dihydropyridines and Edema

Dihydropyridine calcium channel blockers (DHPCCBs) are widely used to treat hypertension and chronic coronary artery disease. One common adverse effect of DHPCCBs is peripheral edema, particularly of the lower limbs. The side effect could lead to dose reduction or discontinuation of the medication. The combination of DHPCCBs and renin-angiotensin system blockers has shown to reduce the risk of DHPCCBs-associated peripheral edema compared with DHPCCBs monotherapy. We performed the current systematic review and network meta-analysis of randomized controlled trials (RCTs) to estimate the rate of peripheral edema with DHPCCBs as a class and with individual DHPCCBs and the ranking of the reduction of peripheral edema. The effects of renin-angiotensin system blockers on DHPCCBs network meta-analysis were created to analyze the ranking of the reduction of peripheral edema. A total of 3312 publications were identified and 71 studies with 56,283 patients were included. Nifedipine ranked highest in inducing peripheral edema (SUCRA 81.8%) and lacidipine (SUCRA 12.8%) ranked the least. All DHPCCBs except lacidipine resulted in higher relative risk (RR) of peripheral edema compared with placebo. Nifedipine plus angiotensin receptor blocker (SUCRA: 92.3%) did not mitigate peripheral edema and amlodipine plus angiotensin-converting enzyme inhibitors (SUCRA: 16%) reduced peripheral edema the most. Nifedipine ranked the highest and lacidipine ranked the lowest amongst DHPCCBs for developing peripheral edema when used for cardiovascular indications. The second or higher generation of DHPCCBs combination with ACEIs or ARBs or diuretics lowered the chance of peripheral edema development compared to single DHPCCB treatment.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Edema; Humans; Hypertension; Network Meta-Analysis; Nifedipine

Abstract The aim of this meta-analysis was to compare the efficacy and safety profile of manidipine 20 mg with that of amlodipine 10 mg. A systematic research of quantitative data produced or published between 1995 and 2009 was performed. Head-to-head randomized controlled trials (RCTs) of 12 months minimum duration reporting comparative efficacy (changes in systolic and diastolic blood pressure) and safety (total adverse events and ankle oedema), were included. Four high-quality RCTs, accounting for 838 patients (436 received manidipine and 402 received amlodipine) were included. The efficacy of manidipine and amlodipine was statistically equivalent: effect size for DBP = -0.08 (p = 0.22) and SBP = -0.01 (p = 0.83). The global safety of manidipine was significantly better than amlodipine: the relative risk (RR) for adverse event was 0.69 (0.56-0.85), and particularly for ankle oedema RR was 0.35 (0.22-0.54). Publication bias was not significant and the robustness of the analyses was good. These data suggest a better efficacy/safety ratio of manidipine over amlodipine.

Topics: Adult; Amlodipine; Ankle; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Edema; Humans; Hypertension; Meta-Analysis as Topic; Nitrobenzenes; Piperazines; Publication Bias; Randomized Controlled Trials as Topic; Treatment Outcome

Results from clinical studies suggest that the dihydropyridine calcium channel blocker (CCB) lercanidipine may be associated with a lower incidence of peripheral edema than are older dihydro-pyridine CCBs.. The objective of the present study was to conduct a meta-analysis of published data from randomized controlled trials (RCTs) to assess the relative risk (RR) of dihydropyridine CCB-specific adverse events with lercanidipine versus the older dihydro-pyridine CCBs (first generation: amlodipine, felodipine, and nifedipine), and versus the other lipophilic dihy-dropyridine CCBs (second generation: lacidipine and manidipine).. A systematic literature search (all years through August 11, 2008) of MEDLINE, EMBASE, and the Cochrane Library was conducted for English-language reports of single- or double-blind RCTs of > or = 4 weeks' duration that compared the tolerability of lercanidipine with other dihydropyridine CCBs in participants with mild (140-159/90-99 mm Hg) to moderate (160-179/100-109 mm Hg) hypertension.. Eight RCTs (6 used first-generation drugs, and 4 used second-generation drugs) met the criteria for inclusion. Efficacy outcomes for lowering blood pressure did not differ statistically between lercanid-ipine and either generation of medications. Compared with the first generation, lercanidipine was associated with a reduced risk of peripheral edema (52/742 with lercanidipine vs 88/627 with first generation; RR = 0.44 [95% CI, 0.31-0.62]), but not flushing or headache. The frequency of peripheral edema, flushing, and headache did not differ statistically between lercanidi-pine and the second-generation drugs. Study participants were less likely to withdraw from the RCTs because of peripheral edema (RR = 0.24 [95% CI, 0.12-0.47]) or any adverse event (RR = 0.51 [95% CI, 0.33-0.77]) when treated with lercanidipine rather than a drug from the first generation, but not when treated with lercanidipine rather than second-generation drugs.. In this meta-analysis, lercanidipine was associated with a lower risk of peripheral edema and a lower risk of treatment withdrawal because of peripheral edema than were the first-generation, but not the second-generation, dihydropyridine CCBs.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Dihydropyridines; Edema; Humans; Hypertension; Randomized Controlled Trials as Topic; Treatment Outcome

Systemic hypertension is a major global problem contributing to enormous disease burden, premature morbidity and mortality. A substantial majority of hypertensive patients require long-term drug therapy for appropriate blood pressure control. Although there are many classes of antihypertensive drugs for clinical use, calcium channel blockers (CCBs) have a special role in the management of hypertension owing to their well established safety and efficacy among the CCBs; the dihydropyridines (DHPs) are recognized for their predictable efficacy and dependability to achieve the recommended target goals of treatment. The older DHPs, such as nifedipine, felodipine and amlodipine, can cause bothersome side effects, such as ankle edema. The new-generation lipophilic DHP CCBs, such as lercanidipine, offer an advantage of less frequent occurrence of ankle edema. Furthermore, lercanidipine (in contrast to older DHPs) exerts favorable cardiorenal effects. Lercanidipine administered alone or in combination with other antihypertensive drugs represents a useful treatment option for efficient blood pressure control without causing significant adverse effects.

Topics: Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Edema; Humans; Hypertension; Randomized Controlled Trials as Topic

Ankle oedema is a common adverse event during treatment with dihydropyridine (DHP) calcium channel antagonist therapy, the incidence of which is dose related. The three mechanisms put forward to explain the formation of oedema during calcium channel antagonist therapy are arteriolar vasodilation, impairment of the local vascular autoregulation of blood flow and impaired protection against hydrostatic load. The importance of differential arteriolar-venular dilation has been demonstrated in numerous clinical studies. In particular, differences in sympathetic overactivation after arterial vasodilation have been shown to be related to differences in ankle oedema rates. If these results are confirmed, calcium channel antagonists that activate the sympathetic nervous system to a lesser extent, such as manidipine, may become first-choice calcium channel antagonists because of their more favourable adverse event profile.

Topics: Ankle Joint; Arterioles; Calcium Channel Blockers; Dihydropyridines; Edema; Humans; Joint Diseases; Norepinephrine; Randomized Controlled Trials as Topic; Sympathetic Nervous System; Vasodilation

The authors examined the effect of cilnidipine, a unique L/N-type calcium channel blocker, on abnormal nocturnal blood pressure (BP) dipping in Japanese hypertensive patients in the real world. The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N-Channel Blocker Cilnidipine (ACHIEVE-ONE), a large-scale clinical study, was designed to evaluate the effects of cilnidipine in daily medical practice. Among the study, 24-hour ambulatory BP data were obtained from 615 patients and classified according to their nocturnal dipping status as extreme dippers, dippers, nondippers, or risers. A 12-week treatment with cilnidipine significantly reduced 24-hour BP in all groups (P<.001). Changes in nocturnal systolic BP (SBP) from baseline were -17.9 mm Hg from 154.6 mm Hg in risers and -11.9 mm Hg from 142.1 mm Hg, -6.6 mm Hg from 128.5 mm Hg, and 0.1 mm Hg from 115.8 mm Hg in nondippers, dippers, and extreme dippers, respectively. Changes from baseline in nocturnal SBP reduction rate were 8.2% in risers (P<.001) but -7.0% in extreme dippers (P<.001), while no change was observed in the nighttime SBP reduction rate for the total patients (-0.2%±9.6%, P=.617). Cilnidipine partially, but significantly, restored abnormal nocturnal dipping status toward a normal dipping pattern in hypertensive patients.

Topics: Aged; Aged, 80 and over; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Edema; Female; Humans; Hypertension; Hypotension; Incidence; Japan; Male; Middle Aged; Treatment Outcome

To compare changes of body water measured by using bioelectrical impedance analysis (BIA), between lercanidipine and amlodipine therapy.. This is a prospective randomized open-label study in hypertensive outpatients. Eighty patients were randomized into two groups; 1) amlodipine 5 mg/d and 2) lercanidipine 10 mg/d. Patients were assessed for changes in total body water (TBW), extracellular water (ECW) and intracellular water (ICW) at week 4 and 8 after treatment.. At baseline body water in both groups were similar. After treatment, both groups did not have significant changes in body water from baseline. Seven patients in amlodipine group (17.5%) and none of lercanidipine group developed edema; p = 0.012. Among those seven patients, TBW, ECW and ICW all increased significantly from baseline.. BIA did not detected changes of body water in most patients. However, in patients who developed edema, TBW, ECW and LCW significantly increased from baseline with the greatest changes seen in extracellular compartment.

Topics: Aged; Aged, 80 and over; Amlodipine; Antihypertensive Agents; Body Composition; Body Water; Dihydropyridines; Edema; Electric Impedance; Extracellular Fluid; Female; Humans; Hypertension; Intracellular Fluid; Male; Middle Aged; Outpatients; Prospective Studies; Thailand; Treatment Outcome

Use of the combination of an angiotensin-converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB) is considered a rational approach in patients whose hypertension is not controlled by monotherapy, providing better blood pressure (BP) control than the individual components with a lower incidence of adverse effects. In particular, such combinations have been found to reduce the incidence of ankle edema, the most common adverse effect of dihydropyridine annhypertensives.. The present study was undertaken to evaluate the effect on the development of ankle edema of adding the ACEI delapril to the CCB manidipine in patients with mild to moderate essential hypertension.. Patients between the ages of 30 and 70 years who had mild to moderate hypertension (diastolic BP [DBP] >90 and <110 mm Hg) were included in the study. After a 4-week placebo run-in period, eligible patients were randomized to receive 6 weeks each of manidipine 10 mg/d, delapril 30 mg/d, and both in a crossover fashion. There was a 2-week washout period between treatments. Ankle edema was assessed based on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP). Sitting BP, AFV, and PSTP were measured at the end of the placebo run-in period and the end of each active-treatment period.. The study enrolled 40 patients with previously untreated hypertension (21 women, 19 men). Both manidipine and delapril monotherapy were associated with significant reductions from baseline in systolic BP (SBP) (mean [SD], -17.3 [4] and -14.8 [4] mm Hg, respectively; both, P<0.01) and DBP (-14.6 [3] and -12.9 [3] mm Hg; both, P<0.01). Compared with monotherapy, the combination of manidipine and delapril was associated with greater reductions from baseline in SBP (-21.8 [5] mm Hg; P<0.001) and DBP (-18.6 [4] mm Hg; P<0.001). Manidipme monotherapy was associated with significant increases from baseline in both AFV (7.9%; P<0.001) and PSTP (36.6%; P<0.01). Compared with manidipine alone, the combination of manidipine and delapril was associated with less pronounced increases in AFV (3.3%; P<0.05) and PSTP (10.4%; P<0.05). Ankle edema was clinically evident in 3 patients after receipt of manidipine monotherapy and in 1 patient after receipt of combination treatment.. In these patients with mild to moderate essential hypertension, the addition of delapril to manidipine partially counteracted the manidipine-induced microcirculatory changes responsible for ankle edema.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Ankle; Antihypertensive Agents; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Drug Therapy, Combination; Edema; Female; Humans; Hypertension; Indans; Male; Middle Aged; Nitrobenzenes; Piperazines; Treatment Outcome

Calcium channel blockers (CCB) are known to be more efficacious and better tolerated in elderly patients. Lercanidipine is a highly lipophilic CCB with a specific safety profile linked to its pharmacokinetics.. To evaluate and compare the efficacy and safety of lercanidipine according to age.. Two groups of hypertensive patients (G1: aged < 65, G2: aged > or = 65) entered an open study conducted over 56 days. All received lercanidipine 10 mg/d (monotherapy or add-on), titrated to 20 mg/d if blood pressure (BP) was not controlled at D28. BP was measured using a semi-automatic device at doctor's office (three measurements at 1-min intervals) and at home by the patient himself (three measurements in the morning and in the evening at 1-min intervals over the 7 days before D0 and D56).. Seven hundred and fifty-six patients entered the study. Thirty-eight patients dropped out prematurely and 30 were excluded because they were normotensive; 691 patients (G1 n = 375, G2 n = 316) were kept for analysis. At the end of the study, 507 patients were treated with lercanidipine alone (10 mg/d n = 221, 20 mg/d n = 286) and 184 with a combination including lercanidipine (10 mg/d n = 91, 20 mg/d n = 93). Efficacy was not different between the groups excepted home pulse pressure which decreased more in G2. In the office, SBP decreased by 17 and 21 mmHg, respectively, for G1 and G2, and DBP by 9 and 10 mmHg. The prevalence of leg edema was not different between G1 and G2 and was particularly low in both groups (3%).. Lercanidipine was as efficacious and well tolerated in younger patients as in elderly patients.

Topics: Age Factors; Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Edema; Female; Humans; Hypertension; Leg; Male; Middle Aged; Treatment Outcome

To evaluate the safe use of a new calcium channel blocker, lercanidipine, in diabetic chronic renal failure (CRF) patients.. The study recruited 42 diabetic CRF patients (creatinine > 1.4 mg/dl for males, creatinine > 1.2 mg/dl for females, or creatinine clearance < 70 ml/min). Mean age was 68.2 +/- 9.1 years. 53.8% were males and 46.2% females. Three patients were type 1 diabetics and 39 ones were type II. All patients were receiving ACE inhibitors (67.4%) or angiotensin II antagonist (32.6%) therapy but they had higher blood pressure than recommended for CRF patients (130/85 mmHg). No patients were under diuretic treatment. Patients were clinically evaluated 1, 3 and 6 months after starting treatment with lercanidipine. Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment, excluding diuretics. Creatinine clearance was measured using 24 h urine collection.. BP significantly decrease from 163 +/- 18/90 +/- 8 mmHg to 134 +/- 12/77 +/- 9 mmHg. One half of patients showed significant reduction of blood pressure, 26.7% reached the target blood pressure (< 130/85 mmHg) and 20.0% gets optimal BP control (< 130/85 mmHg). No one patient showed untoward effects. No edema was detected nor adverse effects related to vasodilatation were found. Plasmatic creatinine did not change (1.9 +/- 0.5 baseline vs 1.8 +/- 0.5 mg/dl) and creatinine clearance increased at the end visit (40.1 +/- 14.5 baseline vs 45.4 +/- 18.2 ml/min) but the difference was not significant. Proteinuria was unchanged.. Lercanidipine showed a good antihypertensive effect in diabetics CRF patients. It has a good tolerability profile and showed neutral effect on plasmatic lipids. Neither impairment of renal function nor increment in proteinuria were detected.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Edema; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Treatment Outcome

Of the study was to compare the leg oedema-forming potential of two different dihydropyridine calcium channel blockers in postmenopausal women.. A total of 92 postmenopausal hypertensive patients [systolic blood pressure (SBP) 150-179 mmHg or diastolic blood pressure (DBP) 95-109 mmHg were randomized to receive a 4-week treatment with either 10 mg/day lercanidipine (n = 48) or 5 mg/day amlodipine (n = 44), with force-titration to 20 and 10 mg/day, respectively for an additional 4 weeks.. Leg volume was measured by water displacement volumetry, patients were questioned for symptoms and a physical examination was performed to detect the presence of oedema.. A total of 77 patients completed the study, without a major protocol violation and were included in the primary analysis. Leg volume increase from baseline was significantly higher in the amlodipine than in the lercanidipine group (60.4 +/- 8.6 versus 5.3 +/- 8.1 ml; P < 0.001). The percentage of patients with evidence of oedema on physical examination (33.3 versus 9.8%, P = 0.011) and with symptoms of leg swelling (63.9 versus 22%, P < 0.001) and leg heaviness (47.2 versus 12.2%, P < 0.001) was also greater with amlodipine compared with lercanidipine. A positive correlation was found between leg volume and sign or symptoms of oedema (P < 0.001). Both drugs reduced SBP and DBP, with no significant differences between treatments. No correlation was found between leg volume changes from baseline and the antihypertensive effect of either drug.. In postmenopausal females with mild to moderate hypertension the oedema formation of Lercanidipine was significantly less than that of Amlodipine, despite no significant differences in the antihypertensive effect.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure; Blood Volume; Calcium Channel Blockers; Diastole; Dihydropyridines; Drug Evaluation; Edema; Female; Heart Rate; Humans; Hypertension; Leg; Middle Aged; Norway; Postmenopause; Statistics as Topic; Systole; Time Factors; Treatment Outcome; Women's Health

The objective of this 8-week open-label study was to compare the tolerability of lercanidipine, a dihydropyridine calcium-channel antagonist (CA), with that of other CAs in the treatment of hypertension. Subjects already taking amlodipine, felodipine, nifedipine gastrointestinal therapeutic system (GITS), or nitrendipine and experiencing CA-specific adverse effects (AEs) were switched to lercanidipine for 4 weeks and then rechallenged with their initial treatment for 4 weeks. Results showed that at comparable levels of BP, lercanidipine was associated with a significantly lower incidence of ankle edema, flushing, rash, headache and dizziness compared with other CAs (p < 0.001). After 4 weeks of lercanidipine, mean systolic blood pressure (SBP)/diastolic blood pressure (DBP) was 142.1/86.7 mmHg. After rechallenge with other CAs for 4 weeks, mean SBP/DBP was 141.1/86.7 mmHg. In this open-label study, lercanidipine compared with other CA seems to provide a significant improvement in tolerability with comparable antihypertensive effect.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Edema; Endpoint Determination; Female; Flushing; Headache; Heart Rate; Humans; Hypertension; Male; Middle Aged; Patient Dropouts

To compare the effect of amlodipine, a prototype dihydropyridine calcium-channel blocker with lercanidipine, a newer dihydropyridine compound with lipophilic properties, on dependent oedema generation and interference with skin blood flow vasomotion in hypertensive patients.. Single-blind, sequence-randomized, cross-over comparison of amlodipine and lercanidipine. Drugs were given at equipotent doses (10 mg daily and 20 mg daily, respectively) in 22 never-treated mild-to-moderate hypertensive men (age: 48 +/- 5 years). Each treatment was administered for 2 weeks with a 2-week intervening period to restore baseline values.. Dependent oedema formation was quantified through leg weight changes (water displacement method). Blood pressure (the mean of at least 10 determinations) was recorded by an automated oscillometric device and skin blood flow (laser Doppler flowmetry) measured at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, to evaluate the behaviour of cutaneous postural vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing.. Leg weight was increased by both drugs, but the increase was significantly greater during treatment with amlodipine than with lercanidipine. Blood pressure decreased to a similar extent and postural vasoconstriction was antagonized comparably during both treatments.. The oedema-forming potential of amlodipine is greater than that induced by lercanidipine, a difference which emerged in the presence of a comparable drop in blood pressure and could not be attributed to interference with postural vasoconstrictor mechanisms.

Topics: Adult; Amlodipine; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Dihydropyridines; Edema; Humans; Hypertension; Laser-Doppler Flowmetry; Leg; Male; Middle Aged; Skin; Treatment Outcome; Vasoconstriction

Irrespective of their clinical relevance, side effects cannot be considered a negligible problem in antihypertensive therapy. The aim of this trial was to evaluate the tolerability profile of lercanidipine with that of two other calcium antagonists (amlodipine and lacidipine) in elderly hypertensives.. In a multicenter, double-blind, parallel study 828 elderly (aged > or =60 years) hypertensives were randomized to lercanidipine 10 mg/day (n = 420), amlodipine 5 mg/day (n = 200), or lacidipine 2 mg/day (n = 208) (ratio 2:1:1). If blood pressure (BP) control was unsatisfactory (systolic BP/diastolic BP > or =140/90 mm Hg), the dose of the double-blind medication was doubled and, as a further step, enalapril or atenolol (plus diuretic, if needed) was added. Patients were treated for an average of 12 months.. Amlodipine patients had significantly (P <.001) higher rates of edema (19%) and of early study discontinuations due to edema (8.5%) compared with lercanidipine (9% and 2.1%) and lacidipine patients (4% and 1.4%). Similarly, edema-related symptoms (lower limb swelling and heaviness) occurred significantly (P <.01) more often with amlodipine (50% and 45%, respectively) than with lercanidipine (35% and 33%) and lacidipine (34% and 31%). Most edema cases occurred in the first 6 months, a between-treatment difference being evident since beginning of treatment. Other drug-related adverse events did not differ between treatments. Blood pressure was equally and effectively reduced in the three groups.. The two lipophilic dihydropyridine calcium antagonists, lercanidipine and lacidipine, have an antihypertensive effect comparable to that of amlodipine, but a better tolerability profile.

Topics: Aged; Amlodipine; Calcium Channel Blockers; Dihydropyridines; Double-Blind Method; Drug Therapy, Combination; Edema; Female; Humans; Hypertension; Male; Peripheral Vascular Diseases; Treatment Outcome

Combination therapy is required in many patients to achieve goal blood pressure (BP). Calcium antagonists are highly effective antihypertensive drugs in a broad range of demographic groups. Yet, higher doses are associated with an increased frequency of lower extremity edema. The purpose of our open label, single-center clinical trial was to evaluate the use of concomitant pharmacologic therapies to attenuate the lower extremity edema associated with dihydropyridine calcium antagonists therapy using a water displacement technique. Forty-seven patients received 5 mg/day of oral amlodipine for a period of 6 weeks after a 4-week wash-out off of all antihypertensive medications to establish baseline BP. They were then randomized to receive either an additional 5 mg of amlodipine, 25 mg of hydrochlorothiazide (HCTZ), or 20 mg of benazepril for an additional 6 weeks. Blood pressure determinations and water displacement measurements were obtained at the end of the 4-week placebo wash-out period, after 6 weeks of 5 mg/day of oral amlodipine therapy, and after an additional 6 weeks of 5 mg of amlodipine and randomized drug therapy. Adjusted BP reductions (based on pretreatment BP) were -6.8/-3.8 mm Hg for the 10-mg amlodipine group, -9.9/-8.2 mm Hg for the amlodipine (5 mg)/HCTZ (25 mg) group, and -26.2/-16.4 mm Hg for the amlodipine (5 mg)/benazepril (20 mg) group (P < .0167, group 3 v group 1 diastolic BP, which was statistically significant by the improved Bonferroni method). Seventeen of the 47 patients developed at least a 10% increase in lower extremity edema water displacement in response to 5 mg/day of oral amlodipine therapy (36.2%). Adding 5 mg of amlodipine to a baseline of 5 mg of amlodipine resulted in no net change in lower extremity edema (+58.0 mL,+ 0.6% change, n=5). Adding 25 mg of HCTZ reduced lower extremity edema by a mean of 136.3 mL (-11.1% change, n=4). Benazepril reduced water displacement by 204.4 mL (-14.3% change, n=8). Our pilot study indicates that adding an angiotensin converting enzyme inhibitor to a dihydropyridine calcium channel blocker is the most effective way to not only reduce systolic and diastolic BP but also attenuate lower extremity edema. Due to the inherent daily variability of lower extremity edema, power calculations indicate many patients (n=702, 356 in each group) would be needed to compare the antiedema efficacy of the angiotensin converting enzyme inhibitor and the thiazide diuretic.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Body Water; Calcium Channel Blockers; Dihydropyridines; Diuretics; Drug Therapy, Combination; Edema; Female; Humans; Leg; Male; Middle Aged; Pilot Projects; Treatment Outcome

All studies suggesting a lower incidence of edema on lacidipine than on amlodipine are based on subjective scoring. Therefore, we have compared edema formation on two dihydropyridine calcium channel blockers, using an accurate method for quantitative assessment of foot volume. In a randomized study, we treated 62 patients with essential hypertension for 12 weeks starting with either lacidipine 4 mg o.d. (n = 30) or amlodipine 5 mg o.d. (n = 32). At 6 weeks, the doses were increased to that maximally allowed (lacidipine 6 mg, n = 18; amlodipine 10 mg, n = 12) if trough diastolic blood pressure response was insufficient (>90 mmHg and decrease < 10 mmHg). Edema, scored visually, occurred more frequently (p = 0.02) on amlodipine (15/32) than on lacidipine (6/30); this was confirmed by an increase of foot volume above the 95% upper limit of normal variation in 15 patients on amlodipine and in only five patients on lacidipine (p = 0.01). In the whole group of patients, both the increases of foot volume and the decreases of blood pressure just failed to be significantly different between amlodipine and ]acidipine (foot volume, +3.3+/-1.0% on amlodipine and +1.2+/-0.5% on lacidipine, p = 0.08; mean arterial pressure, -11+/-1% on amlodipine and -8+/-1% on lacidipine, p = 0.052). In patients requiring dose increase, the increase of foot volume on amlodipine was more pronounced (p < 0.05), and the antihypertensive effect was larger (p < 0.05) than on lacidipine. In conclusion, our data show a higher incidence of edema on amlodipine than on lacidipine, which has to be explained at least partly by a comparably higher dose c.q. a larger antihypertensive effect of amlodipine. Other mechanisms might have contributed to these differences and need to be explored.

Topics: Adolescent; Adult; Aged; Amlodipine; Ankle; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Edema; Female; Foot; Humans; Hypertension; Joint Diseases; Male; Middle Aged; Single-Blind Method

Topics: Adult; Calcium Channel Blockers; Clarithromycin; Dihydropyridines; Edema; Humans

Hypertension is the most common cardiovascular disease. In Nepal, 27.3% populations are suffering from hypertension. Amlodipine is the most frequently prescribed anti-hypertensive drug. Up to 15% of patients develop pedal edema with amlodipine that may lead to discontinuation. Cilnidipine, a new calcium channel blocker, found equally effective and edema is uncommon in different studies from India. We aimed to study anti-hypertensive effect and to assess resolution of amlodipine induced Pedal edema with clinidipine.. This was a prospective, single centre observational study. Study was conducted in the department of cardiology, Manipal teaching hospital from 7th May to 6th November 2020. Hypertensive Patients who were on amlodipine for at least 6 months and presented with pedal edema were enrolled for the study.. Total of 107 patients were enrolled for the study. The mean age of patients was 56.35 ± 12.84 years, ranged from 29 to 85 years and more than half(52.3 %) were male. Of the 107 patients, 90 (84.1%) patients received 10mg of clinidipine. On follow up, all patients except three (2.8%) had resolution of pedal edema. The blood pressure reduction with clinidipine was comparable with amlodipine (p: >0.05). Three patients who had persistent edema on follow up were on higher dose of clinidipine.. The newer L and N type CCB, Clinidipine has comparable efficacy with amlodipine and well tolerated in our population. Though the incidence of pedal edema is low but can occur with clinidipine especially with higher doses.

Topics: Adult; Aged; Aged, 80 and over; Amlodipine; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Edema; Hospitals, Teaching; Humans; Male; Middle Aged; Nepal; Prospective Studies; Tertiary Healthcare

Calcium channel blockers, specifically dihydropyridine calcium channel blockers (DH CCBs, eg, amlodipine), may cause lower-extremity edema. Anecdotal reports suggest this may result in a prescribing cascade, where DH CCB-induced edema is treated with loop diuretics.. To assess the magnitude and characteristics of the DH CCB prescribing cascade.. This cohort study used a prescription sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of DH CCBs among patients aged 20 years or older without heart failure. Data from a private insurance claims database from 2005 to 2017 was analyzed. Use of loop diuretics associated with initiation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and other commonly used medications was used as negative controls. Data were analyzed from March 2019 through October 2019.. Initiation of DH CCB or negative control medications.. The temporality of loop diuretic initiation relative to DH CCB or negative control initiation. Secular trend-adjusted sequence ratios (aSRs) with 95% CIs were calculated using data from 360 days before and after initiation of DH CCBs.. Among 1 206 093 DH CCB initiators, 55 818 patients (4.6%) (33 100 [59.3%] aged <65 years; 32 916 [59.0%] women) had a new loop diuretic prescription 360 days before or after DH CCB initiation, resulting in an aSR of 1.87 (95% CI, 1.84-1.90). An estimated 1.44% of DH CCB initiators experienced the prescribing cascade. The aSR was disproportionately higher among DH CCB initiators who were prescribed high doses (aSR, 2.20; 95% CI, 2.13-2.27), initiated amlodipine (aSR, 1.89; 95% CI, 1.86-1.93), were men (aSR, 1.96; 95% CI, 1.91-2.01), and used fewer antihypertensive classes (aSR, 2.55; 95% CI, 2.47-2.64). The evaluation of ACE inhibitors or ARBs as negative controls suggested hypertension progression may have tempered the incidence of the prescribing cascade (aSR for ACE inhibitors and ARBs, 1.27; 95% CI, 1.24-1.29).. This study found an excessive use of loop diuretics following initiation of DH CCBs that cannot be completely explained by secular trends or hypertension progression. The prescribing cascade was more pronounced among those initially prescribed a high dose of DH CCBs.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Drug Therapy, Combination; Edema; Female; Humans; Hypertension; Leg; Male; Middle Aged; Young Adult

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Topics: Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Data Interpretation, Statistical; Dihydropyridines; Edema; Humans; Hypertension; Meta-Analysis as Topic; Risk Assessment; Treatment Outcome

Lung injury is a common finding and a frequent cause of death in cases of severe human envenoming by scorpion sting. The present work investigated the effects of pretreatment with a platelet activation factor receptor (PAFR) antagonist and a CXCR2 inhibitor on the lung injury induced by subcutaneous injection of Tityus serrulatus venom (TsV) in mice. Lung injury was assessed by evaluating the extravasation of Evans blue dye, as an index of increased vascular permeability, the neutrophil accumulation (mieloperoxidase activity), the concentration of tumor necrosis factor-alpha (TNF-alpha) and the chemokine KC in the lung after TsV administration. Neutrophil influx was preceded by the production of KC and dependent on CXCR2, as shown by the ability of repertaxin, a CXCR2 inhibitor, to prevent an increase of MPO activity in the lung. Repertaxin had no effect on TsV-induced lethality. The PAFR antagonist (UK-74,505) significantly reduced TsV-induced vascular permeability changes and neutrophil influx in the lungs. The inhibition of neutrophil influx was associated with inhibition of the production of the CXCR2-active chemokine KC. UK-74,505 had no effect on the lethality induced by TsV. In conclusion, these results show that the influx of neutrophils in the lungs of mice injected with TsV is dependent on the activation of PAFR and on PAFR-dependent production of the chemokine KC as well as activation of CXCR2 on neutrophils. Although lung injury may contribute to late lethality after TsV envenoming, acute lethality is not modified by inhibitors of neutrophil influx.

Topics: Animals; Chemokines, CXC; Dihydropyridines; Dose-Response Relationship, Drug; Edema; Granulocyte Colony-Stimulating Factor; Imidazoles; Interleukin-3; Lung Diseases; Male; Mice; Neutrophils; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Recombinant Fusion Proteins; Recombinant Proteins; Scorpion Venoms; Scorpions; Sulfonamides; Time Factors

Topics: Adolescent; Adult; Amlodipine; Calcium Channel Blockers; Child; Child, Preschool; Cyclosporine; Dihydropyridines; Edema; Female; Flushing; Humans; Hypertension; Infant; Male

Topics: Animals; Ankle; Calcium Channel Blockers; Dihydropyridines; Edema; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney

Cerebrocrast (IOS 1.1212; 4-[2-(difluoromethoxy)phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid di(2-propoxyethyl) diester) is a novel derivative of 1,4-dihydropyridine, which does not antagonize Ca(2+) influx in neuronal tissues. Since several classical dihydropyridines possess anti-inflammatory properties, we first studied the effects of cerebrocrast in a model of rat paw edema induced by carrageenan. Cerebrocrast had a preventative effect in this model of inflammation, with maximal activity (32-45% inhibition) in the 0.1-0.25 mg kg(-1) range. It was ineffective when added after the injection of carrageenan. Subsequent in vitro experiments showed that cerebrocrast in the micromolar range inhibited secretion of interleukin-1 beta, interleukin-6 and neurotoxic products by cells of the human monocytic THP-1 line while failing to affect secretion of tumor necrosis factor (TNF-alpha). It also lacked any direct neuroprotective effect against toxic secretions from stimulated THP-1 cells. The data obtained suggest that cerebrocrast may be useful not only in various inflammatory disorders of peripheral tissues, but also in treating neurodegenerative diseases, where inflammatory mechanisms in general and microglial activation, in particular, are thought to play an important role.

Topics: Animals; Anti-Inflammatory Agents; Dihydropyridines; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Forelimb; Humans; Male; Monocytes; Rats; Rats, Wistar; Tumor Cells, Cultured

Topics: Calcium Channel Blockers; Dihydropyridines; Edema; Erythema; Exanthema; Humans; Hyperpigmentation; Hypertension; Male; Middle Aged; Nifedipine

1. The sensory neuropeptide substance P (SP), when released from sensory nerves, has been implicated in the development of neurogenic inflammation. In the present study, using an in vivo model system, we have characterized and investigated the mechanisms underlying SP-induced leukocyte accumulation and oedema formation in the guinea-pig. 2. Intradermally injected SP (i.d., 10(-13) - 10(-9) mol per site), induced a dose- and time-dependent accumulation of 111In-neutrophils, 111In-eosinophils and oedema formation as measured by the local accumulation of i.v. injected 125I-albumin. The leukocyte accumulation evoked by SP was significant at 10(-10) and 10(-9) mol per site, whereas oedema formation was significant at the lowest dose tested (10(-13) mol per site). 3. The NK1 receptor antagonists, CP-96,345 (1 mg kg-1, i.v.) and RP-67,580 (10 micrograms per site, i.d.), significantly attenuated the oedema formation induced by the lower doses of SP. Oedema formation and leukocyte accumulation induced by 10(-9) mol per site SP were unaffected by either antagonist. 4. SP-elicited responses were not significantly affected by the platelet activating factor (PAF) receptor antagonist, UK-74,505 (2.5 mg kg-1, i.v.) or the H1 histamine receptor antagonist, chlorpheniramine (10(-8) mol per site, i.d.). However, the 111In-eosinophil accumulation, but not the 111In-neutrophil accumulation or oedema formation, induced by SP was significantly inhibited by the specific 5-lipoxygenase (5-LO) inhibitor, ZM-230,487 (10(-8) mol per site, i.d.). 5. The accumulation of both 111 In-neutrophils and 111 In-eosinophils induced by SP was abolished in guinea-pigs treated i.v. with an anti-CD18 monoclonal antibody 6.5E F(ab')2 (2.5 mg kg-1). The oedema response was unaffected in these animals.6. These results suggest that SP-induced inflammatory events may be mediated via two mechanisms involving NK1 receptor-dependent and independent pathways. Oedema formation induced by the lower doses of SP may be mediated via the direct activation of NK1 receptors whilst, at higher doses, oedema formation and leukocyte accumulation may be mediated via the release of secondary mediators, possibly mast cell derived, with 5-LO products playing an important role in the leukocyte infiltration. The leukocyte accumulation, but not the oedema induced by SP, is dependent on the expression of the CD18antigen on leukocytes.

Topics: Animals; Antibodies, Monoclonal; Biphenyl Compounds; Chlorpheniramine; Dihydropyridines; Dose-Response Relationship, Drug; Edema; Female; Guinea Pigs; Imidazoles; Indoles; Inflammation; Isoindoles; Neurokinin-1 Receptor Antagonists; Pyrans; Quinolones; Skin; Substance P; Time Factors

Although our understanding of the molecular interactions that mediate the adhesion of leukocytes to venular endothelial cells has greatly expanded, very little is known about the mechanisms that mediate the passage of leukocytes across the vessel wall in vivo. The aim of the present study was to investigate the role of endogenously formed platelet-activating factor (PAF) in the process of leukocyte extravasation induced by interleukin-1 (IL-1). To determine at which stage of emigration PAF was involved, we studied the behavior of leukocytes within rat mesenteric microvessels by intravital microscopy. Rats were injected intraperitoneally with saline, recombinant rat IL-1 beta (IL-1 beta), or the peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) 4 hours before the exteriorization of the mesenteric tissue. In animals treated with IL-1 beta there was a significant increase in the number of rolling and adherent leukocytes within venules (20- to 40-micron diameter) and in the number of extravasated leukocytes in the tissue. Pretreatment of rats with the PAF receptor antagonist UK-74,505 had no effect on the leukocyte responses of rolling and adhesion, but significantly inhibited the migration of the leukocytes across the vessel wall induced by IL-1 beta (76% inhibition). A structurally unrelated PAF antagonist, WEB-2170, produced the same effect (64% inhibition). However, in contrast, UK-74,505 had no effect on the leukocyte extravasation induced by FMLP, indicating selectivity for the response elicited by certain mediators. These results provide the first line of direct evidence for the involvement of endogenously formed PAF in the process of leukocyte extravasation induced by IL-1 in vivo.

Topics: Animals; Azepines; Cell Adhesion; Chemotaxis, Leukocyte; Dihydropyridines; Edema; Imidazoles; Inflammation; Interleukin-1; Leukocytes; Male; Mesentery; Microcirculation; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activating Factor; Platelet Membrane Glycoproteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Recombinant Proteins; Skin; Triazoles

The aim of the present study was to investigate directly and characterize the ability of IL-1 beta in inducing eosinophil accumulation in vivo. For this purpose, we studied the recruitment of 111In-labeled eosinophils in rat skin in response to intradermally injected rat rIL-1 beta. Rat rIL-1 induced a dose-dependent accumulation of 111In-labeled eosinophils, with the maximal response being detected at 5 x 10(-13) mol/site. This response was slow in onset, progressively increasing over the 4-h period investigated. Rat rIL-1 also induced a small level of edema, as measured by the local accumulation of i.v. 125I-labeled albumin, which developed with a time course similar to that of 111In-labeled eosinophil accumulation. Co-administration of the cytokine with the IL-1R antagonist, IL-1ra, or actinomycin D, significantly inhibited the 111In-labeled eosinophil accumulation, and reduced the edema formation, induced by rat rIL-1. In addition, the 111In-labeled eosinophil accumulation was significantly suppressed in animals treated with the PAF antagonist UK-74,505 or an anti-human IL-8 mAb DM/C7. These observations demonstrate for the first time that IL-1 beta is a potent inducer of eosinophil accumulation in vivo. Moreover, the results reveal that this activity of IL-1 beta is receptor mediated and dependent on the induction of proteins that may be involved in the local generation of secondary inflammatory mediators including PAF and an IL-8-like molecule. These findings are consistent with the view that endogenously generated IL-1 may play an important role in the recruitment of eosinophils at sites of allergic inflammation.

Topics: Animals; Antibodies, Monoclonal; Calcium; Chemotaxis, Leukocyte; Dactinomycin; Dihydropyridines; Edema; Eosinophils; Imidazoles; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-8; Leukotriene B4; Male; Platelet Activating Factor; Rats; Rats, Sprague-Dawley; Sialoglycoproteins; Skin

Clinical studies suggest that lacidipine (LA) is better tolerated than other DHP, in terms of peripheral edema. We evaluated edema due to LA, nitrendipine (NT) and nifedipine (NF) in SHR.. Mean arterial pressure (MAP) was measured with an intra-femoral probe. Peripheral edema was determined (i) by the plasmatic distribution of 14C-albumin, (ii) by Evans blue extravasation.. In bolus(ip), LA, NT and NF had non different effects on plasmatic *ALB, i.e. + 3.9 +/- 1.7 (delta % vs control at 60 min; mean +/- SEM, n = 18). Evans blue extravasation (hind paws muscle = EBM) was positively correlated to MAP reduction (EBM = 0.1 x delta MAP + 5.2; p < 0.025), without differences between the molecules. In chronical administration (9 days), at comparable MAP decreases (31 +/- 2 mmHg), there was less edema formation with LA (0.05 mg/kg/j) than with NT (0.5 mg/kg/j) or NF (1.4 mg/kg/j): the variations of *ALB were respectively (% vs control at 45 min after tracer injection; mean +/- SD): + 5% (n = 10) vs. 73% (n = 14; p < 0.01 vs LA) and + 34% (n = 10; p < 0.01 vs LA); no significant change of hematocrit or plasma volume was noted.. Our results confirm, in SHR, that lacidipine induces a very moderate edema formation. This does not seem to be due to a renal effect, nor to an effect on peripheral resistances. It was only observed in chronical administration, which suggests that pharmacokinetic properties of lacidipine are involved.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Edema; Nifedipine; Nitrendipine; Rats; Rats, Inbred SHR; Serum Albumin

1. The effect of the dihydropyridine, platelet activating factor (PAF) receptor antagonist, UK-74,505, on leucocyte accumulation and oedema formation in guinea-pig skin was investigated. The inflammatory reactions studied were elicited by exogenous mediators, a passive cutaneous anaphylactic (PCA) reaction and zymosan particles. 2. Leucocyte accumulation and oedema formation were measured as the local accumulation of i.v. administered 111In-labelled neutrophils or eosinophils together with 125I-labelled albumin. UK-74,505 was either administered i.v. or used to pretreat the radiolabelled leucocytes in vitro prior to their last wash and injection into recipient animals. 3. In vitro, UK-74,505 inhibited PAF-induced elevations in cytoplasmic levels of Ca2+ ([Ca2+]i) in fura-2-loaded guinea-pig neutrophils and eosinophils with IC50 values of 10(-9) M and 7 x 10(-9) M respectively. Neutrophils and eosinophils pretreated with 10(-7) M and 10(-6) M UK-74,505 respectively, and maintained at 37 degrees C, were unresponsive to PAF for the 4 h period investigated. 4. In vivo, using 2 h test periods, i.v. UK-74,505 (0.5 and 2.5 mg kg-1) inhibited the accumulation of 111In-neutrophils, 111In-eosinophils and oedema formation induced by intradermal PAF, but had no effect on responses elicited by leukotriene B4 (LTB4) and zymosan-activated plasma (ZAP, used as a source of C5a des Arg). UK-74,505 (2.5 mg kg-1) was also without an effect on response induced by a PCA reaction but significantly suppressed the 111In-eosinophil accumulation following the intradermal administration of zymosan particles. The 111In-neutrophil accumulation induced by zymosan particles was not, however, affected by UK-74,505. 5. In a second series of in vivo experiments, "'In-leucocytes were pretreated in vitro with UK-74,505 prior to their last wash and injection into recipient animals. Radiolabelled neutrophils, and eosinophils were pretreated with 10-7 M and 10-6 M UK-74,505 respectively, concentrations previously shown to block the leucocyte responses to PAF in vitro for up to 4 h. The in vitro pretreatment of the cells with the PAF antagonist, whilst not affecting the responses to intradermally-injected PAF, suppressed the"'In-eosinophil accumulation response induced by zymosan particles.6. The results of this study indicate that PAF is not involved in neutrophil accumulation, eosinophil accumulation and oedema formation induced by LTB4, ZAP and a PCA reaction. Endogenous PAF does, however, ap

Topics: Animals; Blood Proteins; Calcium; Dihydropyridines; Edema; Eosinophils; Female; Guinea Pigs; Imidazoles; Leukotriene B4; Neutrophils; Passive Cutaneous Anaphylaxis; Peritoneal Cavity; Platelet Activating Factor; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Skin; Zymosan

A series of 5-[3-(1,6-dihydropyridyl)]-2H-tetrazol-2-acetic acids (15-21), esters (7-14, 22-23) and amides (24-27) were synthesized in order to investigate the effect of alpha-substituents (R1 = H, Me) and 1,6-dihydropyridyl substituents (R2 = aryl, alkyl; R3 = phenoxy or amino) on antiinflammatory activity. Compounds having a R1 = H substituent generally exhibited greater activity. R2-aryl substituents showed higher potency except when R1 was Me in the acetic acid ester group of compounds. The relative potency order with respect to the R3-substituent was NH2 > PhO. When the R2-substituent was an aryl moiety, the effect of the R4-substituent on antiinflammatory activity was acid (R4 = OH) > or = ester (R4 = OMe), but when the R2-substituent was an alkyl group, the order of potency was generally ester > acid. Methyl 2-methyl-2-(5-[3-(6-i-butyl-1-phenoxycarbonyl-1,6-dihydropyridy l)]-2H- tetrazol-2-yl)acetate (13) was the most effective antiinflammatory agent in the group, reducing inflammation 93%, relative to ibuprofen's 52% inhibition, at 5 hr after a 100 mg/kg po dose.

Topics: Acetates; Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dihydropyridines; Edema; Esters; Rats; Structure-Activity Relationship; Tetrazoles

The interference of the novel platelet-activating factor (PAF) receptor antagonist compound PCA 4248 with paw edema induced by antigen in sensitized boosted or unboosted mice was studied. Although PAF-induced edema was of similar intensity in non-sensitized and in both groups of sensitized mice, PCA 4248 was less effective in inhibiting paw edema induced by PAF in boosted mice. Paw edema induced by antigen in unboosted mice was refractory to PCA 4248 under conditions where edema in boosted mice was inhibited. Our results demonstrate that the PCA 4248 displays an anti-PAF activity in non-sensitized mice that is reduced by the booster injection of antigen. PAF plays an important role in the anaphylactic edema in boosted but not in unboosted mice.

Topics: Animals; Dihydropyridines; Edema; Injections, Intraperitoneal; Male; Mice; Ovalbumin; Platelet Activating Factor

This study investigated the effect of the platelet-activating factor (PAF) receptor antagonist, PCA 4248, on the rat pleurisy caused by PAF, serotonin, bradykinin, histamine or allergen. The pleurisy was assessed by measuring liquid extravasation and leucocyte infiltration. Oral pretreatment with PCA 4248 (2.5-20 mg/kg) completely inhibited the pleural exudation caused by intrathoracic (i.t.) injection of PAF (1 microgram/cavity) (ED50 = 6.1 mg/kg), partially (42% reduction) the one induced by serotonin (100 micrograms/cavity), but was inactive against histamine (200 micrograms/cavity) or bradykinin (50 micrograms/cavity). PCA 4248 blocked the increase in the number of neutrophils, eosinophils and mononuclear cells observed 6 h after the i.t. injection of PAF, as well as the selective eosinophil accumulation noted 24 h later. In actively sensitized rats, PCA 4248 (20 mg/kg) failed to modify the increase in the total leucocyte counts noted 4 h after ovalbumin (12 micrograms/cavity), but dose dependently inhibited the pleural exudation observed within 1 h and the late eosinophil infiltration noted 24 h post-antigen. These observations led us to suggest that PCA 4248 is a potent PAF antagonist with anti-serotoninergic properties. Its interference with exudation and eosinophil infiltration caused by allergen is consistent with the interpretation that PCA 4248 may be useful in the management of allergic dysfunctions.

Topics: Allergens; Animals; Bradykinin; Dihydropyridines; Edema; Eosinophils; Exudates and Transudates; Female; Histamine; Hypersensitivity; Leukocyte Count; Male; Neutrophils; Platelet Activating Factor; Platelet Membrane Glycoproteins; Pleurisy; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Serotonin

1. The contribution of platelet-activating factor (PAF) to platelet deposition and oedema formation induced by exogenous soluble mediators, zymosan particles and associated with a reversed passive Arthus (RPA) reaction in rabbit skin was investigated by use of a novel long-acting PAF receptor antagonist, UK-74,505. 2. Oedema formation and platelet accumulation were simultaneously measured by i.v. injection of [125I]-albumin and 111In-labelled rabbit platelets. UK-74,505 was either administered i.v. or used to pretreat radiolabelled platelets in vitro before their injection into recipient animals. Platelets pretreated with UK-74,505 were also labelled with the fluorescent calcium indicator, Fura-2, to assess their ex vivo reactivity to PAF at the end of the in vivo experiment. 3. UK-74,505 (0.5 mg kg-1), administered i.v., inhibited PAF-induced oedema formation, but did not affect oedema induced by zymosan particles, bradykinin (BK), histamine, formyl-methionyl-leucylphenylalanine (FMLP), zymosan-activated plasma (ZAP, as a source of C5a des Arg), leukotriene B4 (LTB4) or interleukin-8 (IL-8). 4. UK-74,505, administered i.v. also suppressed the small platelet accumulation induced by exogenous PAF, but had no effect on accumulation induced by IL-8 or ZAP. Although oedema induced by zymosan was not affected by i.v. UK-74,505, zymosan-induced platelet accumulation was significantly attenuated by the antagonist. 5. The RPA reaction in rabbit skin was associated with marked oedema formation and platelet accumulation which were both inhibited by i.v. UK-74,505. 6. In vitro, UK-74,505 inhibited aggregation and the increase in intracellular calcium concentration induced by PAF in rabbit washed platelets in a concentration-dependent manner (IC50 = 1.6 x 10-8 M and 1.1 x 10-8 M, respectively). Platelets pretreated with 10-6 M UK-74,505, and maintained at 37 degrees C,were unresponsive to PAF, whilst responding normally to thrombin, for up to 4 h.7. In a second series of in vivo experiments, platelets were labelled with 111In and loaded with Fura-2.The platelets were then pretreated with 10-6 M UK-74,505, washed, and injected into recipient rabbits.These platelets, prepared from blood samples taken at the end of the in vivo experiments, exhibited an 80% reduction in their response to PAF as measured ex vivo with Fura-2. However, in contrast to the effects of i.v. UK-74,505, platelets pretreated with the antagonist did accumulate effectively in the RPA reaction, a sig

Topics: Animals; Arthus Reaction; Blood Platelets; Calcium; Dihydropyridines; Edema; Fura-2; Imidazoles; In Vitro Techniques; Indium Radioisotopes; Platelet Activating Factor; Platelet Aggregation; Rabbits; Serum Albumin; Skin; Zymosan

The potential participation of PAF-acether (PAF) on the paw oedema triggered by enterolobin was investigated. Intraplantar injections of enterolobin (5-20 micrograms/paw) yielded a dose response curve for oedema which appeared after 30 min, peaked in the interval between 2-4 h and faded after 24 h. The pre-treatment with BN 52021, but not with other PAF antagonists such as PCA 4248 or WEB 2086, significantly blocked enterolobin-induced oedema. To clarify better the discrepant results obtained with the PAF antagonists, desensitization to PAF was performed. The oedema triggered by enterolobin was not modified in PAF desensitized animals. It was concluded that the paw inflammation induced by enterolobin does not require PAF mechanism.

Topics: Animals; Azepines; Dihydropyridines; Diterpenes; Edema; Ginkgolides; Lactones; Male; Plant Proteins; Platelet Activating Factor; Rats; Rats, Wistar; Triazoles

Thirteen 5-[3-(1,4-dihydropyridyl)]-2H-tetrazol-2-acetic acids (18-30), seventeen esters (4-17, 32, 35, 41) and eight amides (31, 32-34, 36-40) were synthesized in order to investigate the effect of alpha-substituents (R1 = H, Me) and 1,4-dihydropyridyl substituents (R2 = aryl, alkyl; R3 = phenoxy, methoxy or amino) on anti-inflammatory activity. The effects of the R1, R2 or R3-substituents were variable but highly interdependent. The relative order of anti-inflammatory potency was generally acid greater than amide and ester. Methyl 2-methyl-2-(5-[3-(4-phenyl-1-carbamoyl-1,4-dihydropyridyl)]-2H- tetrazol-2-yl) acetate (35) was the most effective anti-inflammatory agent in the group, reducing inflammation 96% at 5 hr after a 50 mg/kg po dose, relative to ibuprofen's 52% inhibition at 5 hr after a 100 mg/kg po dose.

Topics: Acetates; Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Dihydropyridines; Edema; Esters; Prodrugs; Rats; Structure-Activity Relationship; Tetrazoles

A group of N-substituted-1,4-dihydropyridylacetic acids (13-16), esters (4-12), and amides (17-23) were synthesized in order to investigate the effect of 4-substituents (R2 = Ph, n-Bu or Me) and alpha-substituents (R3 = H, Me) on antiinflammatory activity. In the acetic ester class of compounds, the relative activities (R2-substituents) were Ph greater than n-Bu greater than Me. The presence of an R3 methyl substituent enhanced activity. Increasing the length of the alkyl ester substituent enhanced activity, since the tri-ester (7) was more active than the bis-ester (6), and the bis-ester (11) was more active than the mono-ester (10). The relative order of antiinflammatory potency was generally ester greater than amide greater than acid. Methyl 2-methyl-2-(-1-[4-phenyl-3-(4,4-dimethyloxazolin-2-yl)-1,4-dihy dropyridyl]) acetate (9) was the most active antiinflammatory agent in the series, reducing inflammation 73.9% at 3 hr after a 100 mg/kg po dose.

Topics: Acetates; Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dihydropyridines; Edema; Esters; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Rats; Rats, Inbred Strains; Structure-Activity Relationship