Polar pathway for percutaneous absorption.
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Aspartic Acid↗
Biomedical subjects
B Berner
Publications and source records attributed to B Berner.
Treatment of steroid-resistant graft-versus-host disease after allogeneic bone marrow transplantation with anti-CD3/TCR monoclonal antibodies.
Acute graft-versus host disease (GVHD), one of the major complications of allogeneic bone marrow transplantation (BMT), occurs in 30-50% of all patients transplanted from HLA-identical sibling donors and in 50-80% of all patients transplanted from an unrelated or HLA-mismatched family donor, despite GVHD prophylaxis with methotrexate and cyclosporin. We report our experience with OKT3/BMA031 treatment in 14 patients with severe steroid-resistant GVHD following allogeneic BMT. Three of 5 patients treated in the early post-transplant period with OKT3 remitted and 2 of 3 became long-term survivors. Two patients treated for extensive chronic GVHD showed only minor responses. Five of 7 patients treated with BMA031 showed a partial remission; no complete remission was seen after treatment with this antibody. Shortly after the introduction of OKT3 or BMA031 therapy a rapid decline of the lymphocyte count, especially the CD3+ subset, was observed coinciding with a relative increase of CD56+ lymphocytes and of gamma/delta TCR+ T cells. Increasing numbers of CD3+ lymphocytes preceded recurrence of acute GVHD in three patients. In contrast, persisting CD3-lymphocytopenia was associated with complete clearance of acute GVHD. The incidence of infectious complications following OKT3 or BMA031 therapy was high (42%). Thus, to improve treatment results of severe acute GVHD, prophylactic or pre-emptive strategies are required to reduce the rate of fatal viral and fungal infections.
Acute Disease↗
Fractionated high-dose rate brachytherapy for intracranial gliomas.
PURPOSE: To develop a catheter system for fractionated high-dose rate (HDR) brachytherapy for intracranial gliomas. METHODS AND MATERIALS: The catheter system for stereotactic placement as well as delivery of the high-dose rate iridium-192 source wire is described. The force of the impulse wave from the source wire entering brain equivalent material was measured. Dose volume histograms for the first 5 patients treated are presented. RESULTS: The catheter system was found to be satisfactory. The maximum force of the impulse wave was less than 1 acceleration of gravity (which is safe). The patients tolerated the treatment well with no significant problems related to the catheters being left in situ for up to 14 days. CONCLUSION: Based on this pilot experience a phase I dose escalating and morbidity study has been initiated.
Brachytherapy↗
Fractionated brachytherapy: catheter insertion and dosimetry.
The incorporation of the Omnitron device, a robotic isotope handling system, into a program of brachytherapy for glial tumors has made it possible to hyperfractionate treatment in 15-20 sessions over a 2- to 3-week period, which offers considerable theoretical advantage over conventional single dose regimens. Stereotactic catheter placement is by contrast-enhanced MR guidance, and takes advantage of the three-dimensional planning offered by voxel orientation. Initial placement is based on orientation to the three customary planes, with oblique planes added to define intercatheter placement more accurately. Catheters may be placed asymmetrically through the tumor or even at different angles of insertion to get the optimal conformation. Dosimetry is based on three-dimensional reconstruction in the Omnitron planning console, and takes advantage of the optimized localization of each catheter position. High-dose isotope insertion is performed robotically, with isotope position and dwell times controlled by computer. The phase I study demonstrates a wide safety margin and suggests better survival than would be expected with conventional management.
Brachytherapy↗
Pharmacokinetic characterisation of transdermal delivery systems.
The key aspects of the pharmacokinetics of transdermal delivery systems including time lag, steady-state plasma levels and decline phase are illustrated in this review. The 7 currently marketed transdermal systems [nitroglycerin (glyceryl trinitrate), estradiol, clonidine, fentanyl, nicotine, scopolamine (hyoscine) and estradiol/norethisterone acetate] are discussed, as are systems in development. Single-dose absolute bioavailability studies characterise the period of onset, the steady-state plateau and the declining phase, and typify transdermal delivery. More complex temporal profiles result from interactions with enhancers or removal of the system before steady-state conditions are achieved. Clinically these systems are used to achieve multiple peak serum estradiol concentrations after application of transdermal estradiol, and an initial peak systemic concentration of testosterone after application of transdermal testosterone. Multiple-dose, dose proportionality and skin site bioequivalence studies are needed for the full pharmacokinetic characterisation of a transdermal delivery system. The relationship of system design to variability is discussed. Although the data are limited, population factors, cutaneous metabolism and tolerance all appear to influence the disposition of drugs administered transdermally. For example, the route of delivery influences which nitroglycerin metabolite predominates. Furthermore, as a result of tolerance to nitrates, a transdermal delivery system must be removed for 8 to 12 hours for optimal effect. Therefore, transdermal delivery systems, designed on the basis of pharmacokinetic principles and concentration-effect relationships, have the potential to provide optimal therapy for the treatment of some conditions.
Administration, Cutaneous↗
Human transbuccal absorption of diclofenac sodium from a prototype hydrogel delivery device.
The buccal delivery of the nonsteroidal antiinflammatory drug, diclofenac sodium (Voltaren), from a prototype hydrogel was studied in man in a randomized crossover design of buccal delivery and i.v. infusion. After a 30-min delay, plasma levels of diclofenac increased to near steady-state levels of 100 ng/ml by 3 hr. With each subject serving as his own control, the i.v. infusion data facilitated the calculation of a mean steady-state flux of diclofenac sodium of 2.1 +/- 0.6 mg/cm2-hr across human buccal mucosa and a time lag of 1.0 +/- 0.5 hr. The large flux of this ionized species indicates that the traditional lipoidal model of buccal permeation based on the partition coefficient is inadequate.
Absorption↗
Influence of skin irritants on percutaneous absorption.
The effects of the application of skin irritants on the in vitro percutaneous absorption of three model compounds of diverse physico-chemical properties, caffeine, indomethacin, and hydrocortisone, were investigated. Norephedrine and imipramine, basic drugs with a known skin irritation potential, were employed to damage the skin. Treatment with norephedrine increased the permeation of caffeine and hydrocortisone by two- to fourfold, while absorption of indomethacin declined an order of magnitude. A similar result was obtained for the effect of treatment with imipramine on transport of caffeine. Pretreatment with imipramine promoted hydrocortisone absorption 10-fold but, unlike norephedrine, did not alter indomethacin permeation. While both treatments in vivo caused an increase (norephedrine > imipramine) in the pH on the surface of skin and after tape-stripping the skin, only norephedrine caused changes in transepidermal water loss in vivo in man. Since imipramine was the more severe irritant as judged by erythema, alterations by irritants of barrier function appeared rather complex.
Adult↗
Variational analysis of the transdermal delivery rate from two prototypical ethanol-water nitroglycerin TTS devices and Transderm-Nitro 10 in the normal population.
The performance of two prototypical ethanol-water flux-enhanced transdermal therapeutic systems were compared to the performance of commercial Transderm-Nitro 10. This was a single-center, open-label, three-treatment, randomized crossover study in six healthy subjects who completed the study. Concurrent with each transdermal treatment, an infusion of the stable isotope [15N]3-nitroglycerin was administered. The use of double isotope methodology was incorporated into this study to minimize the variation introduced by fixed-effect error on the evaluation of transdermal flux. The objectives of this study were to isolate experimentally and characterize the average flux enhancement of each prototype, to determine the temporal profile of delivery, and to evaluate the components of variance of drug delivery from each transdermal system. The results of this study showed that the two flux-enhanced transdermal systems with different fill volumes both produced flux enhancement factors of 2 to 3 relative to Transderm-Nitro 10. Prototype B demonstrated a 57% reduction in intersubject variation relative to Transderm-Nitro 10 indicative of enhanced control of drug permeation across a subject population. Prototype A, while reducing intersubject variations, was less than optimal. Both prototypes demonstrated comparable intrasubject variation relative to Transderm-Nitro 10, indicating similar stability for within-subject transdermal drug delivery. The flux enhancement and variational properties of Prototype B were consistent with those intended based on mechanistic considerations of mutual nitroglycerin and ethanol-coupled transdermal delivery.
Administration, Cutaneous↗
Steady-state pharmacokinetics and pharmacodynamics of benazeprilat in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats.
The effects of the simultaneous steady-state intravenous infusion of benazeprilat, the active metabolite of benazepril HCl, and angiotensin I (AI) on mean arterial blood pressure were investigated in the conscious, unrestrained spontaneously hypertensive rat (SHR) and its normotensive parent strain, the Wistar-Kyoto (WKY) rat. A competitive inhibition model is applied and the limits of its validity are discussed. Deviations from the model are apparent at high drug infusion rates and may relate to the effect of benazeprilat on the clearance of AI. The strains differ in the amounts of angiotensin converting enzyme (ACE) or responsiveness to angiotensin II (AII), the drug clearances, and either the pharmacology or the distribution of the drug. Since the latter two differences are drug dependent, prediction between strains is rendered difficult. This steady-state approach relates the hypertension in the SHR to the amount of ACE or responsiveness to AII and renal function.
Angiotensin I↗
Enhanced transport in a therapeutic transdermal system.
Ethanol was incorporated into a transdermal therapeutic device to enable the controlled delivery of enhancer and drug to the skin surface. A variety of control membrane laminates were examined for swelling and adhesion strength following equilibration with ethanolic solutions to identify a mechanically stable control membrane laminate. In vitro skin permeation analysis of the control membrane laminate showed that ethanol flux was linearly related to the ethanol volume fraction. A reservoir-type therapeutic transdermal system incorporating ethanol was developed to provide constant release of drug and ethanol through skin for 24 h. In vitro ethanol skin permeation rates were constant for 24 h and adhesion was stable over 16 wk at 40 degrees C using a transdermal reservoir device.
Adhesiveness↗
The relationship between pKa and skin irritation for a series of basic penetrants in man.
For a series of bases, which penetrate through human skin in vitro at similar rates (0.056-0.49 microM/cm2/hr), penetrant pKa is shown to correlate with erythema, edema, and color meter readings. As estimates of irritation, erythema, edema, and redness measurements are highly linearly correlated. For the selected series, irritation becomes significant for bases with a pKa greater than 8. The irritation potential of acids with pKa less than or equal to 4 has been previously reported; pKa appears highly predictive of acute skin irritation for acids and bases in man.
Adult↗
Dose-response and failure pattern for bulky or barrel-shaped stage IB cervical cancer treated by combined photon irradiation and extrafascial hysterectomy.
From 1975 to 1987, 80 patients with bulky or barrel-shaped Stage IB cervical cancer were treated with preoperative irradiation and Cs-137 intracavitary implant therapy, before a planned extrafascial abdominal hysterectomy, using a consistent treatment policy. Of the hysterectomy specimens obtained, 37% were positive histologically at 89 +/- 2.3 days after the start of radiotherapy and at 4 to 6 weeks after the completion of radiation therapy. Sixty-three percent were negative after a total external and internal cervix irradiation dose of 9642 cGy at point T. The average point A dose contributed by intracavitary therapy was 2104 cGy. The survival rate at 5 years was 84%: At 10 years the survival rate was 78%. The failure pattern was analyzed for patients who had positive and negative specimens. The patients with positive specimens failed pelvically or pelvically and distantly. Patients with negative specimens failed in extrapelvic or distant metastatic sites. Preoperative radiotherapy led to excellent local and pelvic control of tumor, and the failures became predominantly distant metastases. The combined radiosurgical therapy was tolerated well and allowed surgical staging of disease. This permitted earlier and selective consideration of adjunctive therapy (i.e., paraaortic irradiation, chemotherapy, or chemoradiotherapy). The dose-response data give insight into the effects of photon radiotherapy on bulky or barrel Stage IB cervical cancers and correlate histologic status with failure pattern, outcome, and long-term survival.
Adult↗
Ethanol:water mutually enhanced transdermal therapeutic system. I: Nitroglycerin solution properties and membrane transport.
The solution properties of aqueous ethanol donor solutions were characterized for the particular case of an increased flux nitroglycerin transdermal system. Permeation through porous and nonporous polymer membranes was investigated and modelled. While the permeation of ethanol through the porous membranes is adequately described by theory, clogging of pores occurs in the presence of lactose. Permeation through ethylene vinyl acetate membranes reflects interactions of the solute and solvent with the polymer.
Administration, Cutaneous↗
Ethanol: water mutually enhanced transdermal therapeutic system II: skin permeation of ethanol and nitroglycerin.
An optimal concentration range of aqueous ethanol produces 5-10-fold increases in nitroglycerin flux across skin and ethanol skin permeation that are far greater than reported previously. For aqueous ethanol solutions saturated with nitroglycerin with an ethanol volume fraction less than or equal to 0.7, the flux of nitroglycerin across skin is linear with the ethanol flux and is traced to a linear solubility relationship and a constant diffusion coefficient.
Administration, Cutaneous↗
Ethanol and water sorption into stratum corneum and model systems.
Sorption of ethanol and water into stratum corneum, delipidized stratum corneum, and triolein as a simple model lipid was investigated. Optima in ethanol sorption and flux are related to dehydration of keratins. There was no optimum for solubility in triolein; a linear cosolvency is observed with ethanol:triolein mixtures. A model is proposed which qualitatively predicts the key features of ethanol-enhanced skin permeation on the basis of these solubility phenomena and a constant diffusion coefficient.
Ethanol↗
Preparation and characterization of a reconstituted stratum corneum film as a model membrane for skin transport.
A zwitterionic surfactant, 6-eicosyldimethyl ammoniohexanoate (C20AH), completely disaggregates stratum corneum into individual cells. The cells can be cast into a film of reconstituted stratum corneum (RSC). Such films prepared from pig and human skin mimic intact human stratum corneum in microscopic, mechanical, and barrier evaluations. The films are useful as model membranes for skin transport experiments.
Animals↗
The relationship of pKa and acute skin irritation in man.
The relationship between pKa and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15-88 micrograms/cm2/hr). Skin irritation and pKa are correlated for pKa less than or equal to 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa; erythema at 24 hr appears to be the most sensitive parameter to variation in pKa when pKa less than or equal to 4.
Adult↗
Mixed schedules for neutron therapy.
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Brachytherapy↗