Assessing oral health and the minimally important differences in oral health-related quality of life of non-diabetic and diabetic patients: a cross-sectional study.

BACKGROUND: Non-diabetics and diabetics might have different oral health problems and impacts on their oral health-related quality of life (OHRQoL). Comparison of oral health status and coping strategies between these patients, and evaluation of factors associated with OHRQoL might facilitate better treatment planning for improved patient-centred outcome. METHODS: One hundred and eleven non-diabetics and 107 diabetics attending a public hospital were clinically examined and evaluated for coping strategies (abbreviated coping orientation to problems experienced) and OHRQoL [short-form oral health impact profile (OHIP-14S)]. Factors associated with OHRQoL were analysed through correlation/partial correlation. Minimally important differences (MID) of OHIP-14S were calculated to confirm associations between attachment loss, caries, and tooth loss with OHRQoL. RESULTS: Non-diabetics had worse periodontal status. Diabetics had more missing teeth. Non-diabetics and diabetics employed maladaptive coping to manage oral health problems. Overall, non-diabetics reported worse OHRQoL. Determination of MID showed that non-diabetics with high-severe attachment loss and <20 teeth experienced poorer OHRQoL. Diabetics with caries, high-severe attachment loss, and <25 teeth experienced poorer OHRQoL. CONCLUSION: Different factors were associated with OHRQoL of non-diabetics and diabetics. Delivery of treatment aimed at maintaining teeth in a periodontally healthy and caries free state, and provision of more chewing units might help improve OHRQoL of diabetics. © 2024 Australian Dental Association.

Smoking cessation in dental setting: a narrative review on dental professionals' attitude, preparedness, practices and barriers.

Integration of smoking cessation program into routine oral health care has been advocated by World Health Organization since it brings extensive benefits to oral health. By tobacco cessation, patients are less prone to progression of periodontal disease, have less future tooth loss, have reduced risks of oral mucosal lesions and head and neck cancers. Evidence indicates that dentists are in a favorable position to deliver effective smoking cessation advice to improve patients' oral health. This article aims to present the current situation of smoking cessation in dental setting, including dental management of smoking patients, perceptions of dentists and dental students towards smoking cessation, challenges dental professionals face when carrying out cessation interventions. Patients' perspectives are also evaluated to provide a clearer picture of smoking cessation practice in the dental field. Review of past surveys show most patients welcome smoking cessation advice from dental practitioners. Meanwhile dentists may have wrong assumption that patients would disapprove them if they advise patient to quit smoking. On top of that, main obstacles identified are lack of training, inadequate treatment time and insufficient knowledge towards smoking cessation guidelines and referral routes. With regard to the potential barriers, evidence demonstrates that more trainings on smoking cessation strategies are needed. Future research in this aspect is also indicated to further foster the practice of smoking cessation counselling in dental setting.

The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the fifth international EUFEPS/AAPS conference.

The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far were co-organised together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop US-FDA joined as co-sponsor - to support global harmonisation of regulatory recommendations for bioequivalence (BE) assessment. At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main conclusions were drawn: (1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a majority of the workshop participants were in favour of a more frequent application of such approaches. The regulatory conditions relevant in this context need further concretisation and harmonisation between the regions. Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE development programmes. (2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously, BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions. Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in fed state. (3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e.g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and, despite significant progress already achieved during previous years, more research is needed before they may be fully accepted for regulatory purposes. (4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure into BE assessment with more restrictive criteria and the importance of comparison of the product-related within-subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were presented and discussed but need further consideration before harmonisation can be achieved. The highly interactive meeting and extensive exchange between regulators and scientists from industry and academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation.

Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS)-Based Biowaivers: A workshop Summary Report.

The workshop "Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers" was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions. Lecture and panel discussion topics covered case studies at IND, NDA, and ANDA stages, typical deficiencies relating to permeability assessment supporting BCS biowaiver, types of evidence that are available to demonstrate high permeability, method suitability of a permeability assay, impact of excipients, importance of global acceptance of permeability methods, opportunities to expand the use of biowaivers (e.g. non-Caco-2 cell lines, totality-of-evidence approach to demonstrate high permeability) and future of permeability testing. Breakout sessions focused on 1) in vitro and in silico intestinal permeability methods; 2) potential excipient effects on permeability and; 3) use of label and literature data to designate permeability class.

Theory-based behavioral change interventions to improve periodontal health.

Periodontal disease is a significant global health burden affecting half of the world's population. Given that plaque and inflammation control are essential to the attainment of periodontal health, recent trends in preventive dentistry have focused on the use of behavioral models to understand patient psychology and promote self-care and treatment compliance. In addition to their uses in classifying, explaining and predicting oral hygiene practices, behavioral models have been adopted in the design of oral hygiene interventions from individual to population levels. Despite the growing focus on behavioral modification in dentistry, the currently available evidence in the field of periodontology is scarce, and interventions have primarily measured changes in patient beliefs or performance in oral hygiene behaviors. Few studies have measured their impact on clinical outcomes, such as plaque levels, gingival bleeding and periodontal pocket reduction, which serve as indicators of the patient's disease status and quality of oral self-care. The present narrative review aims to summarize selected literature on the use of behavioral models to improve periodontal outcomes. A search was performed on existing behavioral models used to guide dental interventions to identify their use in interventions measuring periodontal parameters. The main models were identified and subsequently grouped by their underlying theoretical area of focus: patient beliefs (health belief model and cognitive behavioral principles); stages of readiness to change (precaution adoption process model and transtheoretical model); planning behavioral change (health action process approach model, theory of planned behavior and client self-care commitment model); and self-monitoring (self-regulation theory). Key constructs of each model and the findings of associated interventions were described. The COM-B model, a newer behavioral change system that has been increasingly used to guide interventions and policy changes, is discussed with reference to its use in oral health settings. Within the limitations of the available evidence, interventions addressing patient beliefs, motivation, intention and self-regulation could lead to improved outcomes in periodontal health. Direct comparisons between interventions could not be made due to differences in protocol design, research populations and follow-up periods. The conclusions of this review assist clinicians with implementing psychological interventions for oral hygiene promotion and highlight the need for additional studies on the clinical effects of behavioral model-based interventions.

The Global Bioequivalence Harmonisation Initiative (GBHI): Report of EUFEPS/AAPS fourth conference.

This report provides a summary of the 4th International Conference on Global Bioequivalence Harmonisation Initiative (GBHI) that was co-organised by the European Federation of Pharmaceutical Sciences (EUFEPS) and the American Association of Pharmaceutical Scientists (AAPS). The goal of the GBHI conference is to offer the most informative and up to date science and regulatory thinking of bioequivalence (BE) in global drug development to support the intended process of a scientific global harmonisation. The workshop provided an open forum for pharmaceutical scientists from academia, industry and regulatory agencies to discuss three BE topics of interest, (a) BE assessment for long-acting injectables and implants, (b) necessity of fed BE studies for immediate-release products and (c) procedures to demonstrate equivalence of orally inhaled products. Moreover, in keynote lectures, a potential road map to an international BE reference product was discussed, and visions and perspectives for future global BE harmonisation activities have been presented. The meeting delivered a cutting-edge insight into the topics in an interactive and at the same time focused way.

Subgingival glycine powder air-polishing as an additional approach to nonsurgical periodontal therapy in subjects with untreated chronic periodontitis.

BACKGROUND AND OBJECTIVE: Glycine powder air-polishing (GPAP) is an alternative approach to removing subgingival plaque biofilms for effective periodontal therapy. This study aimed to investigate the effect of subgingival GPAP as an additional approach to nonsurgical periodontal treatment in subjects with chronic periodontitis. MATERIAL AND METHODS: Twenty-seven nonsmoking subjects were recruited. Two quadrants in each subject were randomly assigned, according to a split-mouth design, to receive scaling and root planing (SRP) and GPAP (Test group) or SRP and air flushing with water (Control group) at sites with probing depth ≥5 mm. Clinical parameters, gingival crevicular fluid volumes and the concentrations of interleukin-1ß and interleukin-1ra in gingival crevicular fluid were measured at baseline and 1, 3 and 6 months after the treatments. RESULTS: At baseline, no statistically significant difference in periodontal and gingival crevicular fluid parameters was found between the Test and Control groups. Overall, the periodontal conditions of all subjects showed significant improvement after the treatments. Notably, the Test group showed greater reduction in gingival crevicular fluid volume (0.37 ± 0.26 µL) than the Control group (0.23 ± 0.30 µL) at 3 months (P < .05). The gingival crevicular fluid levels of interleukin-1ß and interleukin-1ra showed a significant decrease in both groups at 6 months, and no significant difference was found between the groups. CONCLUSION: These preliminary results suggest that GPAP, as an additional approach to nonsurgical periodontal treatment, may be beneficial for the short-term improvement of subclinical inflammation when measured by gingival crevicular fluid volume. Further longitudinal studies with larger sample sizes are required to clarify the exact benefits of GPAP treatment for controlling inflammation and maintaining long-term periodontal health.

Exploring Staphylococcus epidermidis in atopic eczema: friend or foe?

BACKGROUND: Staphylococcus aureus (SA) colonization/infection is important in the pathophysiology of childhood atopic dermatitis (AD), but the role of Staphylococcus epidermidis (SE) is unknown. AIM: To evaluate if SE co-infects with SA and is associated with more severe disease. METHODS: Associations between bacteriological culture results of skin swabs (taken from the most severely affected area and at the antecubital fossa) and SCORing Atopic Dermatitis (SCORAD) score, skin hydration, transepidermal water loss (TEWL) and quality of life (QoL) were evaluated. RESULTS: In 100 consecutive patients with AD (aged 12.4 ± 4.8 years), SE was present in 28% and 32% of the swabs taken from the most severe area and the flexural area (antecubital fossa), respectively, whereas SA was present in 69% and 55%, respectively. Binomial logistic regression showed that SE was inversely associated with SA growth in the most severely affected skin site [adjusted odds ratio (aOR) = 0.42, 95% CI 0.22-0.81; P = 0.01], frequency of emollient usage (aOR = 0.50, 95% CI 0.29-0.87; P = 0.01) and frequency of oral antihistamine usage (aOR = 0.81, 95% CI 0.65-0.10, P < 0.05), but positively associated with objective SCORAD (aOR = 1.04, 95% CI 1.00-1.02; P < 0.05). SE in the antecubital fossa was not associated with SA growth, disease severity, QoL or any clinical parameters. CONCLUSIONS: SE may not be just a commensal bystander in the skin microbiota. The organism amensalistically displaces SA and is associated with more severe disease.

Efficacy of sodium hypochlorite (bleach) baths to reduce Staphylococcus aureus colonization in childhood onset moderate-to-severe eczema: A randomized, placebo-controlled cross-over trial.

BACKGROUND: Staphylococcus aureus (S. aureus) colonization/infection is an important factor in the pathophysiology of atopic dermatitis (AD). Clinical trials have demonstrated conflicting efficacy of diluted bleach baths in treating moderate-to-severe AD. We conducted a double-blinded, placebo-controlled (water), cross-over trial among patients with AD to investigate the efficacy of bleach baths in reducing S. aureus colonization and AD severity. METHOD: In this cross-over trial, 40 patients with moderate-to-severe AD were randomized to receive twice-weekly bleach and water baths, each for four consecutive weeks with a four-week wash-out period in between. Condition of S. aureus growth and SCORing Atopic Dermatitis index (SCORAD) were recorded at baseline and four-weekly intervals. Patients' blood was collected in first and second visits to investigate blood eosinophil count, serum levels of total IgE and specific IgEs against Staphylococcal enterotoxins A and B. In every visit, Children Dermatology Life Quality Index (CDLQI), skin hydration (SH), transepidermal water loss (TEWL) and usage frequency of prohibited medications (topical antibiotic, steroid and oral antihistamine) were recorded. RESULTS: All 40 patients completed the trial, but 14 were non-adherent. By intention-to-treat (ITT) approach, comparing with water baths, bleach baths conferred no significant efficacy in CDLQI, SH, TEWL, blood eosinophil count, total IgE and the two specific IgEs over four weeks. Water baths caused a greater reduction in affected area of SCORAD than bleach baths (-5.7 ± 15.4 for water vs. 0.6 ± 12.4 for bleach; p = 0.03) by ITT, and in objective SCORAD and affected area (p < 0.05) from per-protocol approach. Bleach baths reduced topical corticosteroid use (mean difference = 1.1 ± 2.6 days/week; p = 0.014) and topical antibiotic use (mean difference = 1.0 ± 2.8 days/week; p = 0.044) in within-group analysis. CONCLUSIONS: This study demonstrated that a four-week, twice-weekly regime of diluted bleach baths is not more useful than water baths in reducing S. aureus colonization/infection and improving AD. A longer treatment period is needed to evaluate if the short treatment duration was the main cause for the discrepancy in outcome from other bleach-bath trials. The usage of a portable bath tub obviates the problems associated with unavailability of bathing facilities in some families.

Dairy and nondairy beverage consumption for childhood atopic eczema: what health advice to give?

BACKGROUND: Many parents of children with atopic eczema (AE) practise empirical dietary avoidance and supplementation, and seek healthcare advice on whether consumption of dairy and nondairy beverages may be beneficial or detrimental for this condition. AIM: We investigated if frequency of consumption of beverages was associated with disease severity and quality of life (QoL). METHODS: Parent-reported frequency of drinks and beverages were recorded in consecutive children with AE, and disease severity (Nottingham Eczema Severity Score; NESS), QoL (Children's Dermatology Life Quality Index; CDLQI), skin hydration (SH), transepidermal water loss (TEWL), blood pressure (BP), resting heart rate (RHR) and body mass index (BMI) were evaluated. RESULTS: AE was associated with worse QoL than miscellaneous non-AE skin diseases (P < 0.001). Compared with children without AE, there was a trend for children with AE to drink less milk (P = 0.06) and more miscellaneous beverages (such as Chinese herbal tea and soymilk; P = 0.03). In children with AE, NESS correlated with CDLQI (ρ = 0.66, P < 0.001) and reduced SH (ρ = -0.32, P < 0.001), whereas CDLQI correlated with a higher RHR (ρ = 0.25, P < 0.01). Multiple logistic regression showed that male sex (OR = 0.44, 95% CI 0.20-0.97; P = 0.04) and drinking fresh milk (OR = 0.42, 95% CI 0.20-0.93; P = 0.03) were independent factors associated with less severe disease. Moderate to severe impairment of CDLQI was associated with NESS (OR = 1.48, 95% CI 1.28-1.71; P < 0.001) and RHR (OR = 1.05, 95% CI 1.02-1.08; P < 0.01) but not with reported habits of beverage consumption. Concerning cardiovascular health in AE, frequency of formula milk consumption was associated with RHR (ρ = 0.17, P = 0.04), and soft drink consumption was associated with higher systolic blood pressure (SBP) (ρ = 0.18, P = 0.04). CONCLUSION: This study provides evidence for parental/patient guidance. Children with AE who reported more fresh milk consumption had less severe disease. There was no correlation between consumption of nondairy beverages with disease severity or QoL, but frequency of soft drink consumption correlated with SBP. With these results being supported by a literature review, it is reasonable to advise parents that fresh milk can be consumed by unsensitized children with AE. Soft drinks and other beverages should not be consumed in excess for optimal cardiovascular health and for other health reasons.

Patient acceptability, efficacy, and skin biophysiology of a cream and cleanser containing lipid complex with shea butter extract versus a ceramide product for eczema.

OBJECTIVES: To investigate patient acceptability, efficacy, and skin biophysiological effects of a cream/cleanser combination for childhood atopic dermatitis. SETTING: Paediatric dermatology clinic at a university teaching hospital in Hong Kong. PATIENTS: Consecutive paediatric patients with atopic dermatitis who were interested in trying a new moisturiser were recruited between 1 April 2013 and 31 March 2014. Swabs and cultures from the right antecubital fossa and the worst eczematous area, disease severity (SCORing Atopic Dermatitis index), skin hydration, and transepidermal water loss were obtained prior to and following 4-week usage of a cream/cleanser containing lipid complex with shea butter extract (Ezerra cream; Hoe Pharma, Petaling Jaya, Malaysia). Global or general acceptability of treatment was documented as 'very good', 'good', 'fair', or 'poor'. RESULTS: A total of 34 patients with atopic dermatitis were recruited; 74% reported 'very good' or 'good', whereas 26% reported 'fair' or 'poor' general acceptability of treatment of the Ezerra cream; and 76% reported 'very good' or 'good', whereas 24% reported 'fair' or 'poor' general acceptability of treatment of the Ezerra cleanser. There were no intergroup differences in pre-usage clinical parameters of age, objective SCORing Atopic Dermatitis index, pruritus, sleep loss, skin hydration, transepidermal water loss, topical corticosteroid usage, oral antihistamine usage, or general acceptability of treatment of the prior emollient. Following use of the Ezerra cream, mean pruritus score decreased from 6.7 to 6.0 (P=0.036) and mean Children's Dermatology Life Quality Index improved from 10.0 to 8.0 (P=0.021) in the 'very good'/'good' group. There were no statistically significant differences in the acceptability of wash (P=0.526) and emollients (P=0.537) with pre-trial products. When compared with the data of another ceramide-precursor moisturiser in a previous study, there was no statistical difference in efficacy and acceptability between the two products. CONCLUSIONS: The trial cream was acceptable in three quarters of patients with atopic dermatitis. Patients who accepted the cream had less pruritus and improved quality of life than the non-accepting patients following its usage. The cream containing shea butter extract did not differ in acceptability or efficacy from a ceramide-precursor product. Patient acceptability is an important factor for treatment efficacy. There is a general lack of published clinical trials to document the efficacy and skin biophysiological effects of many of the proprietary moisturisers.

Dissolution and in vivo evidence of differences in reference products: impact on development of generic drugs.

The WHO List of International Comparator Pharmaceutical Products (CPP) For Equivalence Assessment of Interchangeable Multi-Source (Generic) Products will address an important issue in developing new generic drugs because it will identify the 'correct' reference product. This list will reduce unnecessary clinical studies in jurisdictions requiring new generics to be compared with brand products sold locally. Eventually, by employing the CPP, there will be a world-wide standard for brand and generic drugs, assuring the same level of quality internationally. The strategy of a single global reference is meritorious, but there are several hurdles to overcome. Most important is that the same brand may differ in dissolution and/or bioavailability in various jurisdictions, including some drugs with a narrow therapeutic index like phenytoin. Several examples are provided in this manuscript. This issue of regional differences has relevance, not only to the WHO list, but also to the matter of how safety and efficacy was established for that product in the first place. Normally, phase III clinical studies are conducted on a product manufactured in a single site, set to one standard. If the product differs in bioavailability in different jurisdictions, one is left with the question: 'which product has remained true to the original formulation?' Alternatively, if safety and efficacy is maintained with all formulations, then one is faced with the question: 'are the criteria currently employed for bioequivalence unnecessarily restrictive?'

High variability in drug pharmacokinetics complicates determination of bioequivalence: experience with verapamil.

PURPOSE: For the assessment of bioequivalence it is assumed that drug clearance in each subject on each of the study days is the same and any observed differences in AUC and/or Cmax between a brand and generic formulation are due to differences in bioavailability. We hypothesized that this assumption was invalid for highly variable drugs such as verapamil and tested it by comparing bioavailability for the brand vs itself. METHODS: To avoid any contribution from potential formulation differences, we evaluated bioavailability for isoptin SR 240 mg tablets in 9 healthy volunteers on 2 occasions separated by 1 week as part of a larger study. A validated HPLC assay was used to measure serial blood samples over 36 hours. RESULTS: The AUC0-1 varied 3.8 fold among subjects and 5/9 subjects had > 30% difference in AUC0-1 on the 2 days. After log transformation, the mean AUC0-1 +/- %cv (ng.h/mL) on Occasion 1 (878 +/- 38) was 23% greater (p = 0.031) than on Occasion 2 (713 +/- 41). The 90% confidence interval of Occasion 1/Occasion 2 was 106-143%. The Cmax varied > 9 fold (30-278 ng/mL) among subjects. The intrasubject difference between days ranged from -46% to +298%. The 90% confidence interval was 72-152% for Cmax. Since the same lot of Isoptin was used in the same subjects on 2 occasions, the observed differences must be due to biological variability in verapamil pharmacokinetics, not formulation differences. CONCLUSIONS: The intra-subject biological variability complicates bio-equivalence assessment and can lead to an erroneous assumption of bioinequivalence.

Double-cycle high-dose chemotherapy with peripheral blood stem cells and hematopoietic growth factor support in patients with advanced solid tumor. A pilot study by the Hong Kong Biotherapy Group.

BACKGROUND: High-dose chemotherapy with autologous bone marrow transplantation has been useful in some patients with advanced breast, lymphoma, or germ cell tumors. Double-cycle high-dose chemotherapy may be able to deliver an even higher total dose within a given time period. It is important to determine whether peripheral blood stem cells and hematopoietic growth factors can diminish the hematopoietic toxicity of such a treatment. METHODS: From November 1989 to May 1991, 14 patients were enrolled in two cycles of high-dose chemotherapy consisting of cyclophosphamide, 4.5 g/m2; cisplatin, 150 mg/m2; and etoposide, 900 mg/m2 in each cycle. The first five patients received peripheral blood stem cells harvested from 8-10 leukaphereses during steady state. The next nine patients, besides receiving peripheral blood stem cells mobilized by growth factors, also received either granulocyte-macrophage colony-stimulating factor (GM-CSF) at 250 micrograms/m2/day by two subcutaneous (s.c.) injections given 12 hours apart from day 6 until neutrophil recovery or granulocyte colony-stimulating factor (G-CSF) at 200 micrograms/m2 as daily s.c. injections. RESULTS: For the first five patients, there was a median of 14 days from the first day of absolute marrow suppression to neutrophil count exceeding 500/microliters and a median of 15 days for a platelet count exceeding 20,000/microliters. For the next nine patients, with the use of either G-CSF or GM-CSF, there was a median of 8 days for a neutrophil count exceeding 500/microliters and and a median of 11 days for a platelet count exceeding 20,000/microliters. CONCLUSION: With the use of peripheral stem cells and growth factors, high-dose chemotherapy could be given safely every 30 days with acceptable toxicity. A high complete response rate was seen in patients with nasopharyngeal carcinoma and in patients with small cell and non-small cell lung cancer who either had not received previous chemotherapy or who had responded to previous chemotherapy.

Short-duration in vitro interleukin-2-activated mononuclear cells for advanced cancer. A Hong Kong biotherapy pilot study trial.

BACKGROUND: In vitro studies have demonstrated that a brief exposure of peripherally collected mononuclear cells to high-dose human recombinant interleukin-2(rIL-2) will generate a population of pulsed lymphokine-activated killer (LAK) cells. These cells have similar cytotoxicity against natural killer cells and resistant and sensitive target cells as compared with the standard LAK cells incubated for 3-7 days with rIL-2. Therefore, the authors conducted a pilot study to investigate the activity of pulsed LAK cells in patients with advanced cancer. METHODS: Nineteen patients were enrolled in a pilot study, and pulsed LAK cell treatment was administered two times per week for 4 weeks, followed by similar cycles if patients remained free of disease progression and unacceptable toxic effects. RESULTS: Toxic effects consisted mainly of fever, chills, nausea, and dizziness but were self-limiting and mild. Most cycles were administered on an outpatient basis. There were six partial responses (31%), occurring in two of three patients with renal cell carcinoma, two of four with hepatocellular carcinoma, one of seven with non-small cell lung carcinoma, and one of one with ovarian carcinoma. Two minimal responses were seen in one case each of melanoma and carcinoma of colon. Nine other patients had disease stabilization for 16 weeks, and two additional patients had disease progression. Phenotyping of peripheral mononuclear cells showed increases in CD56 and CD25 populations with no in vivo rIL-2 being administered after treatment with pulsed LAK cells. CONCLUSIONS: The relative ease in generating pulsed LAK cells and the associated mild toxic effects enable prolonged stimulation of the effector cells of the patients against sensitive tumor targets, with a response rate comparable to those of high-dose rIL-2 and LAK cell treatment. Therefore, it may be a theoretically ideal adjuvant for patients with renal cell carcinoma, melanoma, and hepatoma and other applicable patients after bone marrow transplantation. The initial high response rate in patients with late-stage renal cell carcinoma and hepatocellular carcinoma indicates the need for additional confirmation.

Competitive binding of sulfamethazine and its N-acetylated metabolite.

The protein binding of sulfamethazine (SMZ) was studied in rabbit serum. Serum solutions comprising various concentrations (approximately 0.01-3 mM) of SMZ and its major metabolite, N4-acetylsulfamethazine (AcSMZ), were prepared. These 'control' samples were also mixed via a Latin square design to study the interactive binding of SMZ and AcSMZ to the proteins. Equilibrium dialysis was conducted for 8 h. Post-dialysis measurement of SMZ/AcSMZ radioactivity in the buffer and serum chambers provided the free and bound fractions based upon equilibrium total serum concentrations. There was no significant change of protein concentration before and after dialysis. The 'control' data revealed concentration-dependent binding for both drugs while the interaction study clearly indicated the presence of competitive binding. Scatchard plots suggested the presence of more than one binding site. As a result, three different competitive binding models were examined via computer analysis of the observations. The most appropriate binding model was identified to consist of specific binding (protein concentration, Pt; dissociation constant, Kd) and nonspecific binding (Nsp). The mean (SD) 'control' parameter estimates for PtSMZ, PtAcSMZ, KdSMZ, KdAcSMZ, NspSMZ, NspAcSMZ were: 0.562(0.041), 0.605(0.024), 0.078(0.006), 0.031(0.002) [mM], 0.205(0.054), and 0.229(0.043), respectively. In the interaction study these values were: 0.599(0.022), 0.479(0.019), 0.091(0.004), 0.023(0.001), 0.228(0.020), and 0.434(0.061), respectively. The findings indicate that both drugs bind to albumin but the affinity of AcSMZ is greater than SMZ. Theoretically, the metabolite can therefore alter the in vivo SMZ binding thereby in turn causing apparent nonlinear acetylation based upon the pharmacokinetics of total SMZ concentrations.