摘要:

The human stratum corneum constitutes a relatively impermeable barrier to the transdermal absorption of most substances, including polypeptides and proteins. This double‐blind, randomized, crossover study in 13 normal men evaluated whether a low level of electrical current could induce changes in cutaneous permeability sufficient to produce absorption of a polypeptide. We compared cutaneous absorption of 5 mg of leuprolide (a 9 amino acid luteinizing hormone releasing hormone analogue) in transdermal patches containing 0.2 mA electrical current (active) and in patches containing no electrical current (passive). Serum luteinizing hormone (LH) concentration was measured 12 times during an 8‐hour period as a measure of drug effect. Similar baseline LH levels were seen in each group: active = 11.3 ± 3.1 mIU/ml and passive = 13.7 ± 4.7 mIU/ml (pnot significant). Significant elevations of LH were seen in active compared with passive patches (p= 0.0084). As predicted, passive patches produced no elevation of LH concentration (LH = 11.8 ± 7.1 mIU/ml at 4 hours). However, active patches produced elevations comparable to those achieved with subcutaneous administration of the drug (LH = 56.4 ± 49.6 mIU/ml at 4 hours andp= 0.003 compared with passive). The patches were well tolerated without significant cutaneous toxicity. It is concluded that the use of low levels of electrical current can induce changes in the permeability of the stratum corneum. These changes are sufficient to promote the transdermal absorption of therapeutically relevant amounts of a polypeptide. This has major importance for our understanding of skin permeability and for the development of new techniques for drug administration.Clinical Pharmacology and Therapeutics(1988)44, 607–612; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1988.201

年代:1988

数据来源: WILEY

摘要:

Bradykinin is a potent pain‐producing substance, yet little is known about its role in inflammation. The present study measured circulating levels of immunoreactive bradykinin in a clinical model of acute inflammation (oral surgery) and chronic inflammation (rheumatoid arthritis) and in the rat carrageenan model of inflammation. The effects of a kallikrein inhibitor (soybean trypsin inhibitor) on blocking bradykinin synthesis in vitro and its analgesic actions in the rat model were also evaluated. Levels of immunoreactive bradykinin increased threefold to fourfold during oral surgery. Levels were twofold to threefold greater in patients with rheumatoid arthritis compared with control subjects. Levels of immunoreactive bradykinin increased twofold in rats during carrageenan inflammation. Soybean trypsin inhibitor blocked synthesis of bradykinin in vitro and possessed analgesic activity in rats. The results indicate that the bradykinin system is activated during inflammation. Kallikrein inhibitors may represent a new class of analgesic/antiinflammatory drugs.Clinical Pharmacology and Therapeutics(1988)44, 613–621; doi:10.1038/clpt.1988

ISSN:0009-9236    

DOI:10.1038/clpt.1988.202

年代:1988

数据来源: WILEY

摘要:

We have studied the disposition of cyclophosphamide, its major cytotoxic metabolite phosphoramide mustard, and the synthetic glucocorticoid dexamethasone in nine patients receiving high‐dose cyclophosphamide daily for 2 days before bone marrow transplantation. The total body clearance of cyclophosphamide was observed to increase from 93 ± 27 ml/min on the first day to 178 ± 83 ml/min on the second day. This was associated with an increase in the clearance of dexamethasone from 369 ± 104 ml/min to 526 ± 123 ml/min. An increased rate of formation of phosphoramide mustard with higher peak concentrations was also seen. Simulation studies show that these changes are most likely the result of an increase in the hepatic metabolism of cyclophosphamide. These results show that high‐dose cyclophosphamide causes an increase in its own clearance and that of dexamethasone through an apparent induction of hepatic‐metabolizing enzymes detectable 24 hours after initial exposure to cyclophosphamide.Clinical Pharmacology and Therapeutics(1988)44, 622–628; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1988.203

年代:1988

数据来源: WILEY

摘要:

Concern over rational drug therapy has led to the close scrutiny of clinical pharmacology and therapeutics teaching. Course syllabuses and timetables portray the official curriculum but rarely reflect true pharmacology and content. The teaching of clinical pharmacology and therapeutics can be uniquely and comprehensively analyzed with a computer‐based curriculum data base that has the capacity to identify overlap, integration, omissions, and correlations. We have developed such a system and applied it to the analysis of one medical school curriculum. Pharmacology and therapeutics teaching represents 22% of the curriculum; however, the majority occurs outside the pharmacology‐controlled courses. Overlap is extensive and unplanned. Our data indicate that the true curriculum differs greatly from that in curriculum schedules and probably from that in the minds of most curriculum planners and teachers. Collaboration among pharmacologists and clinical pharmacologists and many other curriculum officers and teachers is essential if education in this area is to be improved.Clinical Pharmacology and Therapeutics(1988)44, 629–633; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1988.204

年代:1988

数据来源: WILEY

摘要:

Ritodrine is a β2‐adrenergic agonist that is used clinically for the management of preterm labor. The β2activity of ritodrine produces the relaxation of smooth muscles and is believed to act directly on the β2‐receptors of the myometrium. Reports in the literature suggest that ritodrine is inactivated by sulfate and glucuronide conjugation, but this has not been verified in humans. Studies on animal models indicate that the sulfate conjugate is a major urinary metabolite of ritodrine. Recent investigations of maternal and neonatal urinary excretion of ritodrine indicate that 80% to 90% of the drug is in the form of conjugates. The purpose of this study was to determine the nature of these conjugates. Our study indicates that both the mother and neonate excrete glucuronide and sulfate conjugates of ritodrine. The sulfate conjugate accounts for 45% of maternal excretion and 66% of neonatal excretion; the glucuronide conjugate accounts for 38% and 23% of maternal and neonatal excretion, respectively. Significantly different metabolic profiles suggest that the neonate may be capable of forming conjugated metabolites of ritodrine.Clinical Pharmacology and Therapeutics(1988)44, 634–641; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1988.205

年代:1988

数据来源: WILEY

摘要:

The plasma clearance after oral administration of a completely absorbed drug that is metabolized by the liver depends on its intrinsic clearance. In cirrhosis the bioavailability of a flow‐dependent drug increases because of both portosystemic shunting and hepatocyte dysfunction. A drug with a high extraction ratio, lidocaine, and a drug with a low extraction ratio, theophylline, were administered to 27 patients with cirrhosis and 16 control subjects. We found a significant impairment of both theophylline clearance (p<0.001) and lidocaine clearance (p<0.001) and an increase in the lidocaine peak concentration (p<0.001). The three parameters were significantly correlated with each other. The impairment of theophylline metabolism did not correlate with other indexes of disease severity, whereas lidocaine clearance was lower and lidocaine peak level higher in patients with decompensated cirrhosis and evidence of portal hypertension. Thus impairment in lidocaine disposition, which reflects both hepatocyte dysfunction and portosystemic shunting, correlated closer with the severity of liver disease than did theophylline metabolism.Clinical Pharmacology and Therapeutics(1988)44, 642–649; doi:10.1038/clpt.1988

ISSN:0009-9236    

DOI:10.1038/clpt.1988.206

年代:1988

数据来源: WILEY

摘要:

We sought to evaluate the effectiveness of esmolol vs placebo in 40 patients emerging from general anesthesia for neurosurgery. Efficacy was defined as a decrease in systolic blood pressure to within 20% above average ward pressure. The need for additional antihypertensive agents to control blood pressure was also used to define efficacy. During the infusion period 20 of 21 (95%) of the esmolol‐treated patients and two of 19 (11%) of the patients receiving placebo had return of systolic blood pressure to within 20% of average ward pressure (p<0.001). One out of 21 (5%) esmolol‐treated patients and 14 of 19 (74%) of the placebo group required intervention with additional antihypertensive medications (p<0.001). Esmolol was found to be effective in controlling hypertension that develops on emergence from general anesthesia in patients undergoing neurosurgery.Clinical Pharmacology and Therapeutics(1988)44, 650–653; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1988.207

年代:1988

数据来源: WILEY

摘要:

The clinical tolerance and pharmacokinetics of cyclosporine during a prolonged intermittent intravenous infusion (3.5 mg/kg/day three times) followed by an 8 mg/kg daily oral dose was evaluated in eight renal transplant recipients in the immediate postoperative period. Cyclosporine was analyzed from whole blood samples by HPLC. Despite peak drug concentrations of 1463 ± 754 ng/ml during the infusion period, no adverse pulmonary effects were noted; renal function, urine output, and mean arterial pressure also appeared to have been unaffected. The mean trough cyclosporine concentration was 141 ± 50 ng/ml; however, two patients had trough values below sensitivity. Kinetic analysis after the third dose of intravenous cyclosporine revealed a mean total body clearance of 0.31 ± 0.1 L/min and a volume of distribution of 2.88 ± 1.1 L/kg, whereas the elimination half‐life was 12.8 ± 3.8 hours and the mean residence time was 9.5 ± 5.1 hours. After conversion to oral therapy the bioavailability ranged from 0.11 to 0.47, with a mean value of 0.27. Subsequently there was an unpredictable pattern of bioavailability within patients, with mean values of 0.27 ± 0.13 and 0.30 ± 0.25 during the second and third oral study periods, respectively. These data suggest that despite adjusting the intravenous cyclosporine dosage to account for acute changes in patient body weight, variable kinetics may result in subtherapeutic trough values, even when cyclosporine is administered by prolonged infusion. The clinical implications of fluctuating cyclosporine bioavailability and a potential alternative approach to dosing are discussed.Clinical Pharmacology and Therapeutics(1988)44, 654–664; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1988.208

年代:1988

数据来源: WILEY

摘要:

Thirty subjects with chronic moderate to severe pain who were receiving oxycodone/acetaminophen (oxy/APAP) for analgesia were initially evaluated for at least 7 days for oxy/APAP requirements for pain control. Each subject then received, in a randomized double‐blind fashion, either 600 mg ibuprofen or placebo for an additional 7 days while hospitalized. Oxy/APAP usage was recorded daily along with efficacy and toxicity parameters. Overall global evaluations were also recorded on completion of the study. Comparison of mean differences before and after treatment with ibuprofen or placebo indicated a marked decrease in oxy/APAP use with ibuprofen (p<0.01) and a slight increase in use in the placebo group. Reduction in oxy/APAP usage occurred within 24 hours and maximized at 5 days. Overall global scores showed a marked preference for the ibuprofen combination over placebo (p<0.01). Daily pain intensity (p<0.05) and pain relief scores (p<0.05) also improved with the addition of ibuprofen. This study indicates that ibuprofen is efficacious in the management of chronic cancer pain, resulting in both enhanced analgesia and a reduction in concomitant narcotic use.Clinical Pharmacology and Therapeutics(1988)44, 665–669; doi:10.1038/clpt.1988

ISSN:0009-9236    

DOI:10.1038/clpt.1988.209

年代:1988

数据来源: WILEY

摘要:

This study was designed to evaluate the effects of domperidone, a peripheral dopaminergic antagonist, in diabetic patients with symptomatic orthostatic hypotension. Nine patients were admitted to the hospital, placed on a diet containing 150 mEq sodium, and studied for periods of 4 hours, on different days, in the following conditions: (1) supine position, (2) upright posture (UP), (3) UP after 10 mg domperidone, intravenously in bolus, and (4) UP after 3 days of domperidone, 30 mg orally. Before domperidone the mean blood pressure observed in supine position of 132 ± 37/75 ± 6 mm Hg fell to 75 ± 22/57 ± 13 mm Hg after 2 hours in UP. Acute domperidone did not change the blood pressure response to UP. After 3 days of oral domperidone and in UP for 2 hours, the mean blood pressure value of 89 ± 21/61 ± 8 mm Hg was higher than that before domperidone (p<0.05), with relief of symptoms in all patients. This blood pressure response to UP has been maintained in six patients who completed 6 months of therapy. No differences were observed in plasma renin activity, aldosterone, sodium, and potassium and in 4‐hour urinary excretion of aldosterone, epinephrine, norepinephrine, and dopamine, determined during the UP tests. Administration of domperidone for 3 days reduced the falls in creatinine clearance and the urinary excretion of sodium and potassium induced by UP but did not alter the blood pressure and aldosterone dose‐response curves to angiotensin II. Although the mechanism of action is not defined, it is concluded that domperidone is effective for the treatment of orthostatic hypotension in patients with diabetes.Clinical Pharmacology and Therapeutics(1988)44, 670–674; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1988.210

年代:1988

数据来源: WILEY