subsequently, a progressive decline in tacrolimus blood levels was observed. In spite of an increased tacrolimus dosage, target levels were measurable only temporarily in the context of further deteriorations of kidney function (Fig. 1). Significant reductions in the peak level of tacrolimus (Cmax) and the area under the curve (AUC) following one oral dose of 1.5 mg tacrolimus were found when compared to tacrolimus kinetics in the same patient three days after discontinuation of sevelamer, with Cmax 9.9 vs. 13.1 ng/ml and AUC7 4.02 vs. 9.69 ng×h/ml (Fig. 2). For performance of the pharmacokinetic study, tacrolimus levels were measured immediately before and 1, 2, 5, and 7 hr after intake of the drug by immunoassay (EMIT by Dade Behring), the calculation of the AUC was performed by the trapezoidal rule. Informed consent was obtained from the patient.FIGURE 1.: Time course of serum creatinine, tacrolimus blood levels (with the detection limit of the assay being 2.5 ng/ml), and daily tacrolimus dosage.FIGURE 2.: Tacrolimus blood levels in ng/ml (assay detection limit 2.5 ng/ml) following one dose of tacrolimus 1.5 mg p.o., with and without sevelamer 3×800 mg p.o.Sevelamer hydrochloride is a nonabsorbable, polymeric phosphate binder that does not contribute to calcium load, aluminium toxicity, or changes in acid-base status. Within the intestinal lumen, the cationic sevelamer binds phosphate through ion exchange. Sevelamer is known to reduce absorption of vitamin D, E, K, and folic acid. More importantly, decreases in the peak concentration and AUC of mycophenolate mofetil have been described (1). There are conflicting data regarding the interaction of sevelamer with cyclosporine; a marked decrease in trough levels was described in a patient on hemodialysis, whereas the pharmacokinetic profile of cyclosporine in patients with a stable graft function after renal transplantation was not significantly affected by sevelamer (1,2). Although no other drug interactions have been substantiated so far, it is recommended to take any accompanying medication at least one hour before or three hours after a dose of sevelamer when changes in absorption of oral medications may have significant clinical consequences. This is the first time a decrease in tacrolimus blood levels with concomitant intake of sevelamer is reported. A direct binding of lipophilic substances by sevelamer as discussed for cyclosporine seems to be the most likely mechanism of interaction (3).

Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1).

The multidrug resistance (MDR1) gene product P-glycoprotein is a membrane protein that functions as an ATP-dependent efflux pump, transporting exogenous and endogenous substrates from the inside of cells to the outside. Physiological expression of P-glycoprotein in tissues with excretory or protective function is a major determinant of drug disposition and provides a cellular defense mechanism against potentially harmful compounds. Therefore, P-glycoprotein has significant impact on therapeutic efficacy and toxicity as it plays a key role in absorption of oral medications from the intestinal tract, excretion into bile and urine, and distribution into protected tissues such as the brain and testes. There is increasing interest in the possible role of genetic variation in MDR1 in drug therapy. Numerous genetic polymorphisms in MDR1 have been described, some of which have been shown to determine P-glycoprotein expression levels and substrate transport. Furthermore, some of these polymorphisms have an impact on pharmacokinetic and pharmacodynamic profiles of drug substrates and directly influence outcome and prognosis of certain diseases. This review will focus on the impact of genetic variation in MDR1 on expression and function of P-glycoprotein and the implications of this variation for drug therapy and disease risk.

Anti-emetics

SUMMARYNausea and vomiting are common symptoms of migraine, which can be controlled with a variety of anti-emetics including phenothiazines and antihistamines. Metoclopramide and domperidone have an additional prokinetic effect which may be important in migraine to overcome gastric stasis and enhance absorption of oral medication.

Eletriptan in acute migraine: A double-blind, placebo-controlled comparison to sumatriptan

To the Editor: Goadsby et al.1 present the data of a double-blind, placebo-controlled, parallel-group comparison of the two triptans, eletriptan and sumatriptan. This comparison warrants attention. First, a double-dummy design was used in which eletriptan was compared with encapsulated sumatriptan. I question this design, as opposed to the proper (and also easier) way of conducting a comparative trial encapsulating both medications. The authors realize that it may be problematic, because “the encapsulated sumatriptan was bioequivalent to the commercial tablet (Pfizer, data on file).” How bioequivalent are the encapsulated and nonencapsulated sumatriptan preparations? Were the data obtained in a setting relevant to the study—that is, during (moderate or severe) migraine headache? Volan2 conducted ground-breaking work in the 1970s and others confirmed that the absorption of oral medications is impaired during migraine headache. Bioequivalency is essential in studies comparing a nonencapsulated product with an encapsulated one. The actual data on bioequivalency should have been presented in the article, allowing the reader to judge the degree of bioequivalency him- or herself. The second issue concerns optimum dose, which is important in comparative trials because the results are generally considered relevant only when the medications are compared in their optimum dosages. With regard to the triptans, optimum dose determination has been based on the highest effective dose with placebo-level adverse events, the lowest effective dose with maximum therapeutic benefit, or both. According to Pfaffenrath et al.,3 the optimum dose of sumatriptan was determined as 50 mg, which is both the highest effective dose with placebo-level adverse events and the lowest effective dose with maximum therapeutic benefit. At a satellite symposium of the 9th Congress of the International Headache Society (Barcelona, Spain, 1999), Jackson presented pooled data on the efficacy of eletriptan 20, 40, and 80 mg in comparison with placebo. The …

ATG-FRESENIUS S BOLUS THERAPY IN PROPHYLAXIS AFTER RENAL TRANSPLANTATION - EARLY RESULTS

317 Monoclonal or policlonal antilymphocyte antibodies have been successfully used in organ transplantation as induction therapy. Generally the medication is given for the first 7-10 days. The aim of this study was to asses the safety and efficacy of high single dose (9mg/kg) ATG Fresenius S given perioperatively to the kidney allograft recipients before revascularization. Eighty, adult first cadaveric kidney recipients were included into the study. Excluded from the trial were recipients of kidney from living donor, patients (pts) with chronic liver disease, trombocytopenia (<80000/mm3), leucopenia (<4000/mm3), gastrointestinal disorders, which could interfere with absorption of oral medications and patients with a history of malignancy. All pts received triple drug immunosuppresion (Neoral, steroids and Cellcept which was substituted by azathioprine after 4 months) and were randomised to receive ATG or not. During last twelve months 76 pts were so far randomised in two centres (centre A-64, centre B-12). The follow up period ranges from 1 month up to 1 year. (Table 1)Table 1Rejections till 120 day (till conversion to AZA) (Table 2)Table 2The preliminary results are very promising, the rejection rate in bolus group seems to be much lower than in control. No significant side effects and serious adverse event differences in both group were observed.

Digestive Enzyme Adjunct to Oral Headache Medication to Improve Absorption and Reduce Vomiting

Objective: To report a case in which a digestive enzyme complex (Nature's Plus Digestive Enzymes: pancreatin, pepsin, ox bile extract, malt diatase, and papain) apparently improved the absorption and efficacy of an oral headache medication and alleviated vomiting associated with the headache. Case Summary: A 47-year-old white woman with a history of adverse drug reactions and allergies had been experiencing one to four disabling headaches per week for 2 years. One or two headaches each week would be accompanied by vomiting. This patient experienced adverse effects with most standard headache medications. For 40 months since taking a complex of digestive enzymes as an adjunct to her headache medication, the patient's vomiting has been eliminated, and her postheadache symptoms have been reduced. Discussion: Altered digestive processes are a common finding in severe headache episodes. Exogenous digestive enzymes may facilitate the absorption of oral medication during gastric disruption and consequently increase drug efficacy and the relief of symptoms. Conclusions: Digestive enzymes merit further study to ascertain their effectiveness in increasing the absorption and efficacy of oral medications prescribed for headaches accompanied by emesis.