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Dementia
Published in Henry J. Woodford, Essential Geriatrics, 2022
Unfortunately, more recent studies have not suggested a similar benefit. The HOPE3 study randomised people aged 70 and over (n = 3,038; mean age 74; mean BP 140/79 mmHg; median follow-up 5.7 years), judged to be at intermediate risk of vascular events, to receive candesartan/hydrochlorothiazide or placebo.77 BP control did not affect the rate of cognitive or functional decline compared to placebo. The SPRINT-MIND trial compared strict to lenient BP control (n = 9,361; mean age 68 [28% aged 75 or over]; median follow-up 5.1 years).78 The primary cognitive outcome of probable dementia was not significantly reduced (HR 0.83; 95% CI 0.67–1.04; 3.2% v 3.8%), but they did detect a reduction in a secondary outcome of MCI (HR 0.81; 95% CI 0.69–0.95; 6.1% v 7.5%; NNT 364 per year). So, despite the intuitive logic, lowering BP in early old age has only very limited evidence for reducing dementia in later life. In addition, the calcium channel blocker, nilvadipine, was compared to placebo for people with mild to moderate AD (n = 511; mean age 73; mean Standardised MMSE [SMMSE] 20; duration 78 weeks).79 Despite lower BP, no benefit was detected in preventing the progression of cognitive decline.
Granulation of Poorly Water-Soluble Drugs
Published in Dilip M. Parikh, Handbook of Pharmaceutical Granulation Technology, 2021
Albert W. Brzeczko, Firas El Saleh, Hibreniguss Terefe
The biggest challenge of the ASD in practice is their physical stability. The amorphous drug is not physically stable and tends to transform into crystalline counterpart, which does not have the dissolution and solubility advantages as the amorphous drug presents. PVP is not only well known as a solubilizer in solid dispersion, it is also widely recognized as a very effective amorphous stabilizer. Studies on celecoxib–PVP–meglumine ternary system suggested that PVP functions more as stabilizers and meglumine functions more like solubility enhancers in their amorphous solid dispersion [110]. The dissolution rate and saturation solubility of nilvadipine were found substantially decreased compared with the initial dissolution test of nilvadipine ASD [111]. The amorphous form physical stability of nilvadipine was improved by the use of nilvadipine/PVP/microcrystalline cellulose ternary solid dispersion system.
Hypertension and the kidney
Published in H. Gavras, The Year in Hypertension 2004, 2004
BACKGROUND. Although calcium antagonists are used as first-line antihypertensive agents, controversy abounds regarding their renal microvascular effects. Since calcium antagonists elicit a predominant vasodilatation of the afferent arteriole, they might ostensibly aggravate glomerular hypertension. Recently, novel types of calcium antagonists have been developed, some of which are reported to dilate efferent as well as afferent arterioles. This review attempted to characterize the renal microvascular action of calcium antagonists, and evaluated the consequences of renal injury following the treatment with these antagonists. In contrast to the predominant action on afferent arterioles of conventional calcium antagonists (e.g. nifedipine, nicardipine, amlodipine, and diltiazem), novel antagonists (e.g. manidipine, nilvadipine, benidipine, and efonidipine) potently dilated both afferent and efferent arterioles. The vasodilator action on efferent arterioles appears to be mediated in part by the blockade of T-type calcium channels, particularly through the inhibition of the intracellular calcium release mechanism. The comparison of the anti-proteinuric action of calcium antagonists in subtotally nephrectomized rats showed that efonidipine and enalapril, both possessing vasodilator action on efferent arterioles, exerted more prominent action than other calcium antagonists. Finally, in patients with chronic renal disease, a 48-week treatment with efonidipine reduced proteinuria, and this effect was seen even when the mean arterial blood pressure failed to fall below 100 mmHg. In conclusion, although calcium antagonists potently inhibit afferent arteriolar constriction, efferent arteriolar responses to these agents vary, depending on the types of calcium antagonists used. The divergent actions of these agents on the efferent arteriole may alter glomerular haemodynamics differently, and could affect the final outcome of underlying renal diseases.
Antihypertensive agents in Alzheimer’s disease: beyond vascular protection
Published in Expert Review of Neurotherapeutics, 2020
Thibaud Lebouvier, Yaohua Chen, Patrick Duriez, Florence Pasquier, Régis Bordet
Following exciting preclinical results, the rather old drug nilvadipine has recently gained its way to clinical trials. In a proof-of-concept case report of a mild AD patient, nilvadipine elevated both the regional cerebral blood flow and the Mini-Mental State Examination (MMSE) score [93]. Recapitulating the beneficial short-term effects observed with nimodipine, a six-week, open-label study gathering 55 patients with mild to moderate AD showed that nivaldipine was well tolerated and there was a treatment benefit on the MMSE and executive functions [94,95]. The recent 18-month European multicentre NILVAD trial was designed to demonstrate a positive effect of nilvadipine, based on this encouraging data. The study enrolled more than 500 people with mild to moderate AD according to the 1984 NINCDS-ADRDA criteria, and compared a once-daily dose of 8 mg nilvadipine to placebo during 78 weeks [96]. The study failed to demonstrate any effect of nilvadipine on the cognitive outcome. However, in predefined subgroup analyses, there was less cognitive decline in patients with MMSE >20, in males and in APOE ε4 carriers [97]. As found in the aforementioned case-report, a subgroup of patients in the NILVAD trial showed an increase of cerebral blood flow in hippocampal regions [98].
Advances in ophthalmic preparation: the role of drug nanocrystals and lipid-based nanosystems
Published in Journal of Drug Targeting, 2020
Maria Christina Camasmie Peters, Edson dos Santos Neto, Lis Marie Monteiro, Megumi Nishitani Yukuyama, Marcella Gabrielle Mendes Machado, Isabela Fernandes de Oliveira, Maria Helena Ambrosio Zanin, Raimar Löbenberg, Nádia Bou-Chacra
Aiming to study a topical pathway treatment that could target the posterior eye segment, nilvadipine nanosuspensions were prepared for treating retinal dysfunction. Their instillation attenuated retinal disorders. Besides, peripheral edema in the retina, which is known as a side effect of nilvadipine, was not observed in this repetitive instillation test. 2-hydroxypropyl-β-cyclodextrin (HPβCD) was used in this formulation as a surfactant to prevent the aggregation of solid nanoparticles [40]. This unconventional approach, which substituted the non-ionic stabilisers usually applied in these formulations, allowed increasing the drug water saturation solubility. A concentration of up to 12.5% of HP-β-CD was found not to be toxic or irritating in rabbit eyes [42].