Reduction In Drug Concentration Research Articles

Emergency care drugs' chemical stability after eight weeks’ deployment in the prehospital setting

Temperature conditions vary in emergency service vehicles, which may pose a risk to the integrity of the drugs on board, possibly rendering them ineffective and increasing morbidity and mortality in patients. AimThis study assessed the stability of four emergency care drugs (adrenaline, etomidate, ketamine, and rocuronium) after eight weeks of deployment in the prehospital context. MethodsThe study adopted a longitudinal quantitative design to evaluate the chemical stability of emergency care drugs. The study was conducted at four emergency medical service bases in Ballito, Durban and Pietermaritzburg, South Africa. The primary outcome was the relative reduction in drug concentration from the labelled concentration after four and eight weeks. High-performance liquid chromatography-mass spectrometry (HPLC-MS) analysed samples to determine the concentration of active ingredients in the drug samples. ResultsHPLC analysis was done on 176 samples. The ambient temperature ranged from 18.7 to 44 °C in the first four weeks, averaging 26.8 °C ± 3.0. At 4 and 8 weeks, Adrenaline decreased 24.93 % and 22.73 %, respectively. Etomidate's control had 3.06 mg/ml, not the 2 mg/ml on the bottle. After 4 and 8 weeks, the samples had 3.10 and 3.15 mg/ml active components, respectively. Ketamine degraded over 30 % after four weeks but not beyond that. The Ketamine package states 10 mg/ml. However, we found 17.46 mg/ml. Rocuronium was 6.45 mg/ml in the control, although the manufacturer specified 10 mg/ml. At four weeks, the concentration was 6.70 mg/ml; at eight weeks, 6.56. ConclusionThis study suggests that adrenaline and ketamine degrade by more than 20 % within four weeks of deployment in the prehospital field, whereas etomidate and rocuronium remain stable after eight weeks.

ID: 216262 Longitudinal Data From the Targeted Drug Delivery (TDD) Product Surveillance Registry: Inflammatory Mass

TDD with programmable intrathecal drug delivery systems (IDDS) has been approved for chronic malignant and nonmalignant pain treatment since 1991 and severe spasticity since 1992. Intrathecal inflammatory mass (IM) is a known risk of intrathecally delivered opioid compound. IM’s, or granulomas, are sterile masses that develop proximal to the intrathecal (IT) catheter tip, consisting of inflammatory cells and fibroblasts. Rates of IM have been decreasing over time. We conjecture that this is due to education, research, and changes in clinical practice with reduction of drug concentrations and dosing.

Detection of drugs and metabolites in hair before and after treatment with freely available agents chosen to effectively remove drugs from the hair matrix – A case study

Hair analysis is commonly used to control abstinence or provide evidence for drug use or drug exposure. While dyeing and coloration of hair have been proven to potentially reduce drug concentrations in hair, relatively little is known about the reduction of drug concentrations after extensive use of ‘household remedies’. In this study, a male subject with known past drug intake applied multiple washing procedures including the use of egg yolk, olive oil and vinegar in addition to common hair shampoo for one week in order to intentionally reduce drug concentrations in hair. Solutions with varying compositions were applied to the head for one hour per day. Hair samples were taken before and after the washing procedure from different parts of the skull. For drug analysis the samples were divided into two segments (0–3 cm and 3–6 cm). The analyses comprised methanol extraction and LC-MS/MS detection of cocaine and metabolites, designer stimulants, opioids and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) as well as alkaline hydrolysis followed by liquid-liquid extraction and GC MS/MS detection for Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN). The following drugs or drug metabolites were detected in the hair samples before the washing procedure in accordance with the information given by the subject: cocaine, benzoylecognine, cocaethylene, amphetamine, MDMA, nortilidine, 3-fluorophenmetrazine, ketamine, norketamine and the cannabinoids THC, CBD, CBN and THC-COOH. The concentrations differed depending on the location of hair sampling. After the washing procedure, drug concentrations in hair were significantly reduced (up to about 70%). In some cases, the drug concentrations fell below the values mentioned in the ‘CTU’ criteria for driving liability diagnostics. It is possible to significantly reduce drug concentrations in hair with products available for everyone. In cases with initial drug concentrations close to ‘cut-off’ values, such procedures might lead to ‘false negative’ results.

Towards understanding microbial degradation of chloroquine in large saltwater systems

Circulating saltwater aquariums hosting marine animals contain a wide range of microorganisms, which have strong implications on promoting animal health. In this study, we investigated the degradation of chloroquine phosphate, an anti-parasitic bath pharmaceutical used in saltwater quarantine and exhibition systems, and attributed the reduction in drug concentration to microbial degradation of chloroquine associated with pipeline microbial communities. To advance our knowledge on chloroquine degradation in aquatic systems, we conducted microbial and chemical analyses on three tropical saltwater systems. Our findings show that aquarium microbiome composition is shaped by sampling location (i.e., tank water and pipeline; PERMANOVA R2 = 0.09992, p = 0.0134), chloroquine dosing (PERMANOVA R2 = 0.05700, p = 0.0030), and whether the aquarium is occupied by marine animals (PERMANOVA R2 = 0.07019, p = 0.0009). Several microbial taxa belonging to the phyla Actinobacteria, Bacteroidetes, Chloroflexi, and Proteobacteria, along with functional genes related to pathways such as phenylethylamine degradation and denitrification, appeared to have differential (relative) abundance between samples where chloroquine degradation was observed and those without degradation (Benjamini-Hochberg adjusted p-value <0.05). Together, these results provide practical mitigation options to prevent or delay the development of chloroquine-degrading microbial communities in saltwater aquariums. Our results further demonstrate the need to improve our understanding of the interactions between nitrogen availability and microbial activity in saltwater systems.

Drug dosing during pregnancy-opportunities for physiologically based pharmacokinetic models.

Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed.

Plasmid-mediated quinolone resistance – PMQR MECHANIZMY OPORNOŚCI NA FLUOROCHINOLONY

Abstract Fluoroquinolones(FQ) are broad-spectrum antimicrobial agents widely used to treat a range of infections in clinical medicine. However, the surveillance studies demonstrate that fluoroquinolone resistance rates increased in Enterobacteriaceae in the past years. FQ inhibit bacterial DNA synthesis by interfering with the action of two bacterial enzymes - DNA gyrase and topoisomerase IV. There are two categories of quinolone resistance mechanisms: chromosomally encoded and acquired. Mutations in chromosomal genes encoding gyrase and topoisomerase IV are the most common mechanisms responsible for high-level fluoroquinolone resistance. Mutations can occur also in regulatory genes which control the expression of native efflux pumps located in bacterial membrane. Furthermore, three mechanisms of plasmid-mediated quinolone resistance (PMQR) have been discovered so far, including Qnr proteins, the aminoglycoside acetylotransferase variant - AAC(6’)-Ib-cr, and plasmid-mediated efflux pumps - QepA and OqxAB. Although the PMQR mechanisms alone cause only low-level resistance to fluoroquinolone, they can complement other mechanisms of chromosomal resistance and facilitate the selection of higher-level resistance. Moreover, plasmids with PMQR mechanisms often encode additional resistance traits (ESBLs, pAmpC, KPC) contributing to multidrug resistance (MDR). This review is focused on a range of molecular mechanisms which underlie quinolone resistance. 1. Introduction. 2. Mechanisms of fluoroquinolone action. 3. Chromosomally-encoded fluoroquinolone resistance. 3.1. Mutations changing the functions of target enzymes. 3.2. Reduction of drug concentration in the cytoplasm - efflux pump. 4. Plasmid-mediated quinolone resistance. 4.1. Qnr proteins. 4.2. AAC(6’)-Ib-cr enzyme. 4.3. Plasmid-mediated efflux pump: QepA i OqxAB. 4.4. The impact of PMQR on fluoroquinolone susceptibility level. 5. Summary

Formulation and evaluation of fast Dissolving tablets of Antihypertensive Drug

Over a decade, the demand for development of fast dissolving tablets (FDT) enormously increased as it has significant impact on the patient compliance. Fast dissolving tablets are appreciated by a significant segment of populations particularly who have difficulty in swallowing. Hypertension is a medical condition in which blood pressure is chronically elevated, If not, effectively treated it may lead to stroke, myocardial infarction, heart failure and is a leading cause of chronic kidney failure. Antihypertensive are the class of drugs that are used to treat hypertension. Metoprolol tartarate is a s1-selective adrenergic blocking agent and is prescribed widely in cardiovascular diseases like hypertension. Administration of conventional tablets of Metoprolol tartarate has been reported to exhibit fluctuations in the plasma drug levels resulting in either manifestation of side effects or reduction in drug concentration at the receptor site. Administration to patients who cannot swallow, such as elderly, stroke victims, healthcare facility & bedridden patients such as those affected by renal failure; and the patient who refuse to swallow such as pediatric, geriatric and psychiatric patients which results in high evidence of inefficient therapy. The present study nine batches of fast dissolving tablets of Metoprolol tartarate were successfully prepared using Crospovidone, Sodium starch glycolate, Fenugreek and Isapghula husk by direct compression method. Based on results formulation containing Crospovidone (8%) and Sodium starch glycolate (8%) F(2), was identified as ideal and better formulation among all formulations developed for Metoprolol tartarate tablets. From study it is concluded that the formulated fast dissolving tablets of Metoprolol tartarate of batch F2, were superior and effective in achieving better patient compliance.

Development and Evaluation of Optimized Gastroretentive Mucoadhesive Tablets of Famotidine for Gastro-Esophageal Reflux Disease

The aim of the present investigation was to increase the gastric residence time of Famotidine by designing and optimization of gastroretentive mucoadhesive tablet, thereby improving bioavailability of Famotidine. Famotidine conventional tablets have been reported by many Scientists to exhibit poor oral bioavailability and fluctuations in plasma drug concentration. This results, either in precipitation of side effects or reduction in drug concentration at the target site. Famotidine is a histamine H2-receptor antagonist. It is widely prescribed in active duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome and gastro esophageal reflux disease. The effective treatment requires administration of 20 mg of Famotidine 4 times a day. A conventional dose of 20 mg can inhibit gastric acid secretion up to 6 hours but not up to 12 hours. An alternative dose of 40 mg leads to plasma fluctuations; thus a sustained release dosage form of famotidine is desirable. The short biological half-life of drug (2.5-4 hours) also favors development of a sustained release formulation. Thus objective of present study to reduce the dosing frequency by developing, optimizing and evaluating gastroretentive mucoadhesive tablet for sustain release. A 32 full factorial design is employed to study the effect of independent variables like Carbopol-940 and HPMC K100M, which significantly influence characteristics like ex-vivo mucoadhesive strength and in-vitro drug release. Tablets were prepared by direct compression technique. No significant change was observed in physical appearance, drug content, hardness, mucoadhesive strength, in vitro dissolution pattern after the stability tasting for one month.&#x0D;

Onconase induces autophagy sensitizing pancreatic cancer cells to gemcitabine and activates Akt/mTOR pathway in a ROS-dependent manner

Onconase® (ONC) is a member of the RNase super-family that is secreted in oocytes and early embryos of Rana pipiens. Over the last years, research interest about this small and basic frog RNase, also called ranpirnase, constantly increased because of its high cytotoxicity and anticancer properties. Onconase is currently used in clinical trials for cancer therapy; however, the precise mechanisms determining cytotoxicity in cancer cells have not yet been fully investigated. In the present manuscript, we evaluate the antitumoral property of onconase in pancreatic adenocarcinoma cells and in non-tumorigenic cells as a control. We demonstrate that ONC stimulates a strong antiproliferative and proapoptotic effect in cancer cells by reporting for the first time that ONC triggers Beclin1-mediated autophagic cancer cell death. In addition, ONC inhibits the expression of mitochondrial uncoupling protein 2 (UCP2) and of manganese-dependent superoxide dismutase (MnSOD) triggering mitochondrial superoxide ion production. ONC-induced reactive oxygen species (ROS) are responsible for Akt/mTOR pathway stimulation determining the sensitivity of cancer cells to mTOR inhibitors and lessening autophagic stimulation. This indicates ROS/Akt/mTOR axis as a strategy adopted by cancer cells to reduce ONC-mediated cytotoxic autophagy stimulation. In addition, we demonstrate that ONC can sensitize pancreatic cancer cells to the standard chemotherapeutic agent gemcitabine allowing a reduction of drug concentration when used in combination settings, thus suggesting a lowering of chemotherapy-related side effects. Altogether, our results shed more light on the mechanisms lying at the basis of ONC antiproliferative effect in cancer cells and support its potential use to develop new anticancer strategies.

Formulation and Evaluation of Sustained Release Mucoadhesive Atenolol Tablets for Gastric Retention

An oral sustained release gastroretentive dosage form comes out as better alternative for drugs having narrow absorption window. Atenolol conventional tablets have been reported by many scientists to exhibit poor oral bioavailability and fluctuations in plasma drug concentration. This results, either in precipitation of side effects or reduction in drug concentration at the target site. Thus objective of present study was to develop, optimize and evaluate a gastroretentive, mucoadhesive tablet for sustained release. A 22 factorial design was employed to systematically study the drug release profile and bioadhesive strength. Sodium carboxymethyl cellulose (CMC) and carbopol 934P were selected as independent variables. Tablets were prepared by direct compression and were evaluated for tablets characteristics, swelling study, adhesion strength and percent drug released. Optimized formulation was compared with marketed formulation (ATEN-50). In vitro wash off test was applied to study the gastroretentive behavior.Tablets prepared show good tablet characteristics, optimum swelling behavior and high adhesion strength. The optimized batch follows zero order drug release profile with non fickian transport mechanism. The mucoadhesion time for optimised batch (M4) was found to be more than four hours and compared with plain tablet which was found to be very less (less than half hour).Thus, the gastroretension by mucoadhesion proven to be a potential tool for drug atenolol which improves its bioavailability with reduction in dosing frequency and dose related side effects.

Synergistic cytotoxicity of red beetroot (Beta vulgaris L.) extract with doxorubicin in human pancreatic, breast and prostate cancer cell lines

Although a wide variety of cytotoxic plant extracts and phytochemicals are known to act synergistically with anticancer drug doxorubicin (D), their clinical application is hindered by safety concerns of such combination therapy. Our earlier studies showed that red beetroot (Beta vulgaris L.) extract (B), approved by Food and Drug Administration and European Union as red food color E162, reduced multi-organ tumor formations in various animal models when administered in drinking water. This led us to postulate that a long-term daily exposure to low doses of B through diet might be safe and sufficient to produce cancer chemopreventive effect in humans. Further, our recent comparative cytotoxic investigation with B and D in several human cancer cell lines indicated their potential for synergistic activity. Since B is considered safe for human use with no known toxicity, we conducted the present study to evaluate its synergistic antiproliferative activity with D against pancreatic (PaCa), breast (MCF-7) and prostate (PC-3) tumor cells of human origin. Different concentrations of B and D (0.29-290 μg/ml) and in various combinations (B:D ratio = 1:0, 1:1, 5:1, 1:5 and 0:1) were tested for cytotoxic effects against the three cancer cells. The viability of cells was assessed after 72 h incubation with various combinations of B and D using the trypan-blue staining method. The cytotoxic data were analyzed by the combination index method of Chou and Talalay to establish synergy between B and D. The results indicated that an overall positive reduction in drug concentration was achieved by D when combined with B in its cytotoxicity profile in the three human cancer cells tested. The synergistic cytotoxicity was best when the B:D ratio of 1:5 was used in PaCa cells at IC50, IC75 and IC90 dose levels and in MCF-7 cells at IC90 dose level. These results warrant further studies on the potential of red beetroot extract-doxorubicin combination in treating human cancers.

In vitro inhibition of breast cancer spheroid-induced lymphendothelial defects resembling intravasation into the lymphatic vasculature by acetohexamide, isoxsuprine, nifedipin and proadifen

Background:As metastasis is the prime cause of death from malignancies, there is vibrant interest to discover options for the management of the different mechanistic steps of tumour spreading. Some approved pharmaceuticals exhibit activities against diseases they have not been developed for. In order to discover such activities that might attenuate lymph node metastasis, we investigated 225 drugs, which are approved by the US Food and Drug Administration.Methods:A three-dimensional cell co-culture assay was utilised measuring tumour cell-induced disintegrations of the lymphendothelial wall through which tumour emboli can intravasate as a limiting step in lymph node metastasis of ductal breast cancer. The disintegrated areas in the lymphendothelial cell (LEC) monolayers were induced by 12(S)-HETE, which is secreted by MCF-7 tumour cell spheroids, and are called ‘circular chemorepellent induced defects' (CCIDs). The putative mechanisms by which active drugs prevented the formation of entry gates were investigated by western blotting, NF-κB activity assay and by the determination of 12(S)-HETE synthesis.Results:Acetohexamide, nifedipin, isoxsuprine and proadifen dose dependently inhibited the formation of CCIDs in LEC monolayers and inhibited markers of epithelial-to-mesenchymal-transition and migration. The migration of LECs is a prerequisite of CCID formation, and these drugs either repressed paxillin levels or the activities of myosin light chain 2, or myosin-binding subunit of myosin phosphatase. Isoxsuprine inhibited all three migration markers, and isoxsuprine and acetohexamide suppressed the synthesis of 12(S)-HETE, whereas proadifen and nifedipin inhibited NF-κB activation. Both the signalling pathways independently cause CCID formation.Conclusion:The targeting of different mechanisms was most likely the reason for synergistic effects of different drug combinations on the inhibition of CCID formation. Furthermore, the treatment with drug combinations allowed also a several-fold reduction in drug concentrations. These results encourage further screening of approved drugs and their in vivo testing.

The Effects of pH and Ionic Strength on Topical Delivery of a Negatively Charged Porphyrin (TPPS4)

Meso-tetra-[4-sulfonatophenyl]-porphyrin (TPPS(4)) is a charged porphyrin derivate used in photodynamic therapy (PDT) by parenteral administration. This study means to investigate potential enhancement for its topical delivery by determining the TPPS(4) dependence on the environmental characteristics and applying iontophoresis. In order to accomplish this task, cathodal and anodal iontophoresis as well as passive delivery of the drug were studied in vitro and in vivo in function of its concentration, pH and ionic strength. A reduction in drug concentration as well as the NaCl elimination from donor formulation at pH 2.0 increased TPPS(4) passive permeation through the skin in vitro. Iontophoresis improved TPPS(4) delivery across the skin when applied in solutions containing NaCl at pH 2.0, regardless electrode polarity. However, at pH 7.4, the amount of TPPS(4) permeated by iontophoresis was not different from that one permeated after passive experiments from a solution containing NaCl. Despite the fact that iontophoresis did not improve TPPS(4) transdermal delivery at this specific condition, in vivo experiments showed that 10 min of iontophoresis quickly and homogeneously delivered TPPS(4) to deeper skin layers when compared to passive administration, which is an important condition for topical treatment of skin tumors with PDT.

In situ biochemical demonstration that P-glycoprotein is a drug efflux pump with broad specificity.

While P-glycoprotein (Pgp) is the most studied protein involved in resistance to anti-cancer drugs, its mechanism of action is still under debate. Studies of Pgp have used cell lines selected with chemotherapeutics which may have developed many mechanisms of resistance. To eliminate the confounding effects of drug selection on understanding the action of Pgp, we studied cells transiently transfected with a Pgp-green fluorescent protein (GFP) fusion protein. This method generated a mixed population of unselected cells with a wide range of Pgp-GFP expression levels and allowed simultaneous measurements of Pgp level and drug accumulation in living cells. The results showed that Pgp-GFP expression was inversely related to the accumulation of chemotherapeutic drugs. The reduction in drug concentration was reversed by agents that block multiple drug resistance (MDR) and by the UIC2 anti-Pgp antibody. Quantitative analysis revealed an inverse linear relationship between the fluorescence of Pgp-GFP and MDR dyes. This suggests that Pgp levels alone limit drug accumulation by active efflux; cooperativity between enzyme, substrate, or inhibitor molecules is not required. Additionally, Pgp-GFP expression did not change cellular pH. Our study demonstrates the value of using GFP fusion proteins for quantitative biochemistry in living cells.

Carbamazepine levels in head hair of patients under long-term treatment: a method to evaluate the history of drug use.

Carbamazepine (CBZ) concentrations were determined in the sections of head hair from 40 patients (22 males and 18 females), ages 5 to 81, who were receiving this drug systemically. Hair treatment included dissolution, liquid phase extraction procedures, and immunoassay (Abbott TDx) or high-pressure liquid chromatography (HPLC) analytical techniques. The mean values of CBZ levels in the hair from the 1st section (close to hair root) to the 5th section for female patients were 26.82, 19.18, 17.28, 15.09, and 14.62 micrograms/g according to HPLC measurements. Immunoassay gave generally slightly higher results. The mean values of CBZ in the hair sections according to the immunoassay technique were 30.53, 21.90, 19.83, 17.45, and 16.99 micrograms/g, respectively, from the 1st to the 5th sections. The corresponding mean values for male patients by HPLC and immunoassay techniques were 21.97, 17.30, 15.03, 13.02, and 11.21 micrograms/g and 25.98, 20.52, 17.15, 14.87, and 12.31 micrograms/g. Generally, a reduction of drug concentrations in hair from the first to the subsequent segments was observed. Higher amounts of CBZ were deposited in black, untreated hair (e.g., not dyed or permed). CBZ concentrations in hair sections were found to be dependent on the dosage (r = 0.979, p < or = 0.001) but not on the gender. The data indicate the possible use of hair section testing as a marker of the dosage history and the compliance of patients under long-term treatment with CBZ.