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PubMed2006

Cancer stem cells in human gastrointestinal cancers.

The concept of cancer stem cell has developed in leukemia. Recently, it has expanded to include solid tumors such as brain or breast tumors. However, the descriptions are not recognized in human gastrointestinal cancers. We used flow cytometry and the DNA-binding dye (Hoechst 33342) to isolate side population (SP) cells from various human gastrointestinal system cancer cell lines. The SP cell fraction is considered to contain abundant stem cells. Fifteen of 16 cancer cell lines from the gastrointestinal system contained 0.3-2.2% SP cells. We studied the characteristics of the SP cells in hepatic or colon cancer cell lines. The results demonstrated that cancers of the gastrointestinal system do contain SP cells that show some characters of so-called stem cells. In this paper, we report our study results with a review of the literature.

ATP-Binding Cassette Transporters↗
PubMed1989

Usefulness of nifedipine for myocardial ischemia and the nifedipine gastrointestinal therapeutic system.

Although conventional treatment of angina pectoris with nifedipine capsules involves frequent daily dosing, a new vehicle for the once-daily delivery of this potent but insoluble calcium channel blocking agent has been developed. With the gastrointestinal therapeutic system (GITS) formulation, constant effective drug levels of nifedipine are delivered for a full 24-hour period. When nifedipine GITS 30, 60 or 90 mg was administered once daily to patients with stable angina pectoris taking beta blockers, clinical effectiveness was demonstrated both by an increase in time to angina and by exercise time compared with placebo. Improvement was noted to be more significant with the higher doses of nifedipine administered once daily. This study indicates that nifedipine GITS provides additional antianginal protection in patients with exercise-induced angina secondary to coronary artery disease who are receiving a fixed dose of beta blocker.

Angina Pectoris↗
PubMed2005

Doxazosin gastrointestinal therapeutic system: a review of its use in benign prostatic hyperplasia.

Doxazosin, a well established treatment in patients with bothersome lower urinary tract symptoms from benign prostatic hyperplasia (BPH), is available in a new controlled-release formulation, doxazosin gastrointestinal therapeutic system (GITS). Doxazosin GITS (Cardura XL, Cardular PP Uro, Diblocin PP Uro) has an altered pharmacokinetic profile, which allows a higher initial dosage to be used than with the standard formulation and less titration steps to reach a clinically effective dosage. In two large, double-blind, randomised studies (one was placebo-controlled) in patients with BPH, doxazosin GITS (4-8 mg once daily) was as effective as the standard formulation (2-8 mg once daily), and both were more effective than placebo, after 13 weeks' treatment in improving symptom scores, health-related quality of life (HR-QOL), and maximum urinary flow rate (Qmax). Doxazosin GITS was at least as well tolerated as the standard formulation of doxazosin in clinical studies in patients with BPH.

Adrenergic alpha-Antagonists↗
PubMed1990

Antihypertensive effectiveness of nifedipine gastrointestinal therapeutic system in the elderly. The Modern Approach to the Treatment of Hypertension (MATH) Study Group.

The Modern Approach to the Treatment of Hypertension (MATH) trial was conducted to determine the therapeutic safety and efficacy of the once-a-day nifedipine gastrointestinal therapeutic system (GITS) formulation in a large and diverse cohort of patients with mild-to-moderate hypertension. One of the goals of the MATH study was to evaluate the clinical utility of nifedipine GITS in elderly hypertensives. This analysis compares the safety and efficacy of nifedipine GITS in elderly patients (greater than or equal to 65 years of age) and nonelderly patients (adults less than 65 years of age). A total of 222 elderly and 933 nonelderly patients from 127 centers were evaluated. Following a 2 week placebo washout phase, patients were titrated over 1 to 6 weeks on nifedipine GITS 30 to 180 mg/day, increasing in 30 mg increments to achieve goal blood pressure, defined as sitting diastolic blood pressure of less than 90 mm Hg and a 10 mm Hg decrease from baseline. Therapy was maintained at the optimal dose for an additional 12 weeks. Hemodynamic and laboratory parameters were assessed at baseline and at the final treatment visit. Baseline parameters were comparable between patient groups except for systolic blood pressure, which was significantly greater in the elderly compared with nonelderly patients (164 +/- 18 v 150 +/- 14 mm Hg, respectively, P less than .0001). After 12 weeks of therapy with nifedipine GITS, sitting and standing systolic and diastolic blood pressure was significantly decreased from baseline for both elderly and nonelderly patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1998

Comparison of effects of controlled onset extended release verapamil at bedtime and nifedipine gastrointestinal therapeutic system on arising on early morning blood pressure, heart rate, and the heart rate-blood pressure product.

We assessed the differential effects of a chronotherapeutic agent (controlled-onset extended release [COER] verapamil), administered at bedtime versus a conventional, homeostatic therapy (nifedipine gastrointestinal therapeutic system [GITS]) taken in the morning, on early morning and 24-hour blood pressure (BP), heart rate (HR), and the HR x systolic BP product. The study was a multicenter (n = 51), randomized, double-blind prospective clinical trial with a 10-week treatment period. Dose titration was performed by study investigators based on systolic and diastolic BP values at the doctor's office. Ambulatory BP monitoring was performed at placebo baseline, after 4 weeks of stable double-blind therapy, and at end of the study. Twenty-four-hour BP profiles were studied in 557 hypertensive patients. Changes in BP, HR, slope of the rate of rise of BP and HR, and the HR-systolic BP product during the 4 hours from 1 hour before to 3 hours after awakening were evaluated. The study was powered to show equivalence between the 2 regimens, predefined as a difference between treatment groups in mean change from baseline in early morning BP of +/- 5 mm Hg systolic and +/- 3 mm Hg diastolic. Changes in the early morning BP fell within the definition of equivalence for the 2 treatment strategies (-12.0/-8.2 mm Hg for COER-verapamil and -13.9/-7.3 mm Hg for nifedipine GITS). Changes in both the early morning HR and rate-pressure product were significantly greater following COER-verapamil therapy versus nifedipine GITS (HR, -3.8 beats/minute vs +2.6 beats/minute, p < 0.001 and HR-systolic BP product, -1,437 beats/min x mm Hg vs -703 beats/min x mm Hg, respectively, p < 0.001). Changes in ambulatory BP demonstrated clinically similar reductions for the awake period, but nifedipine GITS lowered systolic BP to a greater extent than COER-verapamil during sleep (-11.0 vs -5.8 mm Hg, p < 0.001). COER-verapamil and nifedipine GITS had equivalent effects (+/- 5/3 mm Hg) on early morning BP. In addition, both extended-release calcium antagonists effectively lowered 24-hour BP. However, COER-verapamil had greater effects than nifedipine GITS on early morning hemodynamics (HR, HR-systolic BP product, rate of rise of BP and HR) and lesser effects during sleep due to its intrinsic pharmacologic properties and chronotherapeutic delivery system.

Analysis of Variance↗
PubMed2003

Safety and effectiveness of replacing standard doxazosin with doxazosin in the gastrointestinal therapeutic system (GITS) formulation in elderly hypertensive patients.

The objective of this paper is to evaluate the safety and effectiveness of using doxazosin standard formulation in elderly hypertensive patients who were either uncontrolled or newly diagnosed, and replacing standard doxazosin with doxazosin in the gastrointestinal therapeutic system (GITS) formulation. We designed a postmarketing surveillance, open-label non-comparative, multicentre, clinical study covering primary care patients aged 65 years or older diagnosed with essential uncontrolled arterial hypertension. The study covered a period of 6-9 months, divided into two phases. Phase I involved a minimum of three and maximum of six months in treatment with standard doxazosin; phase II began with the changeover from standard doxazosin to the GITS formulation and lasted 12 weeks. Of the 1705 patients initially enrolled, 1292 (75.8%) completed the study. Reduction in systolic blood pressure was 22.3 mmHg (13.7%) in phase I, and 3.9 mmHg (2.77%) in phase II; reduction in diastolic blood pressure was 12.4 mmHg (13.2%) in phase I, and 2.4 mmHg (2.9%) in phase II. The percentage of controlled patients was 40.5% (691/1705) by the end of phase I and 45.3% (776/1705) by the end of phase II. A total of 154 patients suffered adverse events (AE), 127 during phase I and 27 in phase II. We conclude that doxazosin in its two formulations is effective and safe for the purpose of lowering blood pressure in elderly patients.

Aged↗
PubMed2003

Transdermal selegiline: targeted effects on monoamine oxidases in the brain.

BACKGROUND: The oral administration of monoamine oxidase (MAO) inhibitors has the potential to cause a hypertensive reaction after the ingestion of tyramine-containing compounds. Because transdermal drug administration bypasses gastrointestinal absorption, it is possible that inhibition of MAO-A in brain may be achieved without enzyme inhibition in the gastrointestinal system, thereby eliminating the possibility of this drug interaction. These studies determined whether the transdermal administration of selegiline has differential effects on MAOs in brain versus the gastrointestinal system. METHODS: Rats were exposed to various doses of selegiline via a transdermal patch for up to 30 days, and MAO-A and MAO-B activities were determined in brain regions and gastrointestinal tissue. RESULTS: In all brain regions, transdermal selegiline, at doses that produced maximal MAO-B inhibition, led to a dose- and time-dependent MAO-A inhibition. The inhibition of MAOs in gastrointestinal tissue was less than that in brain, and doses that produced maximal MAO-A inhibition in brain inhibited MAO-A in gastrointestinal tissue by only 30%-40%. CONCLUSIONS: Results suggest that transdermal selegiline preferentially inhibits MAO-A in brain relative to the gastrointestinal system. As a consequence, transdermal selegiline should be devoid of the potential to cause a hypertensive reaction after the ingestion of tyramine-containing compounds.

Administration, Cutaneous↗
PubMed2003

Metabolic effects of chronic glipizide gastrointestinal therapeutic system on serum glucose, insulin secretion, insulin sensitivity, and hepatic insulin extraction in glucose-tolerant, first-degree relatives of African American patients with type 2 diabetes: new insights on mechanisms of action.

We examined the long-term metabolic effects of a potent sulfonylurea (SU), glipizide gastrointestinal therapeutic system (glipizide GITS) in normal glucose-tolerant (NGT), first-degree relatives of African American patients with type 2 diabetes in a randomized, placebo-controlled, double-blind manner for 24 months and 6 months after discontinuation of glipizide GITS. Fifty NGT African American first-degree relatives (n = 50)) were randomized to receive either glipizide GITS (GITS, 5 mg/d) or identical placebo (PLAC). The NGT consisted of NGT/GITS (n = 16; mean age, 43.1 +/- 8.7years; body mass index [BMI], 34.8 +/- 10) and NGT/PLAC (n = 34; 45.5 +/- 9.7 years; BMI, 31.3 +/- 3.1years). Each of the subjects underwent an oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT) at baseline and at yearly intervals for 2 years. Insulin sensitivity (Si) and glucose effectiveness (Sg) were determined by Bergman's minimal model method. Hepatic insulin extraction (HIE) was calculated as the molar ratio of C-peptide and insulin. The mean fasting serum glucose, insulin, and C-peptide levels in the NGT/GITS were not different from that of the NGT/PLAC. After oral glucose challenge, mean serum glucose responses slightly increased (P = not significant [NS]) at 12 and 24 months in the NGT/GITS group when compared with the baseline, 0 month, but remained unchanged in the NGT/PLAC group. In addition, serum insulin and C-peptide responses significantly increased in the NGT/GITS group, but were unchanged in the NGT/PLAC group at 12 and 24 months versus 0 month. The HIE, during OGTT, decreased by 30% from the baseline (0 month) values in the NGT/ GITS, but remained unchanged in the NGT/PLAC group at 12 and 24 months. Mean Si decreased by 30% from the baseline in the NGT/GITS group by 12 and 24 months, but remained unchanged in the NGT/PLAC group. However, the disposition index (DI) remained normal in the NGT/GITS and the NGT/PLAC groups. The DI data in the NGT/GITS group suggested that beta cells maintained the ability to compensate for the lower Si during the chronic GITS administration in our high risk African Americans. Chronic GITS was well tolerated without any symptoms of either hypoglycemia or weight gain in the NGT/IGTS group. After discontinuation of GITS, the altered metabolic parameters significantly improved, returning to baseline values in the NGT/IGTS group in 6 months. In summary, chronic glipizide GITS administration (5 mg/d) was associated with increased beta-cell secretion, peripheral hyperinsulinemia, reduced Si, and reduced HIE in glucose-tolerant, first-degree relatives of African American patients with type 2 diabetes. These metabolic changes were reversible within 6 months after discontinuation of glipizide GITS. Our study defines a unique mode of action of glipizide GITS in African Americans at high risk for type 2 diabetes. We conclude that the use of glipizide GITS in the primary prevention of type 2 diabetes in nondiabetic first-degree relatives of patients with type 2 diabetes impaired glucose homeostasis.

Adult↗
PubMedDate not supplied

The efficacy and safety of once-daily nifedipine administered without food: the coat-core formulation compared with the gastrointestinal therapeutic system formulation in patients with mild-to-moderate hypertension. Nifedipine Study Group.

A parallel-group, randomized, double-blind, forced-titration, multicenter study was done to compare the efficacy and safety of once-daily nifedipine coat-core (NIF CC) and once-daily nifedipine gastrointestinal therapeutic system (NIF GITS) dosed in the fasting state in patients with mild-to-moderate essential hypertension. Both formulations have been shown to effectively and safely lower blood pressure in placebo-controlled trials. After a 4-week placebo run-in period, 228 patients were randomized to 4 weeks of treatment with either NIF CC 30 mg daily or NIF GITS 30 mg daily. This period was followed by a forced-titration period to nifedipine 60 mg daily for an additional 4 weeks of double-blind therapy. After the 30-mg treatment period (the primary time point), there were no statistically significant differences between treatment groups in mean change from baseline in trough supine diastolic blood pressure, the primary efficacy variable (NIF CC patients, -7.0 mm Hg; NIF GITS patients, -8.4 mm Hg; P = 0.139). Also, because the upper bound of the treatment difference confidence interval was < 3.0 mm Hg, equivalence--as defined in the protocol--was established. After the 60-mg treatment period, the change from baseline in trough supine diastolic blood pressure was significantly greater for patients treated with NIF GITS than for patients treated with NIF CC (NIF GITS patients, -12.0 mm Hg; NIF CC patients, -8.4 mm Hg; P < 0.001). Because the upper bound of the confidence interval was > 3 mm Hg, equivalence cannot be claimed. No statistically significant differences were noted for the comparison of mean 24-hour ambulatory blood pressure monitoring changes. Both formulations were well tolerated.

Adult↗
PubMed1999

Effects of doxazosin in the gastrointestinal therapeutic system formulation versus doxazosin standard and placebo in mild-to-moderate hypertension. Doxazosin Investigators' Study Group.

The alpha 1-blocker doxazosin is a well-established therapy for hypertension and benign prostatic hyperplasia; however, in its standard form, a multiple-step titration regimen is usually required. The new gastrointestinal therapeutic system (GITS) formulation of doxazosin greatly minimizes the need for titration by changing drug-delivery rate and the pharmaco-kinetic profile. To demonstrate this in hypertensive patients, we assessed the effects of doxazosin GITS 4 or 8 mg once daily versus doxazosin standard 1-8 mg once daily, and placebo, in an integrated analysis of two multicenter, double-blind, randomized, parallel-group trials. Each trial included a 2-week washout period and 12 weeks of therapy. One study compared doxazosin GITS, doxazosin standard, and placebo in 392 patients with mild hypertension [blood pressure (BP) 95-105/ < or = 180 mm Hg]; the other study compared doxazosin GITS with doxazosin standard in 315 patients with mild-to-moderate hypertension (BP 95-115/ < or = 220 mm Hg). The primary outcome measure was the proportion of responders (sitting diastolic BP < 90 mm Hg or 10-mm Hg decrease from baseline 24 h after the dose) at the final visit for the per-protocol population. Mean baseline BP and heart rate were well matched in each group. Approximately 64% of patients with doxazosin GITS (198 of 309 patients) and 68% with doxazosin standard (207 of 304 patients) achieved goal BP response at the final visit versus 36% with placebo (25 of 70 patients; p < 0.05). The majority with doxazosin GITS (60%) remained at the initial 4-mg starting dose. Doxazosin GITS was as effective as doxazosin standard, and both were more effective than placebo in controlling BP in mild-to-moderate hypertension. Doxazosin GITS was well tolerated, and fewer patients with the GITS formulation discontinued therapy because of side effects compared with doxazosin standard or placebo. Syncope was not reported with doxazosin GITS. Whereas the efficacy of doxazosin GITS at 4 or 8 mg is equivalent to that of the standard regimen in this combined analysis, the GITS formulation appears to eliminate the need for titration in most patients.

Adult↗
PubMed1996

The effect of glipizide gastrointestinal therapeutic system on islet cell hormonal responses to a test meal in NIDDM.

OBJECTIVE: To determine whether the abnormal glucagon and amylin secretions in NIDDM are secondary to hyperglycemia and relative hypoinsulinemia. RESEARCH DESIGN AND METHODS: A total of 13 patients with NIDDM were studied before and after treatment with glipizide gastrointestinal therapeutic system (GITS) in a randomized double-blind placebo-controlled fashion. Of the 13 subjects, 9 were randomized to the glipizide GITS arm and 4 were randomized to the placebo arm of the study. Serum glucose, insulin, C-peptide, plasma glucagon, and plasma amylin concentrations were measured under fasting and postprandial (post-Sustacal ingestion) conditions. The Sustacal challenge was performed at baseline and after 12 weeks of treatment with either glipizide GITS or placebo. RESULTS: Glipizide GITS treatment resulted in a significant reduction in hyperglycemia and increases in insulin and C-peptide secretion. Hyperglucagonemia was not ameliorated, and amylin secretion was not altered after glipizide GITS treatment. Placebo-treated patients did not show significant changes in any of the parameters measured. CONCLUSIONS: Glipizide GITS treatment failed to ameliorate the hyperglucagonemia of NIDDM and did not alter amylin secretion even though it increased insulin secretion and significantly ameliorated the hyperglycemia. These observations suggest that NIDDM related abnormalities in some of the islet cell hormonal responses are the result of changes inherent in the islet cells and may be independent of hyperglycemia and relative hypoinsulinemia.

Amyloid↗
PubMed1987

Nifedipine gastrointestinal therapeutic system.

Convenient once-a-day dosage regimens are highly desirable in general, and especially for the treatment of asymptomatic diseases such as essential hypertension. Nifedipine is an insoluble, short-acting calcium channel blocker that presents a difficult technical challenge for formulation in a constant 24-hour delivery dosage form. Once-a-day dosage forms have been developed based on the gastrointestinal therapeutic system (GITS) push-pull osmotic pump configuration in three strengths with different drug delivery rates (mg/hour) per dose (mg), as 1.7/30, 3.4/60, and 5.1/90. The delivery rates of drug from these systems are controlled by their drug loading, composition of osmotic components, membrane properties, and dimensions. The release rates are independent of pH in the range from gastric pH = 1.2 to intestinal pH = 7.5. The release rates are independent of stirring rate and therefore unlikely to be influenced by motility in the gastrointestinal tract. The drug release rate from the nifedipine GITS dosage form in vivo in the gastrointestinal tract of dogs has been found to be equal to the release rate in vitro, indicating that the in vitro test is predictive of in vivo delivery. Following administration of the nifedipine GITS dosage forms to human subjects, absorption rates, calculated from resulting plasma concentrations, indicate that the cumulative amount of drug absorbed in humans over 24 hours is proportional to the amounts of drug delivered in vitro. Plasma concentrations are therefore predictable and remain relatively constant throughout the 24-hour dosing interval.

Animals↗
PubMed1989

The nifedipine gastrointestinal therapeutic system in the treatment of hypertension.

As the number of antihypertensive agents increases, the choice of optimal therapy becomes more difficult. Certainly, hemodynamic derangements caused by the disease state as well as therapy must be considered. Patient convenience and quality of life are also issues that must be addressed. Preliminary experience suggests that the gastrointestinal therapeutic system (GITS) push-pull osmotic pump formulation of nifedipine is safe and efficacious in the treatment of hypertension. In 1 study, nifedipine GITS was compared with sustained-release propranolol in patients with mild to moderate hypertension already receiving diuretics. Using a 2-week placebo run-in, double-blind study design, patients were randomly assigned to receive nifedipine GITS (n = 31) in doses of 30, 60 or 90 mg once daily, or sustained-release propranolol (n = 32) in doses of 80, 160 or 240 mg once daily. Previous diuretic therapy was continued. Sitting and 5-minute standing blood pressure and heart rate measurements were obtained 24 hours after dosing. At the end point of treatment, both nifedipine GITS and sustained-release propranolol reduced blood pressure compared with placebo (p less than 0.001) in the sitting and standing positions. Nifedipine GITS was more effective than sustained-release propranolol in reducing standing (p less than 0.005) and sitting (p less than 0.001) systolic blood pressure and sitting diastolic blood pressure (p less than 0.02). Sustained-release propranolol caused a greater reduction in standing (p less than 0.001) and sitting (p less than 0.0006) resting heart rate than nifedipine GITS. Both drugs were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemistry, Pharmaceutical↗
PubMed2001

Comparative effects of mibefradil and nifedipine gastrointestinal transport system on autonomic function in patients with mild to moderate essential hypertension.

BACKGROUND: L-type dihydropyridine calcium channel blockers (CCBs) have been implicated in increased cardiovascular events in patients with hypertension, perhaps due to adverse effects on autonomic nervous system (ANS) function. Blockade of T-type calcium channels may limit ANS dysfunction by inhibition of T channel-mediated neuroendocrine effects. OBJECTIVE AND DESIGN: This double-blind, parallel group study compared the effect of nifedipine gastrointestinal transport system (GITS) (L-type CCB) versus mibefradil (T-type CCB) on ANS function in patients with mild-moderate essential hypertension. METHODS: Sixteen patients (10 male, 6 female; age 57.2 +/- 2.3 years), diastolic blood pressure (DBP) < 95 mmHg were randomized to nifedipine 30 mg daily or mibefradil 50 mg daily (2 weeks), then nifedipine 60 mg daily or mibefradil 100 mg daily (4 weeks). Sympathetic nervous system activity (SNSA) was assessed using norepinephrine kinetics. Parasympathetic nervous system activity (PSNA) was assessed from 24 h Holter recordings of heart rate variability (HRV). Non-invasive baroreflex sensitivity (BRS) provided integrated assessment of ANS. RESULTS: Patient groups were well matched at baseline. Achieved DBP was lower in patients treated with mibefradil compared with nifedipine, (83.4 +/- 1.7 versus 95.25 +/- 3.3 mmHg). There were no significant differences in SNSA and BRS between groups, however the root mean square of successive differences and high frequency power (HFP) were increased in mibefradil compared with nifedipine-treated patients [(+ 1.07 +/- 1.6 versus -3.36 +/- 1.2 ms, P < 0.05) and (+ 0.28 +/- 0.1 versus -0.23 +/- 0.1 ms2, P < 0.01), respectively]. Furthermore, Ln HFP/Ln total power was increased from week 0 to week 6 in the mibefradil-treated group, (0.71 +/- 0.02 versus 0.74 +/- 0.03, P = 0.046). CONCLUSION: No differences existed between effect of L- and T-type CCBs on SNSA and BRS. However, T-type CCBs increased PSNA, independent of achieved changes in heart rate.

Autonomic Nervous System↗
PubMed1997

The natriuretic effect of nifedipine gastrointestinal therapeutic system remains despite the presence of mild-to-moderate renal failure.

BACKGROUND: Calcium channel blockers facilitate the renal excretion of sodium and this effect is maintained during chronic administration of these drugs. However, it is unknown whether this natriuretic effect remains despite the presence of a decreased renal function. OBJECTIVE: To compare the natriuretic capacity of nifedipine gastrointestinal therapeutic system (GITS) and lisinopril in patients with mild-to-moderate chronic renal failure. METHODS: An open-label, randomized, comparative study was conducted to compare the natriuretic capacity of nifedipine GITS and lisinopril in the presence of mild-to-moderate renal failure (creatinine clearance 30-80 ml/min). After a wash-out period of 4 weeks an intravenous saline infusion (30 ml/kg of body weight of isotonic saline in 4 h) was performed and repeated after 4 weeks of active therapy. Two sex- and age-matched groups of hypertensive patients (n = 25) were included in the study. Renal failure was diagnosed as secondary to nephrosclerosis in all the patients. RESULTS: A significant increase in the renal capacity to excrete the sodium load was observed in patients receiving nifedipine GITS (n = 11) but not in those taking lisinopril (n = 13). Both drugs controlled blood pressure to a similar extent. No changes were observed in body weight, glomerular filtration rate and renal plasma flow (measured as inulin and paraaminohippurate clearances). A significant drop was observed in urinary albumin excretion after lisinopril, but not after nifedipine. Heart rate was higher in nifedipine group. CONCLUSION: The natriuretic capacity of nifedipine GITS remains despite the presence of mild-to-moderate chronic renal failure. Such an effect takes place in the absence of changes in renal hemodynamics, suggesting that it is caused by a direct tubular effect.

Administration, Oral↗
PubMed2002

A postmarketing, open-label study to evaluate the tolerability and effectiveness of replacing standard-formulation doxazosin with doxazosin in the gastrointestinal therapeutic system formulation in adult patients with hypertension.

BACKGROUND: The antihypertensive doxazosin works to decrease perivascular muscular tone, causing vasodilatation and hence a decrease in peripheral vascular resistance. To prevent the sharp decrease in blood pressure (BP), syncope, and other postural effects that may occur at the beginning of therapy with this drug, the dose must be adjusted. A new formulation, doxazosin gastrointestinal therapeutic system (GITS), allows slow release of the active agent so therapeutic serum levels are reached within 24 hours, rendering dose adjustment unnecessary and eliminating any first-dose effects. OBJECTIVES: The goals of this study were to evaluate the tolerability and effectiveness of (1) using doxazosin in the standard and new GITS formulations in adult patients with hypertension who either had uncontrolled or newly diagnosed disease, and (2) replacing standard-formulation doxazosin with doxazosin in the GITS formulation. METHODS: This was a postmarketing, open-label, noncomparative, multicenter clinical study covering primary care patients diagnosed with essential uncontrolled arterial hypertension (AHT). Subjects could be patients who were undergoing drug therapy before enrollment or those diagnosed with AHT and/or treated for the disease for the first time on entering the study. The study covered a period of 6 to 9 months, divided into 2 phases. Phase 1 involved a minimum of 3 and maximum of 6 months of treatment with standard-formulation doxazosin. Phase 2 commenced with the changeover from standard-formulation doxazosin to the GITS formulation and lasted 12 weeks. The principal study variables included BP and the development of adverse events (AEs). At every visit, the patients were asked by an investigator whether they had suffered any AEs since the previous contact. RESULTS: Of the total of 4,512 patients initially enrolled, 3537 (78.4%) completed the study. A total of 285 patients were excluded for failing to comply with the inclusion criteria, leaving 4,227 patients for analysis. In most instances, premature withdrawal from the study (16.3% [690/4,227]) was due to loss to follow-up (37.2% [257/690]), followed by the development of AEs (27.8% [192/690]). Fifty-nine percent (2,493/4,226) of patients analyzed were men and 41.0% (1,733/4,226) were women (sex data not recorded for 1 patient), with a mean age of 62.4 years (SD, 10.6). Among the patients participating, 54.8% (2,316/4,227) presented with some type of associated disease. The percentage of patients undergoing monotherapy was 70.7% (2,987/4,227); the remainder (29.3% [1,240/4,227]) underwent a combined-therapy regimen using another antihypertensive drug in conjunction with doxazosin. The mean initial systolic and diastolic BPs were 160 +/- 10.63 mm Hg and 95.26 +/- 7.21 mm Hg, respectively. Reduction in systolic BP was 20.9 mm Hg in phase 1 and 3.8 mm Hg in phase 2. In the case of diastolic BP, the reduction was 13.3 mm Hg in phase 1 and 2.6 mm Hg in phase 2. The percentage of patients with controlled disease was 47.9% (1,891/3,949) by the end of phase 1 and 63.4% (2,242/3,537) by the end of phase 2. A total of 322 (7.6%) patients presented with 343 AEs. 37 (0.9%) of which were deemed severe (0.6% in phase 1 and 0.3% in phase 2). Limitations included the following: (1) the design of this study did not allow comparison of the 2 formulations regarding effectiveness or tolerability: (2) the patients who remained in the study after phase 1 were those less susceptible to toxicity from doxazosin; and (3) it is probable that the nonresponders were more likely to drop out of the study. CONCLUSIONS: Doxazosin in the standard formulation was effective and well tolerated for the purpose of lowering BP. Patients who tolerated the standard formulation also tolerated the switch to the GITS formulation. Finally, this substitution did not negatively impact the effectiveness of treatment of AHT.

Adult↗
PubMed2000

Double-blind trial of the efficacy and tolerability of doxazosin in the gastrointestinal therapeutic system, doxazosin standard, and placebo in patients with benign prostatic hyperplasia.

BACKGROUND: The alpha(1)-blocker doxazosin mesylate is an established efficacious and welltolerated treatment for benign prostatic hyperplasia (PBH). However, its clinical utility can be limited by the need for multiple titration steps, starting at an initial dose of 1 mg, increased up to 8 mg once daily, to achieve optimal therapeutic response. A new controlled-release gastrointestinal therapeutic system (GITS) formulation of doxazosin mesylate enhances the pharmacokinetic profile and drug delivery rate, reducing the plasma doxazosin mesylate peak-to-trough ratio and minimizing the need for titration. OBJECTIVE: A study was conducted to assess the effects of doxazosin GITS 4 or 8 mg once daily, doxazosin standard 1 mg to 8 mg once daily, and placebo, in 795 men with BPH. This randomized, double-blind, multicenter Scandinavian study included a 2-week washout period, 2-week single-blind placebo run-in phase, and 13-week double-blind treatment phase. Doxazosin GITS was initiated at 4 mg once daily and titrated to 8 mg once daily after 7 weeks, if indicated, and doxazosin standard was initiated at 1 mg once daily, titrated to 2 mg after 1 week, to 4 mg at 3 weeks, and to 8 mg at 7 weeks if indicated, to achieve symptom control. The primary outcome measures were mean changes from baseline to the final visit for International Prostate Symptom Score (I-PSS) and maximum urinary flow rate adjusted for baseline values. RESULTS: Both doxazosin GITS and doxazosin standard significantly improved the symptoms of BPH, as evidenced by least-squares mean reductions in total I-PSS of -8.0+/-0.3 and -8.4+/-0.3 from baseline, respectively, compared with a reduction of -6.0+/-0.4 in patients on placebo. Doxazosin GITS and doxazosin standard produced clinically comparable improvements in maximum urinary flow rates, with a greater improvement observed earlier following treatment with doxazosin GITS than with doxazosin standard. Both active treatments produced significantly greater increases in maximum urinary flow rate compared with placebo. Nearly half of the patients on doxazosin GITS achieved symptom relief at the 4-mg starting dose. A similar number of patients in both doxazosin groups were titrated to the maximum dose of 8 mg for both formulations. The overall incidence of adverse events was similar among patients treated with doxazosin GITS and placebo, and slightly higher in those on doxazosin standard. There was no apparent difference in the type of adverse events reported for the two formulations of doxazosin, although most adverse events were reported at a lower frequency with doxazosin GITS. CONCLUSIONS: Doxazosin GITS is significantly more effective than placebo in reducing the clinical symptoms of BPH and improving maximum urinary flow rate, and as effective as doxazosin standard. A therapeutic effect equivalent to that of doxazosin standard was achieved with doxazosin GITS with fewer titration steps, in a manner that appeared to be better tolerated. Because treatment with doxazosin GITS starts with an effective dose for many patients, it is likely that this clinical profile will result in the need for fewer patient visits than with doxazosin standard therapy.

Adrenergic alpha-Antagonists↗
PubMed2005

Nifedipine gastrointestinal therapeutic system--hypertension management to improve cardiovascular outcomes.

Hypertension is a major cardiovascular risk factor, and its increasing prevalence is of great clinical concern. Despite the availability of numerous effective therapies, hypertension remains under-diagnosed and under-treated. Hypertension often coexists with other risk factors, and current guidelines recommend a multifactorial approach to management, with the aim of not only controlling blood pressure but also reducing overall cardiovascular risk. Nifedipine gastrointestinal therapeutic system (GITS) is a long-acting formulation of a calcium channel blocker. Once-daily dosing with nifedipine GITS has been shown to achieve smooth and continuous blood pressure control, identical to conventional first-line diuretic therapy. Small-scale clinical trials have also shown that nifedipine GITS positively affects markers of atherosclerotic disease, which may signify an additional clinical benefit, but this is yet to be demonstrated. The recently completed ACTION (A Coronary Disease Trial Investigating Outcome with Nifedipine GITS) trial provides further evidence that nifedipine GITS can be used safely in high-risk patients to treat angina, lower blood pressure and significantly improve clinical outcomes.

Adult↗