An improved synthesis of methyl p-hydroxyphenylalkanoates

Friedel-Crafts reaction of isopropoxybenzene with methyl α-chloro-α-(methylthio)acetate1 afforded methyl α-methylthio-p-isopropoxyphenylacetate2d, which was readily converted into methyl p-isopropoxyphenylacetate3 by reductive desulfurization with zinc dust in acetic acid. Methylation of3 with sodium hydride and methyl iodide gave methyl α-(p-isopropoxyphenyl)propionate5. Methyl p-hydroxyphenylalkanoates (4, 6), useful intermediates for some medicines, were easily prepared by treatment of3 and5 with titanium tetrachloride, respectively.     

Operative treatment of hypertrophic obstructive cardiomyopathy and aortic valve disease in infants

BACKGROUND: The indications for operative intervention for symptomatic hypertrophic obstructive cardiomyopathy (HOCM) in infancy and childhood are not well defined because of the rarity of the lesion. The traditional surgical procedure consists of septal myectomy. In an attempt to further improve the outcome of HOCM associated with concentric left ventricular hypertrophy and aortic valve disease in infancy, we have combined resection of the left ventricular septum and free wall with a Ross-Konno procedure. METHODS: Three infants (aged 3, 4, and 10 months) with HOCM (left ventricular aortic gradients of 75, 95, and 110 mmHg), associated concentric left ventricular hypertrophy, and valvar aortic stenosis (n = 1) or combined valvar aortic stenosis and regurgitation (n = 2) underwent extensive resection of fibroelastosis and subendocardial myocardium of the left ventricular septum and free wall in combination with a Ross-Konno operation. All three patients had marked systolic anterior motion of the mitral valve. The length of the incision into the ventricular septum was 1.8, 2.0, and 2.3 cm. RESULTS: In all three patients this procedure resulted in a marked reduction of width of the left ventricular septum (median 9 mm vs 14 mm preoperatively) and the left ventricular posterior free wall (median 8 mm vs 12 mm preoperatively) and an almost twofold increase of the left ventricular end-diastolic volume (median 13.5 cm3 vs 7.0 cm3 preoperatively). The neo-aortic valve functioned normally. Systolic anterior motion of the anterior leaflet of the mitral valve had completely resolved in two patients and had markedly regressed in the remaining patient. At follow-up of 15, 17, and 26 months, two patients had absence of a left ventricular outflow tract gradient and the third patient had a residual sub-valvar gradient of 15 mmHg. CONCLUSIONS: The reported procedure may be a valuable technique in severe forms of hypertrophic cardiomyopathy associated with aortic valve disease. The operation results in enlargement of the left ventricular stroke volume and improvement of the left ventricular diastolic function, restores aortic valve anatomy and function, and abolishes or decreases systolic anterior motion of the mitral valve.     

Synthesis of hexaprofen [2-(4-cyclohexylphenyl) propionic acid]

A novel preparative method for hexaprofen, which is a potent antiinflammatory agent, is described. Friedel-Crafts reaction of cyclohexylbenzene with ethyl α-chloro-α-(methylthio) acetate1 and α-chloro-α-(methylthio) acetonitrile2 afforded ethyl 2-(methylthio)-2-(4-cyclohexylphenyl) acetate7 and 2-methylthio-2-(4-cyclohexylphenyl) acetonitrile8, respectively. Compounds7 and8 were converted into the corresponding ethyl 2-methylthio-2-(4-cyclohexylphenyl) propionate9 and 2-methylthio-2-(4-cyclohexylphenyl) propionitrile10 by methylation with sodium hydride and methyl iodide. Hexaprofen13 was prepared by hydrolysis of ethyl 2-(4-cyclohexylphenyl) propionate11 and of 2-(4-cyclohexylphenyl) propionitrile12 followed by desulfurization of compounds9 and10.     

Serotonergic and noradrenergic function in depression: clinical correlates

The present study was conducted in order to investigate the relationships between central noradrenergic (NA) and serotonergic (5-HT) function and clinical characteristics of a major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. We measured growth hormone response (ΔGH) to clonidine (CLO) (an α2 NA agonist), as an index of central NA function, and prolactin response (APRL) to d-fenfluramine (d-FEN) (a specific 5-HT releaser/uptake inhibitor), as an index of central 5-HT function, in 53 medication-free depressed inpatients. On the basis of their CLO and d-FEN test responses, patients were classified into 4 groups. Group 1 (blunted ΔPRL(d-FEN) alone [11 %]) was characterized by a recent violent suicide attempt, a high degree of medical damage, and mild anxiety. Group 2 (blunted ΔGH(CLO) alone [32%]) was characterized by an absence of a history of suicide attempt and by severe anxiety. Group 3 (combination of blunted ΔGH(CLO) and APRL(d-FEN) [18%]) was characterized by a history of suicide attempts, total duration of the illness of over W years, age over 40 years, and more than 3 previous hospitalizations. Group 4 (no abnormality [39%]) had no specific clinical profile. These results suggest that, in depression, specific psychopathological features may be linked to 5-HT and/or NA dysfunction. However, our results also suggest that NA and/or 5-HT dysfunction are less likely to be the primary cause of mood disorders but are more indicative of failure of compensatory mechanisms involved in affective homeostatic processes.     

Association of hyperglycemia and markers of hepatic dysfunction with dextrose infusion rates in Korean patients receiving total parenteral nutrition.

The association of hyperglycemia and markers of hepatic dysfunction with dextrose infusion rates in Korean patients receiving total parenteral nutrition (TPN) was studied. A retrospective study of 122 patients with normal glucose levels and liver function tests (LFTs) was conducted. Pharmacy and medical records of all patients who received TPN from three university-affiliated teaching hospitals in Korea between January 1998 and December 1999 were reviewed. Each patient was categorized as receiving dextrose at (1) < or = 5 or > 5 mg/kg/min and (2) < or = 4, 4.1-5, 5.1-6, or > 6 mg/kg/min. Fifty-five patients received dextrose at a rate of > 5 mg/kg/min for 15.1 +/- 12.8 days and 67 patients at a rate of < or = 5 mg/kg/min for 10.1 +/- 6.8 days. Two patients in each group did not have follow-up glucose levels. Of the 53 patients in the > 5 mg/kg/min group, 16 exhibited hyperglycemia, compared with 21 of the 65 receiving lower rates of dextrose infusion. Elevated aspartate transaminase was the most common abnormal LFT value in both groups (25% and 29% in the < or = 5- and > 5-mg/kg/min groups, respectively). In the group receiving dextrose at > 5 mg/kg/min, 22.2% had two hepatic enzyme levels elevated concurrently, while 18.5% had two hepatic enzyme levels elevated in the group receiving dextrose at < or = 5 mg/kg/min. Regression analysis revealed that duration of TPN and dextrose infusion rate were positively correlated with blood glucose levels and that duration of TPN was positively correlated with abnormal LFT values. A retrospective study of Korean patients revealed no significant difference in the risk of hyperglycemia or hepatic dysfunction between those receiving < or = 5 and > 5 mg/kg/min dextrose infusion in their TPN.     

A prospective trial of short‐fractionation radiotherapy for the palliation of liver metastases

The purpose of this study was to prospectively examine the effectiveness and tolerability of a simple radiotherapy technique for the palliation of symptomatic liver metastases. Twenty‐eight patients with symptomatic liver metastases were enrolled from seven centres, and received targeted (partial or whole) liver irradiation consisting of 10 Gy in two fractions over 2 days. Symptoms at baseline were hepatic pain (27 patients), abdominal distension (19), night sweats (12), nausea (18) and vomiting (eight). Twenty‐two patients (76%) had failed previous treatment with chemotherapy, hormonal therapy and/or high‐dose steroids. Symptoms and potential toxicities were prospectively assessed at the time of treatment, then 2, 6 and 10 weeks later. Individual symptom response rates were 53?66% at 2 weeks. Partial or complete global symptomatic responses were noted in 15 patients (54%) overall. The treatment was well tolerated with two patients (7%) experiencing grade 3 toxicity (one vomiting and one diarrhoea); however, four patients reported temporary worsening of pain shortly after treatment. This simple and well‐tolerated treatment achieves useful palliation.     

Tailgut cyst in a neonate

Tailgut cyst is a rare lesion of developmental origin located in the retrorectal space, which usually presents as a multilocular cystic mass. It is usually found in adults, and neonatal cases are extremely rare. The authors report a tailgut cyst in a neonate that was found by prenatal ultrasonogram, which was like a teratoma in gross appearance.     

Pronounced synergistic promotion of N-bis(2-hydroxypropyl)nitrosamine-initiated thyroid tumorigenesis in rats treated with excess soybean and iodine-deficient diets.

We have reported that excess soybean treatment and iodine deficiency synergistically interact, resulting in remarkable induction of thyroid hyperplasias in rats. In the present study, modifying effects of excess soybean and iodine-deficient diets were investigated in the post-initiation phase of N-bis(2-hydroxypropyl)nitrosamine [DHPN]-initiated thyroid tumorigenesis in rats. AIN-93G in which casein was replaced with gluten was used as a basal diet to avoid possible iodine contamination. In Experiment 1, F-344 rats of both sexes were sc injected with DHPN at a dose of 2800 mg/kg body weight and then fed a diet containing 0%, 0.8%, 4%, or 20% defatted soybean for 12 weeks, with proportional replacement of gluten by soybean flour. Although no thyroid proliferative lesions were found in any group, the absolute thyroid weights were significantly (p < 0.01) elevated with the 20% soybean treatment. In Experiment 2, after similar sc injection of DHPN, rats were fed a basal diet or a diet containing 20% soybean under iodine normal or deficient conditions for 12 weeks. Soybean feeding to both sexes under iodine deficient but not normal conditions dramatically enhanced the development of thyroid follicular adenomas (p < 0.01) and adenocarcinomas (p < 0.05), in good agreement with decrease in thyroxine and increase in thyroid-stimulating hormone. Thus co-exposure to excess soybean and iodine deficiency results in synergistic promotion of DHPN-initiated thyroid tumorigenesis in rats, of which mechanisms appear to primarily involve effects on serum hormone levels.