Evaluation of the human prediction of clearance from hepatocyte and microsome intrinsic clearance for 52 drug compounds.

We compare three different approaches to scale clearance (CL) from human hepatocyte and microsome CL(int) (intrinsic CL) for 52 drug compounds. By using the well-stirred model with protein binding included only 11% and 30% of the compounds were predicted within 2-fold and the average absolute fold errors (AAFE) for the predictions were 5.9 and 4.1 for hepatocytes and microsomes, respectively. When predictions were performed without protein binding, 59% of the compounds were predicted within 2-fold using either hepatocytes or microsomes and the AAFE was 2.2 and 2.3, respectively. For hepatocytes and microsomes there were significant correlations (P = 8.7 x 10(-13), R(2) = 0.72; P = 2.8 x 10(-9), R(2) = 0.61) between predicted CL(int in vivo) (obtained from in vitro CL(int)) and measured CL(int in vivo) (obtained using the well-stirred model). When CL was calculated from the regression, 76% and 70% of the compounds were predicted within 2-fold and the AAFE was 1.6 and 1.8 for hepatocytes and microsomes, respectively. We demonstrate that microsomes and hepatocytes are in many cases comparable when scaling of CL is performed from regression. By using the hepatocyte regression, CL for 82% of the compounds in an independent test set (n = 11) were predicted within 2-fold (AAFE 1.4). We suggest that a regression line that adjusts for systematic under-predictions should be the first-hand choice for scaling of CL.

Competitive CYP2C9 inhibitors: enzyme inhibition studies, protein homology modeling, and three-dimensional quantitative structure-activity relationship analysis.

This study describes the generation of a three-dimensional quantitative structure activity relationship (3D-QSAR) model for 29 structurally diverse, competitive CYP2C9 inhibitors defined experimentally from an initial data set of 73 compounds. In parallel, a homology model for CYP2C9 using the rabbit CYP2C5 coordinates was built. For molecules with a known interaction mode with CYP2C9, this homology model, in combination with the docking program GOLD, was used to select conformers to use in the 3D-QSAR analysis. The remaining molecules were docked, and the GRID interaction energies for all conformers proposed by GOLD were calculated. This was followed by a principal component analysis (PCA) of the GRID energies for all conformers of all compounds. Based on the similarity in the PCA plot to the inhibitors with a known interaction mode, the conformer to be used in the 3D-QSAR analysis was selected. The compounds were randomly divided into two groups, the training data set (n = 21) to build the model and the external validation set (n = 8). The PLS (partial least-squares) analysis of the interaction energies against the K(i) values generated a model with r(2) = 0.947 and a cross-validation of q(2) = 0.730. The model was able to predict the entire external data set within 0.5 log units of the experimental K(i) values. The amino acids in the active site showed complementary features to the grid interaction energies in the 3D-QSAR model and were also in agreement with mutagenesis studies.

Elective lymph node dissection in stage I cutaneous malignant melanoma of the head and neck. A report from the Swedish Melanoma Study Group.

The effect of elective lymph node dissection in patients with cutaneous malignant melanoma of the head and neck was investigated in a retrospective study. Of 517 patients in clinical stage I, 84 underwent elective dissection of the ipsilateral neck lymph nodes. In six of these patients, lymph node metastases were demonstrated at histopathological examination. There was a slight reduction in the incidence of recurrent disease in the regional lymph nodes in the group of patients who had undergone elective lymph node dissection, but this difference was not statistically significant. No significant differences were seen between the two groups regarding overall survival of disease-related survival.

Cutaneous malignant melanoma of the head and neck. Analysis of treatment results and prognostic factors in 581 patients: a report from the Swedish Melanoma Study Group.

BACKGROUND: Results of surgical treatment of cutaneous malignant melanoma (CMM) have been highly variable, probably because of patient selection. Therefore, a study of representative patients with this disease was performed. METHODS: In a defined area of Sweden, 581 patients were analyzed. Clinical records and histopathologic findings were reviewed. The minimum follow-up time was 7 years. Prognostic factors were evaluated by the Cox proportional hazards model. RESULTS: Evaluation of sex distribution, age, and anatomic site of the primary tumor showed that the patients were representative of all Swedish patients with CMM of the head and neck. The mean patient age at diagnosis was 64 years for both sexes. Fifty-three percent of the patients were women. Female patients had more tumors of the face than did male patients, whereas male patients were overrepresented among patients with tumors of the auricle-external ear canal and scalp-neck area. Localization to the face was observed in 68%, which is an overrepresentation of three to four times when skin surface is taken into consideration. Twenty-four percent of the patients had lentigo maligna melanoma. Only 33% of the patients had superficial spreading melanoma. In univariate analyses, sex, anatomic site of the primary tumor, histogenetic type, Clark level of invasion, and tumor thickness had prognostic power. In a multivariate analysis, tumor thickness, anatomic site of the primary tumor, and sex of the patient were independent prognostic factors. CONCLUSIONS: In representative patients with CMM of the head and neck, tumor thickness, anatomic site of the primary tumor, and sex of the patients were independent prognostic factors.

Salivary duct carcinoma--a clinicopathologic study of 12 cases.

Salivary duct carcinoma (SDC), a recently defined malignant tumor usually of major salivary glands, has probably been included in the group of adenocarcinomas, NOS. As yet, only a few descriptions of its clinical behavior have appeared. We have found 12 cases of SDC treated at our institution since 1970 and have reviewed their presentation and course. Despite total parotidectomy in most cases and radiotherapy in all, most patients have succumbed to their tumors, six with distant metastases. SDC appears to be a highly malignant tumor requiring aggressive combined therapy for locoregional control. The high incidence of systemic spread indicates a need for effective chemotherapy on an adjuvant basis.

[Histologic scoring system for various cancers of the external ear]. / Histologisches Punktesystem bei verschiedenen Karzinomen des äusseren Ohres.

A histological scoring system was created to determine the aggressiveness of basal cell carcinomas of the head and neck and to determine which squamous cell carcinomas of the external ear will develop metastases. Basal cell carcinomas of the external ear were the most aggressive. The parameters depth of growth and mode of invasion were the most valuable in predicting metastases.

[Dilatation of esophageal strictures using a balloon catheter]. / Dilatation der Oesophagusstrikturen mit einem Ballonkatheter.

The technique of balloon catheter dilatation of benign esophageal strictures is presented. A general anesthetic is unnecessary which is an advantage in older patients. Moreover, the encouraging results and the absence of complications support the opinion that balloon catheter dilatation is an excellent alternative in the treatment of esophageal strictures.

Neural beta-adrenergic dilatation of the facial vein in man. Possible mechanism in emotional blushing.

Ring preparations of the superficial buccal segment of the human facial vein, taken from extirpated tissue in 12 patients during neck surgery, were studied in vitro. The vein developed a maintained intrinsic myogenic tone in response to passive stretch and was supplied with alpha- as well as beta-adrenoceptors, both of which could be influenced by transmural nerve stimulation (TNS) and noradrenaline. These unusual characteristics for a vein are basically similar to the ones described for the rabbit facial vein by Pegram, Bevan & Bevan (1976). In man there seemed to be an inter-individual difference with regard to the abundance of 'innervated' alpha- and beta-adrenoceptors. Facial vein specimens from some subjects thus responded with prompt and pronounced net dilatation to TNS with maximum at 4 Hz and those from others with net constriction with maximum at 16 Hz. The latter showed a reversal into neural beta-adrenergic dilatation after alpha-adrenergic blockade. The human external jugular vein was devoid of intrinsic tone and beta-adrenoceptors. It is tentatively proposed that a beta-adrenergic neuro-effector mechanism in superficial ramifications of the facial vein in man might be involved in the emotional blushing reaction.

Sleep apnea syndrome caused by acromegalia and the treatment with a reduction plasty of the tongue. Case report.

Obstructive sleep apnea syndrome was every likely caused by an enlarged tongue in a 60-year-old man with acromegalia. The diagnosis was confirmed by polygraphic sleep recordings and by roentgenologic examination. The patient was treated with a tongue-reduction plasty which gave him good subjective relief and better sleep. A whole night polygraphic sleep recording showed a couple of hours of normal sleep without apneas or arousals. The last part of the night was, however, still disturbed by several apneas with concomitant arousals.

Sleep apnea syndrome--an alternative treatment to tracheostomy.

Two patients with obstructive sleep apnea syndrome had polygraphic recordings demonstrated upper airway obstruction and sleep with extremely short sleep latency, severely disturbed nightsleep resulting in sleep deprivation, and excessive daytime sleepiness. Radiological investigation showed the upper airway obstruction to be caused by the tongue falling back occluding the pharynx. Nasopharyngeal intubation relieved the symptoms. The patients were trained to perform this treatment themselves every night, demonstrating that this treatment is an attractive alternative to the conventional tracheotomy.