Synthesis and Enhancing Effect of Transkarbam 12 on the Transdermal Delivery of Theophylline, Clotrimazole, Flobufen, and Griseofulvin

Purpose Dodecyl-6-aminohexanoate (DDEAC) is a transdermal permeation enhancer with excellent activity, low toxicity, and no dermal irritation. We hypothesized that DDEAC reacts with air CO₂ to form a two-chain ammonium carbamate—Transkarbam 12 (T12)—which is responsible for the enhancing effect. Methods DDEAC and T12 were synthesized, their structures were confirmed by spectral methods, and their enhancing activity was studied using the Franz diffusion cell and human skin. A high-performance liquid chromatography method was developed for determination of T12, and its biodegradability was evaluated using porcine esterase. Results Only the carbamate salt T12 was responsible for the high enhancing activity; DDEAC tested under argon to avoid reaction with CO₂ was inactive. T12 enhanced transdermal permeation of drugs covering a wide range of physicochemical properties, including theophylline (enhancement ratio up to 55.6), clotrimazole (7.7), flobufen (5.0), and griseofulvin (24). The activity was pH-dependent, further confirming the importance of the carbamate structure. The metabolization of T12 followed a second-order kinetics with t_1/2 = 31 min. Conclusion Our results indicate that T12 is a promising biodegradable permeation enhancer for a wide range of drugs, and the structurally novel group of carbamate enhancers warrants further investigation.     

Enantiospecific effects of chiral drugs on cytochrome P450 inhibition in vitro

1.?The aim of this work was to examine the differences in the inhibitory potency of individual enantiomers and racemic mixtures of selected chiral drugs on human liver microsomal cytochromes P450.

2.?The interaction of enantiomeric forms of six drugs (tamsulosin, tolterodine, citalopram, modafinil, zopiclone, ketoconazole) with nine cytochromes P450 (CYP3A4, CYP2E1, CYP2D6, CYP2C19, CYP2C9, CYP2C8, CYP2B6, CYP2A6, CYP1A2) was examined. HPLC methods were used to estimate the extent of the inhibition of specific activity in vitro.

3.?Tamsulosin (TAM) and tolterodine (TOL) inhibited CYP3A4 activity with an enantiospecific pattern. The inhibition of CYP3A4 activity differed for R-TAM (K_i 2.88?±?0.12?µM) and S-TAM (K_i 14.22?±?0.53?µM) as well as for S-TOL (K_i 1.71?±?0.03?µM) and R-TOL (K_i 4.78?±?0.17?µM). Also, the inhibition of CYP2C19 by ketoconazole (KET) cis-enantiomers exhibited enantioselective behavior: the (+)-KET (IC₅₀ 23.64?±?6.25?µM) was more potent than (?)-KET (IC₅₀ 66.12?±?12.6?µM). The inhibition of CYP2C19 by modafinil (MOD) enantiomers (R-MOD IC₅₀?=?51.79?±?8.58?µM, S-MOD IC₅₀?=?48.62?±?9.74?µM) and the inhibition of CYP2D6 by citalopram (CIT) enantiomers (R-CIT IC₅₀?=?68.17?±?5.70?µM, S-CIT IC₅₀?=?62.63?±?7.89?µM) was not enantiospecific.

4.?Although enantiospecific interactions were found (TAM, TOL, KET), they are probably not clinically relevant as the plasma levels are generally lower than the drug concentration needed for prominent inhibition (at least 50% of CYP activity).     

Biodegradable derivatives of tranexamic acid as transdermal permeation enhancers.

The purpose of this work was to develop a novel approach to transdermal permeation enhancer design, based on utilizing some favorable properties of their metabolites. As an example of this concept, a series of carbamic acid salts of tranexamic acid (TXA) esters was synthesized, because TXA was previously shown to improve skin barrier homeostasis. Enhancement activities of 1% TXA derivatives dispersed in both hydrophilic and lipophilic vehicles were evaluated in vitro using human skin and theophylline as a model drug. Dispersed in an aqueous donor vehicle, the dodecyl ester showed the enhancement ratio (ER) of 4.3+/-0.9, which is almost 2 times higher than that of 1-dodecylazepan-2-one (Azone; 2.2+/-0.7). From an isopropyl-myristate suspension, the decyl ester was the most effective enhancer (4.9+/-1.4), while Azone was inactive. Decomposition of the carbamate in a slightly acidic environment was shown by FTIR; hydrolysis of the pertinent ester by porcine esterase was monitored by TLC and HPLC. Biodegradable enhancers of this type could mediate easier and faster recovery of the skin barrier after transdermal delivery through the action of the released TXA.     

Videofluoroscopic evidence of aspiration predicts pneumonia and death but not dehydration following stroke

In order to assess the risk of pneumonia, dehydration, and death associated with videofluoroscopic evidence of aspiration following stroke, the clinical records of 26 patients with aspiration and 33 randomly selected, case-matched, dysphagic controls without videofluoroscopic evidence of aspiration were reviewed. The videofluoroscopic modified barium swallow technique included 5 ml-thin and thick liquid barium, 5 ml barium pudding, and 1/4 cookie coated with barium, plus additional 20 and 30 ml of thin liquid barium. Patients were assessed a mean of 2±1 SD months poststroke and were followed for a mean of 16±8 SD months poststroke. The odds ratio for developing pneumonia was 7.6 times greater for those who aspirated any amount of barium irrespective of its consistency (p=0.05). The odds ratio for developing pneumonia was 5.6 times greater for those who aspirated thickened liquids or more solid consistencies compared with those who did not aspirate, or who aspirated thin liquids only (p=0.06). Dehydration was unrelated to the presence or absence of aspiration. The odds ratio for death was 9.2 times greater for those aspirating thickened liquids or more solid consistencies compared with those who did not aspirate or who aspirated thin liquids only (p=0.01). Aspiration documented by modified videofluoroscopic barium swallow technique is associated with a significant increase in risk of pneumonia and death but not dehydration following stroke.     

Ceramide analogue 14S24 ((S)-2-tetracosanoylamino-3-hydroxypropionic acid tetradecyl ester) is effective in skin barrier repair in vitro

Stratum corneum ceramides are fundamental for maintaining the skin barrier properties. Their content is decreased in some skin diseases, e.g. atopic dermatitis, and ceramide supplementation is one of the therapeutic approaches. In the present study we have designed novel ceramide analogue 14S24 ((S)-2-tetracosanoylamino-3-hydroxypropionic acid tetradecyl ester) as a potential barrier-repairing agent. We report a convenient two-step synthesis of this analogue with high yields. The ability of 14S24 to repair the disturbed skin barrier was evaluated in vitro on the porcine skin. After 2 h application of 14S24 on the skin disrupted by lipid extraction, the permeability decreased significantly almost to the values of the native skin. The compound is effective in 0.1% aqueous suspension and its effect is comparable with physiological skin lipids under the same condition. The comparison of 14S24 and skin ceramides was made via computer modelling and the in silico physico-chemical parameters are reported. We suggest that allylic hydroxyl, that is essential for the apoptogenic activity of ceramides, is not a necessary component of the skin barrier-forming ceramides. The main result of this study is to demonstrate that simpler and easier-to-synthesise ceramide analogues could be effective in the skin barrier repair.     

Incidence and peculiar changes in the electrocardiogram of patients after cerebrovascular insults.--Epidemiological study of 70--105-year-old people (author's transl)]

An epidemicological study of 70 to 105-year-old people revealed a frequency of cerebrovascular insults from 1,8% of living and of 23,9 respectively 34,4% of deceased men or women. As typical changes of the electrocardiogram in recent insults are to be found prolongations of the QT-interval, large and often terminal negative T-waves as well as large and high, but over the left precordium often negative U-waves.     

Effects of clinically relevant acute hypercapnic and metabolic acidosis on the cardiovascular system: an experimental porcine study

Introduction

Hypercapnic acidosis (HCA) that accompanies lung-protective ventilation may be considered permissive (a tolerable side effect), or it may be therapeutic by itself. Cardiovascular effects may contribute to, or limit, the potential therapeutic impact of HCA; therefore, a complex physiological study was performed in healthy pigs to evaluate the systemic and organ-specific circulatory effects of HCA, and to compare them with those of metabolic (eucapnic) acidosis (MAC).

Methods

In anesthetized, mechanically ventilated and instrumented pigs, HCA was induced by increasing the inspired fraction of CO₂ (n = 8) and MAC (n = 8) by the infusion of HCl, to reach an arterial plasma pH of 7.1. In the control group (n = 8), the normal plasma pH was maintained throughout the experiment. Hemodynamic parameters, including regional organ hemodynamics, blood gases, and electrocardiograms, were measured in vivo. Subsequently, isometric contractions and membrane potentials were recorded in vitro in the right ventricular trabeculae.

Results

HCA affected both the pulmonary (increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR)) and systemic (increase in mean arterial pressure (MAP), decrease in systemic vascular resistance (SVR)) circulations. Although the renal perfusion remained unaffected by any type of acidosis, HCA increased carotid, portal, and, hence, total liver blood flow. MAC influenced the pulmonary circulation only (increase in MPAP and PVR). Both MAC and HCA reduced the stroke volume, which was compensated for by an increase in heart rate to maintain (MAC), or even increase (HCA), the cardiac output. The right ventricular stroke work per minute was increased by both MAC and HCA; however, the left ventricular stroke work was increased by HCA only. In vitro, the trabeculae from the control pigs and pigs with acidosis showed similar contraction force and action-potential duration (APD). Perfusion with an acidic solution decreased the contraction force, whereas APD was not influenced.

Conclusions

MAC preferentially affects the pulmonary circulation, whereas HCA affects the pulmonary, systemic, and regional circulations. The cardiac contractile function was reduced, but the cardiac output was maintained (MAC), or even increased (HCA). The increased ventricular stroke work per minute revealed an increased work demand placed by acidosis on the heart.