摘要:

This report updates previous studies that documented the existence of a significant lag between new drug introductions in the United Kingdom and in the United States. During the 11‐year period from 1977 through 1987, the United Kingdom led the United States in the number of first introductions of new drugs (114 versus 41), in average lead time for mutually available drugs (60.7 versus 28.9 months), and in the number of exclusively available drugs (70 versus 54). Analysis by therapeutic category indicated large United Kingdom leads in the introduction of respiratory (5.1 years), cardiovascular (3.2 years), central nervous system (3.2 years), and anti‐cancer (2.9 years) agents, and shorter leads for anesthetic and analgesic (2.0 years), gastrointestinal (2.0 years), endocrine (1.4 years), and anti‐infective (0.8 years) agents. A comparison of the 5‐year period from 1983 through 1987 with the previous 5‐year period (1978 through 1982) showed no change in the length of the lag time (1.9 years for each period). These results indicate that the United States continues to lag behind the United Kingdom in the availability of new drugs.Clinical Pharmacology and Therapeutics(1989)46, 121–138; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1989.116

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)46, 139–145; doi:10.1038/clpt.1989.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.117

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)46, 146–148; doi:10.1038/clpt.1989.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.118

年代:1989

数据来源: WILEY

摘要:

Azathioprine therapy can cause acute myelosuppression. Toxicity is in part caused by the incorporation of azathioprine‐derived 6‐thioguanine nucleotides (6‐TGN) into deoxyribonucleic acid (DNA). The enzyme thiopurine methyltransferase (TPMT) plays an important role in azathioprine catabolism. TPMT activity is controlled by a common genetic polymorphism, and one in 300 subjects has very low enzyme activity. Azathioprine was withdrawn in five study patients because of acute myelosuppression. The duration of azathioprine treatment was 21 to 70 days (median, 28), and the daily oral dose was 1.0 to 2.5 mg/kg. Sixteen control patients who had been taking oral azathioprine (1.1 to 2.0 mg/kg daily for more than 6 months) with no history of myelosuppression were studied. All subjects had normal liver and kidney function. When compared with the control group, the five patients with myelosuppression had very low TPMT activities and abnormally high 6‐TGN concentrations. Inherited low TPMT activity appears to be a major risk factor for acute azathioprine‐induced myelosuppression.Clinical Pharmacology and Therapeutics(1989)46, 149–154; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1989.119

年代:1989

数据来源: WILEY

摘要:

Pharmacokinetics and systemic effects of recombinant tissue‐type plasminogen activator (rt‐PA) were studied in 18 healthy male volunteers after 30‐minute intravenous infusions of placebo, 0.25 mg/kg rt‐PA, and 0.5 mg/kg rt‐PA. Highly comparable pharmacokinetic parameters were obtained after analysis of rt‐PA as both an antigen and an activity. Mean clearance (antigen) was 620 ± 70 (SD) ml/min, volume of distribution at steady state was 8.1 ± 0.8 L, initial volume of distribution was 4.4 ± 0.6 L, and dominant half‐life was 4.4 ± 0.3 minutes. The pharmacokinetics of rt‐PA were linear, showed low interindividual variation, and are compatible with rapid hepatic elimination of the protein. Systemic plasminogen activation was minimal as assessed by hemostatic assays of plasma samples treated with anti‐rt‐PA Immunoglobulin G (IgG) to inhibit in vitro fibrinogenolysis. Circulating fibrinogen levels, clotting times, and coagulation factors were unchanged; plasminogen and α2‐antiplasmin decreased maximally to 85% and 65% of baseline values, respectively. The data are consistent with the fibrin specificity of t‐PA, which is derived from its role in physiologic fibrinolysis.Clinical Pharmacology and Therapeutics(1989)46, 155

ISSN:0009-9236    

DOI:10.1038/clpt.1989.120

年代:1989

数据来源: WILEY

摘要:

We attempted to assess compliance using both a pharmacologic indicator (low‐dose phenobarbital) and a return tablet count in 225 patients who were taking part in three separate studies. There were 216 patients (96%) who kept a follow‐up appointment after 28 days; 161 patients appeared to have good compliance (90% to 109%) by return tablet count. Of these 161 patients, 51 (32%) had plasma phenobarbital concentrations (corrected for dose and weight) that were less than 90% of the lowest value previously found in normal volunteers, which suggested poorer compliance. When compared with the age‐related volunteer values, 77 (48%) had values that were less than 90% of the lowest volunteer value. There were 6 of 10 patients with apparently excessive (≥ 110%) compliance by return tablet count and 4 of 12 who failed to return their container who also had phenobarbital concentrations that were less than 90% of the lowest volunteer value. We concluded that return tablet count grossly overestimates compliance.Clinical Pharmacology and Therapeutics(1989)46, 163–168; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1989.121

年代:1989

数据来源: WILEY

摘要:

To assess medication compliance over time, we prospectively performed pill counts among 121 ambulatory hypertensive subjects for ⩽ 12 months. Prescribed regimens consisted of pinacidil or hydralazine administered four times a day and of secondary drugs administered up to twice daily. Surreptitious pill counts occurred every 1 to 12 weeks. Among a middle‐aged subject group that had been selected for high rates of compliance, we observed mean compliance rates that approximated 100%. We noted marked intrasubject and intersubject variability for any one medication, between medications, and over time. From baseline blood pressures (±SE) of 155.5 ± 1.9/97.3 ± 1.0 mm Hg, subsequent mean blood pressures varied by compliance subgroup: “hypocompliers” (<80%), 151.3/91.0 mm Hg; “hypercompliers” (⩾ 120%), 147.6/91.4 mm Hg; and “eucompliers” (80% to 119%), 143.3/88.5 mm Hg (systolic blood pressure:F1,52= −220.9, NS; diastolic blood pressure:F1,52= −121.4, NS). We concluded that weekly pill counts indicated marked intersubject and intrasubject variability, obscured by long‐term averages; that compliance lapses appeared to be random; and that excessive medication‐taking was the most consistent with “pill dumping.”Clinical Pharmacology and Therapeutics(1989)46, 1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.122

年代:1989

数据来源: WILEY

摘要:

The objective of this study was to investigate the effect of cadralazine in patients who had previously had hydralazine‐induced lupus. There were 11 patients included in the study, 10 of whom were treated for 6 months with 15 or 20 mg cadralazine given once daily in combination with β‐blockers and diuretics. All patients had a history of hydralazine‐induced lupus and were slow acetylators. None of the patients included in this study showed any current signs or symptoms of drug‐induced lupus. No evidence of lupus‐like symptoms or of immunologic laboratory abnormalities were found during the study period. Side effects associated with vasodilator therapy were noted in some patients but were transient and mild. We concluded that a cross‐reaction between cadralazine and hydralazine does not seem likely to occur and that cadralazine, because of its chemical properties, probably will not give rise to drug‐induced lupus.Clinical Pharmacology and Therapeutics(1989)46, 177–181; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.123

年代:1989

数据来源: WILEY

摘要:

N‐Acetylprocainamide (NAPA) absorption and disposition were profiled in five patients with ventricular arrhythmias by the simultaneous intravenous administration of NAPA‐13C and oral administration of a 500 mg NAPA hydrochloride tablet. NAPA distribution was modeled with a three compartment mammillary system. The central compartment volume of 14.1 ± 2.6 L (mean ± SD) was similar to expected intravascular space, corrected for NAPA partitioning between erythrocytes and plasma. Other compartment volumes, intercompartmental and nonrenal clearances, and the steady‐state distribution volume of 1.45 ± 0.09 L/kg were similar to normal subject values. The least‐squares estimate of 1.67 for the NAPA renal clearance/creatinine clearance ratio was similar to the value of 1.68 previously reported for functionally anephric patients and showed the expected age‐associated decrease. The oral NAPA dose was 78.0% ± 11.7% absorbed and interindividual variation in NAPA absorption was correlated with fast intercompartmental clearance (r= 0.89,p= 0.045). Because fast intercompartmental clearance partly reflects splanchnic blood flow, hemodynamic changes may affect NAPA bioavailability, as has been found for procainamide.Clinical Pharmacology and Therapeutics(1989)46, 182–189; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1989.124

年代:1989

数据来源: WILEY

摘要:

Pharmacokinetics of zidovudine (azidothymidine, AZT) was investigated after oral administration (200 mg) in 25 HIV seronegative subjects: 14 patients with severe renal impairment (creatinine clearance 6 to 31 ml/min), five hemodialyzed anuric patients, and six healthy subjects. Plasma and urine concentrations of zidovudine and its glucuronidated metabolite (GAZT) were measured simultaneously by HPLC assay. In healthy subjects, GAZT concentrations were higher than those of AZT; AUC values were 23.7 ± 1.9 and 5.2 ± 0.6 µmol · hr/L, respectively. Formation of GAZT rate‐limits its elimination: GAZT half‐life (t½) parallels that of AZT, which is around 1 hour. In uremic patients, AZT concentrations were moderately increased (AUC = 11.7 ± 1.1 µmol · hr/L), whereas t½and mean residence time (MRT) remain unchanged despite the decreased renal clearance (16 ± 2 versus 220 ± 58 ml/min) and decreased urinary excretion (1.6 ± 0.3 versus 8.1 ± 1.0% of the dose). In contrast, GAZT concentrations are markedly increased (AUC = 402.9 ± 88.6 µmol · hr/L). As a consequence of the decreased renal clearance (27 ± 3 versus 331 ± 42 ml/min), elimination is the rate‐limiting step and t½is increased (8 ± 2 versus 0.9 ± 0.1 hr). Contribution of a 4‐hour hemodialysis session to AZT elimination appears to be negligible, whereas elimination of GAZT is enhanced. On the sole basis of AZT pharmacokinetic data, no particular dose adjustment appears to be necessary in patients who have severe renal impairment (creatinine clearance between 10 and 30 ml/min). However, high levels of GAZT should be anticipated with the usual dosage regimen.Clinical Pharmacology and Therapeutics(1989)46, 190

ISSN:0009-9236    

DOI:10.1038/clpt.1989.125

年代:1989

数据来源: WILEY