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Biomedical subjects

R A Hamilton

Publications and source records attributed to R A Hamilton.

At least 19 recordsLinked to original sources
PubMed1996

Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the beta2-adrenergic receptor is associated with reduced phospholamban protein.

To assess the effect of targeted myocardial beta-adrenergic receptor (AR) stimulation on relaxation and phospholamban regulation, we studied the physiological and biochemical alterations associated with overexpression of the human beta2-AR gene in transgenic mice. These mice have an approximately 200-fold increase in beta-AR density and a 2-fold increase in basal adenylyl cyclase activity relative to negative littermate controls. Mice were catheterized with a high fidelity micromanometer and hemodynamic recordings were obtained in vivo. Overexpression of the beta2-AR altered parameters of relaxation. At baseline, LV dP/dt(min) and the time constant of LV pressure isovolumic decay (Tau) in the transgenic mice were significantly shorter compared with controls, indicating markedly enhanced myocardial relaxation. Isoproterenol stimulation resulted in shortening of relaxation velocity in control mice but not in the transgenic mice, indicating maximal relaxation in these animals. Immunoblotting analysis revealed a selective decrease in the amount of phospholamban protein, without a significant change in the content for either sarcoplasmic reticulum Ca2+ ATPase or calsequestrin, in the transgenic hearts compared with controls. This study indicates that myocardial relaxation is both markedly enhanced and maximal in these mice and that conditions associated with chronic beta-AR stimulation can result in a selective reduction of phospholamban protein.

Animals↗
PubMed1995

Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitor.

Transgenic mice were created with cardiac-specific overexpression of the beta-adrenergic receptor kinase-1 (beta ARK1) or a beta ARK inhibitor. Animals overexpressing beta ARK1 demonstrated attenuation of isoproterenol-stimulated left ventricular contractility in vivo, dampening of myocardial adenylyl cyclase activity, and reduced functional coupling of beta-adrenergic receptors. Conversely, mice expressing the beta ARK inhibitor displayed enhanced cardiac contractility in vivo with or without isoproterenol. These animals demonstrate the important role of beta ARK in modulating in vivo myocardial function. Because increased amounts of beta ARK1 and diminished cardiac beta-adrenergic responsiveness characterize heart failure, these animals may provide experimental models to study the role of beta ARK in heart disease.

Adenylyl Cyclases↗
PubMed1995

Pharmacokinetics and renal function in patients with rheumatoid arthritis receiving a standard dose of oral weekly methotrexate: association with significant decreases in creatinine clearance and renal clearance of the drug after 6 months of therapy.

OBJECTIVE: To determine the pharmacokinetics of a standard oral dose of 7.5 mg in a cohort of patients beginning methotrexate (MTX) and continuing the drug over 24 months. METHODS: Twenty-one patients underwent pharmacokinetic testing after receiving a dose of 7.5 mg of oral MTX and concomitant nonsteroidal antiinflammatory drug (NSAID) therapy. Studies were performed at the time of MTX initiation, and after 6 and 24 months of therapy. RESULTS: No significant differences with time were observed in area under the serum concentration versus time curve (AUC), maximal MTX concentration achieved postdosing (Cmax) or time to maximal MTX concentration (Tmax). Renal clearance of MTX at 6 months decreased by a mean (+/- SD) of 23.8 (40.3) cc/min (p = 0.014). Creatinine clearance decreased by 8.6 cc/min (17.2) (p = 0.033) at 6 months. CONCLUSION: No differences in AUC, Tmax, or Cmax were observed over a 2 year period in patients with rheumatoid arthritis on a standard 7.5 mg dose of MTX. Renal clearance and creatinine clearance both decreased significantly after 6 months of treatment. This effect may be clinically relevant in certain individuals as MTX is renally excreted.

Aged↗
PubMed1995

Examination of pharmacokinetic variables in a cohort of patients with rheumatoid arthritis beginning therapy with methotrexate compared with a cohort receiving the drug for a mean of 81 months.

OBJECTIVE: To compare pharmacokinetic variables of a 7.5 mg dose of MTX in a cohort of patients with rheumatoid arthritis (RA) beginning therapy with the drug with a cohort of patients receiving the drug for a mean period of 81 months. METHODS: Standard pharmacokinetic measures were performed in 35 patients beginning MTX therapy and 15 patients who had received the drug for a mean of 81 months. RESULTS: No significant differences in area under the serum concentration versus time curve (AUC), maximal methotrexate concentration following dosing (Cmax), time to Cmax (Tmax), bioavailability (F), urinary MTX, renal clearance of MTX or creatinine clearance were observed between the 2 cohorts. CONCLUSION: We were unable to demonstrate significant differences in pharmacokinetic variables in these cohorts with a 7.5 mg standard dose of MTX. It is possible that a difference may exist when a standard higher dose of MTX is compared in these types of patients.

Administration, Oral↗
PubMed1995

The effects of food on methotrexate absorption.

OBJECTIVE: To determine the effects of food on methotrexate (MTX) absorption in patients receiving MTX for the treatment of rheumatoid arthritis (RA). METHODS: Standard pharmacokinetic variables were determined in patients with RA after their usual maintenance dose of MTX, under fasting conditions and after they ate a standard breakfast. RESULTS: No significant differences in area under the serum concentration versus time curve, maximal MTX concentration after dosing (Cmax), time to Cmax), bioavailability, urinary MTX, renal clearance of MTX, or creatinine clearance were observed between the 2 dosing conditions. CONCLUSION: We observed no significant effect of food on MTX absorption or bioavailability. Patients may consume MTX without regard to meals.

Absorption↗
PubMed1995

The effects of nonsteroidal antiinflammatory drugs on methotrexate (MTX) pharmacokinetics: impairment of renal clearance of MTX at weekly maintenance doses but not at 7.5 mg.

OBJECTIVE: To determine the pharmacokinetics of methotrexate (MTX) with and without nonsteroidal antiinflammatory drugs (NSAID) at a 7.5 mg dose and higher usual maintenance doses of the drug. To determine the difference in pharmacokinetic variables when salicylate and nonsalicylate NSAID are administered with MTX at these doses. METHODS: Thirty patients receiving MTX chronically underwent a study of MTX pharmacokinetics after 7.5 mg doses of MTX with their usual NSAID and after the NSAID were withheld for 5 half-lives. Sixteen additional patients underwent pharmacokinetics studies with and without NSAID while receiving their usual weekly maintenance dose of MTX of 16.6 (3.6) mg (Mean +/- SD). RESULTS: No significant differences in pharmacokinetic variables were observed with and without NSAID at the 7.5 mg weekly dose of MTX. When patients received usual maintenance doses of MTX the renal clearance of MTX NSAID was 91.7 (26.4) ml/min versus 115.3 (34.4) ml/min without NSAID (p = 0.004). Creatinine clearance in patients taking usual maintenance doses increased from 77.5 (13.9) ml/min with NSAID to 95.3 (26.3) ml/min without NSAID (p = 0.05). A reduction in renal clearance of MTX was observed with maintenance dose MTX in both the 4 patients taking salicylates (p = 0.016) and the 12 patients taking nonsalicylate NSAID (p = 0.024). CONCLUSION: NSAID produce significant decreases in renal clearance of MTX and creatinine when patients consume their usual weekly dose of the drug, but not when they take a 7.5 mg dose. This effect is likely to achieve clinical relevance across the dose ranges used to treat patients with rheumatoid arthritis.

Aged↗
PubMed1992

Incidence and cost of hospital admissions secondary to drug interactions involving theophylline.

OBJECTIVE: To determine the incidence and cost of hospital admissions for theophylline toxicity, which occurred as a result of the concurrent use of one of the following medications: cimetidine, erythromycin, or ciprofloxacin. DESIGN: Retrospective chart review (18 months, between June 1989 and November 1990). SETTING: A Department of Veterans Affairs Medical Center. PARTICIPANTS: All patients who were receiving theophylline chronically (913 patients) and also had a prescription for cimetidine (124 patients with 140 treatment courses), erythromycin (66 patients with 93 treatment courses), or ciprofloxacin (39 patients with 59 treatment courses) dispensed. INTERVENTIONS: Each patient's medical record was reviewed to identify hospital admissions within 30 days following the dispensing of the interacting drug. MAIN OUTCOME MEASURES: Admissions were considered to be related to theophylline toxicity if appropriate signs and symptoms were present and the theophylline concentration was above 20 micrograms/mL or had increased significantly from the concentration obtained prior to introduction of the interacting drug. RESULTS: One patient who received cimetidine and one who received ciprofloxacin were admitted for theophylline toxicity (2 of 292 potential interactions, 0.81 percent). Admissions were for 16 and 13 days, respectively, and total costs for the two admissions were $12,864.22 or $44.00, respectively, per potential interaction. The entire admission was not for theophylline toxicity; it appeared that iatrogenic factors contributed to the duration. CONCLUSIONS: The incidence of hospital admissions secondary to theophylline drug interactions with cimetidine, ciprofloxacin, or erythromycin is low, but the admissions represent considerable expense, even when distributed among all patients at risk for the interactions.

Aged↗
PubMed1992

Neural tube defects--prenatal diagnosis and management.

Neural tube defects rank second to congenital heart disease as a major cause of congenital malformation. Recent developments in ultrasound have improved prenatal diagnosis. Due to anomaly scans at 18 weeks gestation and the availability of a genetic clinic, prenatal diagnosis of neural tube defects at the Royal Maternity Hospital was 91.2% during 1987-1989. However, only 50% of parents accept termination of pregnancy and it is questionable if prenatal diagnosis is of benefit to those who wish to continue with the pregnancy. Parents may accept the situation better at birth, having had time to come to terms with it, helped with support from the obstetrician, clinical geneticist, paediatrician, genetic nurse and social worker. For some affected fetuses who have better muscle function and leg movement at term it appears from the literature that the outcome may be improved by caesarean section delivery. In Ireland fetuses with neural tube defects will continue to be delivered, as termination is unacceptable to many, but despite this there may be a positive benefit from prenatal diagnosis of neural tube defects. Prospective randomised controlled trials are needed to confirm benefit from delivery by caesarean section for fetuses with a good prognosis. As a result of prenatal diagnosis of a neural tube lesion the fetus should enjoy benefit in terms of physical morbidity, and the parents should benefit in terms of psychological morbidity.

Abortion, Induced↗
PubMed1992

Evaluation of patient-care interventions by Pharm.D. clerkship students.

A program is described in which Pharm.D. clerkship students provide pharmaceutical care by identifying drug-related problems, suggesting interventions to solve the problems, and documenting the patient's outcome. Four doctor of pharmacy degree students under the direct guidance of a clinical pharmacy preceptor suggested 231 patient-care interventions during their clinical rotations; 219 (94.8%) of the interventions were either fully or partially accepted by the prescriber. The most commonly solved drug-related problems were underdose (31.5%) and overdose (17.4%), followed by untreated indications (14.1%) and drug given without indication (13.7%). The remainder of the drug-related problems that the students solved were improper drug selection, failure to receive drug, adverse drug reactions, or drug interactions. All but 10 interventions were considered by preceptors to be significant contributions to patient care. The interventions were estimated to have decreased drug costs in 50.7% of the cases, increased drug costs in 23.7% of the cases, and not changed drug costs in 25.6% of the cases. Patient outcomes were documented by the students in 58.9% of cases; the desired goals of the accepted intervention were achieved in all documented cases. A preceptor-supervised intervention program was beneficial to Pharm.D. students and patients and was well received by prescribers.

Clinical Clerkship↗
PubMed1992

Use of prescription-refill records to assess patient compliance.

Prescription-refill records were used to assess patient compliance, to evaluate factors previously associated with compliance, and to determine the association between selected drugs and compliance. Records were selected from a computerized database containing prescription-coverage claims, based on the following criteria: (1) the prescriptions were refilled during 1987-1989 and within two times the days' supply after the dispensing date, (2) they involved any of 12 drugs selected for study, (3) they required one to four doses per day, and (4) at least 20 records with the same regimen were available. Compliance was defined as refill within 0.2 times the days' supply after the refill-due date, and it was assessed by calculating the compliance rate and the compliance index (which describes the relationship between the refill-due date and the actual refill date). Data from 19,118 prescription-refill records were analyzed. The compliance index improved slightly as the number of concurrent medications increased, worsened as the number of doses per day increased, and improved as the immediacy of the risk of noncompliance increased. Different medications and indications were associated with different degrees of compliance. Medication compliance generally improves as the number of daily doses decreases, may improve slightly as the number of concurrent medications increases, and varies with the particular drug and indication.

Drug Prescriptions↗
PubMed1991

The management of bleeding in early pregnancy.

Ultrasound scan findings were analysed for 187 women referred to an emergency gynaecological scanning clinic during a seven month period, with bleeding in early pregnancy. One sixth of the women were not pregnant, one third had non-viable pregnancies and one half had viable pregnancies; 9% of this latter group subsequently miscarried. For the majority of women referred to the clinic, bed rest would have been inappropriate. In this study the value of bed rest and hospitalisation was considered uncertain for women with viable singleton pregnancies of 7-14 weeks gestation and bleeding in the previous 24 hours. Only 23 women with otherwise uncomplicated pregnancies met these criteria and consented to recruitment to a randomized controlled trial: three subsequently miscarried. Emergency scanning as a routine part of the gynaecological service is recommended, thus confining bed rest to those women with viable pregnancies. Reliable evaluation of bed rest and hospitalisation for such women will require a multicentre study.

Female↗
PubMed1989

Triplet pregnancy: a 10-year review of 105 cases at Harare Maternity Hospital, Zimbabwe.

During the 10-year period, 1975-1984, 105 triplet pregnancies were delivered at Harare Maternity Hospital, Zimbabwe, among 286,338 pregnancies in the Greater Harare Unit, giving an incidence of triplets of 1:2,727. The mean gestational age at delivery was 32.5 wk with 81 women (77.1%) delivering before 37 wk. Primigravidas delivered at a significantly earlier mean gestational age (P less than 0.05) and had a higher perinatal mortality (P less than 0.001) compared with grand multigravidas. Of the 315 babies, 277 (87.9%) weighed less than 2500 g. The overall perinatal mortality rate was 327%, with a perinatal mortality rate of 146% for infants weighing greater than or equal to 1000 g. Women hospitalised for bed rest during the antenatal period had fewer perinatal deaths compared with those diagnosed during the antenatal period, but not hospitalised for bed rest (P less than 0.02). No difference was found in the mean gestational age at delivery or the mean birth weights between these two groups. Among infants greater than or equal to 28 wk gestation there were fewer perinatal deaths in triplets delivered by cesarean section compared with triplets delivered vaginally (P less than 0.0004). This suggests that cesarean section may offer the optimal mode of delivery in triplet pregnancy.

Adult↗
PubMed1988

Heparin sodium versus 0.9% sodium chloride injection for maintaining patency of indwelling intermittent infusion devices.

In a double-blind study, heparin sodium was compared with 0.9% sodium chloride injection for use in maintaining patency of indwelling devices for intermittent intravenous infusion. Adult patients who required intermittent intravenous devices were randomly assigned to receive 1 mL of a heparin sodium 100 units/mL flush solution or a 0.9% sodium chloride flush solution. Observations were recorded for each catheter, rather than for each patient. Patients were evaluated daily for the development of phlebitis. In the 160 patients for whom complete data on catheter patency were available, there were 307 observations (170 for the heparin group and 137 for the sodium chloride group). No significant difference in the duration of catheter patency or incidence of phlebitis was observed between the groups. A difference in the incidence of phlebitis could not be excluded with confidence, but inasmuch as there was no effect on duration of catheter patency, the clinical importance of this superficial venous phlebitis is questionable. The duration of patency was significantly greater in men than in women. The use of penicillins, cephalosporins, or clindamycin, alone or in combination, was significantly associated with the development of phlebitis for both treatment groups. No other factors were found to correlate with either the duration of catheter patency or incidence of phlebitis. The results of this study indicate that heparin offers no advantage over 0.9% sodium chloride injection in maintaining the patency of intermittent intravenous devices.

Adult↗
PubMed1987

The unbooked patient. Part I. Reasons for failure to attend antenatal clinics.

Two hundred unbooked mothers were questioned after delivery and their reasons for non-attendance at antenatal clinics were determined. The control group consisted of 310 mothers who had booked early and were good clinic attenders. The most significant difference between the two groups was that the unbooked mothers were of lower socioeconomic status and lived in poorer areas situated further from the hospital. The main reasons given for not attending hospital clinics included the expense involved and the fact that the mothers often stayed outside the area during the pregnancy.

Adolescent↗
PubMed1987

The unbooked patient. Part II. Outcome of pregnancy in unbooked coloured patients.

The fetal outcome was compared in 200 unbooked pregnancies and in 310 pregnancies in which the mothers had booked before 22 weeks' gestation. Of the babies born to the unbooked mothers 36% weighed less than 2,500 g compared with only 12.5% in the booked group. Among the unbooked patients the neonatal mortality rate was three times higher than among booked cases. Maternal intrinsic factors, including parity and socio-economic status, made a major contribution to the incidence of low-birth-weight babies. The need for improved attendance at clinics and for education about antenatal care in the coloured population under review is well documented. The introduction of peripheral clinics and free antenatal care could play a major role in improving fetal outcome.

Adolescent↗
PubMed1986

Effect of the acetylator phenotype on amrinone pharmacokinetics.

Ten healthy male subjects were phenotyped with isoniazid for their acetylator status and then received intravenous amrinone at a dose of 75 mg during a period of 10 minutes. Blood samples were drawn at specified times during a 24-hour period after dosing. Plasma concentrations of amrinone were determined by a specific HPLC method. The plasma concentration data were fitted to a biexponential model by nonlinear regression. The mean apparent first-order elimination t1/2 for amrinone in the slow acetylators was 4.4 hours, whereas it was 2.0 hours in the fast acetylators (P less than 0.05). There was little difference in the volume of distribution at steady state. Clearance was lower in the slow acetylators, 16.6 L/hr, than in the fast acetylators, 37.2 L/hr (P less than 0.05). The AUC was higher for the slow acetylators, 4.96 micrograms X hr X ml-1, than for the fast acetylators, 2.20 micrograms X hr X ml-1 (P less than 0.01). Concentrations of amrinone and its N-acetyl metabolite in the urine from each volunteer were determined. The ratio of N-acetylamrinone to amrinone was calculated and, as expected, the fast acetylators had a higher ratio than did the slow acetylators (P less than 0.01).

Acetylation↗