fumarates and Edema

Peripheral edema is a common adverse effect of calcium channel blockers. The addition of a renin-angiotensin system blocker, either an angiotensin-converting enzyme inhibitor or an ARB, has been shown to reduce peripheral edema in a dose-dependent way.. We performed a MEDLINE/COCHRANE search for all prospective randomized controlled trials in patients with hypertension, comparing calcium channel blocker monotherapy with calcium channel blocker/renin-angiotensin system blocker combination from 1980 to the present. Trials reporting the incidence of peripheral edema or withdrawal of patients because of edema and total sample size more than 100 were included in this analysis.. We analyzed 25 randomized controlled trials with 17,206 patients (mean age 56 years, 55% were men) and a mean duration of 9.2 weeks. The incidence of peripheral edema with calcium channel blocker/renin-angiotensin system blocker combination was 38% lower than that with calcium channel blocker monotherapy (P<.00001) (relative risk [RR] 0.62; 95% confidence interval [CI], 0.53-0.74). Similarly, the risk of withdrawal due to peripheral edema was 62% lower with calcium channel blocker/renin-angiotensin system blocker combination compared with calcium channel blocker monotherapy (P=.002) (RR 0.38; 95% CI, 0.22-0.66). ACE inhibitors were significantly more efficacious than ARBs in reducing the incidence of peripheral edema (P<.0001) (ratio of RR 0.74; 95% CI, 0.64-0.84) (indirect comparison).. In patients with hypertension, the calcium channel blocker/renin-angiotensin system blocker combination reduces the risk of calcium channel blocker-associated peripheral edema when compared with calcium channel blocker monotherapy. ACE inhibitor seems to be more efficacious than ARB in reducing calcium channel blocker-associated peripheral edema, but head-to-head comparison studies are needed to prove this.

Topics: Amides; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Drug Therapy, Combination; Edema; Female; Fumarates; Humans; Hypertension; Incidence; Male; Middle Aged; Randomized Controlled Trials as Topic; Renin; Renin-Angiotensin System; Research Design; Treatment Refusal

KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  Aliskiren, the sole oral renin inhibitor approved by the US Food and Drug Administration, is indicated for the treatment of hypertension, either as monotherapy or in combination, with reductions in blood pressure similar to other agents. •  Early evidence suggests that aliskiren confers additional benefit in patients with diabetic nephropathy. Data are not yet available to determine whether protection will extend to cardiovascular disease. •  No initial dosage adjustment is required in elderly patients or for patients with mild to severe renal impairment; however, clinical experience is limited in patients with significant renal impairment, and with renal artery stenosis. •  It appears rational to combine aliskiren with agents that otherwise increase plasma renin activity, including thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. •  While there is a reactive rise in renin in response to aliskiren, probably larger than that induced by angiotensin receptor blockers and angiotensin-converting enzyme inhibitors, there is no evidence that this rise is harmful. •  In placebo-controlled studies, the incidence of edema anywhere in the body was 0.4% with aliskiren compared with 0.5% with placebo. It is unknown whether angioedema rates are higher in blacks with aliskiren. •  Aliskiren is associated with a slight increase in cough, with rates of about one third to one half seen with angiotensin-converting enzyme inhibitors. •  Increases in serum potassium >5.5 meq/L were infrequent in patients with essential hypertension treated with aliskiren alone (0.9% compared with 0.6% with placebo).

Topics: Amides; Antihypertensive Agents; Cough; Edema; Fumarates; Humans; Hypertension; Renin; Treatment Outcome

The aim of this study was to assess the effect of aliskiren and amlopidine on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP).. After 4-week placebo, 120 outpatients with grade 1 - 2 hypertension were randomized to amlodipine 10 mg or aliskiren 300 mg or their combination for 8 weeks in three crossover periods. At the end of each treatment, blood pressure, AFV, PSTP, plasma renin activity (PRA) and norepinephrine were assessed.. Both monotherapies similarly reduced systolic blood pressure (SBP; p < 0.001) and diastolic blood pressure (DBP; p < 0.001), but the reduction was greater with amlodipine/aliskiren combination (SBP: - 24.6 mmHg, p < 0.001 vs monotherapy; DBP: -20.9 mmHg, p < 0.01 vs monotherapy). Amlodipine increased both AFV (+ 28.4%, p < 0.01) and PSTP (+ 80.4%, p < 0.01), while the combination produced a less marked increase in AFV (+ 6.6%, p < 0.01 vs amlodipine) and PSTP (+ 20.1%, p < 0.01 vs amlodipine). Plasma norepinephrine increased with amlodipine (+ 53.5%, p < 0.01) and this increase was not reduced by aliskiren addition. PRA was unaffected by amlodipine, while it was reduced by both aliskiren monotherapy (- 77.7%, p < 0.01) and aliskiren/amlodipine combination (- 75.7%, p < 0.01).. Direct renin inhibition by aliskiren partially counteracts the microcirculatory changes responsible for calcium-channel-induced edema formation, possibly through preferential vasodilation of venous capacitance vessels.

Topics: Amides; Amlodipine; Ankle; Ankle Joint; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cross-Over Studies; Drug Synergism; Drug Therapy, Combination; Edema; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Norepinephrine; Prospective Studies; Renin; Renin-Angiotensin System

Initial multiple drug therapy for hypertension achieves greater and quicker reductions and higher blood pressure (BP) control rates than monotherapy. This 8-week, prospective, multicenter, randomized, double-blind study compared the efficacy and safety of the initial combination of aliskiren/amlodipine with amlodipine monotherapy in African Americans with stage 2 hypertension. After a 1- to 4-week washout, patients received aliskiren/amlodipine 150/5 mg or amlodipine 5 mg for 1 week and then were force-titrated to aliskiren/amlodipine 300/10 mg or amlodipine 10 mg for 7 weeks. At week 8, greater reductions in mean sitting systolic BP were obtained with aliskiren/amlodipine (n = 220) than with amlodipine (n = 223) (least squares mean change [standard error of the mean], -34.1 [1.14] mm Hg vs -28.9 [1.12] mm Hg; P<.001). Ambulatory and central BP measures were consistent with clinic BP findings, although these were conducted in a small subset of patients (n = 94 in ambulatory BP monitoring substudy and n = 136 for central BP). More patients achieved goal BP (<140/90 mm Hg) with aliskiren/amlodipine than with amlodipine at week 8 (57.3% vs 48.0%; P = .051). Both treatment groups had similar adverse event rates (35.0% and 32.7%, respectively). The most common adverse events were peripheral edema (7.7% with aliskiren/amlodipine and 9.0% with amlodipine), headache, fatigue, and nausea. The combination of aliskiren/amlodipine reduced peripheral, ambulatory, and central BP more than amlodipine alone with similar tolerability in African Americans with stage 2 hypertension.

Topics: Adult; Amides; Amlodipine; Black or African American; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Drug Therapy, Combination; Edema; Fatigue; Female; Fumarates; Headache; Humans; Hypertension; Incidence; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Treatment Outcome

The present study was designed to evaluate the anti-inflammatory effects of different doses of aliskiren in two animal models of inflammation.. Sixty-six Wistar rats were allocated into five groups: the first group (six rats) was treated with the vehicle only, without induction of paw edema and granulomatous inflammation, and served as a negative control; the second group (12 rats) was allocated into two subgroups and treated with the vehicle only, with induction of paw edema and granulomatous inflammation, and served as a positive control; the third group (36 rats) was allocated into six subgroups and treated with different doses of aliskiren (15, 30, and 60 mg/kg) in both models; the fourth group (12 rats) was treated with dexamethasone (1 mg/kg) in both models of inflammation. Serum concentrations of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1), and high sensitivity C-reactive protein (hs-CRP) were measured. Skin samples were also sent for histopathological examination.. Aliskiren, in a dose-dependent pattern, significantly decreased inflammation in rat models of inflammation, by attenuating the percentage of exudate, granuloma, and paw edema. Furthermore, it significantly reduced serum concentrations of TNF-α, VCAM-1, and hs-CRP and restored the serum concentration of IL-10. Additionally, significant improvement was seen in the histopathological findings.. In the current study, aliskiren was successful in decreasing inflammation in both models. These findings suggest that aliskiren is a good candidate for the treatment of inflammatory diseases.

Topics: Amides; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Female; Formaldehyde; Fumarates; Inflammation; Male; Rats; Rats, Wistar; Skin

The purpose of the present study was to evaluate the effect of implant porosity on wound healing between solid and porous implants placed within a bony mandibular defect with intraoral exposure.. Solid poly(methyl methacrylate) (PMMA) implants similar to those used currently in clinical space maintenance applications in maxillofacial surgery were compared with poly(propylene fumarate) implants that contained a porous outer surface surrounding a solid core. A 10-mm diameter nonhealing bicortical defect with open communication into the oral cavity was created in the molar mandibular region of 12 adult male New Zealand white rabbits. Of the 12 rabbits, 6 received the hybrid poly(propylene fumarate) implants and 6 received the solid PMMA implants. At 12 weeks, the rabbit mandibles were harvested and sent for histologic staining and sectioning.. Gross inspection and histologic examination showed all 6 poly(propylene fumarate) implants to be intact within the defect site at the termination of the study period, with 3 of the 6 specimens exhibiting a continuous circumferential soft tissue margin. In contrast, 5 of the 6 PMMA-implanted specimens were exposed intraorally with an incomplete cuff of soft tissue around the implant. One of the PMMA-implanted specimens exhibited complete extrusion and subsequent loss of the implant. Fisher's exact test was used to compare the occurrence of oral cavity wound healing between the 2 groups (P = .09).. Although statistically significant differences between the 2 groups were not seen, our results have indicated that advantages might exist to using porous implants for space maintenance. Additional study is needed to evaluate these findings.

Topics: Animals; Biocompatible Materials; Connective Tissue; Disease Models, Animal; Edema; Epithelium; Fumarates; Granulation Tissue; Histiocytes; Lymphocytes; Male; Mandible; Mandibular Diseases; Materials Testing; Mouth Mucosa; Neutrophils; Pilot Projects; Polymethyl Methacrylate; Polypropylenes; Porosity; Prostheses and Implants; Prosthesis Design; Rabbits; Surface Properties; Surgical Wound Dehiscence; Wound Healing

YM-393059 is a novel phosphodiesterase (PDE) 7A and PDE4 dual inhibitor that inhibits both Th1 [interleukin (IL)-2 and interferon-gamma] and Th2 (IL-4) cytokines in vitro [Yamamoto, S., Sugahara, S., Naito, R., Ichikawa, A., Ikeda, K., Yamada, T., Shimizu, Y., 2006. The effects of a novel phosphodiesterase 7A and -4 dual inhibitor, YM-393059, on T-cell-related cytokine production in vitro and in vivo. Eur. J. Pharmacol. 541, 106-114]. To characterize the pharmacological profile of YM-393059, its effects on several acute and chronic inflammation models were examined. In acute inflammation models, YM-393059 significantly suppressed the delayed-type hypersensitivity reaction to sheep red blood cells in mice with an ED(50) value of 17.1 mg/kg. YM-393059 failed to suppress paw edema in the carrageenin-induced edema model in rats. These pharmacological effects were similar to those of cyclosporine, a typical T-cell immunosuppressant. However, YM-393059, but not cyclosporine, significantly inhibited zymosan-induced neutrophil accumulation in mice with an ED(50) value of 25.7 mg/kg. In mouse toluene-2,4-diisocyanate-induced contact dermatitis, a chronic inflammation model, YM-393059 and cyclosporine significantly suppressed ear edema at doses of 30 and 20 mg/kg, respectively. In this model, YM-393059 also tended to reduce the serum immunoglobulin E antibody level, whereas cyclosporine dramatically potentiated it. These results suggest that YM-393059 inhibits both Th1- and Th2-cell-dependent reactions and also the function of neutrophils.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Acute Disease; Animals; Anti-Inflammatory Agents; Carrageenan; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclic Nucleotide Phosphodiesterases, Type 7; Cyclosporine; Dermatitis, Contact; Edema; Erythrocytes; Fumarates; Hypersensitivity, Delayed; Immunosuppressive Agents; Indoles; Inflammation; Male; Mice; Mice, Inbred BALB C; Peritonitis; Phosphodiesterase Inhibitors; Rats; Rats, Sprague-Dawley; Sheep; Sulfonamides; Toluene 2,4-Diisocyanate; Zymosan

Topics: Amides; Analgesics; Animals; Cough; Dose-Response Relationship, Drug; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Edema; Female; Fumarates; Hindlimb; Humans; Male; Motor Activity; Pain; Piperidines; Propionates; Pyridines; Respiration; Self Medication; Spasm; Substance Withdrawal Syndrome; Tail

Topics: Adult; Blister; Edema; Erythema; Fumarates; Humans; Irritants; Male; Nitriles; Pruritus; Skin Diseases; Water

Topics: Anaphylaxis; Anti-Inflammatory Agents; Arsenicals; Carbohydrate Metabolism; Dextrans; Edema; Fluorides; Fumarates; Inflammation; Insulin; Maleates; Malonates; Models, Theoretical; Pharmacology; Rats; Research; Succinates