Chronopharmacokinetic and bioequivalence studies of two formulations of trimipramine after oral administration in man

The bioavailability of two oral formulations of trimipramine, tablets and solution, was performed in twelve healthy volunteers, in a cross-over study. Each formulation was administered in the morning after a fasted period, and in the evening after a meal, in order to evaluate the role of both administration time and food consumption on the plasma kinetic parameters, under usual therapeutic conditions. A high interindividual variability of data was found. First, the extent of bioavailability was identical for the two formulations but the rate of bioavailability seemed to be different, with the p.o. solution, being more rapidly absorbed (tmax = 1.50 h). The effect of administration time was more obvious for the solution as shown by a lower quantitative absorption as well as a delay in time to reach the maximal concentration. Regardless of formulation and administration time, the t1/2 beta was about 10 hours and the mean MRT value was 11 hours.     

Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl) ethylenediamine]dichloroplatinum(II)-complexes, Part II: Biological properties

The activity of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine] dichloroplatinum(II)-complexes (1-PtCl2,R,S; 2-PtCl2, R,R/S,S; 3-PtCl2, R,R; 4-PtCl2, S,S) on several tumor models (MDA-MB 231 breast cancer cell line; P 388 leukemia, mouse; L 1210 leukemia, mouse; L 5222 leukemia, rat; Ehrlich ascites tumor, mouse--wildtype; cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.) is described. For comparison the analogous [1,2-bis(4-hydroxyphenyl)ethylendiamine]dichloroplatinum (II)-complexes (5-PtCl2, R, S; 6-PtCl2, R,R/S,S; 7-PtCl2, R,R; 8-PtCl2, S,S) and cisplatin are used. 1-PtCl2 to 4-PtCl2 (OH in 3,3'-positions) show their maximum antitumor effect at lower doses than 5-PtCl2 to 8-PtCl2 (OH in 4,4'-positions). 2-PtCl2 and 6-PtCl2 (R,R/S,S) are more active than 1-PtCl2 and 5-PtCl2 (R,S). 4-PtCl2 and 8-PtCl2 (S,S) are superior to 3-PtCl2 and 7-PtCl2 (R,R). On the L 5222 leukemia 2-PtCl2 (R,R/S,S), 4-PtCl2 (S,S) and 8-PtCl2 (S,S) markedly surpass cisplatin. Strong effects are produced by 2-PtCl2 to 4-PtCl2 on the Ehrlich ascites tumor (wildtype, cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.). The combination of 4-PtCl2 with cisplatin results in a weakly synergistic effect.     

Effect of methylcholanthrene on human natural killer cell cytotoxicity and lymphokine production in vitro

We have developed a simple culture assay system for measuring the in vitro effects of a chemical carcinogen, 3-methylcholanthrene (MCA), on certain activities of human peripheral blood lymphocytes: blastogenesis, cell-mediated cytotoxicity by natural killer cells, interleukin-2 production, lymphotoxin release and percent T-cell subpopulations. After 72 h of treatment with different doses of MCA, blastogenesis was suppressed 23-87% and cell-mediated cytotoxicity was inhibited 45-90%. Interleukin-2 and lymphotoxin production were decreased by 64% and 38%, respectively. On the other hand, MCA treatment at the same doses caused no significant change in the percent of T-cell subsets. We conclude that MCA exerts an inhibitory effect on T-cell functional activity such as interleukin-2 and lymphotoxin production which correlate with a suppression of blastogenesis and natural killer cell activity. This in vitro assay system could be important for future studies in explaining specific inhibitory effects of chemical carcinogens on lymphoid cell function relative to tumorigenesis.     

Endoscopic surgery for early glottic carcinoma

Early glottic carcinoma, specifically stage I or II, can be treated with endoscopic excision, radiation therapy, or open partial laryngectomy. Over the past two decades, this topic has received intensive interest, and controversies have often focused on techniques and outcomes comparing the use of endoscopic excision versus radiation therapy. This article will discuss philosophy, techniques, and outcomes of resection using the endoscopic approach to early glottic carcinoma. Optimization through appropriate instrumentation, staging, and technical details are critical to postoperative oncologic and vocal outcomes. The reader must remember that over 90% of T1 lesions and approximately 75% of T2 lesions are curable, and therefore adherence to the principles described below is important to achieve these outcomes.     

Rekonstruktion und Stabilisierung nach fehlverheilten Frakturen und Pseudarthrosen im Femurbereich mit Marknagel und anderen Osteosyntheseverfahren (LISS-System)

Malunion and nonunion after fracture present many difficulties in trauma surgery. Selection of the best therapy and operative techique requires careful analysis of the complications. Hyperthrophic nonunion of the femur shaft is mostly best treated with locking reamed nails. Significant differences in torsions after nailing can be corrected by repositioning of the distal interlocking screws if recognized sufficiently early. After fracture healing an open rotation osteotomy is necessary; stabilization can be achieved by means of medullary nails or a condylar plate. How a malalignment of the bone axis is corrected depends on the position of a malunion, the functional deficit caused, and the biomechanical demands on the joint. Condylar plates can often solve the problems in this region. There are also guidelines for ¶the treatment of atrophic and infected nonunions (recommended procedures are ¶aggressive debridement, autologous cancellous bone graft, and biological osteosynthesis), but the treatment of individual cases requires a exhaustive knowledge of and experience in this special field. It is quite common for even well-established procedures to fail. When the bone is biologically reduced and this is the reason for malunion newly developed techniques of internal fixation can be applied. The less invasive stabilization system (LISS), combined with autologous cancellous bone grafting if necessary, can result in healing even in a worst-case scenario.     

Cigarettes, alcohol and marijuana are related to pyospermia in infertile men

The relationship of current use of cigarettes, marijuana and alcohol to the parameters of seminal fluid analysis, sperm penetration assay and sperm autoimmunity was studied in 164 men from infertile couples. Current cigarette smokers, marijuana users and heavy alcohol users showed greater numbers of leukocytes in the seminal fluid than did nonusers (p less than 0.02, less than 0.007 and less than 0.01, respectively). In addition, cigarette smokers had lower sperm penetration assay scores than nonsmokers (median 2.5 versus 8.0, p = 0.05). Users of cigarettes, marijuana or alcohol showed no decrease in sperm count, motility or percentage of oval sperm, and no difference in prevalence of antisperm antibodies compared to nonusers. After controlling for past sexually transmitted diseases and multiple substance exposures in a multivariate model, use of cigarettes (p = 0.006), marijuana (p = 0.12) or alcohol (p = 0.098) continued to be associated with a trend toward increased number of seminal fluid leukocytes. Cigarette smoking continued to show a significant decrease in sperm penetration assay score (p = 0.03).     

Airborne emissions at skin surfaces: a potential biological exposure index

 Dermal exposures of methanol were administered in a clinical study designed to compare several biological indicators. Four subjects were exposed in five exposure sessions of varying length. In each session, a sequence of measurements of methanol concentrations in blood, breath, and headspace samples of air at exposed and unexposed skin were collected before and after dermal exposures. Skin headspace samples, collected in gas sampling bags, were designed to reflect equilibrium skin: air partitioning. At exposed skin, headspace samples were highly elevated for at least 8 h following exposure, indicating the presence of a methanol reservoir in skin. After exposure, methanol concentrations at exposed skin showed a rapid initial decline, then a slower first-order decrease. Methanol concentrations were clearly detectable in headspace samples at unexposed skin. Substantial transfer from exposed skin occurred due to mechanical contact and washing. When transfer was restricted, surface concentrations at unexposed skin were similar to levels in breath and were strongly correlated to methanol concentrations in blood. While results are preliminary due to the small sample sizes and several unresolved experimental issues, the simple, rapid, and noninvasive skin headspace measurements appear useful as a biological exposure indicator that clearly shows the presence and site of a dermal exposure, and measurements at unexposed skin reflect concentrations in blood. Received: 14 March 1995/Accepted: 3 November 1995