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Biomedical subjects

P J Perry

Publications and source records attributed to P J Perry.

At least 37 records · Page 2Linked to original sources
PubMed1999

Stabilization of DNA triple helices by a series of mono- and disubstituted amidoanthraquinones.

We have used quantitative DNase I footprinting to measure the relative affinities of four disubstituted and two monosubstituted amidoanthraquinone compounds for intermolecular DNA triplexes, and have examined how the position of the attached base-functionalized substituents affects their ability to stabilize DNA triplexes. All four isomeric disubstituted derivatives examined stabilize DNA triplexes at micromolar or lower concentrations. Of the compounds studied the 2,7-disubstituted amidoanthraquinone displayed the greatest triplex affinity. The order of triplex affinity for the other disubstituted ligands decreases in the order 2,7 > 1,8 = 1,5 > 2,6, with the equivalent monosubstituted compounds being at least an order of magnitude less efficient. The 1,5-disubstituted derivative also shows some interaction with duplex DNA. These results have been confirmed by molecular modelling studies, which provide a rational basis for the structure-activity relationships. These suggest that, although all of the compounds bind through an intercalative mode, the 2,6, 2,7 and 1,5 disubstituted isomers bind with their two side groups occupying adjacent triplex grooves, in contrast with the 1,8 isomer which is positioned with both side groups in the same triplex groove.

Amides↗
PubMed1999

Synthesis and anticancer activities of 4-oxobenzopyrano[2,3-d]pyrimidines.

Several 2-aryl-4-oxoxbenzopyrano[2,3-d]pyrimidines have previously been shown to exhibit in vivo antitumor activity in mice with P388 lymphocytic leukemia. In the present study, a series of novel substituted benzopyrano[2,3-d]pyrimidines have been prepared and tested for cytotoxic activity against a panel of cancer cell lines including the P388 lymphocytic leukemia cell line. The unsubstituted parent compound, some methoxylated derivatives and a cyclohexyl derivative all exhibited potent cytotoxic activity (IC50 values 0.3-0.64 microM). A number of derivatives, including the unsubstituted parent pyrimidine, were shown to cause a significant perturbation in cell cycle kinetics with an observed 2- to 3-fold increase in cells in the G2/M phase of the cell cycle. Furthermore, a polymethoxylated derivative, 2-(3,4,5-trimethoxyphenyl)-9-methoxy-4-oxo-2,3-dihydrobenzopyrano[ 2,3-d]pyrimidine 13, was shown to be selectively active against a number of human ovarian cell lines.

Animals↗
PubMed1999

Testosterone and andropause: the feasibility of testosterone replacement therapy in elderly men.

Andropause, a syndrome in aging men, consists of physical, sexual, and psychologic symptoms that include weakness, fatigue, reduced muscle and bone mass, impaired hematopoiesis, oligospermia, sexual dysfunction, depression, anxiety, irritability, insomnia, memory impairment, and reduced cognitive function. Free testosterone levels begin to decline at a rate of 1% per year after age 40 years. It is estimated that 20% of men aged 60-80 years have levels below the lower limit of normal. Although the causal relationship between declining testosterone levels and development of andropause symptoms is not firmly established, administration of testosterone to this population resulted in improvements in many areas. Most studies to date focused on physical benefits of testosterone replacement and failed to assess psychologic symptoms rigorously. Preliminary data suggest that therapy may benefit elderly men with new-onset depression. Testosterone administration is not without problems, the most worrisome being the potential for increased prostate cancer risk. Despite this concern, a limited number of studies administered the hormone weekly for up to 2 years, with only mild increases in prostate-specific antigen over control values. Currently, insufficient evidence, primarily regarding psychologic safety and efficacy, exists to warrant general administration of testosterone to elderly hypogonadal men. Further clinical investigations of this therapy in men with low testosterone levels and andropause symptoms are justified and necessary.

Aged↗
PubMed1999

Design, synthesis and evaluation of human telomerase inhibitors based upon a tetracyclic structural motif.

There is currently significant interest in the development of inhibitors of human telomerase for the treatment of cancer. We describe here the design and synthesis of a new class of mono-substituted small-molecule inhibitors of human telomerase based upon a tetracyclic structural motif. In contrast to the structurally related molecule 9-hydroxyellipticine, recently shown to inhibit telomerase activity in cell cultures but found to be inactive in a cell-free system, we demonstrate direct inhibition of the telomerase enzyme by the tetracyclic compounds in a modified cell-free TRAP assay. The most potent compounds exhibit activity in the low micromolar range and are thus comparable with some of the more active small-molecule telomerase inhibitors based on planar aromatic chromophores, previously described by ourselves and others. These compounds may represent useful leads for the development of more potent inhibitors of human telomerase.

Amino Acid Motifs↗
PubMed1998

Human telomerase inhibition by regioisomeric disubstituted amidoanthracene-9,10-diones.

Telomerase is an attractive target for the design of new anticancer drugs. We have previously described a series of 1,4- and 2, 6-difunctionalized amidoanthracene-9,10-diones that inhibit human telomerase via stabilization of telomeric G-quadruplex structures. The present study details the preparation of three further, distinct series of regioisomeric difunctionalized amidoanthracene-9,10-diones substituted at the 1,5-, 1,8-, and 2,7-positions, respectively. Their in vitro cytotoxicity and Taq DNA polymerase and human telomerase inhibition properties are reported and compared with those of their 1,4- and 2,6-isomers. Potent telomerase inhibition (telIC50 values 1.3-17.3 microM) is exhibited within each isomeric series. In addition, biophysical and molecular modeling studies have been conducted to examine binding to the target G-quadruplex structure formed by the folding of telomeric DNA. These studies indicate that the isomeric diamidoanthracene-9,10-diones bind to the human telomeric G-quadruplex structure with a stoichiometry of 1:1. Plausible G-quadruplex-ligand complexes have been identified for each isomeric family, with three distinct modes of intercalative binding being proposed. The exact mode of intercalative binding is dictated by the positional placement of substituent side chains. Furthermore, in contrast to previous studies directed toward triplex DNA, it is evident that stringent control over positional attachment of substituents is not a necessity for effective telomerase inhibition.

Anthracenes↗
PubMed1998

Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram.

BACKGROUND: Previous work has suggested factors such as gender, smoking behavior, dose, and age affect the amount of drug a patient requires to achieve a desired plasma concentration of clozapine. Plasma clozapine concentrations ranging from 350 to 504 ng/mL in treatment-refractory schizophrenics and schizoaffective patients produce response rates ranging approximately 55-80%. Without the aid of clozapine plasma concentration monitoring, 3-6 months are recommended for a therapeutic clozapine trial. Data suggest that the lag time to response can be reduced by administering a dose that produces a therapeutic clozapine concentration. METHODS: To generate a clozapine dosing nomogram to predict clozapine steady-state plasma concentrations, a cohort of 71 patients was collected via retrospective chart review and/or patient interview. Clozapine steady-state plasma concentrations and demographic variables were obtained. Multiple-linear regression was utilized to examine the relationship between the plasma clozapine concentration and the independent variables. RESULTS: The dosing model that optimally predicted steady-state clozapine plasma concentrations included the variables dose (mg/day), smoking (yes = 0 and no = 1), gender, and a dose-gender interaction variable. The model explained 47% of the variance in the clozapine concentrations (F = 14.42, p < .001, r2 = .47). Two equations, one for male subjects, i.e., clozapine (ng/mL) = 111 (smoke) + 0.464 (dose) + 145, and one for female subjects, i.e., clozapine (ng/mL) = 111 (smoke) + 1.590 (dose)-149, were derived to predict clozapine steady-state plasma concentrations to serve as a clozapine dosing guide for clinicians. CONCLUSIONS: A clozapine dosing nomogram was constructed as a clinical aid to facilitate clozapine dosing.

Adult↗
PubMed1998

1,4- and 2,6-disubstituted amidoanthracene-9,10-dione derivatives as inhibitors of human telomerase.

A number of 1,4- and 2,6-difunctionalized amidoanthracene-9, 10-diones have been prepared. We have examined their in vitro cytotoxicity in several tumor cell lines and their ability to inhibit the telomere-addition function of the human telomerase enzyme together with their inhibition of the Taq polymerase enzyme. Compounds with -(CH2)2- side chains terminating in basic groups such as piperidine show inhibition of telomerase at telIC50 levels of 4-11 microM. These are thus among the most potent nonnucleoside telomerase inhibitors reported to date. Cytotoxicity levels in human tumor cell lines were at comparable levels for several compounds. Implications for amidoanthracene-9,10-dione telomerase inhibitors as potential anticancer agents are discussed.

Anthraquinones↗
PubMed1998

Olanzapine: a serotonin-dopamine-receptor antagonist for antipsychotic therapy.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, dosage and administration, and cost of olanzapine are reviewed. Olanzapine is a serotonin-dopamine-receptor antagonist indicated for use in the treatment of schizophrenia and other psychotic disorders. The affinity of olanzapine for neuroreceptors is similar to that of clozapine. The drug is well absorbed from the GI tract; food has no effect. Olanzapine is more effective than placebo and equal to haloperidol in reducing psychotic symptoms on two rating scales. However, unlike typical dopamine-receptor antagonists used for antipsychotic therapy, olanzapine is more effective in reducing the negative symptoms of schizophrenia. The most frequent adverse drug reactions (ADRs) associated with olanzapine are somnolence, agitation, insomnia, and headache. Constipation and dry mouth occur as dose-dependent ADRs. Unlike clozapine, olanzapine does not cause agranulocytosis. No cases of tardive dyskinesia or neuroleptic malignant syndrome have been reported. Olanzapine has been associated with slight increases in hepatic transaminases. More study is needed to determine whether olanzapine interacts significantly with other drugs. The recommended starting dosage is 5-10 mg orally once daily. Efficacy beyond six weeks has not been evaluated; patients treated for longer than six weeks should be periodically reassessed. Olanzapine costs about 10 times more than typical antipsychotics because a generic version is not available; however, olanzapine costs less than clozapine therapy and may cost less than haloperidol in terms of total health care costs. Olanzapine offers an effective alternative for treating schizophrenia and has a favorable adverse-effect profile.

Antipsychotic Agents↗
PubMed1998

Effect of exogenous testosterone on prostate volume, serum and semen prostate specific antigen levels in healthy young men.

PURPOSE: We investigate and define the effects of exogenous testosterone on the normal prostate. MATERIALS AND METHODS: A total of 31 healthy volunteers 21 to 39 years old were randomized to receive either 100, 250 or 500 mg. testosterone via intramuscular injection once a week for 15 weeks. Baseline measurements of serum testosterone, free testosterone and prostate specific antigen (PSA) were taken at week 1. Semen samples were also collected for PSA content and prostate volumes were determined by transrectal ultrasound before testosterone injection. Blood was then drawn every other week before each testosterone injection for the 15 weeks, every other week thereafter until week 28 and again at week 40. After the first 15 weeks semen samples were again collected, and prostate volumes were determined by repeat transrectal ultrasound. RESULTS: Free and total serum testosterone levels increased significantly in the 250 and 500 mg. dose groups. No significant change occurred in the prostate volume or serum PSA levels at any dose of exogenous testosterone. Total semen PSA levels decreased following administration of testosterone but did not reach statistical significance. CONCLUSIONS: Despite significant elevations in serum total and free testosterone, healthy young men do not demonstrate increased serum or semen PSA levels, or increased prostate volume in response to exogenous testosterone injections.

Adult↗
PubMed1998

Haloperidol plasma levels and dose optimization.

OBJECTIVE: This study was designed to test the practical utility of haloperidol plasma level determinations in the management of schizophrenic patients who show poor initial responses to haloperidol. METHOD: Inpatients with acute exacerbations of DSM-III schizophrenia (N = 66) were randomly assigned to receive fixed haloperidol doses intended to achieve plasma levels of 8-18 ng/ml or of 25-35 ng/ml. Patients whose scores on the Brief Psychiatric Rating Scale (BPRS) failed to improve by at least 30% at the end of 3 weeks were then subject to dose reassignment. RESULTS: Among the patients who completed the first phase of the protocol, 30 had steady-state haloperidol plasma levels of less than 18 ng/ml, and 22 had levels that exceeded 25 ng/ml; 14 had intermediate plasma levels of 18-25 ng/ml. A survival analysis of time to 30% improvement significantly favored the two lower plasma level groups, although side effect ratings did not differ. Of the 30 patients whose BPRS scores failed to improve by 30% after 3 weeks, 11 and five were randomly assigned to receive lower and higher doses, respectively. Those whose dose was lowered experienced significantly more improvement in the subsequent weeks than did those whose dose was increased. CONCLUSIONS: Haloperidol plasma levels that substantially exceed 18 ng/ml may be countertherapeutic. In particular, increases in dose beyond this level are not efficacious for patients who have not responded to lower doses.

Adolescent↗
PubMed1997

Dexfenfluramine hydrochloride: an anorexigenic agent.

The pharmacology, pharmacokinetics, efficacy, and adverse effects of dexfenfluramine hydrochloride are reviewed. Dexfenfluramine, the dextrorotatory isomer of fenfluramine, is indicated for use in the management of obesity in patients with a body mass index of > or = 30 kg/m2, or > or = 27 kg/m2 in the presence of other risk factors. Unlike fenfluramine, dexfenfluramine is a pure serotonin agonist. Dexfenfluramine may mimic the effect of carbohydrate intake. Systemic bioavailability is about 68%, and the drug is metabolized in the liver. In randomized, placebo-controlled trials, dexfenfluramine was effective in reducing weight in obese patients given the drug for three or six months. In trials lasting one year, the statistically significant weight loss occurred during months 4 to 6. Dexfenfluramine reduces blood pressure, percent glycosylated hemoglobin, and concentrations of blood glucose and blood lipids, but these benefits may be indirect. Dexfenfluramine may also be of some value in controlling eating habits in diabetic patients, preventing weight gain after smoking cessation, and treating bulimia, seasonal affective disorder, neuroleptic-induced obesity, and premenstrual syndrome. Dexfenfluramine's most frequent adverse effects are insomnia, diarrhea, and headache; it has also been associated with primary pulmonary hypertension. The drug should not be combined with other serotonergic agonists because of the risk of serotonin syndrome. The recommended dosage is 15 mg twice daily. Dexfenfluramine is effective in the treatment of obesity in selected patients. Because its efficacy is lost after six months of continuous treatment, it should be viewed primarily as an adjunct to diet and exercise.

Animals↗
PubMed1997

Olanzapine plasma concentrations and clinical response in acutely ill schizophrenic patients.

Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenic patients. After a 2- to 9-day placebo lead-in, 79 inpatients with schizophrenia according to DSM-III-R criteria were placed on an olanzapine dosage of 10 mg/day or 1 mg/day for up to 6 weeks. Blood samples were obtained weekly during this period. Receiver operating characteristic curve analyses of Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale rating scale data suggested a minimum effective therapeutic concentration of 9 ng/mL. Using an intent-to treat analysis, 45% of the patients with olanzapine plasma concentrations > or = 9.3 ng/mL responded (> or = 20% decrease in BPRS), whereas only 13% of the patients with concentrations < 9.3 ng/mL responded. Use of olanzapine plasma concentrations of > 9 ng/mL as a predictor for treatment response in acutely ill schizophrenic patients is practicable because this therapeutic marker significantly increases the likelihood of a patient responding to olanzapine.

Adult↗
PubMed1997

The effects of anabolic steroids on driving performance as assessed by the Iowa Driver Simulator.

The effect of physiologic (100 mg/wk) and supraphysiologic (250 and 500 mg/wk) doses of testosterone cypionate (TC) on automobile driving were studied using the Iowa Driver Simulator. Six normal subject volunteers were studied off TC and on TC once steady-state concentrations were achieved after at least three weeks of dosing. Despite the administration of supraphysiologic testosterone doses, an increase in aggressive driving behavior was not detected. Likewise, corresponding psychometric testing using the Buss-Durkee Hostility Inventory to assess aggression was unable to detect any change in aggression in the test subjects. Although aggressive driving behavior may be increased by testosterone administration, the drug itself may not be responsible for these effects. Supraphysiologic doses greater than 500 mg/wk and a semi-controlled research environment may be necessary to produce this effect since case reports of AAS abuse causing altered driving behavior may be multifactorial in nature.

Adult↗
PubMed1997

Detection of anabolic steroid administration: ratio of urinary testosterone to epitestosterone vs the ratio of urinary testosterone to luteinizing hormone.

Our goal in this study was to determine whether the urinary ratio of testosterone to luteinizing hormone (T/LH) as an indicator of exogenous anabolic steroid (AS) use is superior to the urinary ratio of testosterone to epitestosterone (T/E). After 2 weekly placebo injections, 19 subjects were given testosterone cypionate (TC) injections of 250 or 500 mg/week for 14 weeks followed by 14 weekly placebo injections. Patients were considered to have ceased taking TC if they tested negative 9 weeks after their last injection. For detection of illicit or supraphysiological TC (AS) use, the urinary T/E ratio of > or = 6 yielded a false-negative rate of 46% and a false-positive rate of 4%. However, a urinary T/LH ratio of > or = 30 produced a false-negative rate of only 24% and a false-positive rate of 13%. We conclude that the urinary T/LH ratio of > or = 30 is a more sensitive marker of AS use than the urinary T/E ratio of > or = 6 and remains sensitive for twice as long as urinary T/E.

Adolescent↗
PubMed1997

Testosterone suppression of the HPT axis.

BACKGROUND: Although studies have demonstrated the suppression of normal gonadal function in the experimental setting, the specific mechanisms by which androgenic-anabolic steroids impact male gonadal function remain ill defined. Following 2 consecutive weekly injections of an identically appearing testosterone cypionate (TC) placebo, subjects were randomized to a TC dose of 100 mg/wk, 250 mg/wk, or 500 mg/wk. Following the last weekly injection of active agent the subjects received 12 consecutive weeks of TC placebo injections. RESULTS: Spermatogenesis was impaired by each of the doses of TC employed in this study, but the observed decreases in, sperm count were neither strictly dose dependent nor consistent between individuals treated with the same dose. Basal leuteinizing hormone (LH) and follicle stimulating hormone (FSH) became undetectable 2 weeks after the start of 250 and 500 mg/wk TC injections and were lost within 5 to 6 weeks of starting 100 mg doses. Pituitary gonadotropin responses to leutinizing hormone releasing hormone (LHRH) disappeared more slowly with FSH responses being lost 1 to 3 weeks after the loss of basal FSH activity. Leuteinizing hormone responses to LHRH appeared to be suppressed last, disappearing 4 to 6 weeks after FSH responses to LHRH. CONCLUSIONS: Exogenous testosterone-mediated inhibitory influences on the hypothalamic-pituitary-testicular axis were reversed following the cessation of drug treatment.

Adolescent↗
PubMed1996

Effect of grapefruit juice on cyclosporine pharmacokinetics in renal transplant patients.

This study investigated the effect of grapefruit juice on cyclosporine A (CsA) bioavailability in 10 renal transplant patients. Under CsA steady state conditions, patients were randomly administered their usual dose of CsA with either 8 ounces of grapefruit juice or 8 ounces of water. Using a crossover design, a 12-hr pharmacokinetic study was then conducted. Grapefruit juice increased the area under the concentration versus time curve (4218+/-1497 ng x hr/ml [grapefruit juice] vs. 3415+/-1288 ng x hr/ml [water], P=0.029) and 12-hr trough (244+/-214 ng x ml [grapefruit juice] vs. 132+/-56 ng x ml [water], P=0.09), but it did not change peak concentration (734+/-290 ng x ml [grapefruit juice] vs. 708+/-305 ng x ml [water], P=0.76). In addition, grapefruit juice delayed the time to peak concentration compared with water (5.4+/-3.0 hr [grapefruit juice] vs. 2.8+/-0.8 hr [water], P=0.025). These data suggest that concurrent administration of grapefruit juice with CsA will delay the absorption of CsA and increase the drug exposure of CsA without changing peak concentration.

Adult↗
PubMed1996

Pharmacotherapy for major depression with melancholic features: relative efficacy of tricyclic versus selective serotonin reuptake inhibitor antidepressants.

The effectiveness of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) were contrasted in endogenous/melancholic depression. By reviewing Hamilton Depression Rating data from controlled trials, the data indicate that TCAs are consistently more effective than the SSRIs. Despite the wide use of SSRIs in the treatment of depression, it seems reasonable that clinicians subtype their depressed patients and treat melancholic patients first with a course of TCAs. For melancholic patients who have not responded to a SSRI, pharmacotherapeutic alternatives include (1) a TCA alone; (2) TCA augmentation of the SSRI, or (3) lithium augmentation of the SSRI.

Antidepressive Agents, Tricyclic↗