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Biomedical subjects

R Miller

Publications and source records attributed to R Miller.

At least 181 records · Page 10Linked to original sources
PubMed2000

Validation of population pharmacokinetic parameters of phenytoin using the parallel Michaelis-Menten and first-order elimination model.

This study was conducted to assess whether the parallel Michaelis-Menten and first-order elimination (MM+FO) model fitted the data better than the Michaelis-Menten (MM) model, and to validate the MM+FO model and its parameter estimates. The models were fitted to 853 steady state dose: serum concentration pairs obtained in 332 adults with epilepsy using nonlinear mixed-effects modeling (NONMEM). The MM+FO model fitted the data better than the MM model. The validity of the pharmacokinetic models and the estimated population parameter values was tested using the naive prediction method. The estimation and validation of the pharmacokinetic parameters were undertaken in two separate patient groups (cross-validation) obtained by splitting the data set. Patients were randomly allocated to two equally matched groups (groups 1 and 2). The predictive performance was assessed using 770 paired predicted versus actual dose or measured serum concentrations. The population pharmacokinetic parameters estimated by NONMEM in group 1 were validated in group 2 and vice versa. When predicting steady state serum concentration, the MM+FO model was clearly superior to the MM model (mean bias of 0.91 and 8.13 mg/L, respectively).

Adolescent↗
PubMed2000

Ill-conditioned Shake-and-Bake: the trap of the false minimum.

The alternation of phase refinement with the imposition of real-space constraints is the essence of the Shake-and-Bake procedure. Typically, these constraints prevent trial structures from falling into local minima. Nevertheless, P1 structures appear to migrate to false minima with significant frequency. These false minima are characterized by the presence of a large 'uranium' peak on the corresponding Fourier map. Fortunately, they can be recognized and avoided by considering the values of the minimal function both before and after the application of constraints. However, it appears that finding solutions for large P1 structures is likely also to require parameter-shift conditions different from those that have been found to work well in other space groups. In fact, these conditions often yield an unusually high percentage of solutions.

Algorithms↗
PubMed2000

P1 Shake-and-Bake: can success be guaranteed?

The multi-trial direct-methods procedure known as Shake-and-Bake has been applied to three small proteins (alpha-1 peptide, vancomycin and lysozyme) that crystallize in space group P1. Phase refinement was accomplished through parameter-shift optimization using both the cosine and exponential forms of the minimal function. By extending error-free data to sufficiently high resolution, 100% convergence of trial structures to solution could be achieved in all three cases by using the exponential minimal function and a shift angle in the range 130-150 degrees. These results suggest optimum parameters for other P1 structures and emphasize the importance of collecting data to the highest possible resolution.

Algorithms↗
PubMed2000

HIV associated culture proved tuberculosis has increased in north central London from 1990 to 1996.

OBJECTIVES: To examine rates of culture proved tuberculosis in HIV infected patients in three specialist centres in north central London. METHODS: Cases of tuberculosis in patients with previously documented HIV infection from 1990 to 1996 were identified retrospectively from microbiological/clinical records at Chelsea and Westminster, St Mary's, and University College London Hospitals. RESULTS: Between 1990 and 1996 202 cases of culture proved tuberculosis were identified at the three centres. Of these, 132/202 (65.3%) occurred in homosexual/bisexual men, 41/202 (20.3%) were in patients with heterosexual contact in sub-Saharan Africa, and 29/202 (14.4%) were in "others." Overall 148/202 (73.3%) had pulmonary tuberculosis. The total number of HIV infected individuals seen at the three centres increased from 4298 in 1990 to 5048 in 1996. Rates of tuberculosis in the three centres increased from 0.46% in 1990 to 0.83% in 1996. Part of this increase was due to an increase in tuberculosis among Africans from 1993 to 1996. CONCLUSIONS: Rates of HIV associated tuberculosis increased in these three centres in north central London between 1990 and 1996. In part this was due to an increase in the number of African patients with HIV infection attending the three centres. In addition, there was circumstantial evidence of recent transmission among homosexual men with HIV infection. Prospective "real time" surveillance of tuberculosis in HIV infected patients is needed in order to detect case clustering and to improve tuberculosis control.

Africa↗
PubMed2000

Decreased perihematomal edema in thrombolysis-related intracerebral hemorrhage compared with spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a highly morbid disease process. Perihematomal edema is reported to contribute to clinical deterioration and death. Recent experimental observations indicate that clotting of the intrahematomal blood is the essential prerequisite for hyperacute perihematomal edema formation rather than blood-brain barrier disruption. METHODS: We compared a series of patients with spontaneous ICH (SICH) to a series of patients with thrombolysis-related ICH (TICH). All patients were imaged within 3 hours of clinical onset. We reviewed relevant neuroimaging features, emphasizing and quantifying perihematomal edema. We then analyzed clinical and radiological differences between the 2 ICH types and determined whether these factors were associated with perihematomal edema. RESULTS: TICHs contained visible perihematomal edema less than half as often as SICHs (31% versus 69%, P<0.001) and had both lower absolute edema volumes (0 cc [25th, 75th percentiles: 0, 6] versus 6 cc [0, 13], P<0.0001) and relative edema volumes (0.16 [0.10, 0.33] versus 0.55 [0.40, 0.83], P<0.0001). Compared with SICHs, TICHs were 3 times larger in volume (median [25th, 75th percentiles] volume 69 cc [30, 106] versus 21 cc [8, 45], P<0.0001), 4 times more frequently lobar in location (62% versus 15%, P<0.001), 80 times more frequently contained blood-fluid level(s) (86% versus 1%, P<0.001), and were more frequently multifocal (22% versus 0%, P<0.001). CONCLUSIONS: The striking qualitative and quantitative lack of perihematomal edema observed in the thrombolysis-related ICHs compared with the SICHs provides the first substantial, although indirect, human evidence that intrahematomal blood clotting is a plausible pathogenetic factor in hyperacute perihematomal edema formation.

Aged↗
PubMed2000

Chronic urticaria: a Canadian perspective on patterns and practical management strategies.

BACKGROUND: Chronic urticaria is a common condition and is a source of great frustration to patients. It has been suggested that there may be differences among physicians in their approach to this common clinical entity. OBJECTIVE AND METHOD: A questionnaire was distributed Canada-wide to allergists, dermatologists, and a selection of practitioners with an interest in alternative medicine. The survey included questions on demographics, epidemiology, causative factors, diagnostic methods, therapeutic strategies, follow-up advice, and efficacy of therapies, with emphasis on personal experience. RESULTS: The response rates of allergists and dermatologists were 31% and 36%, respectively. There was wide representation from all regions of Canada and from physicians from all age groups, both genders, different types of practice, and years in practice. The reported incidence per month was 13 and 4 patients for allergists and dermatologists, respectively. The prevalence was 199 and 44 patients by allergists and dermatologists, respectively. Comparison of causative factors showed differences in the experiences of the two groups. Diagnostic investigations were requested in a similar pattern with respect to timing. The specific tests ordered by the groups showing statistical difference were complete blood count (CBC), differential, C4 complement, antinuclear antibodies, and IgE antibody assay. Allergists chose the skin prick test (100%) as the most important allergy test. Dermatologists ranked skin prick (50%), radioallergosorbent test (RAST) (20%), and skin patch (30%) as the most important tests. The top six choices of pharmaceutical therapies chosen by the groups were similar, but in a slightly different order. The responders ranked their personal selection of antihistamines according to effectiveness. Hydroxyzine (Atarax) and cetirizine (Reactine, Allegra) were selected as first and second most effective agents by both groups. The results also show effective experience by both groups with nonsedating and sedating antihistamines. Also, doxepin, ketotifen, and cimetidine are used frequently by both groups. The experience of dermatologists in Canada with respect to other modalities including psoralen ultraviolet A (PUVA) therapy, danazol, chelation, calcium channel blockers, and acyclovir is limited and efficacy is ranked either neutral or ineffective. Allergists reported even less experience with these therapies. CONCLUSION: Allergists and dermatologists across Canada show interesting similarities and differences in their practical approach to the management of chronic urticaria. With the sharing of this information, these two specialties will be better equipped to effectively manage patients suffering from chronic urticaria.

Adult↗
PubMed2000

Immediate coma following inertial brain injury dependent on axonal damage in the brainstem.

OBJECT: Immediate and prolonged coma following brain trauma has been shown to result from diffuse axonal injury (DAI). However, the relationship between the distribution of axonal damage and posttraumatic coma has not been examined. In the present study, the authors examine that relationship. METHODS: To explore potential anatomical origins of posttraumatic coma, the authors used a model of inertial brain injury in the pig. Anesthetized miniature swine were subjected to a nonimpact-induced head rotational acceleration along either the coronal or axial plane (six pigs in each group). Immediate prolonged coma was consistently produced by head axial plane rotation, but not by head coronal plane rotation. Immunohistochemical examination of the injured brains revealed that DAI was produced by head rotation along both planes in all animals. However, extensive axonal damage in the brainstem was found in the pigs injured via head axial plane rotation. In these animals, the severity of coma was found to correlate with both the extent of axonal damage in the brainstem (p < 0.01) and the applied kinetic loading conditions (p < 0.001). No relationship was found between coma and the extent of axonal damage in other brain regions. CONCLUSIONS: These results suggest that injury to axons in the brainstem plays a major role in induction of immediate posttraumatic coma and that DAI can occur without coma.

Animals↗
PubMed2000

Anatomical basis for impotence following haemorrhoid sclerotherapy.

Impotence has been reported as a rare but important complication of sclerotherapy for haemorrhoids. The relationship between the anterior wall of the rectum and the periprostatic parasympathetic nerves responsible for penile erection was studied to investigate a potential anatomical explanation for this therapeutic complication. A tissue block containing the anal canal, rectum and prostate was removed from each of six male cadaveric subjects. The dimensions of the components of the rectal wall and the distance between the rectal lumen and parasympathetic nerves in the periprostatic plexus were measured in horizontal transverse histological sections of the tissue blocks at the level of the lower prostate gland (i.e. the correct level for sclerosant injection). The correct site of sclerosant in the submucosa was on average 0.6 mm (SD 0.3 mm) deep to the rectal mucosal surface and only 0.7 mm (SD 0.5 mm) in thickness. The nearest parasympathetic ganglion cells were a mean of only 8.1 mm (SD 2.0 mm) deep to the rectal lumen. The close proximity of the rectum to the periprostatic parasympathetic nerves defines an anatomical basis for impotence following sclerotherapy. This emphasises the need for all practitioners to be particularly careful when injecting in this area and for strict supervision of trainees.

Aged↗
PubMed2000

Comparative population pharmacokinetic-pharmacodynamic analysis for piroxicam-beta-cyclodextrin and piroxicam.

Piroxicam (Feldene) is indicated for osteoarthritis and rheumatoid arthritis but not analgesia due to its delayed onset of pain relief. Piroxicam-beta-cyclodextrin (PBCD) was developed for pain indication by virtue of the increased absorption rate of piroxicam. Forty-eight patients received a single dose of PBCD or Feldene (10, 20, and 40 mg) in a randomized study, and piroxicam plasma concentration and pain relief were measured. The purpose of the study was to investigate the PK-PD relationship of piroxicam, determine the optimal dose, and evaluate the effect of increased absorption rate on analgesic effect of piroxicam for the pain model studied. The pharmacokinetic data were best described by a two-compartment model with first-order absorption. The absorption rate of PBCD (5/h) was faster than Feldene (1.41/h). Pain relief was found to be increasing with drug concentration in a hypothetical effect compartment (Emax model). The estimated half-life of the equilibration between plasma and effect site was about 2.34 hours. Monte Carlo simulation showed that the time when at least 50% of the patients have a 75% probability of achieving meaningful pain relief (pain intensity difference (PID > or = 1) for PBCD and Feldene at a dose of 20 mg was about 0.5 and 1.5 hours, respectively. PBCD demonstrated an advantage with an onset of pain relief 1 hour earlier than Feldene.

Absorption↗
PubMed2000

Pharmacokinetic/pharmacodynamic modeling in drug research and development.

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration-time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so-called integrated PK/PD-models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD-modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD-modeling from an academic, industrial and regulatory perspective.

Drug Design↗
PubMed1999

Dynamic Surface Elasticity of Micellar and Nonmicellar Solutions of Dodecyldimethyl Phosphine Oxide. Longitudinal Wave Study.

Measurements of the dynamic surface properties are used for the first time for the determination of the mean aggregation number of micelles. An approximate expression for the dilational dynamic surface elasticity of micellar solutions in the concentration region near the CMC is obtained on the basis of the more general theory which has been developed several years ago (B. A. Noskov, Izv. Akad. Nauk SSSR. Mekh Zydkasty i gaza N2, 105 (1989)). If the reverse frequency of external perturbations does not exceed the characteristic time of the slow step of the micellization process, the only properties of micelles which determine the dynamic surface elasticity are the mean aggregation number and the mean diffusion coefficient. The method of longitudinal surface waves has been applied to determine the dynamic surface elasticity of solutions of dodecyldimethyl phosphine oxide in the frequency range from 0.2 to 1.8 Hz. Both the real and the imaginary components of the dynamic surface elasticity depend nonmonotonically on the concentration below the CMC. All the experimental data agree reasonably well with the pure diffusional adsorption mechanism. Above the CMC both components of the surface elasticity decrease faster with the surfactant concentration. This fact can be explained by the contribution of micelles to the mass exchange between the surface layer and the bulk phase. Application of the theory of dynamic surface properties of micellar solutions to experimental data allows us to obtain an estimation of the mean aggregation number of micelles of dodecyldimethyl phosphine oxide. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Exponential Shake-and-Bake: theoretical basis and applications.

The simple cosine function used in the formulation of the traditional minimal principle and the related Shake-and-Bake algorithm is here replaced by a function of exponential type and its expected value and variance are derived. These lead to the corresponding exponential minimal principle and its associated Exponential Shake-and-Bake algorithm. Recent applications of the exponential function to several protein structures within the Shake-and-Bake framework suggest that this function leads, in general, to significant improvements in the success rate (percentage of trial structures yielding solution) of the Shake-and-Bake procedure. However, only in space group P1 is it presently possible to assign optimal values a priori for the exponential-function parameters.

Algorithms↗
PubMed1999

A rating scale for psychotic symptoms (RSPS) part I: theoretical principles and subscale 1: perception symptoms (illusions and hallucinations).

The authors present a new rating scale for the psychotic symptoms of schizophrenia and related psychoses. The scale links specific symptoms of psychopathology to dysfunction and overactivity of dopaminergic mechanisms underlying the processes of reward and selective attention. The Rating Scale for Psychotic Symptoms (RSPS) is a 44-item rating instrument with a seven-point severity scale for each item. Psychotic symptoms are classified into three groups: Pathological amplification of mental images (perception symptoms) (subscale 1), Distraction symptoms (including catatonia and passivity experiences) (subscale 2), and Delusions (subscale 3). A dimensional, rather than a categorical, conceptualization of psychosis is assumed. Rating is accomplished through a manual and a semi-structured interview (SSCI-RSPS). In this first of two papers, general issues about the construction of the scale and the derivation of symptom groups are discussed. Dopamine-mediated modification of cortico-striatal synapses is seen as being of critical importance in all three groups of symptoms. In this first paper, we present subscale I (perception symptoms), which includes both amplified perceptual images (illusions) and hallucinations. A total of seven illusions and 11 hallucinations are rated as individual items.

Behavioral Symptoms↗
PubMed1999

A rating scale for psychotic symptoms (RSPS): part II: subscale 2: distraction symptoms (catatonia and passivity experiences subscale 3: delusions and semi-structured interview (SSCI-RSPS).

In the second paper on the Rating Scale for Psychotic Symptoms (RSPS), distraction symptoms (Subscale 2) and delusions (Subscale 3) are described. Subscale 2 includes distraction symptoms, which arise from one of two mechanisms: the symptom may arise either by loss of attentional focus (LAF) due to a competing channel of information, or by the intrusion of the competing channel into the focus of attention [attentional intrusions (AI)]. The symptom classes resulting from loss of attentional focus (LAF) include motor catatonia, negativism, and thought blocking; the attentional intrusions (AI) symptoms rated include three types of passivity experiences (Schneiderian symptoms): (1) thought insertion, (2) movements or action controlled, and (3) speech controlled by an external force. Subscale 3, consisting of delusions, is organized on the basis of content identification. Nineteen types of delusions are rated. Each item of delusional content is rated along three axes (active elaboration, persistence and active extinction) and complexity, and optionally if primary or mixed (i.e. primary with secondary elaborations). The last section of the paper includes the semi-structured interview (SCI-RSPS) for each of the items, as well as guidelines for practical application of the interview.

Association↗