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Biomedical subjects

M Kolopp

Publications and source records attributed to M Kolopp.

At least 19 recordsLinked to original sources
PubMed2001

Poly(ethylene carbonate)s, part II: degradation mechanisms and parenteral delivery of bioactive agents.

The degradation and drug carrier properties of poly(ethylene carbonate) (PEC) were investigated in vitro and in rats and rabbits. PEC was found to be specifically degraded in vivo and in vitro by superoxide radical anions O2-*, which are, in vivo, mostly produced by inflammatory cells. No degradation of PEC was observed in the presence of hydrolases, serum or blood. PEC is biodegraded by surface erosion without significant change in the molecular weight of the residual polymer mass. The non-hydrolytic biodegradation by cells producing O2-* is unique among the polymers used as biodegradable drug carriers. The main degradation product of PEC in aqueous systems is ethylene glycol, formed presumably by hydrolysis of ethylene carbonate. The splitting off of a five-membered ring structure from the polymer chain indicates a chain reaction mechanism for the biodegradation. PEC is a suitable drug carrier, particularly for labile drugs. Using human interleukin-3 and octreotide as model drugs, surface erosion of the PEC formulations was indicated by a 1:1 correlation between drug release and polymer mass loss.

Animals↗
PubMed2001

Assessment of the phototoxic potential of compounds and finished topical products using a human reconstructed epidermis.

The goal of this study was to design a model system for the assessment of phototoxic potential using a human reconstructed epidermis (HRE, SkinEthic Laboratories, Nice, France), by testing some representative phototoxic (P) and non-phototoxic (NP) compounds and finished topical products. The tissue response to 24-h application of 5-5000 microg/mL of the test agents in the presence and absence of UVA light was analyzed in terms of viability (Lactate Dehydrogenase release), pro-inflammatory activity (IL-8 release and mRNA expression) and morphology (histopathology). 8-Methoxypsoralen (P) and promethazin (P), but not sodium lauryl sulfate (NP) produced cytotoxicity concentration-response curves significantly different between irradiated and nonirradiated tissues. Only irradiated tissues showed morphological damage. Application of tetracyclin (P) in the culture medium, but not topically, induced similar signs of phototoxicity. 6-Methylcoumarine (weak P) was not cytotoxic, yet it increased IL-8 release and mRNA expression only following UVA irradiation. PUVA therapy creams containing 1% 8-Methoxy-psoralen (P) or coal tar (P) decreased viability and induced histologic damage in UVA-exposed tissues. In conclusion, the phototoxic potential of the tested agents was correctly predicted by using a tiered strategy that involves determining cytotoxicity, production of IL-8, and morphological damage following exposure of the HRE to the compounds and UVA light.

Cell Survival↗
PubMed2000

Use of human skin equivalent Apligraf for in vitro assessment of cumulative skin irritation potential of topical products.

The main goal of the present study was to investigate the response of the human skin equivalent Apligraf in vitro to the application of irritant substances and its predictivity as a screening tool for cumulative skin irritant potential in humans. Vaseline, calcipotriol, trans-retinoic acid, and sodium lauryl sulfate were applied to Apligraf in vitro for 24 h. Cell viability (lactate dehydrogenase leakage), release and mRNA expression of the proinflammatory cytokines IL-1alpha and IL-8, and morphological changes were assessed. The same products were applied to 30 healthy volunteers in a double-blind, randomized, vehicle-controlled within-subject study. The skin reactions after repeated 24-h applications over 3 weeks under Finn chamber patches were monitored by visual scoring and biophysical methods (trans-epidermal water loss, chromametry, and blood flow). Sodium lauryl sulfate was cytotoxic to Apligraf, and increased the release and expression of cytokines at low (0.2%, 0. 4%), but not at high (0.8%, 1%) concentrations. It induced severe irritancy in vivo. Trans-retinoic acid increased the expression and release of cytokines with no detectable cytotoxicity and showed moderate irritancy in humans. Although calcipotriol did neither affect cell viability nor the production of cytokines, it induced morphological signs of irritation and was mildly irritant for healthy volunteers. Vaseline was innocuous in vivo and induced no changes in Apligraf. In conclusion, the cumulative skin irritation potential of the tested products could be predicted with Apligraf in a sensitive and specific manner, by monitoring cytotoxicity, proinflammatory cytokines, and morphological changes.

Double-Blind Method↗
PubMed1999

Predictivity of an in vitro model for acute and chronic skin irritation (SkinEthic) applied to the testing of topical vehicles.

An in vitro human reconstructed epidermis model (SkinEthic) used for screening acute and chronic skin irritation potential was validated against in vivo data from skin tolerability studies. The irritation potential of sodium lauryl sulfate (SLS), calcipotriol and trans-retinoic acid was investigated. The in vitro epidermis-like model consists of cultures of keratinocytes from human foreskin on a polycarbonate filter. The modulation of cell viability, the release and gene expression of proinflammatory cytokines, interleukins 1alpha and 8, and morphological changes were evaluated during 3 days as endpoints representative for an inflammatory reaction. The cumulative irritation potential of the topical products was evaluated in a human clinical study by visual scoring and biophysical measurement of inflammatory skin reaction after repeated 24 h applications over 3 weeks under Finn chamber patches. All topical products that were nonirritating in the human study were noncytotoxic and did not induce cytokine expression in the in vitro acute model (day 1 exposure). All irritating controls exhibited specific cell viability and cytokine patterns, which were predictive of the in vivo human data. The ranking of mild to moderate skin irritation potential was based on the lack of cytotoxicity and the presence of cytokine patterns including gene expression specific for each irritant, using the chronic in vitro model (up to 3 days exposure). The human reconstructed epidermis model SkinEthic was shown to be a reliable preclinical tool predicting the irritation potential of topical products. Moreover, it is a useful model in a two-step tiered strategy for screening acute and chronic irritation potential for the selection of vehicles for new topical drugs.

Adult↗
PubMed1998

Blood glucose control on Sunday in IDDM patients: intensified conventional insulin therapy versus continuous subcutaneous insulin infusion.

We have assessed the capacity of continuous subcutaneous insulin infusion (CSII) to maintain good blood glucose metabolic control on Sundays, when waking is delayed, with reference to intensified conventional insulin therapy by multiple daily injections (MDI). The study lasted 3 weeks, including 3 week-ends. A total of 20 IDDM patients were selected for metabolic control: ten were treated by CSII and ten by MDI. Blood glucose was determined at least three times a day (fasting on waking, pre-lunch and pre-dinner). The times of blood glucose determinations and their values were recorded in a memory reflectance meter. Waking, the first blood glucose measurement and the first insulin injection (MDI) or bolus (CSII) were about 1 h later on Sundays than on a weekday (44 +/- 4 min in MDI group, P < 0.04; and 59 +/- 7 min in CSII group, P < 0.02). The times of the pre-lunch and pre-dinner blood glucose determinations were not significantly different. The mean waking and pre-lunch blood glucose values of the MDI group were higher on Sundays (11.5 +/- 3.8 and 9.7 +/- 4.5 mmol/l) than on weekdays (8.7 +/- 2.3 and 7.1 +/- 2.5 mmol/1)(P < 0.01). The pre-prandial blood glucose levels of the CSII group on Sundays and weekdays were not statistically different at any time. Changes in the waking time and the subsequent delay in the first insulin bolus on Sunday may alter blood glucose control in patients on MDI, but CSII allows such changes without any glycemic side effects.

Adult↗
PubMed1995

In vitro tolerability of human nasal mucosa: histopathological and scanning electron-microscopic evaluation of nasal forms containing Sandostatin.

An in vitro human nasal model was developed as a tool to study the local tolerability of nasal powder forms using excised nasal mucosa in a diffusion chamber. The suitability of this model was tested using Sandostatin (SMS) an octapeptide analog of somatostatin, as a reference drug enhanced by Avicel (microcrystalline cellulose) or lactose (100 mesh). The standard nasal spray vehicle was taken as a harmless control and 1% chenodeoxycholate (CDC) as a harmful control in terms of local tolerability. The extent of peptide permeation was determined by measuring SMS concentration in the receiving chamber. The labeling of SMS was detected by immunoperoxidase staining on cross sections. The local tolerability for all tested forms was assessed by histopathological examination and scanning electron microscopy. The apparent permeation coefficient allowed us to rank the absorption of the tested drug forms as Avicel > spray = lactose > 1%CDC. For all formulations, SMS was detected in the epithelium. No changes of the nasal mucosa could be observed with Avicel, lactose or nasal spray vehicle in the presence or absence of SMS. 1%CDC with or without drug showed an immediate destruction of the nasal epithelium. The validation of this in vitro model using human nasal mucosa will be further discussed as a tool for assessing the local tolerability of intranasally applied test substances.

Absorption↗
PubMed1993

Self-monitoring of blood glucose and insulin dose alteration in type 1 diabetes mellitus.

The purpose of this study was to evaluate the relationship between proper use of self-monitoring of blood glucose (SMBG) including knowledge and application of specific algorithms and metabolic control in a group of randomly selected insulin-dependent diabetic patients. We studied 80 patients responding to the following criteria: intensive conventional insulin therapy and SMBG for at least 6 months using a reflectance meter, and previous 5-day hospital education period. The practical knowledge of the guidelines was evaluated by a questionnaire simulating 8 metabolic situations. A computer analysis of the SMBG data for the 3 months preceding the study allowed us to evaluate patient compliance with SMBG (number of blood glucose determinations) and patients' application of the guidelines (percentage of insulin doses modified according to the guidelines). Fifty-nine patients (79%) were compliant with SMBG and had better metabolic control than the non-compliers (HbA1c: 6.7 +/- 1.1% vs. 7.5 +/- 1.9, P < 0.05). Twenty-eight out of the 59 compliant subjects had good knowledge of the guidelines but without patent improvement of glycemic control. Seventeen of these 28 correctly used the algorithms to modify insulin dosage; their HbA1c levels were lower than those of the 11 patients who did not use the algorithms (6.1 +/- 0.9 vs. 7.1 +/- 0.9%, P < 0.05). The percentage of insulin dose modification consistent with the guidelines and the level of HbA1c was negatively correlated in the good-knowledge group. The conclusion is that good metabolic control is linked not only with the degree of knowledge but also with the application of this knowledge.

Adolescent↗
PubMed1992

In situ analysis of adenohypophysis proliferative activity in beagle dogs. Preliminary results.

In order to establish control data on adenohypophysis cell cycle in beagle dogs, two different approaches were used. In the first approach, the adenohypophysis mitotic index (percentage of cells in mitosis: MI) was determined using pituitary glands from 50 control beagle dogs, 10 to 25 months old, from retrospective regulatory safety assessment studies. We found that the MI in males was 0.024 +/- 0.007% and in females 0.068 +/- 0.019%. The second approach involved the determination of the adenohypophysis cell fraction in S phase by means of bromodeoxyuridine (BrdU) anti-BrdU method in 16 control beagle dogs, 8 to 20 months old, from ongoing safety assessment studies. We found that the BrdU labeling index (percentage of BrdU-positive cells per total number of cells: BrdU LI) was 0.053 +/- 0.009% in males and 0.059 +/- 0.015% in females. Analysis of our data indicated that the results obtained from the BrdU LI were more reliable (coefficient of variation [CV] less than 0.07) compared to those obtained from the MI (CV greater than 1.4). No clear difference was found between male and female beagle dogs, regarding adenohypophysis cell proliferation. In both studies, adenohypophysis cell proliferation was found to be age-dependent, with the highest value in immature dogs. No correlation between estrus cycle in females and adenohypophysis cell proliferation was noted.

Animals↗
PubMed1991

A brief review of modern toxicologic pathology in regulatory and explanatory toxicity studies of chemicals.

Macroscopic and histologic evaluation of animal studies for general toxicity and carcinogenicity are cornerstones of the risk assessment of new chemical entities. Standard toxicopathologic evaluation is mainly based on the study of paraffin sections stained with hematoxylin and eosin. There are, however, a number of new approaches and techniques which have improved the objectivity of evaluation and the accuracy of cell identification, and provided deeper insight into the molecular biological mechanisms of toxicity and carcinogenicity. Such approaches include the standardization of the nomenclature, the creation of data banks for morphological alterations, the use of computers to register pathological findings in toxicity studies and to statistically evaluate incidences, and the use of morphometry. Other modern techniques are immunohistochemistry, in situ hybridization, and the assessment of cell kinetics.

Animals↗
PubMed1991

Morphologic and immunohistochemical characterization of Leydig cell tumor variants in Wistar rats.

During a routine long-term drug safety study, lasting approximately 2 1/2 yr, male Wistar rats, treated with a prolactin-inhibiting compound, developed an excess of Leydig cell tumors (LCTs). Most tumors were typical for the rat but a small number showed an unusual variation and some appeared malignant. The variation consisted of glandular and/or tubular structures within the tumor mass which occasionally anastomosed and contained an eosinophilic periodic-acid Schiff (PAS) positive material. In a few of these variants, malignant features such as cellular atypia, capsular, and lymphatic invasion and necrosis were seen. No metastases were detected. Detailed morphological and immunohistochemical investigations were conducted in order to establish the cell of origin of these variants. Glandular/tubular structures were found to stain with varying intensity for vimentin and cytokeratin, but were always negative for beta-tubulin. The results indicated that the cell of origin of these LCT variants was indeed the Leydig cell and that glandular and/or tubular structures within LCTs represented a form of Leydig cell metaplasia.

Animals↗
PubMed1989

Reliability of self-monitoring of blood glucose by CSII-treated patients with type I diabetes.

The reliability of patient-generated data from self-monitoring of blood glucose (SMBG) was studied in 14 patients with type I (insulin-dependent) diabetes mellitus treated by continuous subcutaneous insulin infusion (CSII) (7 women, 7 men). The reflectance meters (Glucometer I, Ames, Elkhart, IN) used by the patients were replaced for a period of 21 days by memory-reflectance meters; patients were unaware of the memory capacity of the new meters and were instructed to continue their practice of recording the meter readings in their logbook. This study compares the data recorded in the memory-reflectance meters with those reported in the logbook. The number of SMBG measurements was different in 11 patients (differences ranging from 2 to 66). Mean glycemia was similar (8.23 +/- 0.36 mM in logbook vs. 8.49 +/- 0.48 mM in memory-reflectance meters), but both the M value and mean amplitude of glycemic excursions (MAGE) index were lower when calculated from logbook data (38 +/- 5 vs. 48 +/- 7 mM, P less than .05 and 6.91 +/- 0.43 vs. 7.72 +/- 0.52 mM, respectively; P less than .05). Overreporting (addition of phantom values in logbook) and underreporting (omission of SMBG measurements from logbook) indexes were 19 +/- 7 and 12 +/- 3%, respectively. Precision (percent of identical values in logbook and in memory-reflectance meters at the corresponding time) was 77 +/- 6.8%. The number of SMBG measurements recorded in the memory-reflectance meter was negatively correlated with glycosylated hemoglobin [HbA1c; (r = -.85, P less than .001)], whereas overreporting was positively correlated with HbA1c (r = .76, P less than .01).

Adult↗
PubMed1989

[Impotence in the diabetic].

Two-hundred-and-two impotent diabetic patients gave their consent to be investigated. Impotence is linked to diabetes mellitus in 58.9% of patients so all the other etiologies have to be systematically eliminated. Neuropathy or arteriopathy, when isolated, are found with the same frequency, but these 2 etiologies are often associated (47 patients). No statistical difference between IDDM and NIDDM was found. Mercury strain gauge plethysmography and venous occlusion coupled to ECG allows detection of arterial lesions in diabetic impotence. Patients agreed to submit to all of the various therapeutic possibilities. Combination of alpha-blockade and good glycemic control induced the best results.

Adult↗
PubMed1988

Circadian and ultradian rhythms in blood glucose and plasma insulin of healthy adults.

The circadian and ultradian variations of blood glucose and plasma insulin have been characterized individually and as a group phenomenon in five healthy young adults studied while adhering as closely as possible to their usual routine of sleep, activity, meal content and timing. Three complementary methods were used to analyze the data: displaying raw data as a function of time; cosinor method according to Nelson and Halberg; and time series analyses as proposed by De Prins and Malbecq. The subjects were studied in the laboratory and their life routine were controlled, but very close to that of their habitual routine. They had mainly ultradian rhythms of blood glucose (mainly about 6 hr) and circadian rhythms of immunoreactive insulin (I.R.I.). Blood glucose ultradian rhythms seem to be mainly but not exclusively mealtime dependent, while I.R.I. circadian rhythms appear to be primarily endogenous in origin. Therefore, the role played by insulin in the control of blood glucose levels seems to be programmed on a circadian basis rather than by a time independent feedback phenomenon as postulated by the conventional homeostatic hypothesis. The advantage of this chronophysiologic approach is to consider circadian rhythms of both I.R.I. and insulin effectiveness as an adaptive phenomenon able to maintain blood sugar changes in the ultradian domain of rhythms.

Activity Cycles↗
PubMed1987

Morphometric study of human hepatic cell modifications induced by fenofibrate.

We have studied liver biopsies obtained in 12 hyperlipoproteinemic (HLP) patients (type II, 6; type IV, 6) treated with diet and fenofibrate, and in 15 patients (type II, 11; type IV, 4) receiving diet only. Electron microscopy of liver biopsies and the morphometric analysis according to the method of Weibel and Rohr showed mitrochondrial changes in patients treated with fenofibrate, these changes depending on the type of hyperlipoproteinemia. In type II HLP, we found a decreased volume of normal mitochondria (fenofibrate, 125.72 +/- 17.04 X 10(-3) cm3/cm3; diet only, 185.84 +/- 8.96 10(-3), P less than .05). In type IV HLP we found a decreased number of giant mitochondria (fenofibrate, 0.08 +/- 0.03 X 10(10) cm-3; diet only, 0.32 +/- 0.08 X 10(10) cm-3, P less than .05) and a decreased volume of altered mitochondria (fenofibrate, 6.00 +/- 1.44 X 10(-3) cm3/cm3; diet only, 13.61 +/- 1.17 X 10(-3), P less than .05). In contrast with the rodent studies, the present study shows no change in the number of volume of peroxisomes.

Adult↗
PubMed1986

Ultradian, circadian and circannual rhythms of blood glucose and injected insulins documented in six self-controlled adult diabetics.

The aim of the study was to document during one to two years individual rhythmic patterns in blood glucose and injected insulin in self-controlled insulin dependent (C-peptide negative) diabetics with home blood glucose monitoring. Two females and four males with diurnal activity from 0700 to 2300 self-determined their blood glucose three to six times a day over a period of 12-27 months. Circadian and ultradian rhythms were analysed for each subject on a monthly basis to document annual rhythms. Blood glucose (BG) estimated circadian acrophases were located between 2200 and 0300 for all patients and months with few exceptions. A correlation was found between circadian mesors and amplitudes of BG in four subjects. Annual changes in BG were validated for each subject with large interindividual differences in peak times. The individual mean of injected insulin (II) varied from 40 to 80 iU with annual changes validated for each subject. A group pattern was observed with a peak time either in the autumn (four patients) or in the summer (two patients). A circadian rhythm of II was detected in almost all monthly means and for all patients. Locations of computed peak time phi of II exhibited a great stability for a given individual but large interindividual differences. Thus the rather constant phi location of BG for all subjects contrasted with interindividual differences in phi locations of II. These results suggest that rhythmic changes in BG and II should be recognized when forming a realistic strategy for timing and dosing time(s) of insulin.

Activity Cycles↗
PubMed1986

Effect of a 12-hour subcutaneous infusion of somatostatin-14 on blood glucose, insulin and glucagon levels in healthy subjects and insulin dependent diabetics.

We compared the influence of a 12-hour subcutaneous infusion of somatostatin-14 on glucose homeostasis in two normal subjects and two insulin-dependent diabetics (IDD). In all cases, somatostatin infusion led to a decrease of blood glucose during the first hours. The diabetogenic effect of somatostatin was confirmed in normal subjects. Postprandial blood glucose response was exaggerated in one insulin-dependent diabetic while in the other, glucose tolerance was improved. Unexpected high levels of immunoreactive somatostatin were measured in insulin-dependent diabetic patients. They might be due to a decreased somatostatin catabolism.

Blood Glucose↗