Role of amino acids at positions 34, 296, and 486 of cytochrome P450 2D6 in the stimulatory and inhibitory effects of psychotropic agents on dopamine formation from p-tyramine.

The effects of psychotropic agents such as fluvoxamine, fluoxetine, paroxetine, milnacipran, and fluphenazine on dopamine formation from p-tyramine catalysed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared with the effects on dopamine formation from p-tyramine by CYP2D6.1. Michaelis constants (Km) and maximal velocity (kcat) values for dopamine formation and inhibition constants (Ki) of the psychotropic agents were determined.For CYP2D6.39, the kcat values for fluvoxamine, fluoxetine, and milnacipran, but not for paroxetine and fluphenazine, gradually increased with increasing concentrations, indicating activation of the catalysed reaction.Fluphenazine competitively inhibited dopamine formation catalysed by all variants, with a higher Ki value for CYP2D6.10. Among the three compounds that have a trifluoromethyl group in their chemical structure, only fluvoxamine and fluoxetine, as well as milnacipran that does not have this group, decreased Km values and/or increased kcat values for dopamine formation, suggesting that the group may not be essential for the activation.These findings indicate that substitution of amino acids at positions 34 and 486 can affect the affinity (Km) and enzymatic activity (kcat), respectively, for milnacipran and that the effect of substitution of arginine to cysteine at the 296th position on the activation would be effector dependent.

Z-plasty and Postoperative Radiotherapy for Anterior Chest Wall Keloids: An Analysis of 141 Patients.

BACKGROUND: The therapies for anterior chest wall keloids include surgical excision, postoperative radiotherapy, silicone taping stabilization, and steroid plaster. However, to date, there is no universally accepted combination treatment strategy for anterior chest wall keloids. METHODS: All consecutive patients with single or multiple anterior chest wall keloids who underwent keloid excision, tension-reducing suturing, z-plasty, and postoperative radiotherapy in 2013-2016 in Nippon Medical School were included in this case series study. Only keloids that arose from small injuries such as folliculitis or acne were selected. The surgery was followed by tension-reducing self-management of the wounds with silicone tape and steroid plaster. The postsurgical radiotherapy modality was 18 Gy administered in 3 fractions over 3 days. The primary study outcome was keloid recurrence during the 24-month follow-up period. Recurrence was defined as the development of stiff and red lesions in even a small part of the scar that did not respond to 6 months of steroid plaster therapy. RESULTS: In total, 141 patients with 141 lesions were enrolled. Of the 141 lesions, 15 (10.6%) recurred. All recurrences were successfully treated by steroid plaster and steroid injection. The recurrence patients did not differ from the nonrecurrence patients in terms of the size of the original keloid or gender distribution. CONCLUSIONS: Anterior chest wall keloids can be successfully treated by customized plans that involve appropriate surgical modalities (including z-plasty) followed by postoperative radiotherapy (18 Gy in 3 fractions over 3 days) and scar self-management with silicone tape and steroid plaster.

Hypertension: a systemic key to understanding local keloid severity.

This study assessed whether hypertension, a circulating factor, influences local keloid severity. This retrospective cross-sectional study involved 304 consecutive patients (13-78 years old) with keloids who were surgically treated in our hospital between January 2011 and August 2013. Their blood pressure (BP), age and gender, and the size and number of their keloids before surgery were recorded. Ordinal logistic regression analyses showed that BP associated significantly with both keloid size and number (all p < 0.0001). Age also associated with keloid size (p < 0.0001). However, a Goodness-of-fit chi-square test showed that the prevalence of hypertension was not higher among keloid patients than in the general Japanese population. This study provides epidemiological evidence for the possibility that primary hypertension may aggravate keloids. We propose that the skin, along with the heart and liver, is a target organ of hypertension. The observations of this study, which require validation with large-scale prospective interventional trials, suggest that keloid patients should be screened for hypertension and that antihypertensive treatments may be of prophylactic and therapeutic value for skin fibrosis.

CASE REPORT Total Management of a Severe Case of Systemic Keloids Associated With High Blood Pressure (Hypertension): Clinical Symptoms of Keloids May Be Aggravated by Hypertension.

INTRODUCTION: Many cases of severe keloid are associated with high blood pressure (hypertension). An analysis of 100 consecutive patients with keloid in our department in 2011 revealed that patients with multiple (>3) or large keloids (>10 cm(2)) were significantly more likely to have hypertension than patients with mild keloids (<2 or <10 cm(2)). In the present paper, a case of severe keloids associated with hypertension is described. How such patients should be treated is discussed. METHODS: This 63-year-old woman had hypertension together with severe keloids that covered her right elbow, wrist joints, and thumb and made it difficult for her to use her right hand. The contractures were released by using surgery and postoperative radiation therapy. The internal medicine clinic started her on a Ca-channel blocker (amlodipine besilate) and an angiotensin II blocker (candesartan cilexetil). RESULTS: The contractures were completely released by a distally based radial artery flap and postoperative 4 MeV electron beam irradiation (15 Gy/3 fractions for 3 days). The angiotensin-converting enzyme inhibitor and the Ca-channel blocker improved the objective symptoms of the remaining keloids. CONCLUSIONS: If patients with severe keloids present, the possibility of hypertension should be considered: the patient may have hypertension already or may be affected in the future. Hypertension may be a risk factor of keloid deterioration. Antihypertensive treatment may reduce symptoms of patients with severe keloids. At present, surgery and postoperative radiotherapy appear to be the only solution to the functional problems experienced by patients with severe keloids.