Combination therapy with indinavir, ritonavir, and delavirdine and nucleoside reverse transcriptase inhibitors in patients with HIV/AIDS who have failed multiple antiretroviral combinations.

PURPOSE: Ritonavir (RTV) and delavirdine (DLV) are inhibitors of cytochrome P450 (CYP) 3A4, the specific CYP that metabolizes indinavir (IDV). We hypothesized that patients who have failed multiple therapies containing protease inhibitors would still respond to IDV if high plasma concentrations were achieved. We retrospectively examined the antiviral efficacy of the combination of RTV, DLV, and IDV in heavily antiretroviral-experienced patients. METHOD: A chart review of patients treated with IDV/RTV/DLV and two nucleoside reverse transcriptase inhibitor (NRTI) drugs was performed. Only patients who failed at least three highly active antiretroviral therapy (HAART) regimens and remained on IDV/RTV/DLV therapy for at least 2 months were included. Plasma concentrations for IDV and RTV were obtained if patients were still on therapy. RESULTS: Ten participants were identified who qualified for this study. The median plasma HIV RNA prior to initiating IDV/RTV/DLV was 359,300 copies/mL. Nine of the 10 patients had failed nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens in the past. Eight out of 10 patients had at reduction in HIV RNA. Four of eight patients maintained the 1 log(10) reduction in HIV RNA past 6 months. Mean CD4 cell count increased from 142+/-99 to 273+/-126 cells/mm(3). Genotypic data available on six patients showed multiple protease gene mutations. Plasma concentration of IDV in three patients (two troughs and one 7 hours postdose) were >1,000 ng/mL. CONCLUSION: Our data suggests that in heavily antiretroviral drug-treated patients, partial antiretroviral response to RTV/IDV/DLV can still be achieved. The use of IDV/RTV/DLV and two NRTIs as salvage therapy has merit in patients who have no viable treatment options. A prospective trial utilizing this drug combination is warranted.

Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401.

UNLABELLED: The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV-infected, methadone-using study subjects. DESIGN: A 24-hour methadone pharmacokinetic study was performed before antiretroviral therapy was begun and after 15 days of therapy. Methadone concentration was measured by a chiral plasma assay because the drug is administered as a racemic mixture of R- and S-methadone, but only the R-isomer is active. Both changes in plasma protein binding and changes in objective and subjective opioid effect were monitored. RESULTS: Ritonavir/saquinavir administration was associated with 40% decrease in total S-methadone AUC0-24hr and 32% decrease in R-methadone area under the curve (AUC)0-24hr, and both changes were statistically significant (p =.001 for both). When AUC was corrected for the changes in protein binding induced by ritonavir/saquinavir, R-methadone free AUC0-24hr decreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes was statistically significant (p =.129 and p =.0537, respectively). This change in methadone exposure was not associated with any evidence of withdrawal from narcotics and no modification of methadone dose was required. CONCLUSIONS: Our data indicate that ritonavir/saquinavir administration is associated with induction of metabolism of methadone but this is greater for the inactive S-methadone. However, approximately 37% of the decrease in the total R-methadone exposure can be explained by protein binding displacement. Ritonavir/saquinavir can be used in HIV-infected people taking methadone without routine dose adjustments.

Delavirdine: clinical pharmacokinetics and drug interactions.

Delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a potent and specific inhibitor of HIV-1 reverse transcriptase. The approved therapeutic regimen for delavirdine is 400mg 3 times daily in combination with appropriate antiretroviral agents; however, a dose of 600mg twice daily appears to provide similar systemic exposure. The steady-state pharmacokinetics of delavirdine are not appreciably affected by food. Delavirdine undergoes extensive metabolism by cytochrome P450 (CYP) with little urinary excretion of unchanged drug. Metabolic drug interactions between delavirdine and nucleoside reverse transcriptase inhibitors are unlikely as their metabolic pathways differ; delavirdine has no effect on the pharmacokinetics of zidovudine. Concomitant use of CYP inducers, such as rifampicin (rifampin), rifabutin, phenytoin, phenobarbital or carbamazepine, should be avoided since delavirdine plasma concentrations are significantly lowered. Reduction in gastric acidity (pH > 3) decreases the extent of delavirdine absorption, so administration of antacids and the buffered formulations of didanosine should be separated from that of delavirdine by at least 1 hour. Delavirdine, unlike other currently available NNRTI agents, is an inhibitor rather than an inducer of CYP isozymes. Consequently, the drug interaction profile and rationale for combining delavirdine with other antiretroviral agents is unique among the current NNRTI agents. Delavirdine inhibits the CYP3A4-mediated metabolism of HIV protease inhibitors and thereby increases systemic exposure to protease inhibitors. The ability of delavirdine to enhance the pharmacokinetic profiles of protease inhibitors may permit the use of simplified administration regimens. Combining delavirdine and indinavir removes the food restrictions during indinavir administration. Furthermore, the superior virological response observed in antiretroviral regimens containing delavirdine and protease inhibitors has been attributed to the favourable pharmacokinetic interactions and the introduction of a new drug class in NNRTI-naïve therapy-experienced patients. Pharmacokinetic drug interactions are an important consideration in selecting an HIV treatment regimen, due to the multiplicity of drugs that are coadministered and the varying direction and magnitude of interaction that can occur. Considerations for utilising delavirdine in a treatment regimen are different than for other NNRTI agents due to the unique drug interaction profile of delavirdine.

Indinavir, nevirapine, stavudine, and lamivudine for human immunodeficiency virus-infected, amprenavir-experienced subjects: AIDS Clinical Trials Group protocol 373.

This prospective, multicenter, open-label study was designed to determine the antiretroviral activity and safety of a 4-drug regimen: 1000 mg indinavir every 8 h with 200 mg nevirapine, 40 mg stavudine, and 150 mg lamivudine, each given twice daily in amprenavir-experienced subjects. The primary end points of the study were the human immunodeficiency virus (HIV) RNA level and CD4 cell count responses. Fifty-six subjects were enrolled and were changed from amprenavir-containing regimens to the 4-drug regimen. Overall, at week 48, 33 (59%) of 56 subjects had HIV RNA levels <500 copies/mL (intent-to-treat analysis, where missing values equal > or =500 copies/mL) and CD4 cell counts increased by 94 cells/mm(3) from baseline. Subjects who had previously taken amprenavir combination therapy were more likely to experience virologic failure than those who had taken amprenavir monotherapy (odds ratio, 7.7; P=.0012). In this study, most subjects who had taken amprenavir-based regimens and who changed to a 4-drug regimen achieved subsequent durable virologic suppression.

Using pharmacokinetics to optimize antiretroviral drug-drug interactions in the treatment of human immunodeficiency virus infection.

Better understanding of the pharmacokinetics of antiretroviral drugs has resulted in the design of combination therapies for the treatment of human immunodeficiency virus (HIV) infection. This has improved the bioavailability and prolonged the plasma half-life of some of the drugs, resulting in enhanced antiviral activity. However, antiviral combination therapy can also result in adverse drug-drug interactions and diminished antiretroviral activity. In this review, we examine drug interactions involving combinations of protease inhibitors, combinations of protease inhibitors with nonnucleoside reverse transcriptase inhibitors, and combinations of nucleoside analogues for the treatment of patients with HIV infection. We discuss examples and mechanisms of pharmacokinetic interactions that improve or decrease antiviral efficacy.

Advances in HIV/AIDS therapy.

Advances in HIV/AIDS therapy have been rapid and profound. An improved understanding of HIV pathogenesis has demonstrated the need for aggressive antiretroviral therapy in most persons with HIV infection. Combinations of at least three drugs are necessary to fully suppress viral replication. Suppression of viral replication prevents the development of drug resistance and allows immune reconstitution to occur. Current therapies do have limitations including side effects, cross-resistance, adherence challenges, and drug interactions. However, most patients have derived great benefit from these therapies. The consequences of immune reconstitution have included resolution of existing opportunistic infections and a markedly reduced risk of new infections. In certain settings, immune reconstitution may allow the discontinuation of opportunistic infection prophylaxis or treatments. The net result has been a substantial improvement in the quality and quantity of life for HIV-infected patients.

The effect of increasing alpha1-acid glycoprotein concentration on the antiviral efficacy of human immunodeficiency virus protease inhibitors.

The effect of a 4-fold increase in alpha1-acid glycoprotein (AGP) on the antiviral efficacy of 5 human immunodeficiency virus (HIV) protease inhibitors (PIs) was examined by the effect of HIV PIs on p24 production in peripheral blood mononuclear cells infected with protease wild-type and PI-resistant HIV isolates. For wild-type virus, the efficacy of the PIs at trough concentrations was unaffected by a 4-fold increase in AGP. With the partially HIV PI-resistant isolate, a 4-fold increase in AGP resulted in 2%, 30%, 37%, 37%, and 42% loss of activity for indinavir, saquinavir, nelfinavir, ritonavir, and amprenavir, respectively. The high-level HIV PI-resistant isolate had a greater loss in activity. The change in IC50 secondary to the addition of AGP was the greatest for ritonavir, nelfinavir, and amprenavir and lowest for indinavir. These data suggest that the target plasma concentration for the highly bound HIV PIs may need to be raised in subjects with elevated AGP who harbor partially PI-resistant isolates.

Lack of an effect of age on beta-adrenoceptor-mediated lipolysis in isolated human adipocytes.

We examined the effect of age on the beta-adrenoceptor response in adipocytes that contain both beta 1- and beta 2-adrenoceptors. Twelve healthy young and 12 old subjects on a 150 mEq/24 h sodium diet underwent gluteal fat biopsies. Isolated adipocytes from all the subjects were stimulated with increasing concentrations of isoproterenol for glycerol release. In 13 of the subjects (7 young and 6 old), we also performed beta-adrenoceptor binding studies on adipocyte membranes. In addition in eight subjects (four young and four old), we also utilized a competitive binding assay to calculate the percent of beta-adrenoceptors that were of the beta 1 subtype. Our data showed that old subjects, when treated under identical conditions as the young subjects prior to fat biopsy, did not demonstrate any differences in the beta-adrenoceptor stimulated lipolysis. The Vmax of lipolysis was 10.6 +/- 1.4 nmoles glycerol/mg lipid/2 h in the young group and 9.9 +/- 1.1 in the old group. The concentrations of isoproterenol that resulted in Vmax and 1/2 Vmax were also the same in the two age groups. The addition of 8-cyclopentyl-1,3-dimethylxanthine (CPT), a specific A1-adenosine receptor antagonist, resulted in mild but equivalent enhancement of glycerol release in both age groups. The beta-adrenoceptor numbers and affinities from adipocyte membranes did not demonstrate age-related differences either (Bmax 106 +/- 17 fmol/mg of protein in the young, and 137 +/- 27 in the old; Kd 79.6 +/- 21.3 pM in the young and 81.9 +/- 16.6 in the old). The percent of beta 1-adrenoceptors on the adipocyte membranes was also similar in the two age groups (35.2 +/- 2.6% in the young; 37.1 +/- 4.5% in the old). In conclusion, we could not demonstrate any differences in the beta-adrenoceptor responses from peripheral adipocytes that contain both beta 1- and beta 2-adrenoceptors, in a group of healthy elderly and young subjects who were subjected to identical dietary and orthostatic conditions prior to the biopsy. These data suggest that neither beta 1- nor beta 2-adrenoceptor responses in human adipocytes show significant changes due to aging.

Treatment with amprenavir alone or amprenavir with zidovudine and lamivudine in adults with human immunodeficiency virus infection. AIDS Clinical Trials Group 347 Study Team.

Amprenavir is a human immunodeficiency virus (HIV) protease inhibitor with a favorable pharmacokinetic profile and good in vitro activity. Ninety-two lamivudine- and protease inhibitor-naive individuals with >/=50 CD4 cells/mm3 and >/=5000 HIV RNA copies/mL were assigned amprenavir (1200 mg) alone or with zidovudine (300 mg) plus lamivudine (150 mg), all given every 12 h. After a median follow-up of 88 days, the findings of a planned interim review resulted in termination of the amprenavir monotherapy arm. Among 85 subjects with confirmed plasma HIV RNA determination, 15 of 42 monotherapy versus 1 of 43 triple-therapy subjects had an HIV RNA increase above baseline or 1 log10 above nadir (P=.0001). For subjects taking triple therapy at 24 weeks, the median decrease in HIV RNA was 2.04 log10 copies/mL, and 17 (63%) of 27 evaluable subjects had <500 HIV RNA copies/mL. Treatment with amprenavir, zidovudine, and lamivudine together reduced the levels of HIV RNA significantly more than did amprenavir monotherapy.

Influence of age on arterial baroreflex inhibition of sympathetic nerve activity in healthy adult humans.

Resting levels of muscle sympathetic nerve activity (MSNA) increase markedly with age in healthy adult humans. An age-related reduction in arterial baroreflex inhibition of MSNA could contribute to these elevations. To test this hypothesis, we measured MSNA using peroneal microneurography in young (age, 25 +/- 1 yr; n = 8) and older (69 +/- 1 yr; n = 7) healthy normotensive men before (baseline control) and during graded constant infusion of phenylephrine hydrochloride (0.5-2.0 microgram . kg-1. min-1) that produced a sustained approximately 10-mmHg increase in arterial blood pressure. Central venous pressure was controlled at baseline levels (+/-1 mmHg) using lower body negative pressure. Resting MSNA was approximately 95% higher in the older compared with the young subjects (43 +/- 5 vs. 22 +/- 3 bursts/min; P < 0.05). However, arterial baroreflex MSNA inhibitory responsiveness was similar in the older compared with the young subjects (254 +/- 112 vs. 259 +/- 40 arbitrary integration units/mmHg, respectively), although the percent reduction in MSNA was smaller in the older men (8.9 +/- 0.7 vs. 5.2 +/- 1.1%/mmHg), due to their elevated baseline levels. The reflex increase in the R-R interval was not different in the two groups (13 +/- 10 vs. 16 +/- 7 ms/mmHg). In summary, our findings suggest that arterial baroreflex inhibition of MSNA is preserved with age in healthy normotensive adult humans. As such, this mechanism does not appear to contribute to the age-related rise in tonic MSNA.

The effect of adenosine on the reduced heart rate response to exercise in the elderly.

BACKGROUND: In a previous study we demonstrated that excessive endogenous adenosine production and/or response was responsible for the blunted tachycardia to bolus intravenous doses of isoproterenol in the elderly. In this study, we tested the hypothesis that excessive endogenous adenosine may also be responsible for the diminished maximal tachycardia with aging. METHODS: Twelve young (mean age 27.3 +/- .61 yr) and 12 older (mean age 66.8 +/- .9 yr) healthy men were asked to perform maximum exercise tests in the presence of placebo or theophylline at plasma concentrations between 15-20 micrograms/ml. Heart rate, oxygen consumption, and respiratory gas exchange ratio were continuously monitored and recorded during the exercise. In addition, plasma lactate, glycerol, renin activity, and catecholamines were measured before and after maximal exercise. RESULTS: Maximum heart rate to exercise was higher in the young (190 +/- 3 bpm in the young, 157 +/- 2 bpm in the old) and increased by 4.5 +/- 1.2 bpm in the young and 9.8 +/- 2.6 bpm in the old with the administration of theophylline that resulted in an equivalent serum concentration in the two age groups. This age difference in the increase was not significant but approached significance at a p value of .07. Maximum VO2 was also greater in the young group and this was unaffected in both groups by theophylline administration. The increase in serum lactate and plasma renin activity (PRA) to exercise was higher in the young group both in the presence and absence of theophylline. CONCLUSIONS: Our data could not identify excessive adenosine in the older group as the cause of diminished maximal exercise heart rate with aging. It is likely that the diminished chronotropic response to exercise in the older humans is due to a mechanism intrinsic to the cardiac excitatory tissue.

Neither dapsone hydroxylation nor cortisol 6beta-hydroxylation detects the inhibition of CYP3A4 by HIV-1 protease inhibitors.

OBJECTIVE: This study examined the use of dapsone N-hydroxylation and cortisol 6beta-hydroxylation, well accepted in vivo probes of cytochrome P4503A4 (CYP3A4) activity, on defining the effect of three HIV protease inhibitors on CYP3A4 activity. METHODS: Subjects from University Hospital Infectious Disease Clinic about to be started on indinavir, and subjects from two clinical studies, one using ritonavir and the other using amprenavir, were recruited to participate in the study. Subjects received dapsone 100 mg p.o. followed by an 8-h urine collection for dapsone, dapsone N-hydroxylamine, cortisol, and 6beta-hydroxycortisol concentrations before HIV protease inhibitor administration, and 3 4 weeks into receiving HIV protease inhibitors. RESULTS: None of the HIV protease inhibitors demonstrated statistically significant alterations in dapsone recovery ratio and 6beta-hydroxycortisol/cortisol ratio. In fact, with ritonavir, the dapsone recovery ratio tended to increase rather than decrease, suggesting induction. These negative results were found despite evidence of CYP3A4 inhibition by these three HIV protease inhibitors via published drug-drug interactions with drugs that are substrates for CYP3A4. CONCLUSIONS: These in vivo assays used to probe CYP3A4 activity are suboptimal, most likely because of the presence of extrahepatic sites of metabolism for both dapsone and cortisol, and multiple CYP isozymes involved in dapsone N-hydroxylation.

Effect of adenosine and histamine receptor stimulation on canine histamine release to pentagastrin.

The effects of adenosine and histamine 2 and histamine 3 receptor agonists on the regulation of gastric histamine release were examined in anesthetized mixed-breed dogs. All compounds were infused directly into the gastrosplenic artery to avoid perturbations in systemic hemodynamics, and the gastric histamine release was stimulated with pentagastrin. The histamine concentration in plasma samples was measured utilizing gas chromatography-negative-ion chemical ionization mass spectroscopy. Pentagastrin consistently stimulated gastric histamine release with the peak stimulation occurring at 5 min, while neither 30 nor 100 microM of adenosine altered the effect of pentagastrin on histamine release. In addition, theophylline at 20 microg/ml exhibited no effect on stimulated histamine release. The histamine 2 receptor agonist dimaprit, at 1 and 3 microM, attenuated pentagastrin-stimulated histamine release at the 5-min time period, but the difference was not sustained at later time points (histamine release from 1.4 +/- 0.6 to 92 +/- 18 ng/min at 5 min with pentagastrin alone; from 1.2 +/- 0.5 to 32 +/- 11 ng/min with pentagastrin plus 1 microM dimaprit, and from 2.0 +/- 1.1 to 32 +/- 9 ng/min with pentagastrin plus 3 microM dimaprit), while the H2 receptor antagonist cimetidine exhibited no effect on pentagastrin-stimulated histamine release. The histamine 3 receptor agonist (R)-alpha-methylhistamine attenuated the pentagastrin-stimulated histamine release at the 5- and 10-min time periods only at 1 microM without showing any effect at the higher (3 microM) concentration. Thioperamide, a H3 receptor antagonist, did not modify pentagastrin-stimulated histamine release. These data demonstrate that adenosine has no modulatory role on gastric histamine release, but histamine via H2 and H3 histamine receptors could modulate its own release but only to a modest degree as compared with the potent effect of the paracrine hormone somatostatin.

Secretin inhibits canine gastric acid secretion in response to pentagastrin by modulating gastric histamine release.

The effect of secretin on pentagastrin- and gastrin-stimulated gastric histamine release and acid secretion was examined in the anesthetized dog model, where all compounds were infused directly into the artery supplying the gastric corpus. Secretin at an infusion rate of 10 ng/kg/min resulted in approximately 90% inhibition of gastric secretion in response to pentagastrin (20 ng/kg/min), whereas at the physiological postprandial concentration of 40 pg/ml it inhibited gastric secretion by approximately 55%. Gastric acid stimulated by gastrin I at the physiological post-prandial concentration of 150 pg/ml was inhibited by secretin at 40 pg/ml by approximately 80%. Pentagastrin stimulated histamine release to a peak of 168 +/- 34 ng/min, which was inhibited to 14 +/- 8 ng/min with the high concentration of secretin and to 85 +/- 21 ng/min at 40 pg/ml secretin. Gastrin I (150 pg/ml) stimulated histamine release to a peak of 10.6 +/- 4.6 ng/min, which was inhibited to 2.1 +/- 0.5 ng/min by secretin (40 pg/ml). Because secretin has been reported to stimulate gastric somatostatin release, we examined the somatostatin secretory rate concomitant with histamine release. Both doses of secretin stimulated gastric somatostatin release, compared with pentagastrin alone. The present data demonstrate that secretin, even at physiological concentrations, can inhibit gastric acid secretion in response to gastrin/pentagastrin, and one of the mechanisms of inhibition involves modulation of gastric histamine release. This effect of secretin on histamine release may be either direct, at the histamine-containing endocrine cells, or indirect, through somatostatin release.

The effect of beta andrenoceptor stimulation of canine stomach on pentagastrin-stimulated histamine release.

The effect of beta adrenergic agonist isoproterenol, infused directly into the gastrosplenic artery in anesthetized mixed-breed dogs, on pentagastrin-stimulated gastric histamine release was examined to clarify the potential mechanisms by which beta adrenoceptor stimulation results in gastric acid inhibition. Two doses of isoproterenol (3 and 10 ng/kg/min) were infused with pentagastrin; histamine and n(tau)-methyl-histamine concentrations were measured in arterial and gastric venous samples, and their gastric secretory rates were calculated. Both doses of isoproterenol decreased histamine-secretory rate to pentagastrin from a peak of 234 +/- 51.5 ng/min with vehicle to 17.7 +/- 4.2 ng/min with the 3 ng/kg/min dose of isoproterenol and to 8.6 +/- 2.9 ng/min with the 10 nk/kg/min dose of isoproterenol. The change in N(tau)-methyl-histamine-secretory rate paralleled the histamine-secretory rate. Concomitantly with the histamine-secretory rate, the effect of beta adrenoceptor agonist on gastric somatostatin secretion was also examined. The lower dose of isoproterenol stimulated somatostatin-secretory rate from 4.0 +/- 1.8 to 31.8 +/- 10.3 ng/min, and the higher dose of isoproterenol increased somatostatin-secretory rate from 6.0 +/- 3.1 to 61.5 +/- 21.5 ng/min, whereas isoproterenol potentiated pentagastrin-stimulated gastric somatostatin release. These data demonstrate that isoproterenol is a potent inhibitor of pentagastrin-stimulated gastric histamine release, and the mechanism may be related to the concomitant somatostatin release. Thus, the most likely mechanism by which beta adrenoceptor stimulation results in inhibition of gastric acid secretion is through down-regulation of gastric histamine release.

The effect of aging on the pharmacokinetics and pharmacodynamics of prazosin.

OBJECTIVE: The effect of age on the pharmacokinetics and pharmacodynamics of prazosin (alpha 1 adrenoceptor blocker) was studied in 20 healthy volunteers. PATIENTS: Ten elderly (61-81 y) and ten young (23-28 y) subjects were studied. All subjects received 1 mg of prazosin orally in a fasting state. Serial blood samples were collected for calculation of oral pharmacokinetics, and blood pressure and pulse rate were measured during blood collection. Subjects remained supine and fasting for the first three hours post drug administration, after which they were allowed to ambulate and eat. RESULTS: The oral pharmacokinetics of prazosin were not different in the two age groups. The serum t1/2 in the elderly was 210 min while in the young group was 139 min. The AUC(zero)-infinity in the two groups was not different. The Cmax was identical in the two groups, and the time to Cmax was 84 min in the elderly and 114 min in the young subjects. Protein binding was 93.4% in the elderly and 93.5% in the young subjects and the serum alpha 1 acid glycoprotein concentration was not different in the two groups of subjects. Even though the pharmacokinetics of prazosin were unchanged by age, the haemodynamic effects of the drug were greater in the elderly. The fall in systolic blood pressure and mean blood pressure was significantly greater in the elderly group at multiple time points after drug administration while the change in diastolic blood pressure was equivalent in the two age groups. Despite a greater decrease in mean blood pressure in the elderly, the compensatory increase in heart rate was similar in the two age groups suggesting a difference in the baroreceptor reflex in the two age groups. CONCLUSION: The results of this study demonstrate that age does not alter the pharmacokinetics of oral prazosin, but the pharmacodynamic response at equivalent plasma prazosin concentration is greater in the elderly.

The role of gastric histamine release in the acid secretory response to pentagastrin and methacholine in the dog.

We have previously demonstrated that both pentagastrin and methacholine can stimulate histamine release from the canine stomach during short term administration of the secretagogues into the gastrosplenic artery. In this study we tested the hypothesis that gastric histamine release determines the acid secretory response to acid secretagogues. Increasing doses of pentagastrin (2, 6, and 20 ng/kg/min) and methacholine (0.1, 0.3, and 1 micrograms/min) were infused into the gastrosplenic artery in dogs, while gastric acid output, histamine and N tau-methyl histamine secretory rates were monitored. Histamine and N tau-methyl histamine concentrations in plasma were measured using GC/NICI-MS. Increasing doses of pentagastrin resulted in increasing gastric output. Total histamine secretory rate expressed as the sum of histamine and N tau-methyl histamine secretory rate showed a significant increase above basal with the two highest doses of pentagastrin. Regression analysis correlating the dose of pentagastrin to gastric acid output gave a correlation coefficient of 0.586 which was very significant. Regression analysis correlating the total histamine secretory rate to acid output gave a correlation coefficient of 0.498 which was also very significant. Increasing doses of methacholine also resulted in a dose-dependent increase in acid output. Histamine secretory rates showed a statistically significant increase above basal only at the 1 microgram/min infusion rate, however, the total histamine secretory rates (histamine + N tau-methyl histamine) were no longer significant at any of the doses of methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of adenosine in promoting cardiac beta-adrenergic subsensitivity in aging humans.

The mechanism by which aging decreases the cardiac chronotropic response in human subjects is unknown. We investigated the role of endogenous adenosine in attenuating the chronotropic response to beta-adrenoceptor stimulation due to aging by employing the adenosine receptor antagonist, theophylline. Sixteen healthy elderly (67.1 +/- 1.3 yrs) and sixteen healthy young (26.1 +/- 0.6 yrs) subjects were studied. The bolus dose of isoproterenol necessary to increase the heart rate 25 beats per minute (I25) was determined by calculating the log dose response curve before and after a 30-min infusion of theophylline (6.5 mg/kg) in each subject. In addition, the effect of theophylline on the orthostatic increase in plasma renin activity (PRA) was determined. The I25 for the elderly and young groups were 34.55 +/- 6.98 and 10.85 +/- 1.93 ng/kg, respectively (p < .01). After theophylline administration, the difference in I25 in the two groups was no longer present (13.32 +/- 2.72 vs 7.46 +/- 1.26 ng/kg). The dose ratios (I25 after theophylline/I25 before theophylline) in the elderly and young groups were 0.43 +/- 0.06 and 0.82 +/- 0.14, respectively (p < .05). After the administration of theophylline, the orthostatic increase in PRA was enhanced more in the elderly subjects (0.53 +/- 0.23 vs 1.54 +/- 0.35 ng AI/ml/hr; p < .01) than in the young (1.31 +/- 0.23 vs 2.49 +/- 0.53 ng AI/ml/hr; p-value n.s.). Plasma norepinephrine changes after theophylline and postural norepinephrine changes after theophylline were not different in the two age groups. Excessive adenosine production or effect is partly responsible for the cardiac chronotropic resistance to isoproterenol and the diminished postural change in PRA in the elderly.

The hypotensive action of captopril and enalapril is not prostacyclin dependent.

Angiotensin converting enzyme inhibitors have been proposed to have a prostaglandin-dependent component to their hypotensive action. The aim of this study was to assess whether the structurally dissimilar angiotensin converting enzyme inhibitors captopril and enalapril stimulate the synthesis of prostacyclin, whether their hypotensive action is blunted by indomethacin, and whether these biochemical or physiologic parameters differ for the two drugs, in white subjects with essential hypertension. Twelve patients were enrolled and 11 finished the study. The study consisted of a double blind, randomized, double-crossover design. All patients received either placebo or 50 mg indomethacin twice a day for 3 weeks; after 1 week of placebo or indomethacin either 50 mg captopril or 10 mg enalapril twice a day was added and continued for 2 weeks. Each patient received every possible combination. Neither captopril nor enalapril stimulated prostacyclin production as determined by measurement of the urinary excretion rate of its main enzymatic metabolite, 2,3-dinor-6-keto-prostaglandin-F1 alpha. Although indomethacin reduced the urinary excretion of the enzymatic metabolite of prostacyclin by more than 50%, it did not influence the hypotensive effect of captopril or enalapril. We conclude that neither captopril nor enalapril have a significant prostacyclin-dependent component to their hypotensive action.