Biomedical subjects

M J Novak

Publications and source records attributed to M J Novak.

34 records · Page 2Linked to original sources

PubMed1994

Suramin: development of a population pharmacokinetic model and its use with intermittent short infusions to control plasma drug concentration in patients with prostate cancer.

PURPOSE: This study aimed to (1) develop a population pharmacokinetic model for suramin; (2) use Bayesian methods to assess suramin pharmacokinetics in individual patients; (3) use individual patients' pharmacokinetic parameter estimates to individualize suramin dose and schedule and maintain plasma suramin concentrations within predetermined target ranges; and (4) assess the feasibility of outpatient administration of suramin by intermittent, short infusions. METHODS: Plasma suramin concentrations were measured by high-performance liquid chromatography (HPLC), and compartmental pharmacokinetic models were fit using a Bayesian algorithm. Population pharmacokinetic models were developed using an iterative two-stage approach. Estimates of each patient's central-compartment volume were used to calculate suramin dosage. Simulation of that patient's suramin clearance was used to predict the time of his next dose. Using this approach, plasma suramin concentration was maintained at between 200 and 300, 175 and 275, 150 and 250, or 100 and 200 microgram/mL in four sequential patient cohorts. The ability of two- and three-compartment, open, linear models to fit the pharmacokinetic data was compared. Population pharmacokinetic parameters were estimated, using both two- and three-compartment structural models in 69 hormone-refractory prostate cancer patients. RESULTS: Target plasma suramin concentrations in individual patients were rapidly achieved. Concentrations were maintained within desired ranges for > or = 85% of treatment duration in all cohorts. A three-compartment, open, linear model described suramin pharmacokinetics better than did a two-compartment, open, linear model. Population pharmacokinetic estimates generated for two- and three-compartment pharmacokinetic models demonstrated modest interpatient pharmacokinetic variability and the long terminal half-life of suramin. CONCLUSION: Suramin can be administered by intermittent short infusion. Adaptive-control-with-feedback dosing facilitated precise control of plasma suramin concentrations and allowed a number of different concentration ranges to be studied. This approach is expensive and labor-intensive. Although we have demonstrated the ability to control drug exposure, simpler dosing schedules require critical evaluation. Population pharmacokinetic parameters generated in men with hormone-refractory prostate cancer will facilitate rational design of such schedules.

Adult↗

PubMed1994

Modeling toxicity and response in carboplatin-based combination chemotherapy.

Data from women with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III or IV) were analyzed to evaluate the pharmacokinetic/pharmacodynamic relationships of carboplatin-based combination chemotherapy. With the equation area under the plasma concentration versus time curve (AUC) = dose/(creatinine clearance + 25), carboplatin AUC was calculated in each of up to six treatment cycles in 224 women with advanced ovarian cancer who had been randomized to receive carboplatin 300 mg/m2 plus cyclophosphamide 600 mg/m2. In addition, for each patient, the predicted nadir count (obtained by rearranging the University of Maryland single-agent carboplatin dosing formula) was compared with the actual observed nadir count, received and relative received dose intensities were calculated, and carboplatin exposure intensity was defined. Relationships were sought between these treatment indices and the clinical outcomes of time to progression and survival. When combined with cyclophosphamide 600 mg/m2, any carboplatin AUC was found to be associated with greater myelotoxicity and a higher likelihood of both leukopenia and thrombocytopenia occurring than had been determined for single-agent carboplatin. Furthermore, the platelet nadir in 83% of patients was equal to or below that predicted to result from the same dose of single-agent carboplatin. There was a relatively narrow range of received dose intensities within this patient population, but carboplatin exposure intensity was calculated as being distributed over a two-fold range within the population. Therefore, received carboplatin dose intensity underestimates the range of plasma drug exposure associated with a fixed dosing regimen of carboplatin. However, there were no consistent relationships between received dose intensity, relative received dose intensity, or carboplatin exposure intensity and the clinical outcomes of time to progression or survival. The relationships between carboplatin exposure and the pharmacodynamic measures of toxicity and response are likely to require definition in each regimen that includes carboplatin and for each tumor type treated.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1993

Impact of cyclophosphamide on relationships between carboplatin exposure and response or toxicity when used in the treatment of advanced ovarian cancer.

PURPOSE: To determine (1) the impact of cyclophosphamide 600 mg/m2 on previously defined relationships between carboplatin area under the plasma concentration versus time curve (AUC) and indices of toxicity and response in women with advanced ovarian cancer; and (2) the relationships between indices of cumulative drug exposure and clinical outcomes. METHODS: Carboplatin AUC = dose/(creatinine clearance [CCr] + 25) and was calculated in 224 women who received carboplatin 300 mg/m2 and cyclophosphamide 600 mg/m2. The likelihood of grade 3 or greater myelotoxicity at any carboplatin AUC was compared with the likelihood of myelotoxicity at the same single-agent carboplatin AUC. The nadir count predicted using the University of Maryland single-agent carboplatin dosing formula was compared with the nadir count observed. Received and relative-received dose-intensity were calculated. Carboplatin exposure-intensity was defined by substituting cumulative carboplatin exposure for total dose. Relationships were sought between these indices and therapeutic outcomes. RESULTS: The incidence of leukopenia and thrombocytopenia at any carboplatin AUC was greater for the two-drug combination than for single-agent carboplatin. The platelet nadir in 83% of patients was less than or equal to the nadir predicted for the same single-agent carboplatin AUC. Despite a narrow range of received dose-intensities, carboplatin exposure-intensity was distributed over a twofold range. There were no relationships between received and relative-received dose-intensity or carboplatin exposure-intensity and time to progression or survival. CONCLUSION: Any carboplatin AUC when administered with cyclophosphamide 600 mg/m2 produces greater myelotoxicity than the same AUC of single-agent carboplatin. Received carboplatin dose-intensity underestimates the range of plasma drug exposure resulting from a fixed carboplatin dosing regimen. Whether higher carboplatin exposures can improve outcome requires prospective validation.

Adult↗

PubMed1993

Laparoscopic herniorrhaphy: results and technical aspects in 450 consecutive procedures.

BACKGROUND: The effectiveness of laparoscopic herniorrhaphy, the patient outcome, and technical aspects have been controversial. We have performed 450 consecutive laparoscopic inguinal herniorrhaphies and have reviewed the rationale, technical aspects, and the outcomes. METHODS: Four hundred and fifty consecutive laparoscopic herniorrhaphies were performed using synthetic mesh for tensionless repair and adhering to surgical principles of preperitoneal herniorrhaphy. Patients were 16 to 83 years of age, 74% men, 26% women. Mesh was transfixed to anatomic landmarks with suture or staples. The peritoneum was closed, separating mesh from abdominal contents. RESULTS: Ninety percent of patients were discharged from perioperative care; 10% were in the hospital 23 hours as a result of urinary retention, cardiac disease, etc. No adhesive or mesh complications occurred. Three hernias recurred at 2 to 4 months after operation. Two were repaired laparoscopically. CONCLUSIONS: Laparoscopic inguinal herniorrhaphy is a safe and effective procedure. It compares favorably with other classic methods of hernia repair (especially use of a tensionless repair with mesh). Patients exhibit minimum morbidity and ambulate soon with minimal discomfort. This repair should be considered preferential in many subsets of patients.

Adolescent↗

PubMed1992

Host mediators in gingival crevicular fluid: implications for the pathogenesis of periodontal disease.

During the past few years, a considerable number of studies have examined different aspects of the host response in gingival crevicular fluid (GCF), including the relationship of specific markers to the active phases of periodontal disease. Various indicators of the acute inflammatory response (the lysosomal enzymes beta-glucuronidase and collagenase, the cytoplasmic enzyme aspartate aminotransferase, and the arachidonic acid metabolite PGE2) have been shown to be associated with clinical attachment loss in chronic adult periodontitis in man and experimental periodontitis in animal models. In contrast, the relationship of indicators of the humoral immune response in GCF to active periodontal disease is equivocal. Furthermore, a number of indicators of the cellular immune response have been identified recently in GCF (i.e., Interleukin-1 alpha, IL-1 beta, tumor necrosis factor-alpha), but their relationship to active phases of periodontal disease have not been studied. The polymorphonuclear leukocyte (PMN) is the cellular hallmark of acute inflammation. Evidence from the GCF studies suggests that hyperreactivity of these cells plays a critical role in the active phases of some forms of periodontal disease. Metabolic activation of PMN can be associated with a number of potentially destructive reactions. The major effector mechanism for tissue destruction that can be specifically identified with the PMN is the synergistic effect of the release of PMN proteases and the generation of reactive oxygen metabolites by these cells. Priming of the PMN, where the PMN response is enhanced by agents that do not initiate the response, may be an important mechanism for PMN activation in the crevicular environment; for example, cytokines such as IL-1 beta and TNF-alpha, and lipopolysaccharides released from subgingival Gram-negative bacteria, can serve this function. The hypothesis proposed here argues that in addition to the severe forms of periodontal disease that have been associated with qualitative or quantitative PMN defects, tissue destruction in the periodontum can be observed with hyperreactivity of these cells. These differing conclusions do not create a dilemma, but may represent opposite ends of a balance that is no longer in equilibrium.

Animals↗

PubMed1991

Depolarization of polymorphonuclear leukocytes by Porphyromonas (Bacteroides) gingivalis 381 in the absence of respiratory burst activation.

Bacteroides spp. may contribute to the chronicity of mixed infections by affecting the normal functions of polymorphonuclear leukocytes (PMN). This study evaluated the physiologic and biochemical responses of human peripheral blood PMN to a variety of strains of the oral periodontal pathogen Porphyromonas (Bacteroides) gingivalis. Strain 381 and ATCC type strain 33277 caused rapid and lasting depolarization of the electrochemical potential that exists across the PMN membrane by a mechanism that was independent of activation of the pertussis toxin-sensitive G protein or protein kinase C. Membrane depolarization did not initiate increases in intracellular calcium or respiratory burst activation, and activity was not inhibited by surface proteolysis or sugars. However, membrane depolarization was associated with inhibition of PMN responses to the chemotactic peptide N-formylmethionyl leucyl phenylalanine. Membrane-depolarizing activity was isolated with the outer membrane of strain 381 by surface extraction of the bacteria by using Zwittergent 3,14, followed by Sephacryl S-200 gel filtration chromatography. The partially purified outer membrane components were heat stable, were not inhibited by tosyl-lysine chloromethyl ketone, and inhibited N-formylmethionyl leucyl phenylalanine-stimulated superoxide production. The results suggest that outer membrane components of P. gingivalis 381 and 33277 have porinlike activity that can depolarize PMN membranes and immobilize PMN responses to chemotactic peptides. This may prove to be an important virulence characteristic of these strains.

Bacterial Outer Membrane Proteins↗

PubMed1991

Diagnosis of periodontal diseases: reaction paper.

With the recent description of 12 different forms and sub-forms of periodontitis by the World Workshop in Clinical Periodontics (1989), increased emphasis has been placed on diagnosis. Dr. Ranney's review addressed the specificity and sensitivity of current diagnostic tests with respect to their ability to differentiate between health and disease and between the individual disease states. Although considerable microbiologic and immunologic data have been accumulated in the past decade, very little of this information has proved to be sufficiently sensitive to be of use in differential diagnosis. Clinical measurements provide us with an insensitive, retrospective analysis of what has already occurred but allow us to diagnose disease based on its natural history. Measures of attachment levels, by use of conventional probes, are only sufficiently sensitive indicators of periodontitis when as much as 20-30% of attachment has already been lost. Current technological improvements in probing measurements and radiographic assessment may increase sensitivity in this area. Future improvements in diagnostic techniques will occur with the advent of sensitive biochemical analyses of gingival crevicular fluid. These assays will provide a more objective analysis of inflammation and, in time, will provide sufficient sensitivity to allow for differentiation between and among the various forms of periodontal disease. Future directions in diagnosis will focus on the identification of disease-susceptible individuals and the prediction of future periodontal breakdown.

Aggressive Periodontitis↗

PubMed1991

Resolution of early lesions of juvenile periodontitis with tetracycline therapy alone: long-term observations of 4 cases.

Our previous studies have demonstrated that early-identified lesions of localized juvenile periodontitis (LJP) can be treated by the use of systemically administered tetracycline alone (1 gm/day for 6 weeks). This therapy results in arrest of disease progression, decreased pocket depths, gains in clinical attachment, and significant repair of alveolar defects. This paper reports on the long-term clinical and radiographic improvement in 4 subjects followed for 1 to 4 years after the completion of tetracycline therapy. Four patients (mean age 14 years) were examined 1 to 4 years following the completion of a single 6 week course of tetracycline. Mean pocket depth was reduced from the initial level of 7.1 mm to 3.6 mm. Mean attachment loss was reduced from 3.8 mm to 0.9 mm and angular bone defects had filled by an average of 72%. Pocket depths and attachment loss continued to decrease during the entire study period, while alveolar bone repair continued to increase. The findings support those of our previous investigation and confirm that: 1) early identified lesions of LJP can be effectively treated with 6 weeks of tetracycline therapy alone; 2) decreases in pocket depth, gains in clinical attachment, and repair of alveolar defects remain stable up to 4 years following antibiotic therapy; 3) clinical and radiographic improvement continues over time and may lead to complete resolution of some lesions; and 4) the reparative/regenerative potential of the periodontium in early onset disease in young individuals may exceed that observed in chronic adult periodontitis.

Adolescent↗

PubMed1990

Acremonium chrysogenum differentiation and biosynthesis of cephalosporin.

On the basis of structure-functional analysis of the development of Acremonium chrysogenum, e.g. under conditions either stimulating antibiotic synthesis or not conductive to production, a scheme was proposed representing the various ways in which morphological differentiation occurs in the culture in dependence on the directions of its metabolism. Three types of culture differentiation were determined. Type 1 differentiation is characterized by the transition of the vegetative stage into the reproductive one with the formation of conidia. Type 2 differentiation is characterized by the formation of typical arthrospores also being the reproductive form. Type 3 differentiation is characterized by the multistage transformation of the mycelium organization into the yeast-like one which is metabolically more active and is a producer of antibiotics and enzymes. In addition to the defined regularities in the development and differentiation of Acremonium chrysogenum structural peculiarities were observed which could be helpful to the search for regulators or specific enzymes taking part in the culture development.

Acremonium↗

PubMed1989

Lectinlike interactions of Fusobacterium nucleatum with human neutrophils.

Fusobacterium nucleatum expresses lectinlike adherence factors which mediate binding to a variety of human tissue cells. Adherence is selectively inhibited by galactose, lactose, and N-acetyl-D-galactosamine. In this study, adherence of F. nucleatum to human peripheral blood polymorphonuclear neutrophils (PMNs) was investigated. The results indicated that the fusobacteria adhered to live and metabolically inactivated or fixed PMNs. Adherence of F. nucleatum resulted in activation of PMNs as determined by PMN aggregation, membrane depolarization, increased intracellular free Ca2+, superoxide anion production, and lysozyme release. Transmission electron micrographs showed that F. nucleatum was phagocytized by the PMNs. Microbicidal assays indicated that greater than 98% of F. nucleatum organisms were killed by PMNs within 60 min. Adherence to and activation of PMNs by F. nucleatum were inhibited by N-acetyl-D-galactosamine or lactose greater than galactose, whereas equal concentrations of glucose, N-acetyl-D-glucosamine, mannose, and fucose had little or no effect on F. nucleatum-PMN interactions. Pretreatment of the fusobacteria with heat (80 degrees C, 20 min) or proteases inhibited adherence to and activation of PMNs, but superoxide production was also stimulated by heated bacteria. The results indicate that interaction of F. nucleatum with PMNs is lectinlike and is probably mediated by fusobacterial proteins which bind to other human tissue cells. Adherence of F. nucleatum to PMNs in the absence of serum opsonins, such as antibodies and complement, may play an important role in PMN recognition and killing of F. nucleatum in the gingival sulcus and in the subsequent release of PMN factors associated with tissue destruction.

Bacterial Adhesion↗

PubMed1989

Effects of levamisole on experimental periodontitis.

Although the chemotaxis and efflux of functionally normal polymorphonuclear leukocytes (PMN) into the periodontal sulcus may have a protective role in periodontitis, these cells are also associated with periodontal tissue destruction. The immunomodulating agent, levamisole hydrochloride, is known to enhance PMN chemotaxis. The present study was designed to evaluate the effects of enhanced PMN chemotaxis on the tissue destruction associated with an experimental periodontitis. Levamisole was administered by oro-gastric intubation to 4 squirrel monkeys (experimental) at 3 mg/kg/bw every 2 days for 18 days. After 2 doses of levamisole, marginal periodontitis was induced around maxillary and mandibular bicuspids and the maxillary first molars by tying plaque-retentive ligatures at the gingival margins. Periodontitis was induced around corresponding teeth in 4 animals (control) which had not received levamisole. All animals were killed 2 weeks after induction of periodontitis. Clinically, gingival inflammation was more pronounced in experimental animals at both 7 and 14 days after periodontitis induction. The progression of periodontitis was evaluated histometrically and alterations in the cell populations characterized using step serial sections. The results were analyzed statistically. No significant differences were observed between the groups with respect to areas of infiltrated supracrestal connective tissue and total numbers of cells present, loss of connective tissue attachment and loss of coronal alveolar bone. However, in experimental specimens, a much denser band of inflammatory cells was evident between the apical extent of the bacterial plaque and the gingival sulcular tissues the connective tissue of which contained significantly fewer inflammatory cells and demonstrated more pronounced fibrogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗

PubMed1988

Tetracycline therapy in patients with early juvenile periodontitis.

Tetracycline therapy, when used in conjunction with surgery or root planing, has been shown to be effective in controlling the progression of juvenile periodontitis. However, the ability of tetracycline alone to control the disease has not been assessed. The present study evaluated the effects of tetracycline therapy, with supragingival plaque control, on clinical attachment levels and radiographic bone height in patients with clinical and radiographic evidence of juvenile periodontitis. The four patients (mean age 15.2 +/- 0.3 yrs) each demonstrated loss of attachment of greater than or equal to 2 mm at one or more probing sites and had accompanying radiographic evidence of early localized bone loss. Following an initial clinical evaluation consisting of pocket depths, attachment levels and standardized radiographs, the patients received systemic tetracycline therapy (1 gm/day for three to six weeks) and oral hygiene instruction. At the completion of antibiotic therapy, patients received a supragingival professional prophylaxis every two weeks for three months, whereupon the initial evaluation was repeated. On comparing the initial and three-month clinical and radiographic data, there were significant decreases in clinical and radiographic measurements. For a total of 85 affected probing sites around 26 teeth, 79% decreased in pocket depth by greater than or equal to 2 mm (with no sites increasing in pocket depth) and 69% gained clinical attachment (with only one site losing attachment of 1 mm). Radiographic measurements revealed an increase in both the height and area of coronal alveolar bone. The findings indicated that six weeks of systemic tetracycline therapy combined with supragingival plaque control was effective in the initial control of early juvenile periodontitis.

Adolescent↗

PubMed1984

Effects of gold salts on experimental periodontitis. III. Ultrastructural observations.

Previous studies showed that the systemic administration of soluble gold salts resulted in significantly less periodontal destruction after 2 weeks of experimentally induced periodontitis. The present study compared the ultrastructural characteristics of the inflammatory lesion in animals receiving gold salts (experimental) with those in animals that had not received gold salts (control). Maxillary gingival biopsy specimens were obtained from the buccal aspect of ligatured teeth after 2 weeks of experimental periodontitis. A cellular and extracellular ultrastructural characterization was done in an "epithelial and superficial connective-tissue zone," and a "deep connective-tissue zone." Experimental (gold-receiving) specimens had an intact sulcular epithelium with narrow intercellular spaces overlying a collagen dense connective tissue. Control specimens had a degenerating disrupted epithelium overlying a collagen-poor connective tissue in which polymorphonuclear leucocytes predominated and often were closely apposed to morphologically altered fibroblasts. The cellular distribution of electron-dense deposits of gold salts was demonstrated, and their possible role in modulating mechanisms of cell cytotoxicity and collagen turnover is discussed.

Animals↗

PubMed1984

Effects of gold salts on experimental periodontitis. I. Histometric evaluation of periodontal destruction.

Systemic administration of gold salts for treatment of arthritis is thought to limit tissue destruction through alteration of inflammatory cell function. The present study ascertained if gold salts could modify the tissue destruction associated with an experimental marginal periodontitis. Therapeutic levels of serum gold salts were established in four squirrel monkeys (experimental) by intramuscular injection of Myochrisine (gold sodium thiomalate 25 mg/ml) at 5 mg/kg/body weight at 4-day intervals for 12 days. Marginal periodontitis was then induced around mandibular bicuspids by tying plaque retentive ligatures at the gingival margins. Periodontitis was induced around corresponding teeth in four control animals which had not received gold salts. Serum levels of gold salts were maintained in experimental animals, and all animals were killed 2 weeks after induction of periodontitis. Progression of periodontitis was evaluated histometrically on step-serial sections, and the results analyzed statistically. Specimens from gold-receiving animals had significantly smaller areas of infiltrated supracrestal connective tissue, and less loss of connective tissue attachment and coronal alveolar bone. Quantitation of total plaque around the ligatures showed no differences; however, there was less plaque located apical to the ligatures in gold-receiving specimens. Although the study design did not permit identification of the relative importance of cellular or microbial factors, it was concluded that administration of systemic gold salts was associated with significantly less periodontal destruction.

Animals↗

PubMed1984

Effects of gold salts on experimental periodontitis. II. Cell population characteristics.

A previous study showed that the systemic administration of soluble gold salts (gold sodium thiomalate) resulted in significantly less periodontal destruction after 2 weeks of experimentally induced periodontitis. In order to provide information on the possible mechanisms of action of gold salts in the experimental periodontitis situation, the present study analyzed and compared the characteristics of the inflammatory cell populations in animals receiving gold salts with those present in animals which had not received gold salts. Maxillary gingival biopsy specimens were obtained from the buccal aspect of ligatured teeth after 2 weeks of experimental periodontitis. Cell populations were characterized and enumerated, on 1-micron sections, in an epithelial and superficial connective tissue zone, and a deep connective tissue zone. Significantly fewer inflammatory cells were present in experimental (gold receiving) specimens, and this reduction was due primarily to fewer polymorphonuclear leucocytes (PMNs). No significant reduction occurred in any other inflammatory cell-type. The reduction in number of PMNs in experimental specimens was associated with a decreased number of morphologically altered, degenerating fibroblasts in the connective tissue compared to the PMN-dominated lesion of control specimens. Mechanisms whereby gold salts can reduce chemotaxis and functional capabilities of inflammatory cells are discussed.

Alveolar Process↗

PubMed1983

A periodontal attachment mechanism without alveolar bone. Case report.

A 22-year-old black male was referred for periodontal therapy because of radiographic evidence of advanced bone loss associated with the posterior teeth. Clinical examination revealed gingivitis, normal sulcus depths, and minimal loss of clinical attachment. Complete blood counts, serum chemistry, and neutrophil function were within normal limits. Histological, histochemical and ultrastructural analysis of an extracted tooth revealed no loss of attachment; large areas of the cementum were collagen-poor and, ultrastructurally, resembled afibrillar cementum. It is proposed that the periodontal attachment mechanism present in this case was associated with a localized failure in normal periodontal development.

Adult↗