Biomedical subjects

J Longstreth

Publications and source records attributed to J Longstreth.

14 recordsLinked to original sources

PubMed2001

Topical permethrin exposure inhibits antibody production and macrophage function in C57Bl/6N mice.

Permethrin was applied to the shaved dorsal interscapular region of C57Bl/6N mice at doses of 0.5, 1.5 or 5.0 microl/day. These doses corresponded to approximately 22-220 mg/kg/day topical insecticide. Mice were exposed to permethrin in this manner daily for 10 or 30 consecutive days, or every other day for 7 or 14 exposures. The splenic macrophage chemiluminescent response was depressed in a dose-dependent manner at 2 and 10 days post-exposure to permethrin. Phagocytic ability of macrophages was not inhibited. Antibody production as shown by plaque-forming cell (PFC) assay decreased significantly after 10 consecutive days of exposure to permethrin. These data indicate that topical permethrin exposure may produce systemic immune effects.

Administration, Topical↗

PubMed2001

Misoprostol therapeutics revisited.

Misoprostol, a prostaglandin E1 analog, is a racemate of four stereoisomers. On administration it rapidly de-esterifies to its active form, misoprostolic acid. Misoprostolic acid is 85% albumin bound and has a half-life of approximately 30 minutes. It is excreted in urine as inactive metabolites. No significant drug interactions have been reported. Besides its gastrointestinal protective and uterotonic activities, misoprostol regulates various immunologic cascades. It inhibits platelet-activating factor and leukocyte adherence, and modulates adhesion molecule expression. It protects against gut irradiation injury, experimental gastric cancer, enteropathy, and constipation. It improves nutrient absorption in cystic fibrosis. Misoprostol has utility in acetaminophen and ethanol hepatotoxicity, hepatitis, and fibrosis. It is effective in asthmatics and aspirin-sensitive asthmatic and allergic patients. It lowers cholesterol and severity of peripheral vascular diseases, prolongs survival of cardiac and kidney transplantation, synergizes cyclosporine, and protects against cyclosporine-induced renal damage. It works against drug-induced renal damage, interstitial cystitis, lupus nephritis, and hepatorenal syndrome. It is useful in periodontal disease and dental repair. Misoprostol enhances glycosoaminoglycan synthesis in cartilage after injury. It prevents ultraviolet-induced cataracts and reduces intraocular pressure in glaucoma and ocular hypertension. It synergizes antiinflammatory and analgesic effects of diclofenac or colchicine and has been administered to treat trigeminal neuralgic pain. It reduces chemotherapy-induced hair loss and recovery time from burn injury, and is effective in treating sepsis, multiple sclerosis, and pancreatitis.

Animals↗

PubMed2000

Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men.

Transdermal delivery of testosterone (T) represents an effective alternative to injectable androgens. Transdermal T patches normalize serum T levels and reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irritation and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the pharmacokinetic profiles after 1, 30, 90, and 180 days of daily application of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/day, respectively) and a permeation-enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel formulation when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 9-14% of the T applied was bioavailable. After 90 days of T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplication serum T levels were outside the normal adult male range. Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch application. Our previous study showed that steady state T levels were achieved 48-72 h after first application of the gel. The pharmacokinetic parameters for serum total and free T were very similar on days 30, 90, and 180 in all treatment groups. After repeated daily application of the T formulations for 180 days, the average serum T level over the 24-h sampling period (C(avg)) was highest in the 100 mg T gel group (1.4- and 1.9-fold higher than the C(avg) in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable over the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the C(avg), whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients. Serum free T levels paralleled those of serum total T, and the percent free T was not changed with transdermal T preparations. The serum dihydrotestosterone C(avg) rose 1.3-fold above baseline after T patch application, but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day, respectively, resulting in a small, but significant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed proportionately with serum T in all study groups; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate.

Administration, Cutaneous↗

PubMed1999

Public health consequences of global climate change in the United States--some regions may suffer disproportionately.

Current risk assessments of the likely regional health impacts of global climate change (GCC) are hindered by two factors. First, dose-response relationships between weather parameters and many of the likely health effects have not been developed, and second, reliable estimates of future regional climates across the United States are still beyond the scope of current modeling efforts. Consequently, probabilistic risk estimates of most of the likely regional health impacts of GCC have such a high degree of uncertainty that their usefulness to health officials dealing with regional issues is very limited. With the numerous pressures on today's health care systems, it is understandable that the possible consequences of GCC have received scant attention from regional health care decision makers. Indeed, the consensus among this community appears to be that any increases in health effects associated with GCC will be easily handled by the current health care system. However, such a position may be naive as the potential exists that an unequal distribution of such effects could overwhelm some regions, whereas others may feel little or no impact. This review of the likely regional impacts of GCC has been structured as a semianalytical look at this issue of distributional effects. Because of the lack of dose-response information and reliable estimates of future regional climates, however, it takes a historical perspective. That is, it assumes that the quality and quantity of health risks a region faces under GCC will be directly related to its recent history of health risks from warm weather/climate-related diseases as well as to the size, characteristics, and distribution of the sensitive subpopulations currently residing within its borders. The approach is semiquantitative; however, it uses national data gathered on a regional level and as such should only be used to generate a hypothesis rather than test it. When applied to the United States, its outcome leads to the hypothesis that if indeed history repeats itself, some states or regions may be more greatly affected by GCC than others, not only because historically they are more prone to summer weather/climate-related diseases, but also because they contain a greater proportion of the sensitive subpopulations in the United States.

Air Pollutants↗

PubMed1998

Health risks.

The health risks associated with ozone depletion will principally be those due to increased ultraviolet B (UV-B) radiation in the environment, i.e., increased damage to the eyes, the immune system, and the skin. Some new risks may also be introduced with the increased use of alternatives to the ozone-depleting substances (ODSs). Quantitative risk estimates are available for some of the UV-B-associated effects, e.g., cataract and skin cancer; however, the data are insufficient to develop similar estimates for effects such as immunosuppression and the toxicity of alternatives. Ocular damage from UV exposures includes effects on the cornea, lens, iris, and associated epithelial and conjunctival tissues. The most common acute ocular effect of environmental ultraviolet radiation (UVR) is photokeratitis. Also known as snowblindness in skiers, this condition also occurs in other outdoor recreationists. Chronic eye conditions likely to increase with ozone depletion include cataract, squamous cell carcinoma, ocular melanoma, and a variety of corneal/conjunctival effects, e.g., pterygium and pinguecula. Suppression of local (at the site of UV exposure) and systemic (at a distant, unexposed site) immune responses to a variety of antigens has been demonstrated in both humans and animals exposed to UV-B. In experiments with animals these effects have been shown to worsen the course/outcome of some infectious diseases and cancers. There is reasonably good evidence that such immunosuppression plays a role in human carcinogenesis; however, the implications of such immunosuppression for human infectious diseases are still unknown. In light-skinned populations, exposure to solar UVR appears to be the most important environmental risk factor for basal and squamous cell carcinomas and cutaneous melanoma. Originally it was believed that total accumulated exposure to UVR was the most important environmental factor in determining risk for these tumors. Recent information now suggests that only squamous cell carcinoma risk is related to total exposure. In the cases of both basal cell carcinoma and melanoma, new information suggests that increases in risk are tied to early exposures (before about age 15), particularly those leading to severe sunburns. Testing of a number of the chlorofluorocarbon (CFC) alternatives indicates that most of these chemicals have low acute toxicity, and low to moderate chronic toxicity. Some chemicals that were originally proposed as alternatives have been dropped from consideration because these tests raised concerns about toxicity and/or manufacturing difficulties. In one instance, high accidental occupational exposure was associated with liver damage, underlining the need for care in the use of these substitutes. Recent quantitative risk estimates have been developed for cataract, melanoma, and all skin cancers combined. These estimates indicate that under the Montreal Adjustments, cataract and skin-cancer incidence will peak mid-century at additional incidences of just under 3 per 100,000 and about 7 per 100,000, respectively.

Animals↗

PubMed1996

Simultaneous first-order and capacity-limited elimination kinetics after oral administration of verapamil.

In this study of the relationship between dose and plasma concentration of verapamil, controlled-release verapamil in doses of 120 mg, 180 mg, 360 mg, and 540 mg were examined. The 48 study subjects received verapamil daily during each of the 4 sequential 5-day dosing segments. Blood samples were collected frequently to obtain first-dose and steady-state (fifth dose) concentration profiles of verapamil. Plasma concentrations of R- and S-verapamil and R- and S-norverapamil were measured by stereospecific assay. Statistical comparisons of pharmacokinetic parameters and mean differences between doses were performed with analysis of variance models. At steady state, area under the concentration-time curve (AUC) values for R- and S-verapamil at both the 120-mg and 180-mg doses were about 1.5 times higher than the corresponding first-dose values. After both first and fifth doses, pharmacokinetic parameters for all four analytes were dose proportional between the 120-mg and 180-mg doses. A dose-proportional relationship also was found between the 360-mg and 540-mg dose levels. However, nonlinearity was found between the 180-mg dose and higher doses, suggesting saturable metabolic pathways. The dose-proportional relationship between the 360-mg and 540-mg doses suggests that other first-order metabolic pathways become dominant. Although results from this study are partially consistent with previously reported nonlinear verapamil kinetics, this is the first clinical study to demonstrate a dose-proportional relationship for verapamil at both low and high input rates (mg/hr). In addition, first-order disposition pathways of verapamil are probably nonexistent at medium input rates and become dominant at higher input rates.

Administration, Oral↗

PubMed1995

The effect of food, time of dosing, and body position on the pharmacokinetics and pharmacodynamics of verapamil and norverapamil.

To evaluate the influence of food, time of dosing, and body position on the steady-state pharmacokinetics of an osmotically controlled formulation of verapamil (COER-verapamil), each of 29 healthy men received one tablet a day at specified times in an open-label, multiple-dose, four-period, crossover study. The verapamil tablets were administered in a randomized, balanced, crossover design: 240 mg at 8:00 AM on an empty stomach, subjects remaining ambulatory; 240 mg at 8:00 AM on an empty stomach, subjects remaining supine for 8 hours; 240 mg at 10:00 PM with a standardized meal, subjects remaining supine for 8 hours; and 240 mg at 10:00 PM on an empty stomach, subjects remaining supine for 8 hours. Plasma verapamil concentrations were measured at steady state over the dosing interval. Steady-state plasma concentrations were achieved by the fourth administration of the drug. Neither food nor posture had any effect on the pharmacokinetics of verapamil or norverapamil, or on hemodynamic measurements. Time of dosing did affect the rate of appearance and elimination of verapamil, but had no effect on the extent of verapamil absorption, norverapamil appearance, or hemodynamic measurements.

Adult↗

PubMed1995

The effect of co-administered drugs on oxaprozin binding to human serum albumin.

The binding of the non-steroidal anti-inflammatory drug oxaprozin to human serum albumin was studied by bioaffinity high-performance liquid chromatography using a column based on immobilized human serum albumin. Displacement studies using marker compounds for the major drug binding sites showed that oxaprozin has a high affinity for the benzodiazepine/indole site and binds to the warfarin site but with a significantly lower affinity. Biochromatography and ultrafiltration techniques were used to screen for possible competition and allosteric interactions between oxaprozin and potential co-administered drugs including non-steroidal anti-inflammatory drugs, antipyretics, hypoglycaemics, inhibitors of angiotensin-converting enzyme, anaesthetics, metal ions and anticancer agents. Competition occurred mainly with drugs bound at the benzodiazepine site (benzodiazepines, various non-steroidal anti-inflammatories).

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Stereoselective determination of verapamil and norverapamil by capillary electrophoresis.

An analytical method has been developed to determine simultaneously the verapamil and norverapamil enantiomers in human plasma using capillary electrophoresis. Among the cyclodextrins tested as chiral selector, only trimethyl-beta-cyclodextrin was suitable to resolve the four enantiomers. The analysis was achieved in less than 10 min. Selectivity, linearity, precision and accuracy were evaluated before the chiral method was successfully implemented for routine use to simultaneously determine the four enantiomers in several thousands of human plasma samples. The robustness of the capillary electrophoretic method and its suitability were demonstrated by the coefficients of variation which were lower than 11%, even at the limit of quantification (2.5 ng/ml), for the analysis of more than one hundred quality control samples.

Capillary Action↗

PubMed1991

Anticipated public health consequences of global climate change.

Human activities are placing enormous pressures on the biosphere. The introduction of new chemicals and the increasing ambient levels of existing chemicals have resulted in atmospheric degradation. This paper reviews some of the adverse effects of stratospheric ozone depletion and global warming. Because the atmospheric effects of ozone depletion are fairly well characterized, quantitative risk estimates have been developed. However, because the atmospheric effects of global warming are less understood, public health problems that could be intensified by climate change are assessed qualitatively. The interactive effects of these two phenomena are also discussed.

Acclimatization↗

PubMed1988

Cutaneous malignant melanoma and ultraviolet radiation: a review.

Cutaneous malignant melanoma (CMM) rates have been increasing in the United States at an average rate of about 4% per year. In 1987, it was estimated that there would be 25,800 cases and 5,800 deaths from CMM in the United States. The exact cause of the increase in unknown, but there is evidence to suggest that increasing exposure to the ultraviolet B (UVB) radiation present in sunlight may be partly responsible. The evidence includes: 1. the fact that higher CMM incidence rates are observed in people with lesser amounts of skin pigment (which blocks penetration of UV); 2. a correlation of higher CMM rates with decreasing latitude and increasing UVB levels; 3. the observation that freckles and nevi (precursors to CMM) are induced by solar exposure; 4. differences in CMM rates between natives and immigrants to sunny climates; 5. high rates of CMM in patients who cannot repair UVB-induced DNA damage; and 6. the indication that sun exposure at early ages and of an intermittent nature results in higher CMM risks. With the concern that depletion of stratospheric ozone could result in increasing levels of UVB, it has become important to understand the relationship between UVB and CMM in order to estimate the increases in CMM that would be expected with ozone depletion. When empirical relationships between UVB and CMM incidence and mortality rates were derived and used to estimate the impact of stratospheric ozone depletion, a 1% depletion of ozone was predicted to result in increases of 1%-2% in CMM incidence and 0.8%-1.5% in CMM mortality.

Dose-Response Relationship, Radiation↗

PubMed1984

Cefotaxime compared with nafcillin plus tobramycin for serious bacterial infections. A randomized, double-blind trial.

In a prospective, randomized, double-blind study, we compared cefotaxime with nafcillin plus tobramycin in the treatment of serious bacterial infections. Of 195 patients with suspected or proven infections who were not neutropenic, definite bacterial infections were identified in 81; 34 of 38 patients given cefotaxime and 26 of 43 given nafcillin plus tobramycin (p less than 0.01) responded to treatment. The difference in response rates occurred primarily in patients with rapidly fatal underlying disease or with an infection outside the urinary tract. A logistic regression analysis showed that treatment with cefotaxime was still associated with a higher response rate after adjusting for several potential confounding factors. Among patients treated for 3 days or more, our criteria for nephrotoxicity were met in 2 of 68 (2.9%) given cefotaxime and 16 of 57 (28.1%) given nafcillin plus tobramycin (p less than 0.001). Prolongation of the prothrombin time and enterococcal colonization did not occur more frequently with cefotaxime. We conclude that cefotaxime may be more effective and less toxic than nafcillin plus tobramycin for patients with serious bacterial infections.

Adult↗

PubMed1980

Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin.

Two hundred fifty-eight patients with suspected sepsis were treated with tobramycin or gentamicin in a prospective, randomized, double-blind trial. One hundred forty-six patients received nine or more doses, had serial determinations of serum creatinine, and were evaluated for nephrotoxicity; 91 were able to cooperate with audiometry and were evaluated for auditory toxicity. Auditory toxicity developed in five of 47 (10 per cent) given gentamicin and five of 44 (11 per cent) given tobramycin. Nephrotoxicity developed in 19 of 72 (26 per cent) given gentamicin and nine of 74 (12 per cent) given tobramycin (P less than 0.025). The severity of the nephrotoxicity was not different; the mean increase in creatinine was 1.3 mg per 100 ml (114.9 mumol per liter) in both groups. Both the tobramycin and gentamicin groups had a similar mean age, initial serum creatinine level, total dose, serum aminoglycoside level, and duration of therapy. We conclude that tobramycin causes nephrotoxicity less frequently than does gentamicin.

Acute Kidney Injury↗

PubMed1977

Phenytoin intoxication during concurrent diazepam therapy.

Phenytoin elimination is a saturable process obeying Michaelis-Menten kinetics. Plasma phenytoin levels are not related linearly to dose, and small changes in enzyme activity produced by concurrent drug therapy could alter plasma levels. Two cases of phenytoin intoxication associated with simultaneous administration of diazepam are reported. Intravenous phenytoin infusions were given and the apparent K(m) and V(max) computed from the resulting plasma phenytoin levels. In one case `K(m)' and `V(max)' were 0.8 μmol/1 and 1.3 μmol/1/hour respectively during concurrent diazepam administration, and 50.3 μmol/1 and 4.4 μmol/1/hour after discontinuation of diazepam. In the second case phenytoin infusion with diazepam gave `K(m)' and `V(max)' values of 0.012 μmol/1 and 0.95 μmol/1/hour. Without diazepam these were 28.8 μmol/1 and 0.92 μmol/1/hour respectively.

Child↗