Chemical labyrinthectomy for the worse ear of adult Nigerians with bilateral Meniere's disease: preliminary report of treatment outcomes.

The objective of this study was to assess the effectiveness of variable titration, low-dose intratympanic gentamycin (ITG) into the worse affected ear of patients with bilateral Meniere's disease (MD). It is a prospective analytic case series conducted in a tertiary care referral hospital in a developing economy and a tertiary care otologic private ENT clinic. Patients with MD who failed or are intolerant to medical treatment were recruited based on the criteria of definite MD and bilateral ear involvement. 0.75 cc of low-dose (40 mg/ml) buffered gentamycin was injected into the worse affected ear and patients followed up every 2 months, and the regime repeated only if subjective vertigo persists. The patient's age, sex, duration of MD symptom, ear first affected, ear selected for ITG, pure tone threshold at each visit, duration of caloric response (in seconds) for the injected ear, status of tinnitus in both ipsilateral (injected) and contralateral ears, total number of injections before last follow-up, and time since last follow-up are entered into the study protocol and analyzed. Nine patients with a mean age of 45 years and mean duration of symptoms of 59 months were treated. The mean total number of injections was 2.8 with a mean follow-up period of 34 months. Three cases showed drop in pure tone average threshold (2.5-7.5 dB) while an increase in threshold was noted in six cases (2.5-5 dB). All cases demonstrated decrease in duration of response to iced water caloric stimulation in ipsilateral ear, and 4/9 of contralateral ear. The variable titration method using low-dose intratympanic gentamycin directed at worse ear of adult Nigerians with bilateral Meniere's disease appears to be highly effective. More studies are needed.

Urinary κ and λ immunoglobulin light chains in normoalbuminuric type 2 diabetes mellitus patients.

BACKGROUND AND AIM: Kidney disease is one of the major chronic microvascular complications of diabetes. Tubular involvement may precede glomerular involvement and the appearance of microalbuminuria. The aim of the study was to evaluate quantitatively immunoglobulin light chains (IgLCs), kappa and lambda excretion in the urine of patients with type 2 diabetes mellitus with normoalbuminuria and with microalbuminuria compared to control group. RESULTS: Urinary IgLCs levels of the control group were significantly lower than diabetic patients with normoalbuminuria and diabetic patients with albuminuria. IgLCs were significantly associated with the duration of disease and negatively with estimated glomerular filtration rate. CONCLUSION: Type 2 diabetic patients can have significantly raised concentrations of urinary IgLCs before microalbuminuria or renal disease occurs. Further investigations are recommended to assess LC evaluation in the early management of diabetic renal disease.

Primary lymphocytes as predictors for species differences in cytotoxic drug sensitivity.

Several in vitro methods have been suggested to predict drug-induced haematotoxicity and species differences; the most commonly used being the clonogenic CFU-GM assay. The aim of the current study was to evaluate whether primary lymphocytes from peripheral blood, assayed with a short-term non-clonogenic assay, could be used to detect species differences in drug sensitivity, and offer an alternative to the CFU-GM assay. The effect of 17 different cytotoxic drugs on lymphocytes from human, dog, rat and mouse was evaluated. A higher sensitivity of human than mouse lymphocytes was seen for topotecan and for 3 of 5 antimetabolites tested. Clear species specificity was also seen for the proteasome inhibitor bortezomib where rodent cells were 50-300 times less sensitive than human cells. Good agreement between our data and published CFU-GM data was observed, suggesting that primary lymphocytes may be a useful model for species difference screening in drug development.

Model for time dependency of cytotoxic effect of CHS 828 in vitro suggests two different mechanisms of action.

CHS 828 is a novel drug belonging to the cyanoguanidines. It has shown promising anticancer activity in many preclinical systems and is currently in early clinical trials. Our aim in this study was to assess the growth inhibitory effect of CHS 828 in comparison with paclitaxel, etoposide, and topotecan as a function of concentration and time. U937 GTB, RPMI 8226/S, MDA 231, primary cells from chronic lymphocytic leukemia, and normal mononuclear cells were exposed to CHS 828 and U937 GTB cells were exposed to paclitaxel, etoposide, and topotecan in 18 concentrations for times ranging from 1 to 72 h. Cell survival was measured after 72-h incubation by using the fluorometric microculture cytotoxicity assay. Nonlinear mixed effect modeling was used to model the concentration-effect curves with a modified Hill equation. Patterns of change of drug potency (IC(50)), slope of the concentration-effect curves, and plateau with time were studied. The log IC(50) for CHS 828 decreased with log time in a sigmoid manner for all cell types tested. Although very steep at short and long incubation, the concentration-effect curves became shallow at intermediate times. The log IC(50) for etoposide and topotecan was decreased with log time in a sigmoid manner. The log IC(50) for paclitaxel decreased linearly with log time. The information obtained from modeling the cytotoxic effect of CHS 828 and changes of IC(50) and slope parameters with exposure time suggests a heterogeneous cell response to CHS 828. This could indicate two distinct mechanisms of induction of cell death.

A hollow fiber model for in vitro studies of cytotoxic compounds: activity of the cyanoguanidine CHS 828.

The hollow fiber assay is currently used as an in vivo model for anticancer drug screening in nude mice, but it can also be used as an in vitro model. In the current study, an in vitro hollow fiber model was used to study the effect and mode of induced cell death of a new cyanoguanidine, CHS 828. Human leukemia, adenocarcinoma and lymphoma cell lines as well as primary cultures of human tumor cells from patients with chronic lymphocytic leukemia (CLL) and ovarian cancer (OC) and normal human lymphocytes were cultured in semipermeable hollow fibers. The fibers were incubated for 3 or 14 days prior to CHS 828 exposure for 72 h, followed by determination of living cell density by MTT staining. For cell morphology, using harvested cultures on cytospin slides had technical advantages compared to using paraffin sections of the formalin-fixed fibers. CHS 828 showed higher antitumor activity on CLL and normal human lymphocyte cultures compared to OC cultures, and cell lines cultured 3 days were more sensitive than those cultured 14 days. Morphological examination of CHS 828-treated cultures revealed a mixture of apoptosis and necrosis.

In vivo activity of CHS 828 on hollow-fibre cultures of primary human tumour cells from patients.

Fresh human tumour cells from patients with ovarian cancer and chronic lymphocytic leukaemia were cultured in semipermeable hollow fibres. The fibres were implanted on immunocompetent rats, which were treated with the cyanoguanidine N-(4-chlorophenoxyhexyl)-N'-cyano-N"-4-pyridylguanidine (CHS 828). CHS 828 showed high antitumour activity against all eight tumour samples; the fibres from control animals had a mean net growth of 73% while CHS 828 treatment induced a 37% mean reduction of cell density, without observable haematological toxicity. The results show a feasibility of using tumour cells directly from patients in the hollow-fibre rat model.

Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats.

PURPOSE: Based on the previously published hollow-fibre assay mainly used for early in vivo anticancer drug screening, we wanted to develop an extended hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal. METHOD: The breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hollow fibres. The fibres were implanted subcutaneously into immunocompetent male Sprague Dawley rats, and the rats were treated with 5-fluorouracil (5-FU, 125 mg/kg), epirubicin (EPI, 10 mg/kg) or cyclophosphamide (CP, 120 mg/kg) intraperitoneally, the new cyanoguanidine CHS 828 (375 mg/kg or 75 mg/kg x 5) orally, or vehicle only. After 6 days the fibres were retrieved and the cell density was evaluated. Haematological parameters were monitored and two to four samples per animal were drawn to determine the pharmacokinetic parameters in NONMEM. RESULTS: Drug treatment had generally low effects on the tumour cells. Of the standard drugs (5-FU, EPI and CP), only CP exerted a statistically significant antiproliferative effect. CHS 828 had only a minor effect as a single dose, but divided into five daily doses had a pronounced effect on both cell lines. 5-FU, EPI and CP all caused a marked decrease in leucocytes, platelets and haemoglobin, while CHS 828 did not seem to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmacokinetics of CP and CHS 828 were both described by one-compartment models. CONCLUSIONS: This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal using the hollow-fibre model.