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Biomedical subjects

H L Friedman

Publications and source records attributed to H L Friedman.

At least 19 recordsLinked to original sources
PubMed1997

Biotransformation of mestranol to ethinyl estradiol in vitro: the role of cytochrome P-450 2C9 and metabolic inhibitors.

Mestranol, the estrogen component of some oral contraceptive formulations, must be demethylated to its active metabolite, 17 alpha-ethinyl estradiol, to produce estrogenic activity. To investigate the transformation of mestranol to ethinyl estradiol, an in vitro assay was used with human liver microsomes from four different donors. Incubation of a fixed concentration of mestranol (3 mumol/L) with varying concentrations of CYP inhibitors revealed strong inhibition of ethinyl estradiol formation by sulfaphenazole, a specific CYP2C9 inhibitor, with an average inhibitor concentration at one half of Emax (IC50) of 3.6 mumol/L (range, 1.8-8.3 mumol/L) and an average maximal inhibitory capacity (Emax) of 75% (range, 60-91%). Troleandomycin (a CYP3A3/4 inhibitor) and quinidine (a CYP2D6 inhibitor), however, produced no substantial inhibitory activity. alpha-Naphthoflavone (a CYP1A1/2 inhibitor only at concentrations < 2 mumol/L and a CYP2C9 inhibitor at higher concentrations) had a weak inhibitory effect on ethinyl estradiol formation (< 20% decrease in mestranol demethylation activity). Of the three antifungal azoles tested, miconazole strongly inhibited mestranol demethylation, with an average IC50 of 1.5 mumol/L (range, 0.7-3.2 mumol/L) and an average Emax of 90% (range, 77-100%), whereas fluconazole displayed relatively weak inhibition only at the highest concentration of 50 mumol/L (mean reduction in demethylation activity was 29%). Itraconazole produced no meaningful inhibition. Strong inhibition of ethinyl estradiol formation by sulfaphenazole suggests a major contribution of CYP2C9 to this reaction.

Adult↗
PubMed1997

Pharmacokinetics and safety of trovafloxacin in healthy male volunteers following administration of single intravenous doses of the prodrug, alatrofloxacin.

Fifteen healthy male volunteers (in four groups) received single 1 h i.v. infusions of alatrofloxacin (CP-116,517) equivalent to 30, 100, 200 or 300 mg of its active metabolite, trovafloxacin (CP-99,219). Blood and urine were sampled over 73 and 72 h, respectively, and plasma levels of alatrofloxacin and serum concentrations of trovafloxacin were determined by HPLC with UV detection. Alatrofloxacin was not detectable in plasma samples collected after the end of infusion, indicating rapid conversion to trovafloxacin. Maximum serum concentrations of trovafloxacin were achieved at the end of the infusions. Mean maximum plasma trovafloxacin concentrations for the four alatrofloxacin doses were 0.4, 1.8, 2.3 and 4.3 mg/L. The mean area under the concentration-time curve increased proportionally with the dose. The elimination half-life (T(1/2)) for trovafloxacin was independent of the dose and the mean T(1/2)s for the 100, 200 and 300 mg equivalent doses of alatrofloxacin were 10.4, 12.3 and 10.8 h. Approximately 10% of the equivalent dose was recovered as unchanged trovafloxacin in the urine. No clinical adverse or laboratory reactions were associated with i.v. administration of alatrofloxacin and its conversion to trovafloxacin. These results indicate that alatrofloxacin is rapidly converted to trovafloxacin and that the pharmacokinetic parameters for this new fluoroquinolone after i.v. administration of its parent compound are similar to those reported after oral administration of equivalent trovafloxacin doses.

Adult↗
PubMed1997

Effect of trovafloxacin, a new fluoroquinolone antibiotic, on the steady-state pharmacokinetics of theophylline in healthy volunteers.

Some fluoroquinolone antibiotics interfere with theophylline clearance, thereby raising concentrations of circulating theophylline and increasing the potential for toxicity. The effect of steady-state serum concentrations of the new fluoroquinolone trovafloxacin on the steady-state pharmacokinetics of theophylline was examined in 12 healthy male volunteers. For 7 days, the subjects received morning and evening theophylline doses adjusted to achieve steady-state plasma concentrations of 8-15 mg/L, the lower end of the therapeutic range. From day 8 to day 15, six volunteers received, in addition to theophylline, 200 mg of trovafloxacin in the morning and placebo in the evening (group A) and six received placebo twice daily (group B). Serial plasma samples obtained over 12 h and 60 h after the morning theophylline dose on days 7 and 14, respectively, were analysed for theophylline by HPLC with UV detection. There were no significant differences in mean Cmax or AUC(0-12) between the two groups on day 7 or on day 14, nor were there significant within-group differences on the two days. On day 14, mean Cmax, AUC(0-12) and T(1/2) (measured on day 14 only) in group A were 10.15 mg/L, 107.32 mg x h/L and 9.0 h, respectively. In group B, the values were 10.81 mg/L, 113.73 mg x h/L and 8.3 h, respectively. The study drugs were well tolerated, and no clinically significant changes in vital signs or laboratory test values were noted. We conclude that steady-state concentrations of trovafloxacin have no clinically significant effect on the steady-state concentrations of theophylline within the therapeutic range in healthy subjects.

Adult↗
PubMed1997

Oral bioavailability of trovafloxacin with and without food in healthy volunteers.

Two studies determined the oral bioavailability of trovafloxacin (CP-99,219) in healthy volunteers under fasted and fed conditions. In a randomized, two-way crossover study, 12 fasting subjects received two 100 mg tablets of trovafloxacin and an equivalent dose of alatrofloxacin (CP-116,517), administered by i.v. infusion over 1 h. Alatrofloxacin, the L-Ala-L-Ala prodrug of trovafloxacin, is rapidly converted in the body to trovafloxacin. After the oral dose of trovafloxacin, the mean Cmax and AUC were 2.2 mg/L and 30.4 mg x h/L, respectively. After the infusion of alatrofloxacin, the Cmax and AUC of trovafloxacin were 3.2 mg/L and 34.7 mg x h/L, respectively. The mean T(1/2) after both treatments was about 11 h. The mean Cl and Vd(ss) of trovafloxacin after the infusion of alatrofloxacin were 1.32 mL/min/kg and 1.13 L/kg, respectively. The mean oral bioavailability of trovafloxacin was estimated to be 87.6% (range 64.8-122.1%). Another randomized, open, three-way crossover study was conducted in 12 healthy male volunteers to investigate the effect of food in the gastrointestinal tract on the bioavailability of trovafloxacin. Each subject received three 100 mg tablets after fasting overnight (treatment A) or after a standard breakfast (treatment B), or 300 mg as oral aqueous suspension after fasting overnight (treatment C). Mean Tmax after treatment B occurred 2.2 h later (3.6 h vs 1.4 h) than after treatment A. Mean Cmax and AUC were 2.3 and 2.6 mg/L and 38.2 and 39.5 mg x h/L after B and A, respectively. About 5% of the administered dose was recovered unchanged in the 24 h urine sample after all three treatments. Thus, the food reduced mean Cmax by 12% but had no appreciable effect on mean AUC. The mean bioavailability of trovafloxacin administered as treatment regimen B was 96.6% relative to that of treatment A. The respective mean bioavailabilities of trovafloxacin as treatments B and A were 91.3% and 94.5% respectively of that of treatment C. The results of these studies indicate that trovafloxacin has good oral bioavailability and that the ingestion of food is unlikely to have a clinically significant effect on the bioavailability of trovafloxacin.

Administration, Oral↗
PubMed1997

Effect of Maalox and omeprazole on the bioavailability of trovafloxacin.

To determine the effect of the concurrent administration of Maalox and omeprazole in the bioavailability of trovafloxacin (CP-99,219), an open, placebo-controlled, randomized, four-way crossover study was conducted in 12 healthy male volunteers. Each received treatments of three 100 mg trovafloxacin tablets in the morning 30 min after 30 mL of Maalox (A), 30 min after placebo (B), 2 h before 30 mL of Maalox (C) and 2 h after 40 mg of omeprazole (D). For treatments A and C, Maalox was also given at 22.00 h the night before the study day, 1 and 3 h after meals and at bedtime on the study day. For B and D, placebo and omeprazole, respectively, were also given at 22.00 h the night before the study day. After treatments A and C, mean area under the curve (AUC) was reduced by 66% and 28% (14.2 and 30.2 mg.h/L), respectively, and mean T(1/2) declined by 33% and 31% (8.3 and 8.5 h), respectively, relative to the values after B (42.1 mg.h/L; 12.4 h). The mean Kel-corrected relative bioavailabilities for A and C were 50% and 104%, respectively, suggesting a large reduction in the initial absorption of trovafloxacin with A. Treatment D had no appreciable effect on mean T(1/2) but mean AUC and Cmax were reduced by 18% and 32%, respectively, relative to B. The mean relative bioavailability after D was 82%. We conclude that the concurrent administration of trovafloxacin and aluminium- and magnesium-containing antacids should be avoided but that co-administration with omeprazole is unlikely to have a clinically significant effect on the extent of absorption of the antibiotic.

Adult↗
PubMed1994

Reproductive health in adolescence.

The health and well-being of adolescents is closely intertwined with their physical, psychological and social development, but this is put at risk by sexual and reproductive health hazards which are increasing in much of the world. Changes in population growth and distribution, the rise of telecommunications, the increase in travel and a decline in the family, as well as a generally earlier start of menarche and later age of marriage are contributing to an increase in unprotected sexual relations before marriage. This, combined with risks from early marriage, result in too early or unwanted pregnancy and childbirth, induced abortion in hazardous circumstances and sexually transmitted diseases, including HIV infection leading to AIDS. With more than half the world's population below the age of 25, and 4 out of 5 young people living in developing countries with inadequate access to prevention and care, there is an urgent need for action. Young women are particularly vulnerable. Mortality and morbidity from early pregnancy whether ending in childbirth or abortion, is much higher for the younger adolescent. Young women, especially those who have less formal education, are more vulnerable to pressures for marriage, or sexual relations before marriage, often with older men. Young people generally lack adequate knowledge about their own development and information on how to get help. Those who could help are rarely trained for working with adolescents, and services which are generally designed for adults or children often deter young people from getting help when they most need it. Policy and legislation relating to sexual and reproductive health issues are often contradictory, and unclear or unenforced.(ABSTRACT TRUNCATED AT 250 WORDS)

Abortion, Induced↗
PubMed1992

Changing patterns of adolescent sexual behavior: consequences for health and development.

Sexuality is a fundamental quality of human life, important for health, happiness, individual development, and indeed for the preservation of the human race. During the dynamic period of adolescence in which the passage from childhood to maturity takes place, sexuality takes on new dimensions; feelings become more intense, relationships become more complex, and the consequences of sexual behavior are radically altered. This not only affects the behavior of young people but also of those who interact with them, their families and peers, and those who work in the health, education, youth, social welfare, and other sectors. In the contemporary world the conditions of life for many young people have also changed, and with it patterns of sexual behavior. In general, earlier puberty, later marriage, a decline in the family leading to less control and more autonomy, and intense exposure to sexual stimuli via the mass media and travel across cultural boundaries have made pre-marital adolescent sexual activity more common. This has added to traditional problems of early marriage, newer problems of early pregnancy, childbirth, and induced abortion outside of marriage, sexually transmitted diseases, and human immunodeficiency syndrome infection leading to acquired immunodeficiency syndrome. But the work of the World Health Organization (WHO), along with many others in the field, strongly suggests that given appropriate information and services, trust and equity between the sexes, young people will behave responsibly and well. In this paper some of the findings from methods developed by WHO for research, training, advocacy, and evaluation, and findings in relation to patterns and determinants of sexual and reproductive health and development will be described, and future directions suggested.

Adolescent↗
PubMed1989

The health of adolescents: beliefs and behaviour.

Adolescence is a period of transition from childhood to adulthood in which interlocking changes in the body, mind and social relationship take place. Healthy development depends on both a propitious environment and the action of adolescents themselves. A stable family, peace, material conditions for physical health, and educational, social and vocational opportunities with a chance to make use of them before marriage, are necessary environment conditions. However, within this context the adolescent must experiment with new behaviours and relationships inevitably courting some risks. Adolescent health is especially linked to behaviour. If the environment is inadequate or dangerous and the adolescent lacks self-esteem, behaviours dangerous to health are more likely to occur. These include: precocious and unprotected sexual behaviour sometimes resulting in too early or unwanted pregnancy and sexually transmitted diseases; the use of tobacco, alcohol and other drugs; injuries arising accidentally from risk taking behaviours especially when combined with alcohol or drugs; intentional injury whether self-inflicted or inflicted by others; and poor eating and habits of hygiene leading to obesity, or emaciation, acne and poor teeth and gums. Adolescent behaviour is often governed by their beliefs about what others think. Two way communication in a trusting atmosphere will reduce myths and misinformation and encourage healthy behaviour. The promotion of health, the prevention of problems, and their treatment and rehabilitation when they arise can best be accomplished with the active co-operation of young people.

Adolescent↗
PubMed1988

The thermodynamics of protein stability. Cold destabilization as a general phenomenon.

A theoretical analysis of the temperature/stability profiles of proteins shows that, where a two-state model represents the denaturation, and where the free energy of denaturation delta G(T) shows a strong temperature dependence, then the protein becomes subject to both high- and low-temperature destabilization. In the simplest case delta G(T) is parabolic, therefore the high temperature TH, where delta (G(TH) = 0, is complemented by a low temperature TL, where delta G(TL) = 0. It is generally stated that the partial molal heat capacity change delta C accompanying the heat denaturation is positive and independent of the temperature. This implies that heating the protein through TL results in a negative delta C which seems physically unsatisfactory. The constant delta C model is explored and a physically more realistic model is advanced which allows for a temperature-dependent delta C which changes sign at some temperature within the range of stability of the native protein; delta G(T) then has the form of a skewed parabola. Experimental heat capacity data for native lysozyme and for a flexible polymer lend support to this model. The molecular basis of cold inactivation of proteins is discussed in the light of the thermodynamic analysis.

Cold Temperature↗
PubMed1986

Chronic treatment with Ro 15-1788 distinguishes between its benzodiazepine antagonist, agonist and inverse agonist properties.

Ro 15-1788 (flumazepil) is an imidazodiazepine that is able to antagonise most of the behavioural actions of the benzodiazepines, as well as having some intrinsic effects. Acute administration of Ro 15-1788 (10 mg/kg) decreases social interaction between male rats and elevates exploratory head-dipping. After 5 days of pretreatment there was tolerance to the former effect, although Ro 15-1788 retained its ability to antagonise the effects on social interaction of the beta-carboline, FG 7142. Ro 15-1788 also retained its ability to elevate head-dipping: additionally, the chronically-treated rats had elevated motor activity and rearing scores. The acute effects of lorazepam in the holeboard were unchanged by chronic pretreatment with Ro-15-1788. The plasma and brain concentrations after acute administration of lorazepam were unchanged following chronic administration of Ro 15-1788. After chronic treatment the brain concentrations of Ro 15-1788 were unchanged. It is unlikely that pharmacokinetic factors could underlie the different behavioural changes following chronic treatment.

Animals↗