bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein translocation across the endoplasmic reticulum membrane in cold-adapted organisms
Authors: Römisch Karin , Collie Nicola , Soto Nelyn , Logue James , Lindsay Margaret , Scheper Wiep , Cheng Chi-Hing C.
Published: June 2003

Secretory proteins enter the secretory pathway by translocation across the membrane of the endoplasmic reticulum (ER) via a channel formed primarily by the Sec61 protein. Protein translocation is highly temperature dependent in mesophilic organisms. We asked whether the protein translocation machinery of organisms from extremely cold habitats was adapted to function at low temperature and found that post-translational protein import into ER-derived microsomes from Antarctic yeast at low temperature was indeed more efficient than into mesophilic yeast microsomes. Analysis of the amino-acid sequences of the core component of the protein translocation channel, Sec61p, from Antarctic yeast species did not reveal amino-acid changes potentially adaptive for function in the cold, because the sequences were too divergent. We therefore analyzed Sec61α (vertebrate Sec61p) sequences and protein translocation into the ER of Antarctic and Arctic fishes and compared them to Sec61α and protein translocation into the ER of temperate-water fishes and mammals. Overall, Sec61α is highly conserved amongst these divergent taxa; a number of amino-acid changes specific to fishes are evident throughout the protein, and, in addition, changes specific to cold-water fishes cluster in the lumenal loop between transmembrane domains 7 and 8 of Sec61α,which is known to be important for protein translocation across the ER membrane. Secretory proteins translocated more efficiently into fish microsomes than into mammalian microsomes at 10°C and 0°C. The efficiency of protein translocation at 0°C was highest for microsomes from a cold-water fish. Despite substantial differences in ER membrane lipid composition, ER membrane fluidity was identical in Antarctic fishes,mesophilic fishes and warm-blooded vertebrates, suggesting that membrane fluidity, although typically important for the function of the transmembrane proteins, is not limiting for protein translocation across the ER membrane in the cold. Collectively, our data suggest that the limited amino-acid changes in Sec61α from fishes may be functionally significant and represent adaptive changes that enhance channel function in the cold.
Study on cavitation starting at the point of separation on a smooth wall in hydraulic oil flow
Authors: Washio S , Takahashi S , Yoshimori S
Published: June 2003

Cavitation starting at the point of separation on a smooth cylindrical wall was observed. At the earliest stage of cavitation, a cavity suddenly emerged at the point of separation with its upstream tip attached to the wall. Differing from incipient cavities arising at projected edges, the present one neither stayed nor formed a stable bubble on the wall. As it moved slightly downstream, the newly born cavity underwent severe deformation: i.e. it grew explosively, then split and ultimately vanished in reverse from the tail back, in as short a period as one ten-thousandth of a second. Flashing light was emitted from the cavity as it expanded, and a transient electric charge was also detected from the oil downstream in synchronization with this light emission. Moreover, a streamline extending from the point of separation was spontaneously visualized. In order to establish the reasons for this visualization, temperature distribution across the streamline was measured, revealing that heat has to be generated at the separation point. Finally, the mechanism of tensile stress and heat generation at the point of separation is theoretically discussed on the basis of Landau's analysis of a boundary layer flow along a separation line.
Closed-loop system disturbance recovery
Authors: Whalley R , Ebrahimi M
Published: June 2003

The regulation of linearized multivariable system models, following input set point and load disturbance changes, is considered. An inner and outer closed-loop control strategy is outlined, enabling targeted recovery rates, offset attenuation and low steady state interaction to be achieved. Proportional control and passive network compensation alone are employed. Gain ratio selection and outer loop tuning are exercised, ensuring thereby the confinement of output perturbations to low-frequency load disturbances and reference input changes. Application studies are presented for purposes of comparison.
Effects of misalignment on load distribution in large face-width helical gears
Authors: Haigh J , Fawcett J N
Published: June 2003

Experimental results, obtained from the UK 8 MW facility for gear research at the University of Newcastle, are presented, which show how the load distribution across a large face-width gear varies with misalignment. Tests were carried out over a range of torque conditions using pinion flanks which were crowned or which had lead modification. The crowned flanks were shown to be more tolerant of misalignment but, at low misalignments, gave slightly higher stress levels than those with lead modification.
Payload sway suppression in rotary cranes by digital filtering of the commanded inputs
Authors: Glossiotis G , Antoniadis I
Published: June 2003

A method is proposed for the suppression of the sway of rotary crane payloads. In contrast to closed-loop control methods which encounter significant practical application problems, the proposed method is based simply on the preprocessing of all the commanded crane inputs by a properly designed finite impulse response (FIR) filter. A four-degrees-of-freedom (4DOF) model for the rotary crane system is considered, incorporating both the hoisting and the slewing motions and thus able to handle cases where hoisting can be simultaneously applied to the rotary motion. Although the resulting dynamic system is strongly non-linear and time varying, the method is shown effectively to suppress, in a quite robust, time and energy efficient way, both the transient as well as the residual sway of the payload. Moreover, additional advantages of the proposed method are that no dynamic modelling of the crane is required, and that the applicability of the method is quite easy and general, without the need for any additional instrumentation and control equipment.
Singularities of mechanisms and the degree of mobility
Authors: Lerbet J , Fayet M
Published: June 2003

The Kinematics, statics and dynamics of singular configurations of mechanisms are analysed. Using Lie group theory, the tangent cone at such a configuration is defined and calculated. It is clear that the structure of the cone is directly linked with one of Lie algebra. The statics and dynamics of singularity analysis are addressed, making it possible to apply the concept of the transitory degree of mobility.
New approach to calculating a dynamically stable criterion for hot strip mills
Authors: Yoshida M , Furumoto H , Yoshikawa M , Morii S
Published: June 2003

A new approach to calculating the dynamical behaviour of hot strip mills is developed within the linear response region. This method is based on a numerical calculation model using FEM for steady-state velocity distribution of metal flow between rolls. By applying the perturbation of roll displacements and velocity to two-dimensional systems, damping and stiffness matrices are obtained by numerical calculation under certain reasonable boundary conditions. The dynamically stable criterion obtained from these matrices is in good agreement with experimental results. In addition, it is made clear that the friction and distortion of the strip flow pattern play an important role in the onset of autonomous vibration.
Extended Hamilton's principle for fluid-structure interaction
Authors: Benaroya H , Wei T , Kuchnicki S , Dong P
Published: June 2003

A variational-based approach is developed to provide a framework for the study of flow-induced vibration. While the model includes experimentally derived functions, there are no ad hoc assumptions or a priori equations that are fit to data.
Free vibration analysis of a rectangular plate carrying multiple various concentrated elements
Authors: Wu J-S , Chou H-M , Chen D-W
Published: June 2003

The dynamic characteristic of a uniform rectangular plate with four boundary conditions and carrying three kinds of multiple concentrated element (rigidly attached point masses, linear springs and elastically mounted point masses) was investigated. Firstly, the closed-form solutions for the natural frequencies and the corresponding normal mode shapes of a rectangular ‘bare’ (or ‘unconstrained’) plate (without any attachments) with the specified boundary conditions were determined analytically. Next, by using these natural frequencies and normal mode shapes incorporated with the expansion theory, the equation of motion of the ‘constrained’ plate (carrying the three kinds of multiple concentrated element) were derived. Finally, numerical methods were used to solve this equation of motion to give the natural frequencies and mode shapes of the ‘constrained’ plate. To confirm the reliability of previous free vibration analysis results, a finite element analysis was also conducted. It was found that the results obtained from the above-mentioned two approaches were in good agreement. Compared with the conventional finite element method (FEM), the approach employed in this paper has the advantages of saving computing time and achieving better accuracy, as can be seen from the existing literature.
Characterization of Eu(III) Adsorbed onto Chitin and Chitosan by Time-resolved Laser-induced Fluorescence Spectroscopy
Authors: Ozaki Takuo , Kimura Takaumi , Yoshida Zenko , Francis Arokiasamy J
Published: June 2003

Chitin and chitosan exhibited high distribution coefficients for Eu(III). On the other hand, analysis by time-resolved laser-induced fluorescence spectroscopy showed that the hydration states of Eu(III) on chitin and on chitosan were significantly different. Europium(III) on chitin interacted with its coordination sites in an inner-spherical manner while that on chitosan interacts in an outer-spherical manner.
Estimation of the Emission of Volatile Organic Compounds (VOCs) in Central Tokyo by the Dynamic Analysis of Their Temporally Increasing Atmospheric Concentrations in Calm Weather Afternoon Conditions
Authors: Miyoshi Takao , Makide Yoshihiro
Published: June 2003

The emissions of VOCs in central Tokyo were estimated by the dynamic analysis of their temporally increasing atmospheric concentrations in the afternoon of weekdays when anthropogenic emissions were most active and the mixing of the atmosphere was extremely small. The results agreed well with the emissions estimated from increments of the averaged atmospheric concentrations above the background concentrations.
Assemblies of Mixed-metal Hexaporphyrins with an Oxo-bridged Iron(III) Porphyrin Dimer in the Center
Authors: Suzuki Masamitsu , Tsuge Kiyoshi , Sasaki Yoichi , Imamura Taira
Published: June 2003

Four novel Fe-Ru mixed-metal hexaporphyrins having an Fe(III)-O-Fe(III) porphyrin dimer unit at the center and four surrounding ruthenium(II) porphyrin units were synthesized, characterized, and structurally analyzed by X-ray crystallography.
Emulsion Drying Preparation of LiFePO4/C Composite and Its Enhanced High-rate Performance at 50 °C
Authors: Myung Seung-Taek , Komaba Shinichi , Takagai Ryohei , Kumagai Naoaki , Lee Yun-Sung
Published: June 2003

LiFePO4/C composite was successfully synthesized by an emulsion drying method. As confirmed by X-ray diffraction and scanning transmission electron microscopic observation, the prepared particle size of LiFePO4 was of about 300 nm and the powder was modified by conductive carbon. Consequentially, the existence of carbon increased the electronic conductivity of LiFePO4/C composite to ca. 10-4 S cm−1 at 25 °C. Because of smaller particle size and enhanced conductivity, the composite showed higher capacity about 140 mA h g−1 (20 mA g−1), excellent cyclability and superior rate capability at 50 °C, i.e., over 90 mA h (g-phosphate)−1 at a current density of 1000 mA g−1.
A Mild, Efficient and Selective Cleavage of Aryl tert-Butyldimethysilyl Ethers Using KOH in Ethanol
Authors: Jiang Zhi-Yong , Wang Yan-Guang
Published: June 2003

An efficient and selective method for the deprotection of aryl tert-butyldimethysilyl (TBS) ethers is described. The protecting group TBS could be cleaved from aryl silyl ethers in the prensence of alkyl TBS ethers using KOH in ethanol at room temperature to give the corresponding phenols in excellent yields (87–99%).
Novel Thermochromic Copolymers with Two Luminescent Colors
Authors: Li Chen , Du Pa , Tian He , Erk Peter
Published: June 2003

A new kind of thermochromic polymers with high fluorescence based on copoly(styrene-maleic anhydride) (SMA) and amino-substituted 1,8-naphthalimide is prepared by the condensed route. Accompanied their thermochromic process, the fluorescence of the copolymers will also change irreversibly from blue to green light when heated.
Promotion of Thermal Dehydration of Poly(vinyl alcohol) Film by Diphenyliodonium Salt
Authors: Yamamoto Yukio , Tagawa Seiichi
Published: June 2003

Thermal dehydration of a poly(vinyl alcohol) (PVA) film was greatly promoted by diphenyliodonium trifluoromethanesulfonate, which is known as a thermally stable photo acid generator. The oxidation of thermally generated PVA radicals by the salt is considered to lead to the dehydration. Liquid-nitrogen trapping of volatile products during the heating largely accelerated the dehydration for the salt-free film but not for the salt-containing film.
Preparation of Gold Nanoplates Protected by an Anionic Phospholipid
Authors: Ibano Daisuke , Yokota Yasuhiro , Tominaga Toshihiro
Published: June 2003

Gold nanoplates were prepared by the photoreduction of NaAuCl4 in the presence of dimyristoyl-l-α-phosphatidyl-Dl-glycerol (DMPG) as a protective agent. When the DMPG concentration is appropriate, hexagonal nanoplates were formed. When the DMPG concentration was lower or higher, spherical particles were predominantly formed.
Highly Stretchable and Powerful Polypyrrole Linear Actuators
Authors: Hara Susumu , Zama Tetsuji , Sewa Shingo , Takashima Wataru , Kaneto Keiichi
Published: June 2003

A polypyrrole (PPy) film, prepared electrochemically from methyl benzoate solution of tetra-n-butylammonium tetrafluoroborate on Ti electrode, showed 12.4% strain and 22 MPa stress induced electrochemically in NaPF6 aqueous solution. The large strain and stress may be due to doping-dedoping of anion and a conformational change of PPy chains.
Empiric Carbapenem Monotherapy in Pediatric Bone Marrow Transplant Recipients
Authors: Nelson Wendelin K , Rayback Priscilla A , Quinones Ralph , Giller Roger H
Published: June 2003

OBJECTIVE:

To determine which carbapenem (imipenem/cilastatin or meropenem) was the preferable empiric antibiotic monotherapy in pre-engrafted pediatric bone marrow transplant (BMT) patients in terms of patient tolerance, therapeutic efficacy, and cost.

METHODS:

We prospectively analyzed 16 pediatric BMT patients who received meropenem, and retrospectively analyzed 16 matched patients who had received imipenem/cilastatin for BMT procedures during the prior 2-year period. We evaluated the patients for evidence of bacterial infection, necessity for concurrent antibiotics, vomiting episodes, duration of concurrent total parenteral nutrition (TPN), and cost of therapy.

RESULTS:

We found no differences in the number of culture proven or clinically suspected breakthrough bacterial infections or the need for concurrent additional antibiotics between the groups. Our analysis found that patients who received meropenem experienced significantly less vomiting than those in the imipenem/cilastatin cohort. Our data showed both direct and indirect cost savings for the meropenem group. The statistical and clinical differences in the number of vomiting episodes between these groups impacted other aspects of patient care, antiemetic use, and TPN duration.

CONCLUSIONS:

By switching to meropenem, we reduced the cost of antiemetic therapy per patient treatment course, and also showed a trend toward reduced duration of TPN. We found that meropenem provided both clinical and fiscal advantages over imipenem/cilastatin as empiric antibiotic monotherapy in neutropenic pediatric BMT patients.
Combination Drug Therapy for Gastroesophageal Reflux Disease
Authors: Cross L Brian , Justice Lori N
Published: June 2003

OBJECTIVE:

To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine2 receptor antagonists in gastroesophageal reflux disease (GERD).

DATA SOURCES:

Clinical literature identified through MEDLINE (January 1966–August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine2; therapy, combination drug; therapy, combined modality; and combinations, drug.

DATA SYNTHESIS:

Approximately 80–90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for ≥60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1-time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear.

CONCLUSIONS:

No studies in patients with GERD demonstrate that the addition of histamine2 receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far — Nocturnal acid breakthrough — Has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs.
Therapeutic Equivalency of Low-Molecular-Weight Heparins
Authors: McCart Gary M , Kayser Steven R
Published: June 2003

OBJECTIVE:

To review the recent literature on the approved uses of enoxaparin, dalteparin, ardeparin, and tinzaparin and the evidence for therapeutic equivalence.

DATA SOURCES:

A MEDLINE search (1993–January 2001) was conducted to identify English-language literature available on enoxaparin, dalteparin, ardeparin, and tinzaparin.

STUDY SELECTION:

All controlled trials evaluating low-molecular-weight heparins (LMWHs) versus standard therapy powered to detect a significant difference were reviewed.

DATA EXTRACTION:

Agents were reviewed with regard to safety and efficacy.

DATA SYNTHESIS:

As a class, LMWHs have chemical, physical, and clinical similarities. LMWHs have greater bioavailability, longer half-lives, a more predictable pharmacologic response, possible improved safety, and similar or greater efficacy compared with unfractionated heparin (UFH). Because of this, enoxaparin, dalteparin, ardeparin, and tinzaparin are being considered as alternatives to UFH or warfarin, and there is potential for therapeutic interchange. Evaluation of clinical trials is limited because of differing diagnostic methods, drug administration times, dose equivalencies, and outcome measurements.

CONCLUSIONS:

Only 1 trial has evaluated 2 LMWHs in a direct comparison in the same study. There is insufficient evidence for determining the therapeutic equivalence of LMWHs.
Granulocyte Macrophage—Colony Stimulating Factor and Oral Mucositis
Authors: Fung Stacey M , Ferrill Mary J
Published: June 2003

OBJECTIVE:

To evaluate the effect of granulocyte macrophage—colony stimulating factor (GM-CSF) in patients with oral mucositis.

DATA SOURCES:

Literature was accessed through MEDLINE (1966–June 2000) and bibliographic searches.

DATA SYNTHESIS:

Published literature assessing the use of GM-CSF to treat or prevent oral mucositis was analyzed.

CONCLUSIONS:

Reports of GM-CSF improving mucositis have been published; however, because of limitations in these reports, insufficient evidence confirms the benefits of GM-CSF. These preliminary studies provide a rationale to conduct well-designed, double-blind, randomized trials to evaluate the safety and efficacy of GM-CSF in the treatment and/or prevention of oral mucositis induced by chemotherapy and/or radiotherapy.
Cost-Effectiveness of Prophylactic Indomethacin in Very-Low-Birth-Weight Infants
Authors: Moya Martin P , Goldberg Ronald N
Published: June 2003

OBJECTIVE:

To perform cost-effectiveness analysis to facilitate the decision-making process surrounding use of indomethacin in preterm infants to lower the incidence of patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), and death.

METHODS:

A MEDLINE literature search from 1966 to July 2000 was performed to identify relevant randomized, controlled trials (RCTs), as well as cohort and retrospective case—control studies. A decision tree was built representing the choice to use or not use indomethacin, and the potential outcome costs. Probabilities of being in each chance node were obtained from this search. Where data probabilities were not clear, a sensitivity analysis was conducted.

RESULTS:

There was no difference in the expected survival per year; however, there was a significant difference when effectiveness was measured as quality-adjusted life years (QALYs), resulting in 11 and 10 years for the indomethacin and control groups, respectively. The indomethacin treatment cost was $95 157 and that of the control groups was $99 955. The cost effectiveness per life expectancy of being in the indomethacin and control groups was $7142 and $7727, respectively. The sensitivity analysis for PDA closure and prevention of IVH for infants eventually developing PDA versus those without PDA showed no difference. The cost-effectiveness analysis per QALY was $8443 for the indomethacin treatment and $9168 for the control group.

CONCLUSIONS:

The prophylactic use of indomethacin is less costly and more effective within an important range of certainty. However, this analysis does not include several potentially confounding factors, such as antenatal steroid use or indomethacin-induced renal toxicity. Depending on the frequency with which these factors arise, economic projections may be considerably altered against the early use of indomethacin.
Gabapentin's Effect on Agitation in Severely and Persistently Mentally III Patients
Authors: Megna James L , Devitt Patrick J , Sauro Marie D , Dewan Mantosh J
Published: June 2003

OBJECTIVE:

To study the effects of adjunctive gabapentin on agitation in severely and persistently mentally ill (SPMI) inpatients.

METHOD:

Eleven chronic SPMI inpatients on stable psychotropic medication regimens were evaluated before and after the initiation of adjunctive gabapentin for six months. The following psychometric tests were used: Brief Psychiatric Rating Scale (BPRS), Corrigan Agitated Behavior Scale (CABS), and Clinical Global Impression (CGI)–Severity. Data collection was accomplished via retrospective chart review. An internal reliability check indicated that a chart review BPRS is significantly predictive of one performed face-to-face.

RESULTS:

Statistically significant reductions were found at six months for each assessment instrument (p > 0.05, two-tailed). BPRS scores were reduced from 40.6 to 33.2, CABS from 34.4 to 25.0, and CGI—Severity from 5.9 to 5.3. The bulk of the BPRS reduction was accounted for by several subscores exclusive of those assessing affective/anxious symptomatology. Adverse effects were minimal. Two patients were discharged 12 and 17 months after implementation of gabapentin.

CONCLUSIONS:

Adjunctive gabapentin appears to be associated with a reduction in agitation in chronically hospitalized SPMI patients. Controlled, prospective trials are needed before any definitive conclusion can be drawn regarding the role of gabapentin in the treatment of this group of patients.
Factors Influencing Cyclosporine Blood Concentration—Dose Ratio
Authors: García-Sáiz Mar , López-Gil Arturo , Alfonso Itziar , Boada Jose N , Armijo Juan A
Published: June 2003

OBJECTIVE:

To analyze the trough cyclosporine concentration—dose ratio (CDR) and its relationship to some commonly available factors such as cyclosporine dosage, patient age, grade of obesity, posttransplant days, serum creatinine, serum bilirubin, and serum cholesterol by multiple linear regression.

METHODS:

The study was performed on 866 samples from 90 transplant recipients (25 kidney, 25 heart, 17 bone marrow, 13 liver, 10 simultaneous pancreas—kidney).

RESULTS:

The results show differences between transplants both in cyclosporine CDR variability (expressed by the coefficients of variation) and in the capability of those factors to explain this variability (expressed by the coefficient of determination). Coefficients of variation were 41% for the 866 samples (from 34% in heart to 55% in pancreas—kidney transplantation) and 28% for the 90 patients' CDR mean values (from 24% in heart to 32% in pancreas—kidney transplantation). All factors, except for the grade of obesity, were related to the cyclosporine CDR for all transplants as a whole. However, differences in the influence of each factor on each transplant were observed. The coefficient of determination based on significant factors was R2 = 0.25 for all samples (from 0.18 in pancreas—kidney to 0.52 in liver transplantation) and R2 = 0.53 for the patients' CDR means (from 0.39 in heart to 0.83 in kidney transplantation).

CONCLUSIONS:

We have quantified the cyclosporine CDR, its variability, and its relationship with some commonly available factors and found significant differences between transplant types. The equations of regression obtained might improve trough cyclosporine CDR estimation as a first step in cyclosporine dosage adjustment in kidney and liver transplant recipients.
Treatment of Resistant Depression by Adding Noradrenergic Agents to Lithium Augmentation of SSRIs
Authors: Ramasubbu Rajamannar
Published: June 2003

OBJECTIVE:

To examine the efficacy of second-line augmentation with noradrenergic antidepressants (NAs) in depressed patients who partially responded to lithium augmentation of selective serotonin-reuptake inhibitors (SSRIs).

CASE SUMMARY:

Six patients with major depression or double depression (major depression and dysthymia) who were partially responsive to lithium and SSRI treatment were given either bupropion or desipramine, in an open clinical manner. Improvement was determined and rated by a psychiatrist based on clinical judgment guided by the Clinical Global Impression (CGI) improvement scale and by the Global Assessment of Functioning (GAF) as described in Axis V in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.

RESULTS:

Among the 6 depressed patients with partial remission (much improved in symptoms and moderate functional improvement: CGI score 2, GAF score 51–60) while taking the SSRI and lithium combination, 2 showed complete remission (very much improved in symptoms and good functioning: CGI 1, GAF 80–100) and 3 achieved near-complete remission (very much improved in symptoms and significant functional recovery: CGI 1, GAF 61–80) when given either bupropion or desipramine. One patient did not show any additional clinical or functional improvement. Second-line augmentation with bupropion was better tolerated than desipramine.

CONCLUSIONS:

This clinical observation suggests that second-line augmentation with NAs may be a viable option to optimize recovery in depressed patients with a partial response to lithium augmentation of SSRIs.
Newer Therapies in the Drug Treatment of Epilepsy
Authors: McAuley James W , Biederman Toy S , Smith Jason C , Moore J Layne
Published: June 2003

OBJECTIVE:

To provide a review of recent developments in the pharmacotherapy of epilepsy.

DATA SOURCES:

A MEDLINE search was performed to identify pertinent literature (1966–June 2001). Selected articles emphasized those published from 1997 to 2001. Bibliographies of identified articles were also evaluated.

STUDY SELECTION AND DATA EXTRACTION:

All identifiable sources written in English.

DATA SYNTHESIS:

Epilepsy is a common neurologic disorder, and antiepileptic drugs (AEDs) are the mainstays of therapy. The focus of this article is on the 3 latest AEDs — Levetiracetam, oxcarbazepine, and zonisamide. We discuss human data published as both original studies and reviews from the last 4 years, except where noted. We apply a general template for all 3 drugs and provide information on clinical trials, adverse effects, pharmacokinetics, drug interactions, and clinical use.

CONCLUSIONS:

Levetiracetam, oxcarbazepine, and zonisamide are reasonable options for many patients whose seizures are not yet controlled or who suffer from intolerable adverse effects. All 3 agents are approved for adjunctive use in patients with partial seizures. Oxcarbazepine also has approval for monotherapy in partial seizures. All 3 drugs are well tolerated by most patients and have characteristics that potentially make them easier to use with medications other than the older AEDs. Further clinical experience is needed before specific recommendations can be given for their place among older and newer AEDs.
Clinical Pharmacology and Pharmacokinetics of Amprenavir
Authors: Sadler Brian M , Stein Daniel S
Published: June 2003

OBJECTIVE:

To review the pharmacokinetics, pharmacodynamics, drug interactions, and dosage and administration information of amprenavir.

DATA SOURCE:

An extensive review of the literature (MEDLINE search from 1994 to April 2001) relating to the clinical pharmacology of the HIV protease inhibitors was conducted. Meeting abstracts or full presentations and data submitted to the Food and Drug Administration were also reviewed.

STUDY SELECTION AND DATA EXTRACTION:

The data on pharmacokinetics, pharmacodynamics, drug interactions, and drug resistance were obtained from in vitro studies and open-label and controlled clinical trials.

DATA SYNTHESIS:

Like all HIV protease inhibitors, amprenavir interrupts the maturation phase of the HIV replicative cycle by forming an inhibitor-enzyme complex, which prevents HIV protease from binding with its normal substrates (biologically inactive viral polyproteins). Amprenavir has an enzyme inhibition constant (Ki = 0.6 nM) that falls within the Ki range of the other protease inhibitors. Amprenavir's in vitro 50% inhibitory concentration (IC50) against wild-type clinical HIV isolates is 14.6 ± 12.5 ng/mL (mean ± SD). Pharmacodynamic modeling indicates that, as is the case with other protease inhibitors, the concentration—response curve for amprenavir plateaus at amprenavir trough values above the IC50 for these isolates. This exposure—activity relationship, plus such favorable pharmacokinetic parameters as a long terminal elimination half-life (7–10 h), makes amprenavir an attractive drug of choice when considering potent antiretrovirals. The higher trough exposure obtained with amprenavir coadministered with ritonavir may allow effective treatment of patients with decreased susceptibility viral isolates and once-daily dosing. Amprenavir has been approved for adults and children; the recommended capsule doses are 1200 mg twice daily for adults and 20 mg/kg twice daily or 15 mg/kg 3 × daily for children <13 years of age or adolescents <50 kg. The recommended dose for amprenavir oral solution is 1.5 mL/kg twice daily or 1.1 mL/kg 3 × daily.

CONCLUSIONS:

The clinical pharmacology, exposure—activity relationship, and drug resistance profile of amprenavir support the use of this potent HIV protease inhibitor in combination antiretroviral regimens, especially for persons who have experienced virologic failure while on protease inhibitor—containing regimens.
Risk of Gastric Injury with Enteric- versus Nonenteric-Coated Aspirin
Authors: Banoob Dalia W , McCloskey William W , Webster William
Published: June 2003

OBJECTIVE:

To evaluate through clinical trials the risk of various aspirin preparations on the gastric mucosa.

DATA SOURCES:

Articles reporting clinical research were accessed through MEDLINE (1980–November 1998). Key search terms included enteric-coated aspirin, buffered aspirin, and gastrointestinal (GI) bleeding.

DATA SYNTHESIS:

Aspirin products are known to cause GI bleeding. Enteric-coated aspirin may provide an additional protective effect on gastric mucosa compared with buffered aspirin. An evaluation of studies comparing various aspirin preparations and the risk of gastric mucosal injury was conducted.

CONCLUSIONS:

For long-term use, enteric-coated aspirin may provide a safer alternative than buffered aspirin; however, further studies are necessary.
Secretin for the Treatment of Autism
Authors: McQueen Joanna M , Heck Amy M
Published: June 2003

OBJECTIVE:

To evaluate the role of secretin in the treatment of children with autism.

DATA SOURCE:

Literature was assessed through MEDLINE, EMBASE, BIOSIS (November 1998–August 2001), and the World Wide Web. Literature included scientific studies, anecdotal reports, and meeting abstracts. Key search terms included autism and secretin.

DATA SYNTHESIS:

Autism is a pervasive developmental disorder. Although several treatments exist, no cure has been identified. New information suggests that secretin may be beneficial for this disorder. A critical evaluation of current information about the use of secretin in autism was conducted.

CONCLUSIONS:

Currently, several anecdotal reports and a few controlled trials with conflicting results have been published regarding the use of secretin in autism. Further studies should be conducted to determine the safety and efficacy of secretin for autism.
Pharmacokinetic Model for Tobramycin in Acinetobacter Meningitis
Authors: Chicano-Piá Pedro V , Cercós-Lletí Ana-Cristina , Romá-Sánchez Eva
Published: June 2003

OBJECTIVE:

To report a case of acinetobacter meningitis treated with a once-daily intravenous dose of tobramycin and to propose a pharmacokinetic model for the drug disposition.

CASE SUMMARY:

A 28-year-old man with chronic hydrocephalus was admitted with a diagnosis of intracranial hypertension. Acinetobacter spp. was detected in the cerebrospinal fluid (CSF); it was sensitive to tobramycin, ampicillin/sulbactam, and colistin. Based on the culture report, multiple daily-dose therapy with tobramycin was started. As the infectious symptoms remained, once-daily therapy was recommended; the optimal dose was calculated with nonlinear regression by least-squares analysis and a Bayesian method, using plasma and CSF samples. The infection was resolved, tobramycin therapy was discontinued, and the patient was discharged from the intensive care unit.

DISCUSSION:

We use once-daily intravenous tobramycin therapy because, although the intrathecal administration of drugs is generally well tolerated, the presence of preservatives may be a source of central nervous system adverse effects. Pharmacokinetic parameters were calculated with plasma and CSF concentration values obtained during the first once-daily dose by using a compartment—effect model which allows fitting of simultaneous plasma and CSF concentrations. The prediction level was determined by the estimation of drug concentrations during the fourth once-daily dose. CSF concentrations of drug were enough to eradicate the clinical signs of infection.

CONCLUSIONS:

Therapy using once-daily intravenous administration of tobramycin may be an adequate alternative for acinetobacter infections in neurosurgical patients when an intrathecal route is initially not recommended. The development of a compartment—effect model can be useful to predict drug concentrations.
Severe Interaction between Ritonavir and Acenocoumarol
Authors: Llibre Josep M , Romeu Joan , López Estibaliz , Sirera Guillem
Published: June 2003

OBJECTIVE:

To report a clinically severe interaction between ritonavir (RTV) and acenocoumarol resulting in a decrease in the anticoagulant effect severe enough to eventually preclude RTV administration.

CASE SUMMARY:

An asymptomatic, HIV-infected, 46-year-old man with mitraortic prosthetic valves receiving acenocoumarol therapy started stavudine, lamivudine, and RTV 600 mg twice daily. His international normalized ratio (INR) decreased dramatically (the opposite of what should be expected). Although the acenocoumarol dose was progressively increased to 3 × the original dose, it was impossible to achieve the previous INR and RTV was withdrawn.

DISCUSSION:

RTV is an inducer of the hepatic isoenzymes CYP1A2, CYP1A4, and CYP2C9/19 and leads to extensive metabolism of acenocoumarol that cannot be balanced by dose increases. This effect is the opposite of what was expected to occur, considering that RTV is also a strong inhibitor of most hepatic isoenzymes.

CONCLUSIONS:

RTV severely decreases the anticoagulant effect of acenocoumarol. It must be added to the list of drugs that affect the action of oral anticoagulants, and it probably should be avoided in patients receiving acenocoumarol.
Amphotericin B Disposition after Aerosol Inhalation in Lung Transplant Recipients
Authors: Marra Fawziah , Partovi Nilufar , Wasan Kishor M , Kwong Evan H , Ensom Mary HH , Cassidy Shawn M , Fradet Guy , Levy Robert D
Published: June 2003

BACKGROUND:

Bronchopulmonary fungal infections continue to be a major cause of morbidity and mortality in lung transplant recipients, and amphotericin B remains the drug of choice for prophylaxis of most fungal infections. Unfortunately, intravenous amphotericin B has numerous serious adverse effects; thus, nebulized amphotericin B could decrease the incidence of adverse effects seen with the intravenous formulation and provide high local concentrations in the lung tissue. We performed a prospective pilot study to characterize the bronchoalveolar lavage (BAL), lung tissue, and plasma concentrations of amphotericin B following inhalation administration to lung transplant recipients.

METHODS:

Amphotericin B 30 mg was administered by nebulizer prior to a routine bronchoscopy. Amphotericin B concentrations in BAL samples from the upper and lower lobes, transbronchial biopsies, and plasma (obtained by drawing a blood sample 30 min after the amphotericin B inhalation) were analyzed by HPLC.

RESULTS:

Eight patients were enrolled in the study (mean age 50.0 ± 16.1 y; number of years posttransplant 3.0 ± 1.9; type of transplant 5 double-lung, 3 single-lung). The mean amphotericin B concentration in the upper and lower lobe BAL samples were 0.68 ± 0.36 and 0.50 ± 0.31 μg/mL, respectively. Amphotericin B concentrations, detected in only 2 of 5 biopsy samples, were 0.118 and 0.03 μg/g. Amphotericin B was detected in the plasma of only 1 patient (0.19 mg/L).

CONCLUSIONS:

This pilot study demonstrated that detectable concentrations of amphotericin B can be attained in both the upper and lower BAL samples following aerosol administration. However, the frequency of the dose and duration of treatment still need to be determined in a larger study.
Warfarin Therapy for Atrial Fibrillation in the Elderly
Authors: Lackie Cynthia L , Garbarino Kenneth A , Pruetz Jennifer A
Published: June 2003

OBJECTIVE:

To evaluate a clinical practice model that addresses special needs for managing anticoagulation in a community-dwelling elderly population with atrial fibrillation and high risk of stroke.

METHODS:

Medical records of 18 patients (mean age 82 y) followed by the Geriatric Ambulatory Program over 2 years, with a target international normalized ratio (INR) of 2.0–3.0, were reviewed. Risk factors for stroke, number and results of INR tests, suspected reasons for suboptimal response, and adverse events were analyzed. Patients were defined as having cognitive impairment if they had a Folstein Mini-Mental State Exam score ≤26. Functional impairment was defined by ≥2 disabilities in activities of daily living.

RESULTS:

Eighty-three percent (15/18) had ≥2 additional stroke risk factors. Fifty-one percent (273/541) of INR responses were therapeutic. Female gender (p = 0.015) and cognitive (p = 0.019) and functional impairment (p = 0.001) were associated with supratherapeutic INR response. All patients with cognitive impairment and 85% of those with functional impairment received caregiver support for medication administration. There were 4 minor bleeding events and no thromboembolic events. The mean number of medications was 9.3 in those with bleeding versus 6.8 in those without bleeding (p = 0.052).

CONCLUSIONS:

Elderly patients with high stroke risk achieved therapeutic INR responses. However, those with significant cognitive or functional impairment require caregiver support and special consideration for anticoagulation management.
Levetiracetam: A Different Approach to the Pharmacotherapy of Epilepsy
Authors: Welty Timothy E , Gidal Barry E , Ficker David M , Privitera Michael D
Published: June 2003

OBJECTIVE:

To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of levetiracetam in the treatment of epilepsy.

DATA SOURCES:

A MEDLINE search restricted to English-language publications was conducted (January 1993–October 2000). Unpublished data provided by the manufacturer and information found in proceedings of professional meetings were also included.

DATA EXTRACTION/STUDY SELECTION:

Information regarding basic pharmacology was collected from studies in animals. Pharmacokinetic data were collected from human trials. Only randomized, placebo-controlled clinical trials were included to describe the efficacy and safety of levetiracetam.

DATA SYNTHESIS:

Levetiracetam is a new antiepileptic drug (AED) that appears to work by a unique mechanism. Animal studies have shown that levetiracetam may prevent epileptogenesis. Levetiracetam is rapidly and completely absorbed, minimally bound to plasma proteins, eliminated through the kidneys, and has a half-life of 6–8 hours. Doses must be adjusted for varying degrees of renal function. In clinical trials, levetiracetam significantly decreased seizure frequency compared with placebo when added to existing AED regimens. One clinical trial indicated that levetiracetam may be effective as monotherapy. Few major adverse effects were reported in the clinical trials; however, several patients reported psychological and psychotic reactions.

CONCLUSIONS:

Levetiracetam is a safe and effective new AED. Its apparent unique mechanism of action makes levetiracetam an important addition to therapy with older medications. Caution should be exercised when administering levetiracetam to individuals who may be prone to psychotic or psychiatric reactions.
Rosuvastatin for the Treatment of Patients with Hypercholesterolemia
Authors: Chong Pang H , Yim Barbara T
Published: June 2003

OBJECTIVE:

To review the currently available information on rosuvastatin in the treatment of primary hypercholesterolemia.

DATA SOURCES:

MEDLEY (2000–January 2001), MEDLIT, MEDLINE, EMBASE, SciSearch, Current Contents, Derwent, Drug, BIOSIS, Adis LMS Drug Alerts, and International Pharmaceutical Abstracts (1994–July 2001) were searched; unpublished data obtained from the manufacturer were also included.

STUDY SELECTION:

Studies evaluating rosuvastatin including abstracts, proceedings, and data on file from the manufacturer were considered for inclusion. English-language literature was evaluated for pharmacology, pharmacodynamics, pharmacokinetics, therapeutic use, and adverse effects of rosuvastatin. Additional relevant citations were used in the introductory material and discussion section.

DATA EXTRACTION:

English-language study abstracts selected for inclusion were limited to those on human subjects. Animal data were included only if human data were not available.

DATA SYNTHESIS:

Rosuvastatin, a new synthetic hydroxymethylglutaryl coenzyme A reductase inhibitor (HMG-CoA RI), recently completed Phase III clinical trials. At a dosage of 1–80 mg/d, the drug significantly reduced total cholesterol and low-density-lipoprotein cholesterol (LDL-C) and produced beneficial effects on other lipid parameters as well. Overall, rosuvastatin was well tolerated.

CONCLUSIONS:

In hypercholesterolemic patients, rosuvastatin reduced LDL-C and other lipid parameters to a greater degree than currently available agents. One advantage of rosuvastatin is that it achieves target LDL-C goals in a greater proportion of treated patients with similar adverse events compared with those treated with other HMG-CoA RIs. The potential to reduce risk for coronary heart disease events and decrease mortality as well as cost comparisons with currently used HMG-CoA RIs remains a subject of further investigation.
Hepatotoxicity Associated with Chronic Acetaminophen Administration in Patients without Risk Factors
Authors: Bolesta Scott , Haber Stacy L
Published: June 2003

OBJECTIVE:

To evaluate the literature regarding the potential of acetaminophen to cause toxicity in adult patients without risk factors, when used chronically in daily doses ≤4 g.

DATA SOURCES:

Key tertiary literature was reviewed, along with searches of MEDLINE (1966–July 2001), International Pharmaceutical Abstracts (1970–May 2001), and PREMEDLINE (July Week 5, 2001). Key search terms included acetaminophen, paracetamol, toxic hepatitis, hepatotoxicity, liver dysfunction, overdose, drug toxicity, and poisoning.

DATA SYNTHESIS:

Most tertiary references state that the maximum daily dose of acetaminophen is 4 g. Patients taking more than this amount, especially those with certain risk factors, are more likely to develop toxicity. However, a few patients may develop toxicity regardless of risk. An evaluation of the literature regarding the toxic potential of acetaminophen when given at doses ≤4 g/d chronically (≥4 d) to adult patients without risk factors was conducted.

CONCLUSIONS:

Acetaminophen should be used cautiously on a chronic basis because several case reports show that it may be hepatotoxic at therapeutic doses.
Influence of Socioeconomic Status on Drug Selection for the Elderly in Canada
Authors: Mamdani Muhammad M , Tu Karen , Austin Peter C , Alter David A
Published: June 2003

OBJECTIVE:

To examine the association between socioeconomic status, as indicated by neighborhood median income levels, and physician drug selection between older, less expensive generic drugs and newer, more expensive brand-name drugs for elderly patients initiating drug therapy in a universal healthcare system.

METHODS:

We conducted a population-based, retrospective, cross-sectional study. Using healthcare administrative databases, we assessed the medication profiles of 128 314 patients from more than 1.4 million residents of Ontario ≥65 years old initiating antipsychotic, hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin), or ocular β-blocker drug therapy from January 1, 1998, through December 31, 1999. We examined the selection of older generic drugs relative to newer brand-name agents for patients in each of 5 income quintiles.

RESULTS:

Overall, brand-name drug prescribing modestly increased with increasing income quintile after adjusting for patient age and gender (61.2% in the lowest income quintile vs. 64.1% in the highest income quintile; p value for trend < 0.001). Significant risk ratios comparing the highest with the lowest income—quintile patients were observed for selection of newer, brand-name antipsychotics (RR 1.14; 95% CI 1.06 to 1.23), older generic statins (RR 0.86; 95% CI 0.77 to 0.95), and newer, brand-name ocular β-blockers (RR 1.13; 95% CI 1.02 to 1.25).

CONCLUSIONS:

This study suggests that income-related differences in treatment selection by physicians may exist. The reasons for these differences and subsequent impact on health outcomes warrant further investigation.