Frovatriptan: a review of drug-drug interactions.

OBJECTIVE: To investigate the potential for interactions involving drugs likely to be coadministered with frovatriptan. BACKGROUND: Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) agonist. Preclinical data suggest that the pharmacokinetic and pharmacological profile of frovatriptan may differ from that of the currently available triptans. METHODS: The potential for interactions between frovatriptan and other drugs was investigated using in vitro methods, studies in healthy volunteers, and retrospective analysis of data from phase I trials. RESULTS: In vitro, frovatriptan was principally metabolized by cytochrome P-450 (CYP) 1A2 but was found not to be an inhibitor or inducer of this or other CYP isoenzymes. Frovatriptan was only a weak inhibitor of monoamine oxidase at very high concentrations in vitro and was not a substrate for this enzyme (unlike some other triptans). Coadministration with moclobemide, at doses known to inhibit monoamine oxidase-A, did not affect the pharmacokinetics of frovatriptan. Binding to plasma proteins was low (15%), and binding to erythrocytes was moderate (60%) and unlikely to be a source of interaction with other drugs. The pharmacokinetics of frovatriptan were not affected by moderate alcohol intake. There were slight increases in area under the curve and maximum concentration on concomitant administration with the combined oral contraceptives, propranolol, and fluvoxamine; and slight decreases in these parameters on concomitant administration with ergotamine and in tobacco smokers; these findings were considered to have no clinical significance in view of frovatriptan's large therapeutic index (well tolerated at doses ranging from 2.5 to 40 mg). These effects can be attributed primarily to modification of CYP1A2 activity but their impact is limited, probably due to frovatriptan also undergoing renal clearance and the likely role of blood cell binding in controlling the amount of unbound drug available for elimination. CONCLUSIONS: Because it has no inhibitory or inducing effect on CYP isoenzymes and is only slightly bound to plasma proteins, it is unlikely that frovatriptan will alter the pharmacokinetics of concomitantly administered drugs. Frovatriptan, therefore, appears to have a low risk of interaction with other drugs, and adjustments of dose are unlikely to be required when it is coadministered with other agents.

Pharmacokinetics and tolerability of a novel 5-HT1D agonist, PNU-142633F.

OBJECTIVES: The objectives of this study were to characterize the safety, tolerability and pharmacokinetics of a single, oral dose of PNU-142633F escalating over the range of 1.0 mg to 100 mg (free base equivalents). METHODS: This was a randomized, double-blind, single-dose, placebo-controlled, dose-escalation trial, with each dose group (1.0, 3.0, 10, 30, 50, 75 and 100 mg) having eight volunteers (six PNU-142633F and two placebo). Clinical laboratory tests, electrocardiogram, Holter monitoring, and assessment of adverse events were used to gauge the tolerability of PNU-142633. Serial blood samples and urine collections were obtained and plasma and urine PNU-142633 concentrations were determined by a validated HPLC fluorescence method. RESULTS: PNU-142633 was well tolerated after oral administration. There were no reports of serious or unexpected adverse events. The most common adverse event that was possibly medication-related was transient dizziness. There were no clinically significant or dose-related effects of PNU-142633 on any vital sign parameters (aural temperature, systolic and diastolic blood pressure, pulse rate or respiratory rate), at any study time or dose. There were no clinically significant ECG changes. Only sporadic abnormalities in clinical chemistry values and hematology were noted. After the 1.0 mg and 3.0 mg doses, plasma concentrations of PNU-142633 were either below or only slightly above the lower limit of quantitation (2 ng/ml). At higher doses (30-100 mg) the terminal half-life was relatively constant at approximately 11 hours. Neither Cmax nor AUC(0-infinity) increased proportionally with the administered dose. The mean percentage of the dose excreted in the urine as intact PNU-142633 increased from 14.3% after the 1 mg dose to 49.3% after the 100 mg dose. CONCLUSIONS: The clinical safety and pharmacokinetic data support the study of this agent as a potential treatment for migraine attacks.

Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist.

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)-cGMP pathway during sexual stimulation, which results in corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 microg/min and doubling every 5 minutes to a maximum rate of 40 microg/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 microg) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment, based on the occurrence of a >25 mm Hg decrease in blood pressure or the incidence of symptomatic hypotension (p <0.01). When a sublingual glyceryl trinitrate tablet was administered on day 5, a 4-fold greater decrease in systolic blood pressure was observed for the subjects during the sildenafil treatment period than during the placebo treatment period. The changes in heart rate were negligible during both glyceryl trinitrate challenges. In conclusion, sildenafil potentiated the hypotensive effects of glyceryl trinitrate, an organic nitrate. Thus, sildenafil administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is contraindicated. In the second crossover study, men with hypertension, who were taking 5 or 10 mg/day of amlodipine, received a single oral dose of 100 mg sildenafil or placebo. Coadministration of sildenafil did not significantly affect the pharmacokinetics of amlodipine. In the 4 hours after dosing, differences in the mean maximum change from baseline in supine systolic and diastolic blood pressures between the sildenafil plus amlodipine and the placebo plus amlodipine treatment periods were -8 mm Hg and -7 mm Hg, respectively (p < or =0.002). The mean maximum supine heart rate increased 2.1 beats/min during sildenafil plus amlodipine treatment and decreased 1.5 beats/min during placebo plus amlodipine treatment (p <0.02). The adverse events in this study were predominantly mild or moderate and did not cause discontinuation of treatment. Adverse events considered to be related to sildenafil treatment included headache, nausea, and dyspepsia. In patients with hypertension who were taking amlodipine therapy, sildenafil produced additive, but not synergistic, reductions in blood pressure. The difference in the mean maximum change from baseline in blood pressure between sildenafil plus amlodipine and placebo plus amlodipine was comparable to the decrease in blood pressure reported for healthy men taking sildenafil alone. (ABSTRACT TRUNCATED)

Candidate genes in complete and partial XY sex reversal: mutation analysis of SRY, SRY-related genes and FTZ-F1.

The sexual phenotype is established in three steps: (1) the sex chromosome constitution; (2) the differentiation of the gonads; and (3) the response of the internal and external genitalia to the hormones produced by the differentiated gonads. Errors that occur at any of these stages can result in defective sexual differentiation. Therefore the investigation of patients with abnormalities of testis development will help elucidate the mechanisms of sex determination and gonadal differentiation. It was in this way that SRY. the primary testis determining gene was identified. De novo mutations in SRY, result in gonadal dysgenesis by disrupting the DNA-binding activity of the SRY protein. However, only 20% of cases of gonadal dysgenesis, are explained by mutations in SRY or its flanking sequences. Therefore, there are several pieces to this puzzle yet to be discovered and it is hoped that mutation analysis of other genes implicated in gonadal development and differentiation may shed some light on aetiology of gonadal dysgenesis in the remaining 80% of cases.

A comparison of the pharmacokinetics of meropenem after intravenous administration by injection over 2, 3 and 5 minutes.

The pharmacokinetics of meropenem were determined in 9 healthy volunteers after the administration of 1 g dose by injection over 2, 3 or 5 min. Peak plasma concentrations were not significantly different across the three rates of administration and, due to the finite time required for complete mixing of the blood in the central compartment, did not always occur at the end of the injection. Overall exposure to meropenem was unchanged by the more rapid rates of administration. Plasma clearance, terminal half-life and volume of distribution were virtually unchanged. Within 10 min after the start of the injection, the plasma concentrations from all three injections were very similar indicating that dosing over 2, 3 or 5 min would result in similar antimicrobial cover and, therefore, comparable efficacy. Comparison of the data derived from the three injections indicated that rapid administration of meropenem did not appreciably alter its disposition pharmacokinetics. Tolerability of meropenem was unchanged with the more rapid administration rate.

Effects of frusemide on the urinary excretion of dopamine and 5-hydroxytryptamine in normal man.

The effects of frusemide on the urinary excretion of dopamine and 5-hydroxytryptamine (5-HT) were investigated in eight healthy male subjects in a randomized, placebo-controlled, cross-over study. Frusemide produced the expected rise in urinary dopamine excretion but it did not affect 5-HT excretion when compared with placebo. The lack of an effect on 5-HT excretion in man contrasts with studies in the rat which have reported a marked increase in 5-HT excretion after administration of this loop diuretic.

gamma-L-glutamyl-5-hydroxy-L-tryptophan, but not gamma-L-glutamyl-L-tryptophan, causes sodium retention in normal man.

1. This randomized, placebo-controlled, cross-over study compared the relative effectiveness of gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP) and gamma-L-glutamyl-L-tryptophan (glu-TRP) in terms of their ability to act as substrates for renal 5-hydroxytryptamine (5-HT) synthesis and their actions on urinary sodium excretion. 2. Urinary excretion of 5-HT and sodium were determined before, during and after 1 h intravenous infusion of an equimolar amount (45 nmol kg-1 min-1) of glu-5-HTP or glu-TRP or placebo in nine healthy male subjects. 3. Cumulative urinary 5-HT excretion over the 4 h after the start of glu-5-HTP infusion was 350-fold greater than that after placebo, and this was associated with a reduction in the urinary excretion of sodium. 4. In contrast, the urinary excretion values of 5-HT and sodium after administration of glu-TRP were not significantly different from those observed on the placebo day. 5. The marked increase in urinary 5-HT excretion and the retention of sodium after administration of glu-5-HTP have been demonstrated in previous studies and result from increased intrarenal generation of 5-HT. The absence of a rise in urinary excretion of 5-HT after glu-TRP infusion suggests that there was no significant conversion of this glutamyl compound to 5-HT within the kidney. As a result, there was no effect on urinary sodium excretion.

Renal metabolism and effects of the glutamyl derivatives of L-dopa and 5-hydroxytryptophan in man.

1. Equimolar amounts of gamma-L-glutamyl-L-3,4-dihydroxyphenylalanine (gludopa) and gamma-L-glutamyl-5-hydroxy-L-tryptophan were infused separately and together in eight healthy, salt-replete male subjects in a placebo-controlled, cross-over study to investigate whether the administration of one amine precursor affects the renal metabolism of the other and to determine whether dopamine or 5-hydroxytryptamine would be generated preferentially. The overall effect on sodium excretion was also measured when both precursors were administered simultaneously. 2. Administration of gludopa was associated with marked increases in the urinary excretion of L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid, together with a rise in the urinary excretion of sodium. gamma-L-Glutamyl-5-hydroxy-L-tryptophan, on the other hand, produced marked increases in the urinary excretion of 5-hydroxy-L-tryptophan, 5-hydroxy-tryptamine and 5-hydroxyindoleacetic acid, and this was accompanied by a slight, but non-significant, reduction in sodium excretion. About 27% of the infused dose of gludopa (on a molar basis) was recovered in the urine as dopamine whereas 15% of the given dose of gamma-L-glutamyl-5-hydroxy-L-tryptophan was excreted as 5-hydroxytryptamine. 3. The urinary excretion values of L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid after the simultaneous infusion of gludopa and gamma-L-glutamyl-5-hydroxy-L-tryptophan were not significantly different from those observed after infusion of gludopa only. Similarly, the urinary excretion values of 5-hydroxy-L-tryptophan, 5-hydroxytryptamine and 5-hydroxy-indoleacetic acid during the co-infusion were similar to those measured after administration of gamma-L-glutamyl-5-hydroxy-L-tryptophan only. The net effect of the concomitant infusion of both glutamyl derivatives was an increase in urinary sodium excretion. 4. Our study in salt-replete individuals suggests that dopamine rather than 5-hydroxytryptamine was preferentially produced when equimolar amounts of their precursors were provided and that the natriuretic effect of dopamine, generated intrarenally from gludopa, was greater than the sodium retaining action of 5-hydroxytryptamine derived from gamma-L-glutamyl-5-hydroxy-L-tryptophan. Comparison of the urinary metabolite data after the separate and concomitant infusion of the two glutamyl compounds provided no evidence of competitive inhibition of synthesis of either amine.

Blood and urine 5-hydroxytryptophan and 5-hydroxytryptamine levels after administration of two 5-hydroxytryptamine precursors in normal man.

Six healthy male subjects received equimolar amounts of two 5-hydroxytryptamine (5-HT) precursors, 5-hydroxy-L-tryptophan (5-HTP) and gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), on two occasions in a randomised cross-over study. There were marked increases in urinary 5-HTP and 5-HT excretion after infusion of both compounds. Mean urinary excretion rate of 5-HT, which was < 0.7 nmol min-1 before dosing, rose to a peak value of 412 +/- 92 nmol min-1 at the end of 5-HTP infusion and 303 +/- 29 nmol min-1 after administration of glu-5-HTP. This occurred without significant changes in blood 5-HT levels measured in platelet-rich plasma. These findings provide further evidence that the increase in urine 5-HT after administration of both 5-HT precursors is largely due to 5-HT synthesised within the kidney.

Effect of coffee and cigarette smoking on the blood pressure of patients with accelerated (malignant) hypertension.

There is a strong association between cigarette smoking and accelerated hypertension. In mild hypertension smoking cigarettes has a distinct pressor effect and caffeine a small but more prolonged pressor action. Coffee and cigarette smoking together have an additive effect on blood pressure (BP). We have examined the interaction of cigarette smoking and drinking coffee on the BP of six patients who presented with accelerated hypertension (mean BP 240/140 mm Hg) and were heavy smokers and caffeine users. After initial control of the BP, the effects of smoking alone, coffee plus smoking, and placebo were examined in a balanced cross-over study. Baseline BP averaged 154/91 mm Hg and remained stable for 90 min after abstention from smoking and caffeine (placebo). Cigarette smoking without caffeine caused a modest rise in BP (mean 9/8 mm Hg), but the combination of coffee plus cigarette smoking caused a progressive increase in BP to an average 21/17 mm Hg (P < 0.05/P < 0.002) higher than placebo values. The effect of coffee was significantly additive to that of smoking alone. Smoking plus coffee ingestion shifted the BP from acceptable (155/94 mm Hg) to poor control (175/107 mm Hg). This pressor effect was observed despite treatment, and with amounts of caffeine and cigarettes which were in no way unusual for these patients. We propose that the association of cigarette smoking with accelerated hypertension may reflect an extreme pressor effect of combined smoking and caffeine use in some patients.

The antinatriuretic action of gamma-L-glutamyl-5-hydroxy-L-tryptophan is dependent on its decarboxylation to 5-hydroxytryptamine in normal man.

1. The effects of inhibition of peripheral aromatic L-amino acid decarboxylase during infusion of the relatively renally selective 5-hydroxytryptamine (5-HT) prodrug, gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), were examined in eight healthy male subjects in a randomised, placebo-controlled, cross-over study. 2. Each subject received oral carbidopa (100 mg) or placebo followed, 1 h later, by a 60 min intravenous infusion of glu-5-HTP (16.6 micrograms kg-1 min-1) or placebo. 3. After administration of glu-5-HTP, cumulative urinary excretion of 5-HT was 430-fold greater than that after placebo, and was associated with a period of sodium retention. 4. Pretreatment with carbidopa substantially attenuated the increase in 5-HT excretion after glu-5-HTP and abolished its antinatriuretic effect. 5. These results are in keeping with the proposition that the antinatriuretic action of glu-5-HTP is dependent on its decarboxylation to 5-HT.

Atrial natriuretic peptide levels in the sleep apnoea/hypopnoea syndrome.

BACKGROUND: Patients with the sleep apnoea/hypopnoea syndrome have increased salt and water excretion at night which has been reported to be associated with an increase in plasma levels of atrial natriuretic peptide (ANP). A study was performed to determine whether any rise in plasma ANP levels was related to nocturnal hypoxaemia. METHODS: Nine patients with sleep apnoea/hypopnoea syndrome were studied on two nights, one breathing air and the other 28% oxygen, the order being randomised. Venous levels of ANP, aldosterone, and renin activity were measured. RESULTS: No decrease in plasma ANP levels on oxygen was seen, and, indeed, there was no evidence of an overnight increase in ANP levels. CONCLUSION: Oxygen therapy does not diminish nocturnal plasma ANP levels in patients with sleep apnoea/hypopnoea syndrome.

A comparison of the renal and neuroendocrine effects of two 5-hydroxytryptamine renal prodrugs in normal man.

1. The effects of 1 h intravenous infusions of equimolar amounts (45 nmol min-1 kg-1) of two putative 5-hydroxytryptamine renal prodrugs, 5-hydroxy-L-tryptophan and gamma-L-glutamyl-5-hydroxy-L-tryptophan, were investigated in a randomized, placebo-controlled, cross-over study in nine healthy male subjects. 2. Cumulative urinary 5-hydroxytryptamine excretion over the 3 h observation period rose by about 370-fold after 5-hydroxy-L-tryptophan and 390-fold after gamma-L-glutamyl-5-hydroxy-L-tryptophan when compared with placebo infusion. Urinary 5-hydroxy-L-tryptophan excretion was three times higher after administration of gamma-L-glutamyl-5-hydroxy-L-tryptophan than after 5-hydroxy-L-tryptophan infusion. Urinary 5-hydroxyindole-3-acetic acid excretion after 5-hydroxy-L-tryptophan infusion was significantly greater than that after gamma-L-glutamyl-5-hydroxy-L-tryptophan administration. Urinary dopamine excretion was not affected by either compound when compared with placebo. 3. 5-Hydroxy-L-tryptophan significantly reduced urine flow rate and urinary sodium excretion. gamma-L-Glutamyl-5-hydroxy-L-tryptophan was antinatriuretic but did not affect urine output. These changes occurred without significant alterations in effective renal plasma flow and glomerular filtration rate. 4. Both 5-hydroxy-L-tryptophan and gamma-L-glutamyl-5-hydroxy-L-tryptophan significantly increased plasma aldosterone concentration without a concomitant rise in plasma renin activity.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of the effects of two putative 5-hydroxytryptamine renal prodrugs in normal man.

1. The effects of 1 h intravenous infusions of equimolar amounts of two putative 5-hydroxytryptamine (5-HT) renal prodrugs, 5-hydroxy-L-tryptophan (5-HTP, 10 micrograms kg-1 min-1) and gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP, 16.6 micrograms kg-1 min-1) were examined in five healthy male volunteers in a randomised, placebo-controlled, cross-over study. 2. Both compounds increased urinary excretion of 5-HT and there was greater extra-renal formation of 5-HT following 5-HTP administration than after glu-5-HTP. 3. Glu-5-HTP was significantly antinatriuretic. 5-HTP reduced mean urinary sodium excretion but this effect was not statistically significant. 4. 5-HTP, but not glu-5-HTP, significantly increased plasma aldosterone. There was no increase in plasma renin activity with either compound. 5. There were no significant changes in pulse rate or blood pressure. Two subjects complained of nausea at the end of 5-HTP infusion but none had any adverse reactions with glu-5-HTP. 6. The results of this study suggest that both prodrugs generate 5-HT in man and that glu-5-HTP is antinatriuretic. The glutamyl derivative may have greater renal specificity than 5-HTP and, as a result, causes less systemic side effects.

The concentration-dependent disposition of intravenous p-aminohippurate in subjects with normal and impaired renal function.

1. The disposition and kinetics of p-aminohippuric acid (PAH) were studied in 27 healthy male volunteers, 10 healthy female volunteers and 10 patients with chronic renal impairment following rapid intravenous injection of 10 mg kg-1. In addition, the renal clearances of PAH and its metabolite N-acetyl-PAH were measured in 10 of the healthy male volunteers following conventional administration of PAH by loading dose and constant infusion, and in another eight during sequential 'step-up' and 'step-down' infusions intended to maintain low, medium and high plasma concentrations below the threshold for onset of saturation of tubular transport. 2. PAH was eliminated rapidly with a mean half-life of less than 30 min in the healthy volunteers and 72 min in the renal patients. The corresponding estimates for acetyl-PAH were 49 and 153 min. In both groups the rate of disappearance of PAH slowed progressively over the period of observation and there was no true log-linear terminal elimination phase. 3. In the healthy volunteers about 50% of the dose was excreted in the urine in 30 min with quantitative recovery in 3 h. In 8 h, 17% of the dose was recovered as acetyl-PAH. In the patients with renal impairment the 8 h recovery was only 83.6% of the dose with 26.9% of the total appearing as acetyl-PAH. 4. The volume of distribution (Vss) of PAH was 16-18 l in the healthy subjects and renal patients. Acetyl-PAH appeared to have a much larger distribution volume (mean 65.5 l in the healthy volunteers). 5. In the healthy volunteers the renal clearance of PAH fell dramatically from 599 +/- 115 ml min-1 1.73m-2 during the first hour after administration to 300 +/- 208 ml min-1 1.73 m-2 during the second hour (P < 0.001). The corresponding renal clearances of acetyl-PAH were 775 +/- 196 and 916 +/- 212 ml min-1 1.73 m-2. In the patients with renal impairment the renal clearance of PAH fell from 194 +/- 83 ml min-1 1.73 m-2 in the first hour to only 61 +/- 19 ml min-1 1.73 m-2 from 4 to 6 h. Over the same period there was no significant fall in the clearances of acetyl-PAH or total PAH (acetyl-PAH + PAH).(ABSTRACT TRUNCATED AT 400 WORDS)

Lithium pretreatment affects renal and systemic responses to angiotensin II infusion in normal man.

1. Renal and systemic responses to infusion of angiotensin II (1.25 and 2.5 ng min-1 kg-1 body weight) were examined in ten normal males 12 h after single doses of 750 mg of lithium carbonate, 250 mg of lithium carbonate (n = 6) or placebo. 2. Baseline mean arterial pressure [mean (SEM)] was higher after 750 mg of lithium [93.1 (1.7) versus 89.5 (1.9 mmHg, P = 0.014], and the subsequent rise in blood pressure during angiotensin II infusion was lower [8.2 (1.8) versus 12.2 (2.4) mmHg, P less than 0.02]. 3. Lithium at a dose of 750 mg increased overnight urinary sodium excretion before the study. The fall in fractional sodium excretion during angiotensin II infusion was reduced after pretreatment with 750 mg of lithium [750 mg of lithium, 2.73 (0.24) to 1.34 (0.08)%; placebo, 2.69 (0.26) to 1.01 (0.11)%; P = 0.02]. The increases in effective filtration fraction [750 mg of lithium, 5.4 (1.0)%; placebo, 8.6 (0.7)%; P less than 0.05] and total effective renal vascular resistance [750 mg of lithium, 3700 (390) dyn s cm-5; placebo 5100 (460) dyn s cm-5; P = 0.03] during angiotensin II infusion were also attenuated after 750 mg of lithium. Responses after 250 mg of lithium did not differ from those after placebo. 4. The fall in plasma renin activity and the increase in plasma aldosterone concentration during angiotensin II infusion were similar on each study day. 5. Renal responses to exogenous angiotensin II are altered after pretreatment with a 750 mg dose of lithium in normal man. This dose of lithium is not an inert marker of sodium handling.

Influence of assay methods on serum concentrations of digoxin during FAB fragment treatment.

The treatment of digoxin intoxication has been revolutionized by digoxin specific antibody fragments (Fab). Serum digoxin concentrations may be inaccurate after this treatment. We report a case of digoxin intoxication where the results of serum concentration determinations were strikingly disparate depending on the assay used. To investigate this discrepancy we compared serum samples spiked with digoxin from 0-50 ng/mL in the presence of increasing concentrations of digoxin specific Fab-fragments. Samples were measured using the Abbott TDx assay with and without ultrafiltration of the sample and the Dade-Stratus radial partition assay. The TDx assay was statistically reduced by the Fab-fragments although the magnitude of the effect was small. The radial partition assay was dramatically affected by the addition of Fab-fragments. The predicted non-Fab bound concentration correlated highly with the measured concentration. When samples were ultrafiltered prior to TDx assay, the measured concentration was dramatically depressed but the regression of predicted non-Fab bound concentration versus observed had a significantly lower slope than for the radial partition assay. We hypothesize that this difference is due to serum protein binding in addition to Fab-fragment binding. We conclude that the radial partition assay gives the best approximation of digoxin concentration remaining unbound to Fab-fragments. Ultrafiltration followed by TDx assay gives an acceptable approximation.

Caffeine restriction: effect on mild hypertension.

OBJECTIVE: To determine the effects on blood pressure of modifying dietary caffeine intake in patients with mild and borderline hypertension by monitoring ambulatory and clinic blood pressure. DESIGN: Four way, randomised, crossover trial of four consecutive two week dietary regimens: normal diet, caffeine free diet alone, caffeine free diet with decaffeinated instant coffee, caffeine free diet with caffeinated instant coffee (instant coffee phases conducted double blind). SETTING: Hospital hypertension clinic, Scotland. PATIENTS: 52 patients (23 men; aged 26-67 years) with untreated borderline or mild hypertension (diastolic blood pressure 90-105 mm Hg) who normally drank a minimum of three cups of coffee daily. MAIN OUTCOME MEASURES: Mean ambulatory blood pressure over 24 hours; mean morning, daytime, and night time ambulatory blood pressure; sitting clinic blood pressure at 1700; plasma caffeine concentration at 1700 on the last day of each regimen. RESULTS: Mean 24 hour ambulatory blood pressure was not different between regimens. There was no difference in blood pressure variability between regimens. During the caffeine free diet alone morning ambulatory diastolic blood pressure was higher (2.8 mm Hg) than during the caffeine free diet with caffeinated coffee. Mean sitting clinic systolic blood pressure was higher at 1700 (4.7 mm Hg) with a caffeine free diet than with the caffeine free diet with caffeinated coffee (p less than 0.05). Dietary compliance as assessed by plasma caffeine concentration was excellent. There was no significant correlation between plasma caffeine concentration and blood pressure. CONCLUSIONS: Drinking caffeinated instant coffee over a two week period does not adversely influence blood pressure in patients with borderline or mild hypertension; abstinence is of no benefit.