Cysteinyl leukotrienes mediate enhanced vasoconstriction to angiotensin II but not endothelin-1 in SHR.

We assessed whether cysteinyl leukotrienes mediate the vasoconstrictor responses to angiotensin II and endothelin-1 in the mesenteric vascular bed of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) perfused ex vivo at a constant flow rate of 5 ml/min with Krebs buffer. Maximal perfusion pressure response (E(max)) but not EC(50) values to angiotensin II (P < 0.001) and endothelin-1 (P < 0.01) were significantly higher in the SHR, whereas the responses to potassium chloride remained unchanged. Inclusion of the selective 5-lipoxygenase inhibitor AA-861 or the cysteinyl leukotriene receptor antagonist MK-571 significantly reduced the vasoconstrictor responses to angiotensin II but not to endothelin-1 and potassium chloride. The reduction in E(max) to angiotensin II was more pronounced in SHR (P < 0.001) than in WKY (P < 0.05) rats. Cysteinyl leukotrienes LTC(4)-, LTD(4)-, and LTE(4) (1 microM)-evoked vasoconstrictor responses were significantly higher in SHR (P < 0.05), whereas LTB(4) failed to evoke any response in either strain. These data suggest that 5-lipoxygenase metabolites, particularly cysteinyl leukotrienes, contribute to the exaggerated vasoconstrictor responses to angiotensin II but not to endothelin-1.

Transdermal iontophoresis. Part II: Peptide and protein delivery.

The advent of sophisticated biotechnological processes has generated an interest in peptide and protein pharmaceuticals. However, the rapid developments in biotechnology are not matched by the developments in the delivery of these molecules. Presently, most of the peptides and proteins are delivered by parenteral route due to their poor oral bioavailability. The inherent discomforts associated with the parenteral therapy has prompted investigations into other nonparenteral routes and drug delivery techniques. Transdermal iontophoresis is one such technique showing good promise in the controlled and enhanced delivery of peptides and proteins. It offers noninvasive, continuous, pulsatile delivery as well as preprogramed complex dosing regimens. Miniature battery powered and wearable patches for peptides and proteins are expected to be on the market by the turn of this century. In continuation of our earlier review, this review explores the potential of transdermal iontophoresis for the delivery of peptides and proteins with the main focus on the suitability of the technique along with the factors to be considered in the design of this drug delivery system and its future prospects.

Transdermal iontophoresis. Part I: Basic principles and considerations.

The skin has increasingly become a route for the delivery of drugs with a range of compounds being considered for transdermal delivery generating a great deal of interest in this area of research. The passive delivery of most compounds across the skin is limited due to the barrier properties afforded by stratum corneum, the outermost layer of the skin. Transdermal iontophoresis is an effective technique for physically facilitating the transport of permeants across the skin by using electromotive force. It is being extensively explored as a potential means for delivery of hydrophilic, large and charged molecules and is also believed to be a future method of choice for peptides and proteins. In this context, this review focuses mainly on the basic principles and considerations of transdermal iontophoresis with particular emphasis on modeling, devices and parameters influencing transdermal iontophoresis.

Transdermal delivery of naloxone: ex vivo permeation studies.

The purpose of this investigation was to study the feasibility of transdermal drug delivery of the potent opioid antagonist naloxone. The pharmacokinetic profile of naloxone makes it a suitable candidate for transdermal delivery. Ex vivo permeation of naloxone through excised rat skin was studied using a diffusion cell. Radiochemical assay of drug concentration and the use of rat as an animal model were adopted in this study. Naloxone possesses characteristics favorable to percutaneous absorption: i.e. a low molecular weight (327.37), water solubility and a good lipid-water partition coefficient of 12.94+/-1.29 at pH 7.4. The flux (microg/cm2/h) values varied from 6.59+/-0.72 in control to 27. 18+/-4.26 in dimethyl formamide. The affinity of naloxone to skin in the presence of propylene glycol was decreased by 6.2 times compared to the control. Fourier transform infrared spectroscopy was used to study the effect of various sorption promoters on intercellular lipid pathways in skin. A change in lipid fluidization corresponding to broadening for both C-H symmetric (near 2850 cm-1) and C-H asymmetric (near 2920 cm-1) stretching was observed. An attempt was made to correlate the molecular weight of sorption promoters with skin affinity values of naloxone.