Intestinal Absorption Studies on Peptide Mimetic α-Methyldopa Prodrugs

Two dipeptide mimetic prodrugs, 1 and 2 , and two tripeptide mimetic prodrugs, 3 and 4 , of l -α-methyldopa were evaluated for intestinal absorption by in-situ single-pass rat jejunal perfusion studies and by in-vitro uptake experiments in brush-border membrane vesicles (BBMVs) prepared from rat intestine. In the perfusion studies, compound 1 demonstrated a 3.5-fold increase in permeability (P_m* = 2.27) as compared with that of α-methyldopa (P_m* = 0.65), indicating that this prodrug was better absorbed in the intestine than its parent drug. Other prodrugs showed no significant improvement in intestinal permeability. The results correlated with the results of BBMV uptake studies. In the presence of an inward proton gradient, compound 1 showed Michaelis-Menton saturable kinetics of BBMV uptake with a low value of K_m (0.06 ± 0.13 mm ) and a high value of V_max/K_m (36.38 nmol (mg protein)^?1/30 s mm ^?1) at a low concentration range and a linear uptake at high concentrations with K_d = 0.14 ± 0.02 mm . Compounds 2 and 3 were mainly taken up in BBMVs via passive diffusion. Compound 4 was taken up in BBMVs basically via the carrier-mediated transport system, while the rate of uptake was much lower than that of compound 1 . The uptake of compounds 1 and 4 was significantly inhibited by dipeptides l -Gly-l -Pro and l -Gly-l -Phe, and cephradine, a β-lactam known to be transported via the dipeptide carrier system, indicating that both compounds were taken up in BBMVs via the H⁺-coupled dipeptide-mediated transport system. In contrast to the complicated uptake profile of α-methyldopa, the higher rate of BBMV uptake with less variation demonstrated on compound 1 suggested that the attached nonessential amino acid moiety, d -phenylglycine, is a feasible delivery tool in carrying the parent drug through the intestine.     

EB病毒与原发性鼻咽部B细胞性淋巴瘤有关与继发性者无关

目的：对１９ 例鼻咽部Ｂ细胞性恶性淋巴瘤与ＥＢ 病毒（ＥｐｓｔｅｉｎＢａｒｒ ｖｉｒｕｓ,ＥＢＶ） 感染的相关性进行研究。方法：利用免疫组织化学及原位杂交方法对ＥＢＶ 进行检测,并用免疫组化及原位杂交双染法标记肿瘤细胞,以鉴定ＥＢＶ阳性的细胞为Ｂ淋巴瘤细胞。结果：ＥＢＶ 编码的小ｍ ＲＮＡ探针（ＥＢＥＲ） 原位杂交显示,８ 例原发性鼻咽部Ｂ细胞性恶性淋巴瘤中３ 例绝大多数肿瘤细胞呈阳性表达,１ 例潜在性膜蛋白１（ｌａｔｅｎｔ ｍｅｍｂｒａｎｅ ｐｒｏｔｅｉｎ １,ＬＭＰ１）阳性。而１１ 例继发性鼻咽部Ｂ细胞性恶性淋巴瘤ＥＢＥＲ全部为阴性。全部病例进行了ＬＭＰ１ 检测,除１ 例原发者,全部阴性。利用ＥＢＥＲＩＳＨ（ＥＢＥＲ原位杂交） 和免疫组化ＣＤ 标记物进行双标记染色证实,ＥＢＥＲ 和ＬＭＰ１阳性细胞为ＣＤ２０ 阳性,ＣＤ４５ＲＯ 阴性。鼻咽部原发性Ｂ细胞性恶性淋巴瘤ＥＢＶ 表达４／８ ,而继发者为０／１１。结论：ＥＢＶ 与鼻咽部原发性Ｂ细胞恶性淋巴瘤有较高的相关性,而与继发性者无关。     

THE EFFECT OF o,p''-DDD ON ADRENAL STEROID REPLACEMENT THERAPY REQUIREMENTS

Two patients with adrenal carcinoma treated with 2,2-bis (2-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane (o,p'-DDD) as adjuvant therapy were studied. Both patients developed hypoadrenalism while on o,p'-DDD and apparently adequate dexamethasone replacement therapy. The hypoadrenalism was overcome by increasing steroid replacement therapy. Dexamethasone levels were measured in the serum by radioimmunoassay and shown to be lowered by o,p'-DDD therapy. A study of the absorption and disappearance of dexamethasone from the circulation in response to a (1 mg oral dose indicated that the steroid was absorbed normally but was cleared more rapidly from the circulation of these two patients than from normal controls. This may be due to a change in the type of metabolites excreted. It is suggested that many of the reported side-effects of o,p'-DDD may be due to hypoadrenalism and may be controlled by greatly increasing the steroid replacement dose. The adequacy of corticosteroid replacement therapy may best be assessed by monitoring the levels of ACTH.     

HYPOTHALAMIC HYPOPITUITARISM FOLLOWING CRANIAL IRRADIATION FOR NASOPHARYNGEAL CARCINOMA

Eight patients, one male and seven females, with no pre-existing hypothalamic-pituitary disease, who developed symptoms of hypopituitarism following cranial irradiation for nasopharyngeal carcinoma were studied 5 years or more after radiotherapy. All were GH deficient. Four of the patients with no GH response during insulin tolerance tests (ITT) showed increased GH in response to synthetic human growth hormone releasing factor (GRF-44). Four patients had impaired cortisol responses to ITT, and gradual but diminished cortisol responses to ovine corticotrophin releasing factor (CRF-41). There was no significant difference between mean peak increments in response to ITT and those in response to CRF-41. TSH responses to TRH were delayed in five and absent in two patients; four of these had low free T4 index. Prolactin was raised in all seven women and increased further in response to TRH. Two patients had impaired gonadotrophin responses to LHRH. None of the patients had clinical or biochemical evidence of diabetes insipidus. These data suggest that post-irradiation hypopituitarism in these patients results from radiation damage to the hypothalamus leading to varying degrees of deficiency of the hypothalamic releasing or inhibitory factors.     

Evaluation of the efficacy of a hospital-based asthma education programme in patients of low socioeconomic status in Hong Kong

BACKGROUND: Good asthma control requires optimal medical treatment in conjunction with appropriate self-management. In the West, the effectiveness of patient education on improving self-management has been well documented. However, data amongst Asian populations are lacking. We performed a pilot study to evaluate the efficacy of a hospital based education programme aimed at improving self-management skills and reducing morbidity in a Chinese population with low socioeconomic status and education level. METHODS: Our asthma education programme was a low-cost programme conducted in essence by specialist respiratory nurses. Patients attending our asthma clinic were instructed during a two-hour educational session on the pathophysiology of asthma, its potential triggers, the appropriate use of medications including proper inhaler techniques, and the self-management of their disease. These instructions were reinforced by video sessions at subsequent outpatient clinic attendance when patients' inhaler and peak flow techniques were checked by the same nurses and their self-management plan re-examined by the attending physicians. Asthma knowledge, inhaler technique, FEV1 and peak expiratory flow (PEF), and patients' self-rating of their asthma were determined at baseline, 6 months and 1 year after the intervention. Morbidity was assessed by the numbers of hospitalizations, unscheduled visits to family physicians and accident and emergency department attendance, courses of oral steroid used and days off work or school at baseline and 1 year. RESULTS: Two hundred and thirty patients were recruited for the study, 83% completing the entire assessment period. The group demonstrated significant improvements in lung function: the mean FEV1 +/- SD increased from 63.6 +/- 20.6% of predicted values at baseline to 68.5 +/- 22.3% at 6 months and 68.6 +/- 22.8% at 1 year (P < 0.05), and the mean PEF +/- SD increased from 64.6 +/- 23.0% of predicted values at baseline to 75.4 +/- 27.0% at 6 months and 76.8 +/- 24.5% at 1 year(P < 0.001). There were also significant improvements in inhaler technique (P < 0.01), asthma knowledge (P < 0.001), patients' self-rating of their asthma (P < 0.05), and reductions in the numbers of hospitalizations (P < 0.01), visits to family physicians (P < 0.001) and accident and emergency department attendance (P < 0.001) during the study period. Patients with moderate to severe asthma as defined by an FEV1 of < 80% of predicted values were most likely to benefit from the programme. CONCLUSIONS: We conclude that patient education is likely to be an essential component in the holistic approach to the management of asthma even amongst Asian populations of low socioeconomic status and education level. Further studies using randomised controlled trials are necessary to consolidate our findings.     

Pigmented nail with atypical melanocytic hyperplasia

We report two cases showing black discoloration of the thumb nail which were histologically found to be acral lentiginous melanoma (ALM) in situ. A pigmented subungual lesion is more frequently malignant than benign and it is generally believed that diagnosis of subungual melanoma during the radial-growth phase is very difficult. Our cases are particularly interesting because atypical melanocytic hyperplasia was confined to the epidermis despite the lesion being present for a long time.     

Pityriasis rubra pilaris in Singapore

Fourteen patients with pityriasis rubra pilaris seen between 1981 and 1989 were evaluated retrospectively. There were nine male and five female patients. There was a bimodal age of onset in early childhood and in adulthood. All the patients had either follicular hyperkeratosis or hyperkeratosis of the palms and soles. Nine patients had erythroderma. The classical forms, either in the children or in the adult patients, were more likely to recover. Several treatment modalities were used and these included steroids, Vitamin A, etretinate, retinoic acid and ultraviolet light (UBV). Nine patients had complete recovery. Four of these patients received only steroids, two cleared while on vitamin A, two cleared while on etretinate and one cleared with methotrexate.