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P Manasco

Publications and source records attributed to P Manasco.

8 recordsLinked to original sources
PubMed2001

Family consent and the pursuit of better medicines through genetic research.

Rapid changes in the science and technology related to genetic research are challenging scientists, health care providers, ethicists, regulators, patient groups, and the pharmaceutical industry to keep pace with ethically grounded, workable guidelines for both the research and clinical applications of human genetics. We describe the genetic research being conducted by one pharmaceutical company (GlaxoSmithKline) and how the company is addressing the ethical, legal, and social issues surrounding this research; discuss an industry working group's attempt to advance pharmacogenetic research by openly addressing and disseminating information on related ethical, legal, and regulatory issues; identify scientific and ethical differences among various types of genetic research; discuss potential implications of family consent on subject privacy and autonomy, data collection, and study conduct; and suggest points to consider when study sponsors, investigators, and ethics committees evaluate research proposals. Public and expert opinion regarding informed consent in genetic research is evolving as a result of increased education, discussion, and understanding of the relevant issues. Five years ago, there was strong support for anonymity in genetic research as a privacy safeguard. Now, an increasingly popular school of thought advocates against anonymity to preserve an individual's ability to withdraw and, if desired, access research results. It is important to recognize this evolution and address consent issues in a reasoned, practical, and consistent way, including input from patients and their families, health care providers, ethicists, scientists, regulatory bodies, research sponsors, and the lay community. Responsibility for assessing issues related to family consent for research should remain with local investigators, ethics boards, and study sponsors. A "one-size-fits-all" perspective in the form of new regulations, for example, would likely be a disservice to all.

Access to Information↗
PubMed2001

Pharmacogenetics: the Rx perspective.

Pharmacogenetics is changing the way medicines are discovered, developed and delivered to patients. In this article, we present the 'prescription' perspective--how the results of pharmacogenetic research will help minimize the risk of costly adverse drug reactions and treatment failures, by providing predictive tools to enable healthcare providers to prescribe the right medicine for the right patient. We discuss the challenges of this research and its clinical application; its implications for drug development; evolving concepts of informed consent; related ethical, legal and social issues; changing definitions of 'genetic testing'; and the creation of an international Pharmacogenetics Working Group.

Ethics, Medical↗
PubMed1999

A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children. Lamictal Pediatric Partial Seizure Study Group.

OBJECTIVE: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures. BACKGROUND: Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children. METHODS: We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period. RESULTS: Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy. CONCLUSIONS: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.

Adolescent↗
PubMed1999

Lamictal (lamotrigine) monotherapy for typical absence seizures in children.

PURPOSE: To investigate whether lamotrigine (LTG) monotherapy is effective and safe for newly diagnosed typical absence seizures in children and adolescents (aged 3-15 years, n = 45). METHODS: A "responder-enriched" study design was used: open-label dose escalation was followed by placebo-controlled, double-blind testing of LTG. Conventional hyperventilation testing with EEG recording was used to confirm diagnoses and assess treatment success defined as complete freedom from seizures. Ambulatory 24-h EEG recordings provided supporting evidence of effectiveness. Safety was assessed by evaluation of adverse events, vital signs, and physical, neurologic, and laboratory examinations. Plasma samples were taken to evaluate the pharmacokinetics of LTG. RESULTS: During initial open-label dose escalation, 71.4% of patients (intent-to-treat) or 82% (per protocol analysis) became seizure free; individual patients responded at doses ranging from 2 to 15 mg/kg/day (median, 5.0). In the placebo-controlled, double-blind phase of the study, statistically significantly more patients remained seizure free when treated with LTG (62%) than with placebo (21%; p < 0.02; for the intent-to-treat analysis). Mean plasma concentrations of LTG, were linearly related to dose, although there was substantial interindividual variation. No patients were withdrawn from the study for any safety-related reason. CONCLUSIONS: LTG monotherapy is effective for typical absence seizures in children and is generally well tolerated.

Adolescent↗
PubMed1997

Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. Lamictal Lennox-Gastaut Study Group.

BACKGROUND: The Lennox-Gastaut syndrome, a severe form of epilepsy that usually begins in early childhood, is difficult to treat. Dose-related drug toxicity is common. METHODS: We conducted a double-blind, placebo-controlled trial of the antiepileptic drug lamotrigine in patients with the Lennox-Gastaut syndrome. Eligible patients had more than one type of predominantly generalized seizure, including tonic-clonic, atonic, tonic, and major myoclonic, and had seizures on average at least every other day. After a 4-week base-line period in which all participants received placebo, we randomly assigned 169 patients (age range, 3 to 25 years) to 16 weeks of lamotrigine (n= 79) or placebo (n=90) in addition to their other antiepileptic drugs. RESULTS: The median frequency of all major seizures changed from base-line levels of 16.4 and 13.5 per week in the lamotrigine and placebo groups, respectively, to 9.9 and 14.2 per week after 16 weeks of treatment (P=0.002). Thirty-three percent of the patients in the lamotrigine group and 16 percent of those in the placebo group had a reduction of at least 50 percent in the frequency of seizures (P= 0.01). There were no significant differences between groups in the incidence of adverse events, except for colds or viral illnesses, which was more common in the lamotrigine group (P=0.05). CONCLUSIONS: Lamotrigine was an effective and well-tolerated treatment for seizures associated with the Lennox-Gastaut syndrome.

Adolescent↗
PubMed1991

Adult height in precocious puberty after long-term treatment with deslorelin.

Precocious puberty often leads to short adult height. Since the introduction of luteinizing hormone-releasing hormone (LHRH) agonist treatment for LHRH-dependent precocious hormone (LHRH) agonist treatment for LHRH-dependent precocious puberty in 1979, several reports have shown increased predicted height among LHRH agonist-treated children. To determine whether the LHRH agonist deslorelin can normalize the adult height of children with precocious puberty, we are conducting a long-term pilot study involving 161 children. This report describes the first 44 children to have attained final or proximate adult height. These children were 7.1 +/- 1.2 (mean +/- SD) yr old (bone age 11.8 +/- 1.5 yr) and had been in puberty for 3.1 +/- 0.3 yr at the start of treatment. They were treated with deslorelin (4 micrograms/kg/day sc) for 4.1 +/- 1.3 yr and had been withdrawn from treatment for an average of 2.4 yr at the time of this study (age 13.6 +/- 0.9 yr). Fourteen of the 44 children, who had grown less than 0.5 cm during the previous year, were considered to have attained adult height. The other 30 children had achieved 98.6% of predicted mature height (Bayley-Pinneau method) and were considered to be at proximate adult height. The final or proximate adult height of these 44 children averaged -1.1 SD compared to the adult height of the normal population. This height was significantly greater than the pretreatment height (-1.1 vs. -2.0 SD, P less than 0.01), but significantly less than both the predicted height at the end of treatment (-1.1 vs. -0.5 SD, P less than 0.01) and the target height derived from the mean height of the parents adjusted for the sex of the child (-1.1 vs. 0.1 SD, P less than 0.01). The observation that the Bayley-Pinneau height prediction at the end of treatment overestimated the actual adult height emphasizes the importance of using final height data to assess the ultimate impact of LHRH agonist treatment. It also indicates the need for caution when predicting the adult height of children who are still receiving treatment. We conclude that deslorelin has improved the adult height of these patients but has not fully restored height to the patients' genetic potential. We hypothesize that further improvement will be seen in patients who are treated with less delay and at a younger bone age.

Body Height↗
PubMedDate not supplied

Applications of pharmacogenetics to drug development: the Glaxo Wellcome experience.

The Genetics Directorate was established at Glaxo Wellcome (GW) in 1997. The goals of the Directorate are to identify susceptibility genes for common diseases with large unmet therapeutic need, apply genetic methods for the targeted development of medicines so that the right medicine is developed for the right patient, assist in translating gene discoveries into target selection, and represent genetics accurately internally within GW and externally (to laypersons, the medical community, the business community, government representatives, and regulatory agencies). As part of the goal of developing the right medication for the right patient, GW has added genetic research to its clinical drug studies in every major therapeutic area. GW worked closely with international ethicists experienced in the area of genetic research to develop the process and documents that are currently in use; these undergo frequent, rigorous review in light of the changing regulatory and legal environment and the needs of clinical investigators and patients. The addition of genetic research to clinical studies was accompanied by significant education efforts within GW and for study-site personnel, ethics committees, and regulatory authorities. Feedback from all those involved is an integral part of implementing GW's genetic research and is used to fine-tune the processes and protocol and consent document templates. A recently completed review of the approval rate from ethics committees in several countries has revealed trends in EC/IRB (Ethics Committees/Institutional Review Boards) questions and concerns about genetic research. This article will focus on the lessons learned from incorporating genetic research into clinical studies at over 1,500 international sites and will include summaries of the feedback from investigators, EC/IRBs, and regulatory authorities. It also will include a discussion of the potential applications of SNP (single nucleotide polymorphism) map technologies to pharmacogenetics by increasing the ability to correlate patients' genetic information with their response to medicines.

Drug Design↗