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PubMed1992

Pharmacodynamic and pharmacokinetic evaluation of a new transdermal delivery system with a time-dependent release of glyceryl trinitrate.

The pharmacokinetics of glyceryl trinitrate (GTN) and its main metabolites as well as the hemodynamic effects of a new transdermal delivery system (TDS) were investigated in ten healthy male volunteers using a single blind, placebo-controlled study design with an application period of active drug of 4 successive days. The adhesive-type matrix system contains 20-mg GTN and released about 75% in a time-dependent manner. The plasma concentrations of GTN and its metabolites 1-2- and 1-3 glyceryl dinitrate reflected the time-dependent release with higher plasma concentrations during the first 12 hours than during the second 12 hours. Continuous administration of the TDS, which released 15 mg GTN/day, caused an accumulation of GTN in the plasma (about 70% greater AUC at the fourth day in comparison with the first day). The total effect per dose on the a/b-ratio of the digital pulse (height of the peak of the systolic wave divided by height of the peak of the dicrotic wave) and the reflex tachycardia were diminished by about 50% and 37%, respectively, at the fourth treatment day. The effect on systolic blood pressure measured under orthostatic conditions was blunted already 8 hours after the first application. The effect of sublingually administered GTN on digital pulse was attenuated during administration and also 1 hour after removal of the last TDS. The effect was restored 8 to 12 hours after removal of the TDS. Thus, the discontinuous release of GTN from the new system does not prevent the decline of hemodynamic efficacy during continuous therapy.

Administration, Cutaneous↗
PubMed1994

Comparison of the pharmacokinetics, pharmacodynamics, and safety of oral (Catapres) and transdermal (M-5041T) clonidine in healthy subjects.

The pharmacokinetic as well as pharmacodynamic properties of a transdermal clonidine, M-5041T (M) and its safety were compared with those of oral clonidine, Catapres (Nippon Boehringer Ingelheim, Hyogo, Japan). One patch of M containing 6 mg of clonidine was applied on the right chest for 3 days or one tablet of Catapres (.075 mg) was given orally every 12 hours for 3 days in eight healthy subjects. The study was conducted by a crossover design with 14 to 16 days' interval between the cross-over. Blood and urine samples for clonidine concentration were obtained, and blood pressure (BP) was measured for a 168-hour period after application of M and for a 96-hour period after initiation of Catapres therapy. Plasma concentration of clonidine increased gradually after application of M and decreased gradually after removal, whereas this parameter increased rapidly during the absorption phase and decreased rapidly in the elimination phase after each dosage of Catapres. Elimination half-life of clonidine after removal of M was significantly greater than that after the final dosage of Catapres. No significant difference was observed in maximum plasma concentration or area under the plasma concentration-time curve between the two trials. The BP lowering effects of M and Catapres did not differ significantly. Adverse symptoms occurred more frequently during Catapres therapy than during treatment with M. Most of these symptoms were observed when plasma clonidine concentration was relatively higher in each trial. These results suggest that M is effective for the treatment of hypertension with a lower incidence of adverse symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMedDate not supplied

Restorative increases in serum testosterone levels are significantly correlated to improvements in sexual functioning.

It is recognized that testosterone (T) levels decrease in men with age, as does sexual function. We hypothesize that T supplementation in hypogonadal men with sexual dysfunction will restore certain elements of sexual function. Hypogonadal male subjects (total T < or = 300 ng/dL, n = 406, mean age 58 years) reporting one or more symptoms of low testosterone were randomized to T gel (50 mg/d and 100 mg/d), T patch, or placebo. Twenty-four-hour pharmacokinetic profiles for T were obtained. The 3 primary end points evaluated at 30 and 90 days posttreatment included a significant change in the frequency of intercourse and nighttime erections per 7-day week as well as a change in sexual desire measured on a Likert-type scale and calculated as a mean daily score. At day 30, a significant increase from baseline in sexual desire was noted for those on 100 mg/d T gel compared with those on 50 mg/d T gel, T patch, or placebo (1.2 vs 0.4, 0.7, and 0.4, respectively). A significant increase from baseline in the frequency of nighttime erections was also noted for those on 100 mg/d T gel compared with those on 50 mg/d T gel or placebo (51% of subjects in the 100 mg/d T gel group had an increase in frequency vs 30% for the 50 mg/d T gel group and 26% in the placebo group). Finally, a significant increase from baseline in the frequency of intercourse was evidenced for those on 100 mg/d T gel compared with those on T patch or placebo (39% of subjects in the 100 mg/d T gel group had an increase in frequency vs 21% for the T patch group and 24% in the placebo group). Similar results were seen for 100 mg/d T gel at day 90 for sexual desire and nighttime erections vs placebo. These data demonstrate a clear relationship between restoring serum T concentrations and improvement in certain parameters of sexual function. We propose that threshold T levels are needed in order to significantly affect improvements in sexual functioning.

Administration, Cutaneous↗
PubMed1989

An evaluation of the acute toxic properties of liquids derived from oil sands.

The acute toxicity of three materials derived from Athabasca Oil Sands--(1) bitumen plus naphtha, (2) untreated naphtha (0-250 degrees C) and (3) synthetic crude oil (0-500 degrees C)--was assessed in a battery of tests. In acute oral studies, all three test materials exhibited a low order of toxicity (LD50 greater than 5.0 g kg-1). The acute dermal LD50 was also low (greater than 3 g kg-1) for each test material. All three materials were judged to be 'slight' ocular irritants. Acute inhalation studies (6-h exposures at the maximum attainable concentrations) produced varied responses. Bitumen plus naphtha administered at a concentration of 1.46 mg l-1 did not cause mortality in exposed rats or mice. Lung discoloration was the only necropsy finding of note. Untreated naphtha administered at a concentration of 10.6 mg l-1 was lethal to essentially all of the mice; but only two rats died. Necropsy findings included elevated weights in the liver and kidneys of the exposed mice, elevated lung weights in male rats and elevated liver weights in female rats. Synthetic crude oil administered at a concentration of (4 mg l-1) was lethal to 5/10 mice, but none of the rats (0/10) died. Severe hair loss was noted in the surviving mice, and slight alopecia was also observed in rats. Both species exhibited elevated liver weight, and elevated lung weight was noted in female rats.

Administration, Cutaneous↗
PubMed1991

Urinary cyclophosphamide excretion in rats after intratracheal, dermal, oral and intravenous administration of cyclophosphamide.

The urinary excretion of unmetabolized cyclophosphamide was studied in rats after intratracheal, dermal, oral and intravenous administration. Rats were given two doses of 1 mg kg-1 cyclophosphamide 48 h apart and urine was collected for 96 h after the first treatment. With the help of a phosphor-specific filter in a flame photometer attached to a gas chromatograph, low levels of cyclophosphamide were determined after derivatization with trifluoroacetic anhydride. Cumulative excretion as a percentage of dose ranged from 4.0 to 6.9 after the first dose and 2.7 to 5.5 after the second dose. The highest rate of excretion after the second administration was observed in rats treated intratracheally, while cumulative excretion was higher (6.9%) after the first than after the second (2.7%) intravenous treatment. The most prolonged excretion was observed after dermal application.

Administration, Cutaneous↗
PubMedDate not supplied

Toxicology of coal liquefaction products: an overview.

Repeated exposure to coal liquefaction products produces a broad range of systemic effects. Among these, growth suppression, anaemia, leucocytosis and other haematological disorders are most prominent. Bone marrow, liver and kidney are the target organs affected by treatment. The effects are more severe with heavy distillates and male rats are more sensitive than females. Other changes included increased serum transaminases, alkaline phosphatase and cholesterol. Depending on the route of administration, the skin or lung may also be affected. Inhalation exposure produces the most severe changes, and oral exposure the least. Distillates containing N-PAHs and sulphur-containing PAHs are also more biologically active. Teratological effects were only observed if animals were exposed to the heavy distillate. Similarly, heavy distillates have mutagenic or carcinogenic properties. Teratological effects, as well as mutagenicity and carcinogenicity, of the coal liquefaction distillates seem to be linked to their PAH content, especially the N-PAHs. From the data presented in this review, it should become evident that the potential effects of coal liquefaction products on human health could be severe, especially with long-term exposure. Limited information exists on the occupational effects to coal liquefaction materials because most of the work to date has been with pilot plants. Careful and good judgement is required in order to extrapolate data from pilot plants to commercial-scale production. Experience in health effects of workers in the petroleum industry and coke-oven operations can serve as a guide for the implementation of industrial hygiene programmes for coal liquefaction operations. These programmes include engineering controls, health education, personal monitoring and hygienic practices, medical surveillance and long-term epidemiology studies, and they should be implemented to make coal liquefaction a healthy and environmentally sustainable industry.

Administration, Cutaneous↗
PubMedDate not supplied

Respiratory hypersensitivity to trimellitic anhydride in Brown Norway rats: a comparison of endpoints.

A rat bioassay has been developed to provide an objective approach for the identification and classification of respiratory allergy using trimellitic anhydride (TMA), which is a known respiratory tract irritant and asthmagen. Particular emphasis was placed on the study of route-of-induction-dependent effects and their progression upon inhalation challenge with TMA (approximately 23 mg m(-3) for a duration of 30 min), which included analysis of specific and non-specific airway hyperreactivity and pulmonary inflammation initiated and sustained by immunological processes. Refinement of the bioassay focused on procedures to probe changes occurring upon challenge with TMA or methacholine aerosols using physiological, biochemical and immunological procedures. Following challenge with TMA, the rats sensitized to TMA showed marked changes in peak inspiratory and expiratory air flows and respiratory minute volume. In these animals, a sustained pulmonary inflammation occurred, characterized by specific endpoints determined in bronchoalveolar lavage (lactate dehydrogenase, protein, nitrite, eosinophil peroxidase, myeloperoxidase). When compared with the naive controls, lung weights were increased significantly, as were the weights of lung-associated lymph nodes following inhalation induction and auricular lymph nodes following topical induction. The extent of changes observed was equal or more pronounced in animals sensitized epicutaneously (day 0:150 microl vehicle/50% TMA on each flank, day 7; booster administration to the skin of the dorsum of both ears using half the concentration and volume used on day 0) when compared with rats sensitized by 5 x 3 h day(-1) inhalation exposures (low dose: 25 mg TMA m(-3), high dose: 120 mg TMA m(-3)). In summary, the findings support the conclusion that the Brown Norway rat model is suitable for identifying TMA as an agent that causes both an immediate-type change of breathing patterns and a delayed-type sustained pulmonary inflammatory response. However, it remains unresolved whether the marked effects observed in the topically sensitized rats are more related to a route-of-induction or dose-dependent phenomenon.

Administration, Cutaneous↗
PubMedDate not supplied

Absorption, disposition and metabolism of di-isononyl phthalate (DINP) in F-344 rats.

Di-isononyl phthalate (DINP; CAS no. 68515-48-0) is a general-purpose plasticizer for polyvinyl chloride. It produced liver and kidney effects when given to rodents at high oral doses, but there were no target organ effects in primates treated under similar conditions. To assist in understanding the basis for these species differences, the pharmacokinetic properties of DINP were evaluated in rodents following both oral and dermal administration. These studies demonstrated that the pharmacokinetic properties of DINP are similar to those of other high-molecular-weight phthalates. When orally administered to rodents, DINP is rapidly metabolized in the gastrointestinal tract to the corresponding monoester, absorbed and excreted, primarily in the urine. Shortly after administration, DINP is found primarily in liver and kidneys, but it does not persist or accumulate in any organ or tissue. It is very poorly absorbed from the skin, but once absorbed it behaves in the same way as the orally administered material. The results of these rodent studies contrast with data from studies involving humans or other primates, which indicate low absorption at low oral doses and much more limited total absorption at high doses. It appears that many, if not all, of the effects of DINP in rodent studies are associated with internal doses that would be difficult, if not impossible, to achieve in humans under any circumstances. Thus, the results of rodent studies may not be very useful in assessing the potential risks to humans from high-molecular-weight phthalates.

Administration, Cutaneous↗
PubMed1992

Impact of short-term estrogen administration on growth hormone secretion and action: distinct route-dependent effects on connective and bone tissue metabolism.

We recently reported that estrogen exerts distinct effects on the GH/IGF-1 axis that are dependent on the route of delivery, probably reflecting a first-pass effect on hepatic IGF-1 production. Oral administration reduces IGF-1 and increases GH levels; transdermal administration elevates IGF-1 without changing GH concentrations. Since mesenchymal tissue is a target for GH and IGF-1 action, we studied changes in the GH/IGF-1 axis following oral (ethinyl estradiol, 20 micrograms/day) versus transdermal (Estraderm 100 TTS, Ciba Geigy, 100 micrograms 17 beta-estradiol per day) estrogen delivery and compared corresponding effects on connective and bone tissue metabolism. Mean 24 h GH levels, IGF-1, markers of fibroblast (procollagen III) and osteoblast (procollagen I, osteocalcin) function, and indices of bone turnover (fasting urinary hydroxyproline and calcium to creatinine ratios, UOHPr/Cr and UCa/Cr) were measured before and after 2 months of either oral or transdermal therapy in two groups of postmenopausal women. Transdermal estrogen administration significantly (p less than 0.05) increased IGF-1, procollagen III, procollagen I, osteocalcin, and UOHPr/Cr. In contrast, oral estrogen administration had a suppressive effect; the levels of IGF-1 (p = 0.001), procollagen III (p = 0.018), procollagen I (p = 0.002), osteocalcin (p = 0.015), and UOHPr/Cr (p = 0.004) were significantly different from those measured during transdermal administration. Both treatments significantly reduced UCa/Cr (p less than 0.015). IGF-1 changes during estrogen therapy were significantly related (p less than 0.05) to changes in procollagen III, procollagen I, osteocalcin, and UOHPr/Cr. Transdermally delivered estrogen stimulates IGF-1 production, increases osteoblastic function, and stimulates bone and nonbone collagen synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed2002

Systemic absorption of topical lidocaine in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster.

Topical lidocaine has been recently marketed as a new treatment for post-herpetic neuralgia. The aim of our study was to characterize the absorption profile of and systemic exposure to lidocaine from patch and gel formulations in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. The bioavailability of lidocaine from the patch formulation averaged 3%, and was similar after single and repeated doses. Systemic exposure to lidocaine and monoethylglycinexylidide (MEGX), the primary active metabolite of lidocaine, after application of lidocaine gel or patches was minimal in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. Considering the benefit versus risk of topical lidocaine, systemic absorption and toxicity of lidocaine seems not to be a significant risk.

Acute Disease↗
PubMed1990

Bioavailability of propranolol following oral and transdermal administration in rabbits.

The systemic bioavailability of propranolol was evaluated following oral and transdermal administration in rabbits. Using a four-way crossover study, the bioavailability of propranolol following oral administration was determined to be 12.3 +/- 5.9%, indicating that propranolol is subject to extensive hepatic first-pass metabolism in rabbits. Transdermal delivery of propranolol, via an adhesive delivery device, resulted in a bioavailability of 74.8 +/- 10.1%, indicating that the transdermal delivery of propranolol can significantly increase systemic bioavailability over oral administration. Skin irritation studies indicated that neither propranolol nor the adhesive used in the device caused any appreciable skin irritation.

Administration, Cutaneous↗
PubMed1992

In vitro release of nitroglycerin from topical products by use of artificial membranes.

An in vitro testing method for measuring the release of nitroglycerin from topical drug products was evaluated. The method involved measuring the amount of nitroglycerin that diffused from ointments and patches through various synthetic membranes into receptor fluid contained in a modified Franz diffusion cell. Plots of the amount of nitroglycerin released against the square root of time for all 10 synthetic membranes were linear. Five membranes (group I) were found to release nitroglycerin at similar rates (difference not significant; p > 0.05). Use of the other five membranes (group II) in diffusion cells resulted in release rates significantly slower than those of group I membranes (p < 0.05). Rapid permeation of nitroglycerin from a solution through a polysulfone membrane demonstrated a lack of significant diffusion barrier properties of this membrane. Rates of release of nitroglycerin from commercially available ointments were found to be similar. A comparison of three commercial nitroglycerin patches revealed that these products released nitroglycerin at different rates in vitro.

Administration, Cutaneous↗
PubMed1994

Liposomes as carriers for topical and transdermal delivery.

The delivery of active agents to the skin by liposome carriers is an interdisciplinary topic of great interest today. Data accumulated over the last decade strongly point to important advantages of these drug delivery systems. A symposium devoted to classic and new approaches in the use of liposomal systems was organized and chaired by M. Mezei and E. Touitou as a part of the Jerusalem Conference on Pharmaceutical Sciences and Clinical Pharmacology, held on May 24-30, 1992, in Jerusalem, Israel. The presentations focused on liposomes as tools in the mechanistic study of absorption promoters (T. Nagai), drug liposomal delivery in the skin strata and structures (N. Weiner), interaction of liposomes and niosomes with the human skin (H.E. Junginger), and design and characterization of caffeine liposomal systems for use in hyperproliferative diseases (E. Touitou). Mezei reviewed biodisposition and clinical studies on liposomal dosage forms containing various drugs.

Administration, Cutaneous↗
PubMed1995

Transdermal delivery of metoprolol. II: In-vitro skin permeation and bioavailability in hairless rats.

The absolute bioavailability of metoprolol (MP) was evaluated following oral and transdermal administration in hairless rats. The absolute bioavailability of MP following oral administration was 3.48 +/- 1.73%, indicating that MP is subject to extensive hepatic first-pass metabolism. Transdermal delivery of MP, via an adhesive delivery device, resulted in a bioavailability of 30.07 +/- 4.84%, indicating that the transdermal delivery of MP can significantly increase systemic bioavailability compared with oral administration. Preliminary skin irritation studies indicated that neither MP nor the adhesive used in the device caused any appreciable skin irritation in the hairless rats.

Adhesives↗
PubMed1991

Absorption of apomorphine by various routes in parkinsonism.

We wanted to determine the absorption and clinical effect of sublingual (SL) and transdermal apomorphine in parkinsonism. Patients received single SL apomorphine doses (N = 7) and the absorption was compared with parenteral (N = 5) and oral (N = 4) doses. One patient received a transdermal dose of apomorphine. The relative bioavailability of SL apomorphine ranged from 10 to 22% of a parenteral apomorphine dose. Oral apomorphine was less than 4% bioavailable, and the transdermal dose did not produce detectable plasma levels. Three patients with motor fluctuations responded to SL apomorphine, with a latency to effect of 20-40 min and a duration of effect of 15-100 min. One patient used SL apomorphine as an adjunct with levodopa, and during 1 month reported a large decrease in "off" periods. We conclude that apomorphine is effectively absorbed by the sublingual route.

Absorption↗