125iodine reimplantation for locally progressive prostatic carcinoma

We treated 13 patients with a second 125iodine implant for local recurrence of prostatic carcinoma. All patients had biopsy proved palpable recurrence without evidence of distant metastases. Full doses of irradiation were used (median matched peripheral dose 170 Gy.). Six patients had complete regression of palpable recurrence, 2 had partial regression, 2 had no apparent response and 3 were unevaluable for local response. Actuarial freedom from local disease progression at 5 years was 51%. Despite a relatively high rate of local disease control the actuarial rate of distant metastases reached 100% at 6 years after reimplantation. There were 2 severe rectal complications and 4 instances of mild to moderate urinary incontinence among the 13 patients. Local regression of recurrent prostatic carcinoma may be achieved with 125iodine reimplantation but most patients still had distant metastases.     

Notes on the use of low magnification telescopes in low vision care

Several areas related to the use of telescopes in low vision are reviewed. These include: contrast sensitivity function; eccentric viewing through a telescope; field of view; telescope used in reverse; and IOL-spectacle lens telescopic systems. Experimental data are included to support selected clinical observations routinely made by low vision clinicians.     

Immunotherapy and whole-body hyperthermia as combined modality treatment of a subcutaneous murine sarcoma

Interleukin–2 and hyperthermia have been used individually to treat a variety of tumors in both experimental and human trials. Combined adoptive immunotherapy and hyperthermia is an exciting new line of investigation. Previous work in our laboratory has shown that combined local hyperthermia and rIL-2 therapy can significantly decrease the rate of tumor growth. In this study, we investigated the effect of combined whole-body hyperthermia (WBHT) and rIL-2 on the growth of subcutaneous MCA-105 murine tumors in C57BL/6 mice. Treatment of both microscopic (day 3) and macroscopic (day 10) tumors was evaluated. In the treatment of microscopic tumors, animals received either no treatment; rIL-2 (3 × 10⁵ IU ip tid) on days 3–7; plus WBHT(41°C for 30 min) on days 3, 5, and 7; or WBHT only on days 3, 5, and 7. In treating macroscopic tumors, animals received either no treatment; rIL-2 on days 10–14; plus WBHT on days 10, 12, and 14; or WBHT only on days 10, 12, and 14. While combined treatment and WBHT alone had no significant effect on the growth of microscopic tumors, combined IL-2 and WBHT significantly reduced the rate of tumor growth of macroscopic tumors. These results suggest that the tumor microenvironment plays a critical role in combined WBHT and rIL-2 therapy, and may be due to effects of WBHT on the tumor vasculature. © 1993 Wiley-Liss, Inc.     

In vitro studies on the effects of flubendazole against Toxocara canis and Ascaris suum

Adult Toxocara canis and Ascaris suum were incubated in vitro in media containing 0.1, 1, 10 or 100 µg/ml flubendazole in order to study drug-derived effects. This incubation was done for 8 h and repeated (in some groups) after 24 h for another 8 h. The onset and intensity of flubendazole-derived effects were dosage-dependent and time-dependent, i.e. the same grade of damage was reached when incubating for a longer period at a low dosage or for a shorter period in medium containing a high amount (10 or 100 µg/ml) of flubendazole. A repeated incubation in drug-containing medium was superior to a single exposure. Flubendazole is apparently able to penetrate into the worm's interior via the cuticle. This became evident in worms with sealed orifices, which showed identical damage to worms which were not sealed. The type of tissue damage due to flubendazole was identical in both worm species when exposed to any of the drug dosages used. The principal mode of action of flubendazole was based on the complete reduction of microtubuli-polymerisation inside the parasite's cells. This apparently led to the complete destruction of the hypodermis, muscle layer and intestine. Flubendazole also stopped the formation of gametes. Summarising, even low concentrations of flubendazole (0.1 µg/ml) led to significant and irreversible damage in all worms studied.     

Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans

The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile]), and verapamil N-demethylation (formation of norverapamil [2,8-bis(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)6-methyl-2-isopropyl-6-azaoctanitrile]. The enzymes catalyzing verapamil O-demethylation have not been characterized so far. We have therefore identified and characterized the enzymes involved in verapamil O-demethylation in humans by using the following in vitro approaches: (I) characterization of O-demethylation kinetics in the presence of the microsomal fraction of human liver, (II) inhibition of verapamil O-demethylation by specific antibodies and selective inhibitors and (111) investigation of metabolite formation in microsomes obtained from yeast strain Saccharomyces cerevisiae W(R), that was genetically engineered for stable expression of human CYP2C8, 2C9 and 2C18.In human liver microsomes (n=4), the intrinsic clearance (CL_int), as derived from the ratio of V _max/K_m, was significantly higher for O-demethylation to D-703 compared to formation of D-702 following incubation with racemic verapamil (13.9±1.0 vs 2.4±0.6 ml^*min^{-1 *}g^-1 mean±SD; p<0.05), S-Verapamil (16.8±3.3 vs 2.2±1.2 ml^* mini^*g^-1, p<0.05) and R-verapamil (12.1±2.9 vs 3.6 ±1.3 ml^*min^{-1 *} g^-1; p<0.05), thus indicating regioselectivity of verapamil O-demethylation process. The CL_int of D-703 formation in human liver microsomes showed a modest but significant degree of stereo selectivity (p<0.05) with a S/R-ratio of 1.41±0.17. Anti-LKM2 (anti-liver/kidney microsome) autoantibodies (which inhibit CYP2C9 and 2C19) and sulfaphenazole (a specific CYP2C9 inhibitor) reduced the maximum rate of formation of D-703 by 81.5±4.5% and 45%, that of D-702 by 52.7±7.5% and 72.5%, respectively. Both D-703 and D-702 were formed by stably expressed CYP2C9 and CYP2C18, whereas incubation with CYP2C8 selectively yielded D-703.In conclusion, our results show that enzymes of the CYP2C subfamily are mainly involved in verapamil O-demethylation. Verapamil therefore has the potential to interact with other drugs which inhibit or induce these enzymes.     

Initial subcutaneous embedding of the peritoneal dialysis catheter-a critical appraisal of this new implantation technique

Background: The objectives of this open non-randomized study were to evaluate the impact of a new peritoneal catheter placement technique on catheter maintenance, and complications possibly related to the access, e.g. leakage, infectious complications, or drainage failure. Method: In a routine clinical setting, a two-cuff swan-neck catheter was implanted surgically, but its external segment was embedded in a subcutaneous pouch initially without exit site to enable uncontaminated wound healing and tight ingrowth of the cuffs. After 4 weeks at the earliest the distal catheter tip was set free by a small incision under local anaesthesia, and CAPD was started. Results: Using this technique, 26 catheters were implanted in 17 males and nine females (mean age 52.3±17.4, range 19-83 years). The catheters were buried subcutaneously for a median of 79.5 (mean±SD 132.2±157.2, range 28-675) days, and were activated in 21 patients. No leaks were seen, and only one abdominal wall abscess secondary to a haematoma was found. Long-term follow up (mean duration of CAPD 467.0±338.1, range 32-1320 days) revealed a very low overall incidence of infectious complications, i.e. 0.80 per patient-year (1 episode per 14.9 patient-months), and the incidence of catheter-related peritonitis amounted to 0.036 per patient-year (1 episode per 27.2 patient-years), only. However, the postoperative course was complicated by seromas in two of 26, and subcutaneous haematomas in 12 of 26 patients, five of which were revised surgically. At catheter activation, fibrin thrombi were found in nine of 21 patients and two had to be operated. Omental catheter obstruction was diagnosed in four patients, and followed by omentectomy. No relationship was seen between thrombus formation and omental obstruction and duration of subcutaneous embedment (P=0.27 and P=0.5 respectively) or patient age (P=0.06 and P-0.13 respectively; Mann-Whitney-test). There was also no relationship with primary omentectomy or haematoma. Conclusion: We conclude that although the very low incidence of infectious episodes favours the new technique, further improvement is necessary to decrease the unacceptable rate of perioperative complications. Subcutaneous embedding of the catheter may then be considered in patients with expected problems of wound healing, and those who wish to be prepared for peritoneal dialysis in time.