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Biomedical subjects

M F Murphy

Publications and source records attributed to M F Murphy.

At least 19 recordsLinked to original sources
PubMed1992

Neonatal alloimmune thrombocytopenia due to anti-P1A1 (anti-HPA-1a): importance of paternal and fetal platelet typing for assessment of fetal risk.

Neonatal alloimmune thrombocytopenia (NAIT), which usually involves sensitization to P1A1 (HPA-1a), may have devastating complications for the fetus. These may be prevented by antenatal treatment of severe cases with either maternally administered high-dose gamma-globulin and/or repeated intrauterine platelet transfusions. Determination of the paternal platelet phenotype is useful for counseling parents who have had one or more affected pregnancies. This report of an unaffected pregnancy in a woman with a history of previous pregnancies complicated by NAIT illustrates the role of paternal and fetal platelet phenotyping in managing existing pregnancies at risk of NAIT.

Adult↗
PubMed1992

Guidelines for platelet transfusions. British Committee for Standards in Haematology, Working Party of the Blood Transfusion Task Force.

Recommendations for the optimal transfusion support of patients likely to receive repeated platelet transfusions. 1. Determine policy for prophylactic platelet support, and select the platelet count below which platelet transfusions will be used. 2. Consider using leucocyte depletion of red cell and platelet concentrates to prevent HLA alloimmunization from the outset. 3. Type patients for HLA-A and B antigens at an early stage. 4. Use random donor platelet concentrates for initial platelet support (either single or multiple donor, depending on availability). 5. If refractoriness occurs, determine whether clinical factors, which may be associated with non-immune consumption of platelets, are present and test the patient's serum for HLA antibodies. 6. Use HLA-matched platelet transfusions if HLA alloimmunization is the most likely cause of refractoriness. 7. If there is no improvement with HLA-matched transfusions, platelet crossmatching may identify the cause of the problem and help with the selection of compatible donors. 8. Discontinue prophylactic platelet support if a compatible donor cannot be found. Use platelet transfusions from random donors to control bleeding and increase the dose, if necessary.

Blood Coagulation Disorders↗
PubMed1992

Social class, marital status, and cancer of the uterine cervix in England and Wales, 1950-1983.

STUDY OBJECTIVE: The aim was to investigate whether trends in mortality from cancer of the cervix uteri by age, marital status, and social class are compatible with current beliefs about the epidemiology of the disease. DESIGN: Data on mortality from cancer of the cervix for single and married women by age and social class were obtained from the Registrar General's Decennial Supplements on occupational mortality for the years 1950-53, 1959-63, 1970-72, and 1979, 1980, 1982, and 1983. Age standardised mortality rates were calculated directly by social class and marital status. SETTING: The data relate to all cases of carcinoma of the cervix reported in England and Wales in the years studied. MAIN RESULTS: There was a marked convergence of mortality between single and married women over the period within every social class grouping examined. The social class differential, however, remained essentially unchanged for both single and married women considered separately. CONCLUSIONS: Trends in mortality by marital status appear to reflect accurately the changes in the pattern of marriage and sexual behaviour that have taken place in the post-war period, whereas the patterns of other risk and protective factors such as screening explain these trends less well. In contrast, it seems likely that factors other than patterns of sexual behaviour and screening operate to maintain the social class differential in England and Wales.

Adolescent↗
PubMed1992

Implications of the study population in the early evaluation of anticholinesterase inhibitors for Alzheimer's disease.

OBJECTIVE: Velnacrine testing for tolerance and safety in both normal elderly subjects and patients with Alzheimer's disease (AD) is reviewed to illustrate the importance of Phase I trials in the target group as more predictive of safety and tolerance for subsequent multicenter trials than those conducted in healthy elderly subjects. DESIGN: Both a single-dose and a randomized, double-blind, placebo-controlled, ascending, multiple-dose study were performed with healthy, elderly men. In the multiple-dose study, the subjects were randomized to four groups of 14, with 10 subjects receiving velnacrine and 4 receiving placebo. The doses were velnacrine 25 (group 1), 50 (group 2), and 100 mg (group 3), respectively, administered twice daily; group 4 received 100 mg three times daily for 28 days. Blood and urine were collected serially for the pharmacokinetic assessment. With AD patients, 24 subjects were randomly assigned to receive either placebo or velnacrine for 10 days in a double-blind, sequential escalation study in a hospital setting. There were three groups of 8 subjects. Six patients in each group received velnacrine and 2 placebo. The three groups received respective dosages of 450, 300, and 225 mg/d three times daily. Adverse events were closely monitored and recorded. PATIENTS/PARTICIPANTS: The multiple-dose test in healthy elderly men included 56 men, aged 60-74 years. Rigorous screening for any potential complications that could affect absorption, distribution, metabolism, or excretion preceded patient entry in the AD patient study. Patients with a history of major psychiatric, neurologic, and cardiovascular disorders were excluded. The patients ranged in age from 56 to 89 years, and were equally distributed between gender. INTERVENTION: Velnacrine was administered in various doses. MAIN OUTCOME MEASURES: We emphasize the extreme adverse effects encountered in the AD patient group compared with the healthy group. Plasma concentrations of velnacrine over time in both groups are given, as well as the drug's half-life and excretion rates. RESULTS: The tolerable dosage predicted by studies performed in healthy elderly subjects was 300 mg/d. This dosage was not tolerable among the AD patients. A dosage as high as 450 mg/d resulted in a tonic seizure in one patient. The predicted dosage of 300 mg/d produced an adverse effect profile in AD patients that included dizziness, nausea and/or vomiting, headaches, and severe diarrhea. AD patients tolerated a dosage of 225 mg/d. CONCLUSIONS: A velnacrine dosage of 300 mg/d that was tolerated in healthy elderly subjects was not tolerated by AD patients.

Aged↗
PubMed1991

Clinical aspects of platelet transfusions.

Refractoriness is the most important complication of platelet transfusion therapy, occurring in about 50% of patients receiving repeated transfusions. The major causes are HLA alloimmunization and non-immune platelet consumption associated with clinical factors such as septicaemia. DIC and splenomegaly. Initial management of alloimmunized patients who are refractory to platelet transfusions from random donors is the use of HLA-matched platelet transfusions, which improve responses to transfusions in about 65% of patients. It may be difficult to provide effective platelet transfusion support for alloimmunized patients not responding to HLA-matched transfusions. There has been much interest in methods for the prevention of HLA alloimmunization. Primary HLA alloimmunization is dependent on the presence of HLA class II antigen-bearing cells in transfusions; pure platelet transfusions are non-immunogenic as platelets only express HLA class I antigens. The use of leucocyte-depleted blood components in multitransfused patients has resulted in a reduction in HLA alloimmunization and platelet refractioness. Improvements in the techniques for leucocyte-depletion of red cell and platelet concentrates and the possibility of inactivation of HLA class II antigen-bearing cells by UV irradiation makes prevention of alloimmunization an attainable goal.

Blood Platelets↗
PubMed1991

Sudden infant deaths and cold weather: was the rise in infant mortality in 1986 in England and Wales due to the weather?

Using the daily number of deaths due to sudden infant death syndrome in England and Wales from 1979 to 1985, and the daily temperature recorded at the London Weather Centre, two models were constructed, one including a temperature term and one without it, and the models used to predict the mortality in 1986. It was found that the model using temperature had a slightly better predictive power and successfully accounted for the increased mortality in February 1986. Thus, we conclude that the excess mortality of February 1986 was associated with the unusually cold weather during that month.

Cold Climate↗
PubMed1991

Evaluation of HP 029 (velnacrine maleate) in Alzheimer's disease.

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is a cholinesterase inhibitor and one of a series of compounds synthesized at Hoechst-Roussel Pharmaceuticals Inc. (HRPI) as a potential therapeutic agent for senile dementia of the Alzheimer type (SDAT). An ongoing clinical development program for HP 029 (velnacrine maleate) reflects a rational, traditional progression from therapeutic concept through clinical evaluation. Prior to the initiation of outpatient studies, sufficient data had been obtained from normal volunteers and hospitalized patients to support the following conclusions: the pharmacokinetic profile of HP 029 in young and elderly normal men is predictable; tolerance and safety data for HP 029 using normal volunteers poorly correlates with experience in patients with SDAT; patients with SDAT exhibit marked intersubject variability in tolerance within a suspected therapeutic dose range; mandatory endpoints for drug discontinuation for outpatients can be reliably established in an inpatient environment. Subsequently, Protocol 201 was initiated as a multicenter, multistage investigation of HP 029 in patients with probable SDAT (NINCDS-ADRDA criteria). A dose-ranging component determined patient eligibility for a subsequent dose-replication phase based upon explicit safety and efficacy criteria defined within protocol. One a priori specified interim analysis was conducted by the sponsor (HRPI) for administrative purposes after completing approximately 50% of the planned sample (September 1989). Results suggested that (1) beneficial effects of HP 029 existed on key and secondary measures for the approximately 30% of enrolled patients; (2) interim results would provide an accurate reflection of the results at the conclusion of the study (1991); (3) HP 029-induced hepatocellular injury appeared to be a reversible, predominantly dose-related event; and (4) cholinergically mediated adverse events are infrequent and clinically inconsequential at dosages less than or equal to 225 mg/day. Post hoc hypotheses based on the interim dataset suggest that: (1) carry-over effects of HP 029 exist within a dose-ranging/dose-replication paradigm that militate against the utility of an "enriched population" design; (2) beneficial effects are more robust on initial exposure to HP 029 with effects discerned on both memory and arousal; (3) patient characteristics associated with toxicity or response are not identified; (4) dosage reduction in subsequent efficacy trials may reduce hepatocellular injury and yield clinically unimportant differences in overall efficacy results.

Aged↗
PubMed1990

Clinical safety, tolerance, and plasma levels of the oral anticholinesterase 1,2,3,4-tetrahydro-9-aminoacridin-1-oL-maleate (HP 029) in Alzheimer's disease: preliminary findings.

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-oL-maleate), an oral anticholinesterase, enhances memory in rodents and may be useful in treating Alzheimer's disease (AD). To assess adverse events in relation to dosage and plasma drug levels, 24 hospitalized AD subjects were randomly assigned to receive placebo or HP 029 for 10 days in a double-blind, sequential escalation study. Maximum daily dosages were 450 mg (group 1), 300 mg (group 2), and 225 mg (group 3), divided into three doses per day. The group 1 trial was discontinued on day 5 because one subject, 6 hours following the second of three scheduled 150-mg doses, had a tonic seizure after protracted vomiting and hyperventilation; adverse events in other patients included nausea, vomiting, abdominal cramps, diarrhea, dizziness, and syncope. Adverse events were generally less severe in group 2, but only two of six HP 029 subjects could complete the trial at 300 mg/day. All group 3 subjects completed the trial at 225 mg/day with drug related, mild adverse events (nausea, vomiting, lacrimation, rhinorrhea) in only two subjects. Although mean plasma drug levels were related to adverse events across dosage groups, they did not adequately predict the occurrence or severity of adverse events in individual subjects. The 225 mg/day dose appears to be safe for use in multicenter outpatient trials of HP 029 efficacy in AD. Further patient studies are ongoing to determine the relation of specific subject characteristics to the metabolic profile of HP 029 and biological response.

Administration, Oral↗
PubMed1990

Platelet transfusions: the problem of refractoriness.

Refractoriness is a complication of multiple platelet transfusions in 30-70% of patients with bone marrow failure. The major causes are HLA alloimmunisation and non-immune platelet consumption; the latter is usually found in patients with DIC, septicaemia or splenomegaly. Initial management of alloimmunised patients who are refractory to platelet transfusions from random donors is the use of HLA-matched platelet donors; this results in improved responses to platelet transfusions in about 65% of these patients. Platelet crossmatching may reveal the presence of platelet-specific antibodies in some patients who are refractory to platelet transfusions from HLA-matched donors and may assist in the selection of compatible platelet donors. The identification of compatible donors is not possible in all refractory patients; alternative approaches such as plasma exchange and high dose intravenous gammaglobulin have been used in such patients with variable results. Insights into the mechanism of HLA alloimmunisation have suggested methods for its prevention. Primary HLA alloimmunisation is dependent on the presence in transfusions of contaminating cells bearing HLA class II antigens; pure platelet concentrates are non-immunogenic as platelets only express HLA class I antigens. Studies using leucocyte-poor blood components for multitransfused patients have demonstrated a reduction in HLA alloimmunisation from about 50-20% and a decrease in the incidence of refractoriness. Improvements in the techniques for leucocyte depletion of red cell and platelet concentrates and the possibility of inactivation of the HLA class II antigen-bearing cells by UV irradiation might make prevention of alloimmunisation an attainable goal in the near future.

Blood Platelets↗
PubMed1990

Management of fetal alloimmune thrombocytopenia by weekly in utero platelet transfusions.

Alloimmune neonatal thrombocytopenia (ANT) may cause intracranial haemorrhage in utero as well as at delivery. Recent management has concentrated on attempts to minimise fetal thrombocytopenia and prevent its complications. This report describes further experience with the use of repeated intravascular transfusions of compatible platelets in utero. The patient studied had already had one infant with intracranial haemorrhage due to ANT. In her next pregnancy, weekly intra-uterine platelet transfusions were given from 26 weeks, but intra-uterine death occurred at 30 weeks after the mother had a heavy fall. In her most recent pregnancy, weekly intravascular transfusions of platelets were given by cordocentesis from 29 to 34 weeks. The fetal platelet count was maintained above 30 X 10(9)/l for almost all of the last 6 weeks of pregnancy before delivery of a normal infant by Caesarean section at 35 weeks' gestation. This approach is effective in preventing severe fetal thrombocytopenia in the last trimester of pregnancy and is contrasted with alternative treatments of ANT. Further data are required to determine the efficacy and risks of these treatments.

Blood Transfusion, Intrauterine↗