Measurement and analysis of unbound drug concentrations

The plasma protein binding of drugs has been shown to have significant effects on numerous aspects of clinical pharmacokinetics and pharmacodynamics. In many clinical situations, measurement of the total drug concentration does not provide the needed information concerning the unbound fraction of drug in plasma which is available for distribution, elimination, and pharmacodynamic action. Thus, accurate determination of unbound plasma drug concentrations is essential in the therapeutic monitoring of drugs. Many methodologies are available for determining the extent of plasma protein binding of drugs, however, in the clinical evaluation of drug therapy, equilibrium dialysis and ultrafiltration are the most routinely utilised methods. Both of these methods have been proven to be experimentally sound and to yield adequate protein binding data. Furthermore, the characterisation of the interactions between drug and protein molecules is essential for the assessment of the pharmacokinetic implications of drug-protein binding. Protein binding parameters which characterise the affinity of the drug-protein association, the number of classes of binding sites, the number of binding sites per class or protein and the binding capacity are useful for predicting unbound drug concentrations. Simple graphical methods have often been used to obtain protein binding parameters, but these methods have limitations and are not useful for drugs with more than 1 class of binding site. Therefore, the fitting of protein binding models which characterise the drug-protein binding interaction for experimental data is the preferred method of calculating binding parameters. Using the appropriate model, values for binding parameters are typically estimated by using nonlinear least-squares regression analysis.     

Methane output and lactation response in Holstein cattle with monensin or unsaturated fat added to the diet

We measured effects of continuous vs twice-daily feeding, the addition of unsaturated fat to the diet, and monensin on milk production, milk composition, feed intake, and CO2-methane production in four experiments in a herd of 88 to 109 milking Holsteins. Methane and CO2 production increased with twice-daily feeding, but the CO2:CH4 ratio remained unchanged. Soybean oil did not affect the milkfat percentages, but fatty acid composition was changed. All saturated fatty acids up to and including 16:0 decreased (P < .01), whereas 18:0 and trans 18:1 increased (P < .001). The 18:2 conjugated dienes also increased (P < .01) when the cows were fed soybean oil. Monensin addition to the diet at 24 ppm decreased methane production (P < .01); the CO2:CH4 ratios reached 15, milk production increased (P < .01), and milkfat percentage and total milkfat output decreased (P < .01), as did feed consumption, compared with cows fed diets without monensin (P < .05). Milk fatty acid composition showed evidence of depressed ruminal biohydrogenation: saturated fatty acids (P < .05) decreased and 18:1 increased (P < .001); most of the increase was seen in the trans 18:1 isomer. As with soybean oil feeding, addition of monensin also increased (P < .05) the concentration of conjugated dienes. The monensin feeding trial was repeated 161 d later with 88 cows, of which 67 received monensin in the diet in the first trial and 21 cows were newly freshened and had never received monensin. Methane production again decreased (P < .05), but this time the CO2:CH4 ratio did not change and all other monensin-related effects were absent. The ruminal microflora in the cows that had previously received monensin seemed to have undergone some adaptive changes and no longer responded as before.     

Long-term outcomes in open pelvic fractures

BACKGROUND: Open pelvic fractures represent one of the most devastating injuries in orthopedic trauma. The purpose of this study was to document the injury characteristics, complications, mortality, and long-term, health-related quality of life outcomes in patients with open pelvic fractures. METHODS: The trauma registry at an adult trauma center was used to identify all multiple system blunt trauma patients with a pelvic fracture from January of 1987 to August of 1995 (n = 1,179). Demographic data, mechanism of injury, and fracture type were determined from hospital records. Short-term outcome measures included infectious complications, mortality, and length of stay in hospital. Long-term outcomes of survivors were obtained by telephone interview using the SF-36 Health Survey and the Functional Independence Measure. RESULTS: Open pelvic fractures were uncommon, occurring in 44 patients (4%). Patients with open fractures were about 9 years younger, on average, than patients with closed fractures (30 vs. 39, p < 0.001). Similarly, patients with open fractures were more likely to be male (75 vs. 57%, p < 0.02), more likely to have been involved in a motorcycle crash (27 vs. 6%, p < 0.001), and more likely to have an unstable pelvic ring disruption (45 vs. 25%, p < 0.001). Open pelvic fracture patients required more blood than closed pelvic fracture patients, both in the first day (16 vs. 4 units, p < 0.001) and during the total hospital admission (29 vs. 9 units, p < 0.001). Five patients with perineal wounds did not receive a diverting colostomy; in turn, these individuals had a total of six pelvic infectious complications (one abscess, two with osteomyelitis, and three perineal wound infections). Overall, 11 patients died, six patients were lost to follow-up, and 27 were long-term survivors (mean duration of 4 years). Chronic disability was common after a pelvic fracture, with problems related to physical role performance and physical functioning, and was particularly severe after an open pelvic fracture (p < 0.05 for both as measured by the SF-36). CONCLUSIONS: Patients with open pelvic fractures often survive, need to be treated with massive blood transfusions, and often require a colostomy. They are frequently left with chronic pain and residual disabilities in physical functioning and physical roles, and many remain unemployed years after injury.     

Outcomes of hand surgery. British Society for Surgery of the Hand

The findings are presented of a conference on Outcomes of Hand Surgery organized by the audit committee of British Society for Surgery of the Hand in 1993. Measures of outcome in terms of movement, power, sensibility, pain, activities of daily living, complications and patient satisfaction are considered, and an example of a patient evaluation measure given as an appendix.     

A cone-and-plate device for the investigation of platelet biomaterial interactions

As part of a class action suit, the author was asked to assess the quality of mental health services in eight prisons in Georgia. This paper describes the background to the suit, reviews selected literature on assessing quality of correctional mental health care, and describes methods used to survey prison mental health services. A standardized survey instrument was developed with probe questions to assess the quality of services. Individual cases were reviewed, inmates were interviewed, and the quality of mental health structures, processes, and outcomes were assessed. Key findings from the survey are summarized. The author concluded that the quality of mental health services in the prisons surveyed was so low overall as to constitute a pattern of deliberate indifference, and that the services were constitutionally inadequate.     

Inflammatory myofibroblastic tumor in children

The authors presented the cases of two children with inflammatory myofibroblastic (IMF) tumor and reviewed the literature to facilitate the preoperative recognition, delineate the clinical features, and describe the natural history of this entity. The first child had IMF tumor arising from the mesentery of the small intestine. He presented with an abdominal mass associated with severe inflammatory response manifested by fever, impaired growth, thrombocytosis, and microcytic, hypochromic anemia. After surgical resection, his fever resolved and his growth rate and the laboratory abnormalities normalized. Five months after initial diagnosis, the fever, anemia, and thrombocytosis recurred along with two tumors arising from the omentum and the abdominal soft tissue. After the second surgery, he remains free of recurrent disease for 30 months. The second child presented with a lung mass that was radiologically indistinguishable from pulmonary sequestration. After surgical resection, she remains free of recurrent disease for 18 months. IMF tumor should be considered in any solid tumor that occurs in association with a chronic inflammatory response. IMF tumor should also be considered in the differential diagnosis of pulmonary sequestration.     

Effectiveness of chlorine dioxide in disinfection on two soft denture liners

OBJECTIVE: The purpose of this study was to evaluate a hydroxylapatite-based material and calcium sulfate when each was used under a resin-modified glass ionomer cement to repair furcation perforations. STUDY DESIGN: Perforations of pulp chamber floors were made in 72 teeth of 9 dogs. Perforations were divided into 3 equal-sized groups and repaired with resin-modified glass ionomer either alone or over an artificial floor. The artificial floor was either a hydroxylapatite-based material or calcium sulfate. Three dogs were killed at each of 3 intervals (1, 3, and 6 months). The tissue response to the tested materials was evaluated clinically, radiographically, and histologically. RESULTS: The hydroxylapatite-based material showed the highest radiographic success; this was followed by calcium sulfate and glass ionomer. From histologic evaluation, the average success rate was found to be 67% for calcium sulfate, 62% for the hydroxylapatite-based material, and 59% for glass ionomer. However, there was no statistical significant difference with the resin-modified glass ionomer when it was used alone and when it was used over a barrier. There was also no significant difference between the hydroxylapatite-based material and the calcium sulfate when they were used as artificial floors. CONCLUSION: The use of an artificial floor may not be necessary when flowable resin-modified glass ionomer cements are used.     

Role of the kdr and super-kdr sodium channel mutations in pyrethroid resistance: correlation of allelic frequency to resistance level in wild and laboratory populations of horn flies (Haematobia irritans)

The kdr and super-kdr point mutations found in the insect sodium channel gene are postulated to confer knockdown resistance (kdr) to pyrethroids. Using an allele-specific PCR assay to detect these mutations in individual horn flies, Haematobia irritans (L.), we determined the allelic frequency of the kdr and super-kdr mutations in several wild and laboratory populations. Wild populations with very similar allelic frequencies had resistance levels that ranged widely from 3- to 18-fold relative to a susceptible population. Conversely, the kdr allele frequency in a lab population with 17-fold resistance was nearly double that found in a heavily pressured wild population with 18-fold resistance. We conclude that, although the kdr mutation confers significant levels of pyrethroid resistance, a substantial component of resistance in insecticidally pressured populations is conferred by mechanisms that are PBO-suppressible. High super-kdr allele frequencies were detected in two resistant lab populations, but in wild populations with equivalent resistance the super-kdr allele frequency was very low. Interestingly, in over 1200 individuals assayed, the super-kdr mutation was never detected in the absence of the kdr mutation.     

Inhibition of experimental autoimmune encephalomyelitis in Lewis rats by nasal administration of encephalitogenic MBP peptides: synergistic effects of MBP 68-86 and 87-99

Induction of mucosal tolerance by inhalation of soluble peptides with defined T cell epitopes is receiving much attention as a means of specifically down-regulating pathogenic T cell reactivities in autoimmune and allergic disorders. Experimental autoimmune encephalomyelitis (EAE) induced in the Lewis rat by immunization with myelin basic protein (MBP) and Freund's adjuvant (CFA) is mediated by CD4+ T cells specific for the MBP amino acid sequences 68-86 and 87-99. To further define the principles of nasal tolerance induction, we generated three different MBP peptides (MBP 68-86, 87-99 and the non-encephalitogenic peptide 110-128), and evaluated whether their nasal administration on day -11, -10, -9, -8 and -7 prior to immunization with guinea pig MBP (gp-MBP) + CFA confers protection to Lewis rat EAE. Protection was achieved with the encephalitogenic peptides MBP 68-86 and 87-99, MBP 68-86 being more potent, but not with MBP 110-128. Neither MBP 68-86 nor 87-99 at doses used conferred complete protection to gp-MBP-induced EAE. In contrast, nasal administration of a mixture of MBP 68-86 and 87-99 completely blocked gp-MBP-induced EAE even at lower dosage compared to that being used for individual peptides. Rats tolerized with MBP 68-86 + 87-99 nasally showed decreased T cell responses to MBP reflected by lymphocyte proliferation and IFN-gamma ELISPOT assays. Rats tolerized with MBP 68-86 + 87-99 also had abrogated MBP-reactive IFN-gamma and tumor necrosis factor-alpha mRNA expression in lymph node cells compared to rats receiving MBP 110-128 nasally, while similar low levels of MBP-reactive transforming growth factor-beta and IL-4 mRNA expressing cells were observed in the two groups. Nasal administration of MBP 68-86 + 87-99 only slightly inhibited guinea pig spinal cord homogenate-induced EAE, and passive transfer of spleen mononuclear cells from MBP 68-86 + 87-99-tolerized rats did not protect na?ve rats from EAE. Finally, we show that nasal administration of MBP 68-86 + 87-99 can reverse ongoing EAE induced with gp-MBP, although higher doses are required compared to the dosage needed for prevention. In conclusion, nasal administration of encephalitogenic MBP peptides can induce antigen-specific T cell tolerance and confer incomplete protection to gp-MBP-induced EAE, and MBP 68-86 and 87-99 have synergistic effects. Non-regulatory mechanisms are proposed to be responsible for tolerance development after nasal peptide administration.