http://academic.oup.com/milmed/article-pdf/146/7/506/24126715/milmed-146-7-506.pdf

Goodman and Gilman's The Pharmacological Basis of Therapeutics

8.4. Culture-negative Pulmonary Tuberculosis CONTENTS in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 8.5. Radiographic Evidence of Prior Tuberculosis: Inactive Tuberculosis . . . . . . . . . . . . . . . . . . . . . 650

American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis.

In the last few decades, pharmaceuticals, credited with saving millions of lives, have emerged as a new class of environmental contaminant. These compounds can have both chronic and acute harmful effects on natural flora and fauna. The presence of pharmaceutical contaminants in ground waters, surface waters (lakes, rivers, and streams), sea water, wastewater treatment plants (influents and effluents), soils, and sludges has been well doccumented. A range of methods including oxidation, photolysis, UV-degradation, nanofiltration, reverse osmosis, and adsorption has been used for their remediation from aqueous systems. Many methods have been commercially limited by toxic sludge generation, incomplete removal, high capital and operating costs, and the need for skilled operating and maintenance personnel. Adsorption technologies are a low-cost alternative, easily used in developing countries where there is a dearth of advanced technologies, skilled personnel, and available capital, and adsorption appears to be the most broadly feasible pharmaceutical removal method. Adsorption remediation methods are easily integrated with wastewater treatment plants (WWTPs). Herein, we have reviewed the literature (1990-2018) illustrating the rising environmental pharmaceutical contamination concerns as well as remediation efforts emphasizing adsorption.

Pharmaceuticals of Emerging Concern in Aquatic Systems: Chemistry, Occurrence, Effects, and Removal Methods.

http://raphe.kaist.ac.kr/publication/2004-EEG%20dynamics%20in%20patients%20with%20Alzheimer’s%20disease.pdf

EEG dynamics in patients with Alzheimer's disease

Separation of polar compounds on polar stationary phases with partly aqueous eluents is by no means a new separation mode in LC. The first HPLC applications were published more than 30 years ago, and were for a long time mostly confined to carbohydrate analysis. In the early 1990s new phases started to emerge, and the practice was given a name, hydrophilic interaction chromatography (HILIC). Although the use of this separation mode has been relatively limited, we have seen a sudden increase in popularity over the last few years, promoted by the need to analyze polar compounds in increasingly complex mixtures. Another reason for the increase in popularity is the widespread use of MS coupled to LC. The partly aqueous eluents high in ACN with a limited need of adding salt is almost ideal for ESI. The applications now encompass most categories of polar compounds, charged as well as uncharged, although HILIC is particularly well suited for solutes lacking charge where coulombic interactions cannot be used to mediate retention. The review attempts to summarize the ongoing discussion on the separation mechanism and gives an overview of the stationary phases used and the applications addressed with this separation mode in LC.

Hydrophilic interaction chromatography.

Background

P-Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P-glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P-glycoprotein substrate talinolol, a β1-blocker without appreciable metabolic disposition but intense intestinal secretion in human beings.



Methods

Pharmacokinetics of talinolol (a single dose of 30 mg administered intravenously or 100 mg administered orally for 7 days) and duodenal expression of the MDR1 gene product P-glycoprotein as assessed by reverse transcriptase-polymerase chain reaction of the MDR1–messenger ribonucleic acid, by immunohistochemistry and Western blot analysis were analyzed before and after coadministration of rifampin (600 mg per day for 9 days) in 8 male healthy volunteers (age 22 to 26 years).



Results

During rifampin treatment, the areas under the curve of intravenous and oral talinolol were significantly lower (21% and 35% P < .05). Treatment with rifampin resulted in a significantly increased expression of duodenal P-glycoprotein content 4.2-fold (2.9, 6.51) (Western blot) and messenger RNA was increased in six of the eight volunteers. P-Glycoprotein expression in biopsy specimens of gut mucosa correlated significantly with the systemic clearance of intravenous talinolol (rs = 0.74; P < .001).



Conclusions

Rifampin induces P-glycoprotein–mediated excretion of talinolol predominantly in the gut wall. Moreover, clearance of talinolol from the blood into the lumen of the gastrointestinal tract may be predicted by the individual intestinal P-glycoprotein expression. Thus we describe a new type of steady-state drug interaction affecting compounds that are subject to transport rather than metabolism. (Clin Pharmacol Ther 2000;68:345-55.)



Clinical Pharmacology & Therapeutics (2000) 68, 345–355; doi: 10.1067/mcp.2000.109797

Induction of P‐glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction

The alkaloid L-(-)-scopolamine [L-(-)-hyoscine] competitively inhibits muscarinic receptors for acetylcholine and acts as a nonselective muscarinic antagonist, producing both peripheral antimuscarinic properties and central sedative, antiemetic, and amnestic effects. The parasympatholytic scopolamine, structurally very similar to atropine (racemate of hyoscyamine), is used in conditions requiring decreased parasympathetic activity, primarily for its effect on the eye, gastrointestinal tract, heart, and salivary and bronchial secretion glands, and in special circumstances for a CNS action. Therefore, scopolamine is most suitable for premedication before anesthesia and for antiemetic effects. This alkaloid is the most effective single agent to prevent motion sickness. Scopolamine was the first drug to be made commercially available in a transdermal therapeutic system (TTS-patch) delivering alkaloid. Recently, pharmacokinetic data on scopolamine in different biozlogic matrices were obtained most efficiently using liquid chromatographic-tandem mass spectrometric (LC-MS/MS) or gas chromatography online coupled to mass spectrometry. Pharmacokinetic parameters are dependent on the dosage form (oral dose, tablets; parenteral application; IV infusion; SC and IM injection). Scopolamine has a limited bioavailability if orally administered. The maximum drug concentration occurs approximately 0.5 hours after oral administration. Because only 2.6% of nonmetabolized L-(-)-scopolamine is excreted in urine, a first-pass metabolism is suggested to occur after oral administration of scopolamine. Because of its short half-life in plasma and dose-dependent adverse effects (in particular hallucinations and the less serious reactions, eg, vertigo, dry mouth, drowsiness), the clinical use of scopolamine administered orally or parenterally is limited. To minimize the relatively high incidence of side effects, the transdermal dosage form has been developed. The commercially available TTS-patch contains a 1.5-mg drug reservoir and a priming dose (140 microg) to reach the steady-state concentration of scopolamine quickly. The patch releases 0.5 mg alkaloid over a period of 3 days (releasing rate 5 microg/h). Following the transdermal application of scopolamine, the plasma concentrations of the drug indicate major interindividual variations. Peak plasma concentrations (Cmax) of approximately 100 pg/mL (range 11-240 pg/mL) of the alkaloid are reached after about 8 hours and achieve steady state. During a period of 72 hours the plaster releases scopolamine, so constantly high plasma levels (concentration range 56-245 pg/mL) are obtained, followed by a plateau of urinary scopolamine excretion. Although scopolamine has been used in clinical practice for many years, data concerning its metabolism and the renal excretion in man are limited. After incubation with beta-glucuronidase and sulfatase, the recovery of scopolamine in human urine increased from 3% to approximately 30% of the drug dose (intravenously administered). According to these results from enzymatic hydrolysis of scopolamine metabolites, the glucuronide conjugation of scopolamine could be the relevant pathway in healthy volunteers. However, scopolamine metabolism in man has not been verified stringently. An elucidation of the chemical structures of the metabolites extracted from human urine is still lacking. Scopolamine has been shown to undergo an oxidative demethylation during incubation with CYP3A (cytochrome P-450 subfamily). To inhibit the CYP3A located in the intestinal mucosa, components of grapefruit juice are very suitable. When scopolamine was administered together with 150 mL grapefruit juice, the alkaloid concentrations continued to increase, resulting in an evident prolongation of tmax (59.5 +/- 25.0 minutes; P < 0.001). The AUC0-24h values of scopolamine were higher during the grapefruit juice period. They reached approximately 142% of the values associated with the control group (P < 0.005). Consequently, the related absolute bioavailabilities (range 6% to 37%) were significantly higher than the corresponding values of the drug orally administered together with water (range 3% to 27%). The effect of the alkaloid on quantitative electroencephalogram (qEEG) and cognitive performance correlated with pharmacokinetics was shown in studies with healthy volunteers. From pharmacokinetic-pharmacodynamic modeling techniques, a direct correlation between serum concentrations of scopolamine and changes in total power in alpha-frequency band (EEG) in healthy volunteers was provided. The alkaloid readily crosses the placenta. Therefore, scopolamine should be administered to pregnant women only under observation. The drug is compatible with nursing and is considered to be nonteratogenic. In conclusion, scopolamine is used for premedication in anesthesia and for the prevention of nausea and vomiting associated with motion sickness. Pharmacokinetics and pharmacodynamics of scopolamine depend on the dosage form. Effects on different cognitive functions have been extensively documented.

Pharmacokinetics and pharmacodynamics in clinical use of scopolamine

Hydrophilic interaction chromatography combined with tandem-mass spectrometry to determine six aminoglycosides in serum

Articaine is the most widely used local anaesthetic agent in dentistry in a number of European countries. The amide structure of articaine is similar to that of other local anaesthetics, but it contains an additional ester group which is quickly hydrolysed by esterases. High performance liquid chromatography has been used to determine the concentrations of articaine and its metabolite articainic acid in serum. Rapid sample preparation is critical in the accurate determination of articaine serum concentrations, since blood and serum are the sites of metabolism. The time to maximum drug concentrations of articaine occurs about 10 to 15 minutes after submucosal injection of articaine 4% 80mg, irrespective of epinephrine (adrenaline). The mean maximum plasma drug concentration is about 400 μg/L for articaine with epinephrine 1: 200 000 and 580 μg/L for articaine without epinephrine. The elimination half-time of articaine is about 20 minutes. The rapid breakdown of articaine to the inactive metabolite articainic acid is related to a very low systemic toxicity and consequently to the possibility of repeated injections. Equal analgesic efficacy along with lower systemic toxicity (i.e. a wide therapeutic range) permits the use of articaine in higher concentrations than other amide-type local anaesthetics. Complete anaesthesia can be observed in nearly 90% of all cases, using articaine 4% 60 to 80mg with epinephrine 1: 200 000. Articaine is better able to diffuse through soft tissue and bone than other local anaesthetics. The concentration of articaine in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. The plasma protein binding rate of articaine and articainic acid is 70%. It has been concluded that an unintentional intravascular injection of articaine 80mg does not cause toxic effects in healthy individuals.

Reinhard Oertel

Papers

Induction of P‐glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction

Pharmacokinetics and pharmacodynamics in clinical use of scopolamine

Hydrophilic interaction chromatography combined with tandem-mass spectrometry to determine six aminoglycosides in serum

Clinical Pharmacokinetics of Articaine

Simultaneous determination of most prescribed antibiotics in multiple urban wastewater by SPE-LC–MS/MS