A new pseudo-peptide of Arg-Gly-Asp (RGD) with inhibitory effect on tumor metastasis and enzymatic degradation of extracellular matrix

A series of pseudo-peptide analogs of the Arg-Gly-Asp (RGD) sequence of fibronectin have been synthe-sized, and their anti-metastatic effects in mice and inhibitory effects on tumor cell invasion in vitro have been examined. The partially modified retro pseudo-peptide of RGD, R_rev-COCH₂CO-D (FC-63), was more effective in inhibiting tumor metastasis than the original RGDS peptide. Replacement of the malonyl moiety of FC-63 with a carboxyethylene linkage (R_rev-COCH₂CH₂-D, FC-303 ) achieved more potent inhibition of lung metastasis of melanoma cells than FC-63. Among the analogs, FC-336, a p-xylylendiamine derivative having two FC-303 moieties, showed the most potent inhibitory effect on experimental lung metastasis produced by i.v. co-injection with B16-BL6 melanoma or colon 26 M3.1 cells in a dose-dependent manner. Multiple administrations of FC-336 after tumor inoculation also showed efficient therapeutic potency against spontaneous lung metastasis of B16-BL6 melanoma in mice. Furthermore, FC-336 effectively inhibited the invasion, migration and adhesion of tumor cells in vitro, but its inhibitory effects were not more than those of RGDS peptide. Zymography analysis revealed that FC-336 inhibited the degradation of gelatin substrate by matrix metalloproteinases (MMPs) produced by tumor cells, while the RGDS peptide did not affect the enzymatic degradation. These findings indicate that the pseudo-peptides of the RGD sequence, possessing the inhibitory property of the degradation by MMPs differently from original RGD-containing peptides, may be advantageous and useful in preventing tumor metastasis. © Rapid Science 1998     

Effect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population.

We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14+/-0.69 ng/ml/mg) and RHAL (1.10+/-1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL=0.68+/-0.31 ng/ml/mg, RHAL=0.28+/-0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70+/-0.23 ng/ml/mg, RHAL=0.31+/-0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69+/-0.14 ng/ml/mg, RHAL=0.40+/-0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (<10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43+/-0.23 ng/ml/mg, 0.34+/-0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18+/-0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.     

Pharmacological evidence that tetraethylammonium-sensitive,iberiotoxin-insensitive K+ channels function as a negative feedback element for sympathetic neurotransmission by suppressing ω-conotoxin-GVIA-insensitive Ca2+ channels in the relaxation of rabbit facial vein

Naunyn-Schmiedeberg's Archives of Pharmacology -     

Depression among caregivers of the frail elderly in urban Japan

A cross-sectional study was conducted in order to investigate the various factors related to the depression in caregivers of the elderly in need of care in urban Japan. The caregivers answered a self-administered questionnaire about various factors that may affect their depression, and also completed a Center for Epidemiologic Studies Depression Scale evaluation (CES-D). Compared with non-depressed caregivers, depressed caregivers attended the elderly longer, while time spent for physical caregiving did not differ between the two groups. Even after controlling confounding factors, time of attending the elderly was an independent factor related to caregiver's depression.     

Optimized 2-methoxyestradiol invasomes fortified with apamin: a promising approach for suppression of A549 lung cancer cells

Certain anticancer agents selectively target the nucleus of cancer cells. One such drug is 2-methoxyestradiol (2ME), which is used for treating lung cancer. To improve the therapeutic effectiveness of these agents, many new methods have been devised. 2ME was entrapped into the core of hydrophobic invasomes (INVA) covered with Phospholipon 90G and apamin (APA). The Box–Behnken statistical design was implemented to enhance the composition. Using Design-Expert software (Stat-Ease Inc., Minneapolis, MN), the INVA component quantities were optimized to obtain spherical particles with the smallest size, that is, a diameter of 167.8 nm. 2ME-INVA-APA significantly inhibited A549 cells and exhibited IC₅₀ of 1.15 ± 0.04 µg/mL, which is lower than raw 2ME (IC₅₀ 5.6 ± 0.2 µg/mL). Post 2ME-INVA-APA administration, a significant rise in cell death and necrosis was seen among the A549 cells compared to those treated with plain formula or 2ME alone. This effect was indicated by increased Bax expression and reduced Bcl-2 expression, as well as mitochondrial membrane potential loss. Moreover, the cell cycle analysis showed that 2ME-INVA-APA arrests the G2-M phase of the A549 cells. Additionally, it was observed that the micellar formulation of the drug increased the cell count in pre-G1, thereby exhibiting phenomenal apoptotic potential. Furthermore, it up-regulates caspase-9 and p53 and downregulates TNF-α and NF-κβ. Collectively, these findings showed that our optimized 2ME-INVA-APA could easily seep through the cell membrane and induce apoptosis in relatively low doses.     

A first-in-human Phase I dose-escalation trial of the novel therapeutic peptide,ALM201, demonstrates a favourable safety profile in unselected patients with ovarian cancer and other advanced solid tumours

Background We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide.Methods We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours.Results Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10–300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1–2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3–18) weeks. Four of 18 evaluable patients (22%) had stable disease.Conclusions Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.Subject terms: Drug development, Drug safety     

Evaluation of the safety of xenon/bandpass light in vitrectomy using the A2E-laden RPE model

Background The purpose of the study was to investigate the brightness of the xenon/bandpass light in vitrectomy and assess its phototoxic effects using A2E-laden retinal pigment epithelial (RPE) cells. Methods The total luminous flux and spectral irradiance of 20- and 25-gauge endoilluminators connected to xenon lamps were measured and compared to those of 20- and 25-gauge endoilluminators connected to a halogen lamp. In vitro, A2E-laden cells were evenly exposed to xenon/bandpass light for 5 to 30 min positioned at 1 cm and 2 cm for a standard light probe and an implantable “chandelier” light probe, respectively, above the cells, and the cell viability was assessed using WST-1 assay. The cell viability was compared with cells exposed to 30 min of halogen light projected through a 20-gauge endoilluminator. Results The maximal total luminous flux of xenon/bandpass light emitted through the 20-gauge endoilluminator was 2.8 times higher than that of the halogen light. The total luminous flux of the 25-gauge endoilluminators was 0.6-1.1 times greater than the 20-gauge endoilluminators connected to the halogen light. The viability of the A2E-laden cells after exposure to the xenon/bandpass light was no different than that of the cells exposed to the halogen light when the total luminous flux of these lights was at the same level. Xenon/bandpass light from an implantable “chandelier” light probe induced A2E-mediated RPE damage to a similar extent as that of the halogen light through a 20-gauge endoilluminator. Conclusions A2E-mediated phototoxicity of xenon/bandpass light is comparable to that of halogen light.