Search PubMed⌕ Search

Biomedical subjects

P J Perry

Publications and source records attributed to P J Perry.

At least 19 recordsLinked to original sources
PubMed2002

The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1.

Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses aromatic hydroxylation reactions. We report here that the cancer preventative agent resveratrol undergoes metabolism by the cytochrome P450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukaemic agent piceatannol. The metabolite was identified by high performance liquid chromatography analysis using fluorescence detection and the identity of the metabolite was further confirmed by derivatisation followed by gas chromatography-mass spectrometry studies using authentic piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compound with known anticancer activity by an enzyme that is found in human tumours. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumours may be functioning as a growth suppressor enzyme.

Antineoplastic Agents↗
PubMed2001

Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach.

BACKGROUND: Numerous case reports have linked clozapine to the development of diabetes mellitus and hyperlipidemia in patients with schizophrenia. However, investigators have been unable to clearly demonstrate this association when compared with a control group receiving conventional antipsychotics. METHODS: Medical and pharmacy claims from the Iowa Medicaid program were used to compare incidence rates for diabetes, hyperlipidemia, and hypertension in 552 patients receiving clozapine and 2461 patients receiving conventional antipsychotics (eg, haloperidol, chlorpromazine hydrochloride), with the use of a retrospective cohort design. Logistic regression was used to compare incidence rates adjusting for age, sex, and duration of available follow-up. RESULTS: No significant differences in overall incidence rates for diabetes, hyperlipidemia, or hypertension were observed in patients receiving clozapine vs conventional antipsychotics. However, among younger patients (aged 20-34 years), clozapine administration was associated with a significantly increased relative risk of diabetes (2.5 [95% confidence interval, 1.2-5.4]) and hyperlipidemia (2.4 [95% confidence interval, 1.1-5.2]), but not hypertension (0.9 [95% confidence interval, 0.4-2.0]). CONCLUSIONS: These data suggest that clozapine may not be an independent cause of diabetes or hyperlipidemia, but instead acts as an effect modifier in susceptible populations by increasing weight or affecting insulin secretion and resistance. This finding requires confirmation in other settings and patient populations and with the other atypical antipsychotics (risperidone, olanzapine, and quetiapine fumarate). The potential long-term medical and economic implications of the early induction of diabetes and hyperlipidemia in patients with schizophrenia warrant further study.

Adult↗
PubMed2001

Bupropion SR vs. methylphenidate vs. placebo for attention deficit hyperactivity disorder in adults.

Despite the increasing recognition of attention-deficit hyperactivity disorder (ADHD) in adults, there are few controlled trials demonstrating the effectiveness of pharmacological treatments, particularly with nonstimulants. One controlled trial found bupropion SR more effective than placebo in the treatment of ADHD adults. We conducted a controlled study to contrast the effectiveness of bupropion SR and methylphenidate to placebo in ADHD adults. A randomized, double-blind, parallel design was used in this study. Following a 7-day placebo lead-in, 30 ADHD (DSM-IV) subjects (18-60 years old) were randomized to bupropion, methylphenidate, or placebo for 7 weeks. Methylphenidate was titrated over 1 week to a maximum dose of 0.9 mg/kg/d divided into 3 doses while bupropion was titrated over 2 weeks to a maximum dose of 200 mg A.M. and 100 mg P.M. Response rates based on Clinical Global Impression improvement ratings in patients receiving bupropion, methylphenidate, and placebo were 64, 50, and 27%, respectively. The difference in response rates between active treatment and placebo was not statistically significant (p = 0.14). Neuropsychological testing demonstrated trends favoring drug treatment on measures of immediate recall and verbal fluency. While bupropion SR may be a viable clinical alternative for adults with ADHD, further investigation is needed.

Adrenergic Agents↗
PubMed2001

Bioavailable testosterone as a correlate of cognition, psychological status, quality of life, and sexual function in aging males: implications for testosterone replacement therapy.

Andropause is a syndrome described in aging males, is composed of a constellation of physical, sexual, and emotional symptoms, and is thought to be related to declining concentrations of serum testosterone. Numerous studies of testosterone replacement therapy in elderly hypogonadal males have documented the physical benefits of such treatment, but have failed to assess cognition, psychological functioning, and quality of life. Male outpatients greater or equal to 55 years of age completed cognitive, psychological, sexual, and quality of life assessments. A serum sample was provided for bioavailable testosterone assay. The associations between bioavailable testosterone concentrations and neuropsychological testing were assessed using Spearman rank correlation. Overall, bioavailable testosterone was not an important determinant of cognitive, psychological, or sexual functioning or of quality of life. The implications for future studies involving testosterone replacement therapy are discussed.

Aged↗
PubMed2001

Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine Trial.

Olanzapine is an atypical antipsychotic that is effective in the treatment of schizophrenia. Olanzapine plasma concentrations > or = 9.3 ng/mL (24 hours postdose) have been identified as a predictor of clinical response in acutely ill patients with schizophrenia. The authors report a receiver operating characteristic (ROC) curve analysis of 12-hour olanzapine concentrations and treatment response from the North American Double-Blind Olanzapine Trial. After a 4- to 7-day placebo lead-in, patients meeting DSM-III-R criteria for schizophrenia were randomly assigned to receive olanzapine, haloperidol, or placebo. Patients who were randomly assigned to receive olanzapine were given daily doses ranging from 2.5 to 17.5 mg/day for up to 6 weeks. Blood samples for the determination of olanzapine plasma concentrations were obtained between 10 and 16 hours (11.7 +/- 1.7 hours) after the last dose was administered. Therapeutic response data and olanzapine concentrations used for analysis were obtained from the endpoint visit for each patient if the patient had been receiving a fixed olanzapine dose for at least the last 2 weeks of the study. Plasma concentrations from previous visits were used if endpoint concentrations were invalid. Response was defined as a > or = 20% reduction in Brief Psychiatric Rating Scale (BPRS) scores and a Clinical Global Impression (CGI) Severity scale score of < or = 3 or a final BPRS score of < or = 35. The final ROC analysis included data from 84 patients and suggested an olanzapine concentration > or = 23.2 ng/mL to be a predictor of therapeutic response. Fifty-two percent of patients with 12-hour olanzapine concentrations > or = 23.2 ng/mL responded, whereas only 25% of patients with concentrations < 23.2 ng/mL responded. Furthermore, an olanzapine concentration > or = 23.2 ng/mL was a predictor of response in the Scale for the Assessment of Negative Symptoms (> or = 20% decrease and endpoint CGI < or = 3). Olanzapine concentrations were found to be a function of olanzapine dose (in milligrams per day) and gender such that prospective olanzapine dosing is feasible. A 12-hour olanzapine plasma concentration of > 23.2 ng/mL was a predictor of therapeutic response in acutely ill patients with schizophrenia. Males required a higher olanzapine dose to reach this threshold concentration than their female counterparts.

Acute-Phase Reaction↗
PubMed2001

Telomerase inhibitors for the treatment of cancer: the current perspective.

Telomerase is a holoenzyme responsible for the maintenance of telomeres, the protein-nucleic acid complexes at the ends of eukaryotic chromosomes that serve to maintain chromosomal stability and integrity. Telomerase activity is essential for the sustained proliferation of most immortal cells, including cancer cells. Since the discovery that telomerase activity is detected in 85-90% of all human tumours and tumour-derived cell lines but not in most normal somatic cells, telomerase has become the focus of much attention as a novel and potentially highly-specific target for the development of new anticancer chemotherapeutics. Herein we review the current perspective for the development of telomerase inhibitors as cancer chemotherapeutics. These include antisense strategies, reverse transcriptase inhibitors and compounds capable of interacting with high-order telomeric DNA tetraplex ("G-quadruplex") structures, so as to prevent enzyme access to the necessary linear telomere substrate. Critical appraisal of each individual approach is provided together with highlighted areas of likely future development.

Animals↗
PubMed2001

Failed challenge with quetiapine after neuroleptic malignant syndrome with conventional antipsychotics.

Neuroleptic malignant syndrome (NMS) is an uncommon but potentially life-threatening adverse effect associated with conventional antipsychotic agents. The syndrome is characterized by muscular rigidity, hyperpyrexia, altered consciousness, and autonomic dysfunction. Few cases of quetiapine-induced NMS have been reported. A 54-year-old man was unsuccessfully challenged with quetiapine after conventional antipsychotic-induced NMS.

Alzheimer Disease↗
PubMed2001

Ziprasidone, a new atypical antipsychotic drug.

Although the introduction of antipsychotic drugs in 1954 was a breakthrough in the treatment of patients with schizophrenia, these agents have a number of adverse effects that limit effectiveness and compliance. The atypical antipsychotic drugs provide an improved tolerability profile, particularly in minimizing extrapyramidal side effects; however, they are associated with significant weight gain, which may be related to growing evidence linking the atypical agents with diabetes and hyperlipidemia. Ziprasidone, a new atypical antipsychotic drug, was demonstrated in clinical trials to be more efficacious than placebo and similar in efficacy to haloperidol in the treatment of schizophrenia. Like the existing atypical agents, ziprasidone has a rate of extrapyramidal side effects similar to that of placebo and does not cause significant elevations in prolactin levels. In contrast, ziprasidone has a low propensity for causing weight gain. For patients requiring an antipsychotic drug, ziprasidone represents a new treatment option with a limited adverse effect profile.

Antipsychotic Agents↗
PubMed2001

DNA tetraplex-binding drugs: structure-selective targeting is critical for antitumour telomerase inhibition.

Four-stranded tetraplex ("G-quadruplex") DNA represents a new paradigm for the design of DNA-interactive antitumour drugs, as the formed DNA-drug complexes have been suggested to interfere with critical telomerase function. The unique structural features presented by tetraplex over duplex DNA have stimulated the design of small ligand molecules able to selectively promote the formation and/or stabilisation of such higher-order DNA structures. Current developments in tetraplex-targeted telomerase inhibitors, and importantly their DNA structural selectivity, are explored.

Antineoplastic Agents↗
PubMed2001

Therapeutic drug monitoring of antipsychotics.

Therapeutic drug monitoring of conventional and atypical antipsychotics offers numerous clinical advantages to the clinician. These include cost savings, decreased risk of toxicity, and improved compliance. Among these drugs, studies of haloperidol, olanzapine, and clozapine have provided the most compelling data to justify therapeutic drug monitoring. Among atypical antipsychotics, although data document the utility of routine monitoring of clozapine and olanzapine blood levels, there are no similar data available for either risperidone or quetiapine. Additionally, the utility of therapeutic drug monitoring is enhanced by the availability of prospective dosing schemes for haloperidol, olanzapine, and clozapine.

Animals↗
PubMed2000

Lack of menstrual cycle effects on hypothalamic-pituitary-adrenal axis response to insulin-induced hypoglycaemia.

OBJECTIVE: Limited data are available on the effects of the menstrual cycle on the hypothalamic-pituitary-adrenal axis (HPA) function. This study evaluates HPA axis reactivity to insulin-induced hypoglycaemia over the menstrual cycle. PATIENTS: Twelve normal women were randomized to placebo and evaluated during three successive menstrual cycles. Menstrual phase was documented by menstrual diary and by oestradiol and progesterone levels at the time of each insulin tolerance test (ITT). Six normal men were included as a comparison in the statistical analysis. MEASUREMENTS: Afternoon ITTs were performed initially on the second or third day of menses in women, then seven more ITTs followed at one or two week intervals during the next 10 weeks. Serum measurements of glucose, adrenocorticotrophin (ACTH) and cortisol were obtained. RESULTS: The glucose and ACTH responses to the ITTs were similar between men and women. Cortisol levels at baseline and during the test were higher in men than in women, although the amount of change was similar. Glucose, ACTH and cortisol response to insulin-induced hypoglycaemia did not vary over the menstrual cycle or during repeat testing in men or women. CONCLUSIONS: These data show that it is unnecessary to control for menstrual cycle during insulin tolerance tests performed at 1600 hours. It is, however, necessary to control for the effect of sex on cortisol levels. Repeat testing more than one week apart does not appear to influence the glucose, ACTH or cortisol response to insulin stress.

Adrenocorticotropic Hormone↗
PubMed2000

Olanzapine: an atypical antipsychotic for schizophrenia.

Olanzapine is a serotonin-dopamine receptor antagonist primarily used in the treatment of psychotic illnesses. It has been shown in numerous large trials to be as equally effective as haloperidol in the acute treatment and maintenance treatment of schizophrenia. However, olanzapine was shown to be more effective than haloperidol in the treatment of negative symptoms and to cause significantly fewer extrapyramidal symptoms. Furthermore, early reports suggest that olanzapine produces less tardive dyskinesia than haloperidol, though longer follow-up data are needed. Current studies have failed to demonstrate the efficacy of olanzapine in the treatment of refractory schizophrenia. One comparison trial of olanzapine versus risperidone has indicated similar efficacy. Clinical trials in acute mania have found olanzapine to be more effective than placebo. However, there is no role for olanzapine monotherapy in bipolar disorder given current studies. Although olanzapine has shown a low rate of extrapyramidal symptoms, it is not without adverse effects. Clinically significant weight gain has been noted with olanzapine in each of the large clinical trials. The degree of weight gain is similar to clozapine and probably greater than that observed with risperidone. The long-term medical consequence of atypical antipsychotic-induced weight gain is not known at this time. While generally considered first-line drugs from an efficacy and adverse effect standpoint, pharmacoeconomic studies are needed to justify the large acquisition cost of olanzapine compared to typical agents.

Antipsychotic Agents↗
PubMed2000

Diabetes mellitus associated with clozapine therapy.

Clozapine is an atypical antipsychotic that is associated with certain adverse effects that limit its usefulness. Published case reports have associated clozapine with impairment of glucose tolerance, including the onset or exacerbation of diabetes mellitus. We report two patients who experienced diabetes mellitus associated with the agent.

Antipsychotic Agents↗
PubMed1999

2,7-Disubstituted amidofluorenone derivatives as inhibitors of human telomerase.

Telomerase is a major new target for the rational design of novel anticancer agents. We have previously identified anthraquinone-based molecules capable of inhibiting telomerase by stabilizing G-quadruplex structures formed by the folding of telomeric DNA. In the present study we describe the synthesis and biological evaluation of a series of analogous fluorenone-based compounds with the specific aims of, first, determining if the anthraquinone chromophore is a prerequisite for activity and, second, whether the conventional cytotoxicity inherent to anthraquinone-based molecules may be reduced by rational design. This fluorenone series of compounds exhibits a broad range of telomerase inhibitory activity, with the most potent inhibitors displaying levels of activity (8-12 microM) comparable with other classes of G-quadruplex-interactive agents. Comparisons with analogous anthraquinone-based compounds reveal a general reduction in the level of cellular cytotoxicity. Molecular modeling techniques have been used to compare the interaction of fluorenone- and analogous anthraquinone-based inhibitors with a human G-quadruplex structure and to rationalize their observed biological activities.

Antineoplastic Agents↗
PubMed1999

Psychosexual effects of three doses of testosterone cycling in normal men.

BACKGROUND: Testosterone is receiving increased attention for contraceptive and therapeutic indications. The potential psychosexual side effects of testosterone therapy and withdrawal are unclear. METHODS: Healthy men between the ages of 21 and 40 years were recruited via advertisement for a randomized, controlled, double-blind study of acute and withdrawal effects of three doses of testosterone. Two weeks of placebo injections were followed by one of three randomized weekly doses of testosterone cypionate (100 mg, 250 mg, or 500 mg) for the next 14 weeks. Twelve weeks of placebo injections followed during the withdrawal phase of the study. Psychosexual effects were monitored throughout the study. RESULTS: All doses of testosterone demonstrated only minimal effects on measures of mood and behavior during acute and withdrawal phases for all study completers. There were no effects on psychosexual function. There was no evidence of a dose-dependent effect on any measure. One noncompleter on 500 mg of testosterone developed a brief syndrome with symptoms similar to an agitated and irritable mania. CONCLUSIONS: Doses of testosterone up to five times physiologic replacement dose appear to have minimal risk of adverse psychosexual effects in the majority of normal men; however, beginning at around 500 mg per week of testosterone cypionate, a minority of normal men may experience significant adverse psychological effects. Because illicit anabolic steroid users may use larger doses of multiple drugs under less restrictive conditions, our study may significantly underestimate the psychological effect of steroid use in the community.

Adult↗
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↗