[Pharmacological and clinical profile of spinal muscular atrophy (SMA) therapeutic drug nusinersen (Spinraza®)].

Nusinersen (Spinraza®) was approved as Japan's first antisense oligonucleotide (ASO) drug for treatment of SMA (spinal muscular atrophy) patients with a deletion or mutation of the survival motor neuron (SMN) 1 gene and ≥1 copy of the SMN2 gene. Nuseinersen is a fully modified 2'-O-(2-methoxyethyl) (2'-MOE) ASO designed to bind the SMN2 pre-mRNA and alter splicing, such that a mature mRNA is produced and is translated as full-length SMN protein. In 4 types of mouse SMA disease models, treatment with nusinersen improved the form of the neuromuscular junction, increased myofiber size, improved righting reflex and grip, and prolonged survival. The efficacy of nusinersen was verified in 2 multinational, randomized, double-blind, sham-controlled clinical studies in SMA patients with differing ages of onset and ages (ENDEAR study and CHERISH study), and improvement and maintenance of motor function by nusinersen were demonstrated regardless of the type of SMA. Moreover, both studies showed that greater efficacy may be obtained with early initiation of nusinersen treatment. Therefore, treatment with nusinersen should be started as early as possible to delay or halt progression of the disease and maximize therapeutic effect. As nusinersen is the only ASO currently available for SMA, it will be widely used, therefore we will expect that nusinersen will contribute to improve patients' QOL and reduce the burden of caregivers and the healthcare system by improving motor function of patients with SMA.

Renoprotective effects of telmisartan in the 5/6 nephrectomised rats.

The purpose of this study was to investigate the renoprotective effect of telmisartan on the advanced stages of nephropathy in rats with 5/6 nephrectomy (5/6 Nx). Telmisartan was orally administered for 12 weeks to rats that previously underwent 5/6 Nx or sham operations. After completion of the administration period, the degree of renal injury was examined histopathologically using indices of glomerulosclerosis and lesions of the renal tubule and interstitium. An immunohistochemical staining for transforming growth factor-beta (TGF-beta1) was also performed. The suppression of urinary protein was statistically significant in surviving animals dosed with telmisartan. The enalapril group's urinary protein was also significantly suppressed for these same parameters in surviving animals. Histopathologically, telmisartan significantly decreased the progression of glomerulosclerosis and the interstitial cell infiltration at all doses tested. As assessed by immunohistochemical staining the TGF-beta1 reactivity in the glomerular tissue tended to decrease in the telmisartan group when compared to the vehicle group. Thus, telmisartan ameliorates the progressive nephropathy in the remaining kidney after 5/6 Nx by non-haemodynamic as well as antihypertensive actions of the drug.

Suppression of atopic-like dermatitis by treatment with antibody to lymphocyte function-associated antigen-1 in NC/Nga mouse.

The effect of a blocking-antibody specific for lymphocyte function-associated antigen-1 (LFA-1) was studied in an atopic-like dermatitis model, which was induced by the repeated application of picrylchloride in NC/Nga mice. Prophylactic treatment with anti-LFA-1 monoclonal antibody (mAb), not therapeutic treatment, significantly inhibited the skin severity score and the acanthosis with ulceration and infiltration of mast cells. Furthermore, the serum immunoglobulin E levels and cytokine production (interleukin-4 and interferon-gamma) by splenocytes stimulated with anti-CD3 antibody were also inhibited by treatment with anti-LFA-1 mAb. Our results suggest that LFA-1 plays an important role in the induction phase of the atopic-like dermatitis model.

[Pharmacological and clinical profile of telmisartan, a selective angiotensin II type-1 receptor blocker].

Telmisartan (Micardis) is a potent, long-lasting, nonpeptide angiotensin II type-1 (AT(1)) receptor blocker (ARB) that is indicated for the treatment of essential hypertension. In receptor binding studies, telmisartan showed a high affinity and selectivity for the human AT(1) receptors compared with AT(2) receptors and a slower dissociation rate from the human AT(1) receptor than those of ARBs. In isolated aorta rings, telmisartan was shown to be an insurmountable antagonist of AII-induced contractions. The inhibitory effects of telmisartan on AII-induced contraction persisted even after wash-out procedures. In animal models such as spontaneous hypertension rats and renovascular hypertensive rats, telmisartan produced the consistent reduction of blood pressure. Furthermore, there were no rebound phenomenon and no tolerance to the drug developed in the repeated oral administration. Telmisartan has a longer terminal elimination half-life (about 24 h) than the other ARBs. In patients with mild-moderate hypertension, trough/peak ratios for telmisartan were above 80%. In Japanese patients with mild-moderate hypertension, telmisartan produced a significant reduction in blood pressure (effective rate: 76.0%) with a good safety profile. Therefore, telmisartan is expected to be effective in the treatment of hypertension, producing sustained 24-h blood pressure control.

Involvement of substance P in scratching behaviour in an atopic dermatitis model.

Substance P is speculated to be a key mediator of itching in atopic dermatitis, possibly acting via the tachykinin NK1 receptor. Thus, we examined the effect of a tachykinin NK1 antagonist, BIIF 1149 CL, on scratching behaviour in a picrylchloride-induced dermatitis model in NC/Nga mice. BIIF 1149 CL ((S)-N-[2-[3,5-bis(trifluoromethyl) phenyl]ethyl]-4-(cyclopropylmethyl)-N-methyl-alpha-phenyl-1-piperazineacetamide, monohydrochloride, monohydrate) at a dose of 100 mg/kg, p.o., significantly inhibited scratching behaviour immediately after administration, and the effect continued up to 6 h. The results suggest that clinical trials of tachykinin NK1 antagonists for the treatment of itching in atopic dermatitis patients would be warranted.

Role of substance P in an NC/Nga mouse model of atopic dermatitis-like disease.

BACKGROUND: Atopic dermatitis (AD) can be exacerbated or induced in genetically predisposed individuals by psychological stress, which causes the release of substance P (SP). Therefore, SP may play an etiological role in the mechanisms underlying AD. METHODS: Changes in the number of mast cells and SP-containing mast cells in lesional skin, and the serum concentrations of SP and IgE during the development of AD-like disease up to 8 weeks after the start of picryl chloride (PiCl) induction in NC/Nga mice were examined. RESULTS: Clinical signs and symptoms seen in PiCl-treated NC/Nga mice as a model of AD-like disease began with erythema and haemorrhage, followed by oedema, superficial erosion, deep excoriation, scaling and dryness of the skin, as well as retarded growth, and the changes were exacerbated with an increase in the number of PiCl applications. An increase in the number of mast cells and eosinophil infiltration was observed in the lesional skin. The increase in SP-positive mast cells in the dermis in this model was significant from 1 week after the start of induction treatment, compared with intact mice, and SP-positive nerve fibres were observed in the dermis. CONCLUSION: SP is a crucial mediator of both dermatitis and scratching behaviour in this model.