Prediction of formulation effects on dermal absorption of topically applied ectoparasiticides dosed in vitro on canine and porcine skin using a mixture-adjusted quantitative structure permeability relationship.

Topical application of ectoparasiticides for flea and tick control is a major focus for product development in animal health. The objective of this work was to develop a quantitative structure permeability relationship (QSPeR) model sensitive to formulation effects for predicting absorption and skin deposition of five topically applied drugs administered in six vehicle combinations to porcine and canine skin in vitro. Saturated solutions (20 µL) of (14) C-labeled demiditraz, fipronil, permethrin, imidacloprid, or sisapronil were administered in single or binary (50:50 v/v) combinations of water, ethanol, and transcutol (6 formulations, n = 4-5 replicates per treatment) nonoccluded to 0.64 cm(2) disks of dermatomed pig or dog skin mounted in flow-through diffusion cells. Perfusate flux over 24 h and skin deposition at termination were determined. Permeability (logKp), absorption, and penetration endpoints were modeled using a four-term Abrahams and Martin (hydrogen-bond donor acidity and basicity, dipolarity/polarizability, and excess molar refractivity) linear free energy QSPeR equation with a mixture factor added to compensate for formulation ingredient interactions. Goodness of fit was judged by r(2) , cross-validation coefficient, coefficients (q(2) s), and Williams Plot to visualize the applicability domain. Formulation composition was the primary determinant of permeation. Compounds generally penetrated dog skin better than porcine skin. The vast majority of permeated penetrant was deposited within the dosed skin relative to transdermal flux, an attribute for ectoparasiticides. The best QSPeR logKp model for pig skin permeation (r(2) = 0.86, q(2) s = 0.85) included log octanol/water partition coefficient as the mixture factor, while for dogs (r(2) = 0.91, q(2) s = 0.90), it was log water solubility. These studies clearly showed that the permeation of topical ectoparasiticides could be well predicted using QSPeR models that account for both the physical-chemical properties of the penetrant and formulation components.

Effects of eight vehicles on transdermal lidocaine penetration in sheep skin in vitro.

This study investigated the effects of vehicles on penetration and retention of lidocaine applied to sheep skin in vitro. Thoracic skin from two sheep was clipped of wool and stored at -20 °C, until used. Skin samples were defrosted and mounted in Franz-type diffusion cells, and then one of the following formulations, each saturated with lidocaine, was added: sodium lauryl sulphate (SLS) 0.5% in water, SLS 1% in water, dimethyl sulphoxide (DMSO) 50% in water (wt/wt), DMSO 100%, isopropyl myristate 100% (IPM), water alone, diethylene glycol monoethyl ether (DGME) 50% in water (wt/wt) and DGME 100%. The penetration of lidocaine in each skin sample was measured over 8 h. Significantly greater lidocaine skin concentrations and flux (J(SS)) were achieved with the nonaqueous vehicles, DMSO 100% (P < 0.00001 and P < 0.01, respectively), followed by DGME 100% and IPM (P < 0.00001 and P < 0.01, respectively). The lag time (t(lag)) for lidocaine penetration in the DMSO 100% vehicle was significantly shorter (P < 0.01) compared with all other vehicles except water. Improved transdermal penetration of lidocaine in the DMSO 100% vehicle was likely due to skin barrier disruption, as determined by differences in pre- and post-treatment transepidermal water loss (TEWL). This study has shown that nonaqueous vehicles enhanced penetration of lidocaine in sheep skin to a greater extent than aqueous vehicles, which has implications for topically applied local anaesthesia in sheep.

Extra-anatomic bypass grafting: a rational approach.

To determine predictors of long-term patency in extra-anatomic bypass grafting, the authors studied retrospectively the charts of 134 patients who underwent bypass grafting (axillofemoral in 17, axillobifemoral in 32 and femorofemoral in 85). Of the study group, 64% were men; the mean age was 65 +/- 12 years (+/- SEM). The indications for grafting were limb salvage (102), claudication (27) and replacement of septic grafts (5), and for using the extra-anatomic route included high risk (83), sepsis (8) and unilateral disease (34). Operative mortality was 6% and the early graft occlusion rate 7.4%. The late death rate was 44%. At 3 years, the life-table patency rates for the various procedures were axillofemoral 52.5%, axillobifemoral 67.7% and crossfemoral 86.9%. Smoking significantly (p less than 0.05) decreased the patency rate, but diabetes did not. However, amputation was more frequent in diabetics. Indications for operation did not alter patency rates, but did affect operative mortality. The authors conclude that extra-anatomic bypass grafting is highly successful, but not as successful as anatomic bypass. When appropriate, the axillobifemoral graft is preferred to the axillounifemoral graft because of its increased patency. Crossfemoral grafts must be carefully monitored to ensure that no donor limb stenosis occurs and this procedure should not be attempted unless the disease is truly unilateral.

Free flaps and irradiated recipient vessels: an experimental study in rabbits.

In an experimental study in rabbits the effect of previous irradiation to the recipient vessels on the survival rate of free flaps was evaluated. Pre-operative radiotherapy was given in a single anterior neck field using a Cobalt60 unit, 1.25 MeV, SSD 80 cm in a fractionated dose corresponding to 5000 rad/5 weeks. An experimental model using paired data was established using two epigastric free flaps in each animal: one anastomosed to the irradiated vessels (carotid and jugular vein) and implanted outside the irradiated field and the other flap anastomosed to the normal femoral vessels and also implanted outside the irradiated field. In a sequential analysis it was found that free flaps anastomosed to irradiated recipient vessels within 12 weeks from the start of radiotherapy failed significantly more often than free flaps anastomosed to normal recipient vessels (p less than 0.10). This supports the view that preference should be given to the use of non-irradiated recipient vessels for microvascular transfer of free flaps.

Bile reflux gastritis and esophagitis.

The authors reviewed 39 patients in whom bile reflux gastritis and esophagitis were diagnosed and treated. All had epigastric pain not relieved by antacids, 26 had heart burn, 13 dysphagia and 7 hematemesis. On endoscopic examination, all had reflux of bile into the stomach with gastritis, 14 had bile in the esophagus and 21 had esophagitis. Results of biopsy in 15 patients were consistent with gastritis or esophagitis. All but one patient had a history of peptic ulcer disease-gastric or duodenal-and 35 had undergone 48 gastric operationns. Treatment was medical but those refractory to medical management underwent operation. A Roux-en-Y diversion of bile was the most successful operative treatment, benefiting 9 of 12 patients. An adequate length of the efferent limb was found to be important as two patients were not improved until this length was increased to 45 cm. Successful treatment depends on the ability to distinguish this syndrome from recurrent acid peptic disease and esophageal reflux due to sphincteric incompetence.

Use of the dog spleen for studying effects of irradiation and chemotherapeutic agents, with suggested uses of other organs.

The irradiation of the exteriorized spleen of the dog, with the animal lead-shielded, produced constant changes in the white blood cells. The time of recovery from the irradiation effect was determined. The normal canine spleen could handle live pneumococci injected into the splenic artery, as proven by sterile cultures of splenic vein samples. The size of the bolus used was determined by repeated trials and proved to be one billion pneumococci per pound of body weight. The capacity of the irradiated spleen to handle this number of pneumococci was impaired. It was found that whole body irradiation, nitrogen mustard, thio-tepa, cyclophosphamide, methotrexate, 5-fluorouracil, vinblastine, and azothioprine all impaired this capacity of the spleen. The dose of the chemotherapeutic agent was the same in milligrams per kilogram as that used in the cancer clinic. A method for determining the recovery time following the use of one or more agents was developed with the repeated use of the spleen model. By extending the methods used with the spleen it was found that similar use could be made, usually without surgery, of the liver, gut, and lungs (and probably the kidney and brain).