Update to the PhRMA perspective on population and individual bioequivalence.
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Chemistry, Pharmaceutical↗
Biomedical subjects
J Cook
Publications and source records attributed to J Cook.
Conjugated linoleic acid suppresses triglyceride accumulation and induces apoptosis in 3T3-L1 preadipocytes.
Four sets of experiments were conducted to examine the influence of conjugated linoleic acid (CLA) isomers during proliferation and differentiation of cultures of 3T3-L1 preadipocytes using physiological culturing conditions. Cultures treated with either albumin [bovine serum albumin (BSA) vehicle] or linoleic acid (LA) served as controls. For the proliferation study (Expt.1), cells were cultured in media containing a crude mixture of CLA isomers or pure LA at 0, 10, 50, or 200 microM for 4 d. Preadipocyte proliferation (cell number, 3H-thymidine incorporation into DNA) decreased as the level of CLA increased in the cultures. In contrast, LA had no impact on DNA synthesis. In Experiment 2a, postconfluent cultures were grown in media containing a crude mixture of CLA isomers or LA at 0, 10, 50, or 200 microM for the next 6 d. Postconfluent cultures supplemented with 50-200 microM CLA had less triglyceride (TG) and were smaller in size than cultures supplemented with similar amounts of LA. In Experiment 2b, postconfluent cultures supplemented with 200 microM of a crude mixture of CLA isomers or LA were harvested on days 1, 3, 6, or 9. Differences in TG content of cultures supplemented with 200 microM CLA compared to control and LA-supplemented cultures became apparent after 3 d of culture. Experiments 3a and 3b examined whether the fatty acid vehicle (BSA vs. ethanol) or the vitamin E status (+/-0.2 mM alpha-tocopherol) of the cultures altered CLA's impact on preadipocyte TG content. In Experiment 3a, ethanol-treated cultures had more TG than non-ethanol-treated cultures regardless of the fatty acid treatment. In Experiment 3b, cultures treated with 100 microM of either a crude mixture of CLA or the trans-10,cis-12 CLA isomer without supplemental vitamin E for 6 d had less TG than CLA-treated cultures containing vitamin E. In Experiment 4, postconfluent cultures were grown in media containing 100 microM LA or either a crude mixture of CLA isomers or the trans-10,cis-12 CLA isomer for 24-96 h to assess CLA's influence on the cell cycle and indices of apoptosis. Cultures treated with 100 microM CLA for 24-96 h had more apoptotic cells than BSA- or LA-treated cultures. Furthermore, cultures treated for 48 h with CLA had fewer cells in the S-phase than control cultures. The effects of the trans-10,cis-12 CLA isomer were more pronounced than those of the crude mixture of CLA isomers. These data suggest that CLA may exert its antiobesity effects by inhibiting proliferation, attenuating TG content, and/or inducing apoptosis in (pre)adipocytes.
3T3 Cells↗
Issues in the delivery of dermatologic surgery for skin cancer.
Significant financial resources need to be dedicated to treating the large numbers of skin cancers in the United States. The goal of the surgical treatment of skin cancer is to provide a high cure rate in a manner that is minimally morbid, convenient, and inherently of high value. Cost-effective delivery of this skin cancer care is critical given the prevalence of cutaneous neoplasia. Dermatologists are the best-trained physicians in the identification and management of melanoma and NMSCs. They are the most highly skilled judges of when intervention is indicated, of which lesions warrant biopsy, and of which treatment techniques are applicable for each individual tumor. These skills take years to develop and are necessary to provide the highest standard of medical and surgical management of skin cancer. As dermatologic surgery continues to evolve and dermatologists in residency receive even more surgical training, the dermatologist will prove to be the surgical skin cancer specialist well into the new millennium.
Biopsy↗
Runaway pacemaker: a case report and review.
We describe a case of runaway pacemaker. The differential diagnosis is discussed and a review of the literature is included for the diagnosis and treatment of pacemaker mediated tachycardia and runaway pacemaker.
Aged↗
Dismantling cognitive-behavioral treatment for panic disorder: questioning the utility of breathing retraining.
Cognitive-behavioral treatment (CBT) protocols for panic disorder (PD) consist of a set of interventions that often includes some form of breathing retraining (BR). A controlled outcome study was designed to assess the necessity of BR in the context of a multicomponent CBT protocol. To accomplish this, patients with PD (N = 77) were randomly assigned to receive CBT with or without BR or to a delayed-treatment control. The main study hypothesis was that patients receiving BR would display a less complete recovery relative to the other active-treatment condition given that BR appears to be a more attractive (but less adaptive) option for some patients. Some data suggested that the addition of BR yielded a poorer outcome. However, findings were generally more consistent with treatment equivalence, questioning whether BR produces any incremental benefits in the context of other CBT interventions for PD.
Adult↗
Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis.
Aberrant apoptosis-mediated cell death is believed to result in a number of different human diseases. For example, excessive apoptosis in the liver can result in fulminant and autoimmune forms of hepatitis. We have explored the possibility that inhibition of Fas expression in mice would reduce the severity of fulminant hepatitis. To do this, we have developed a chemically modified 2'-O-(2-methoxy)ethyl antisense oligonucleotide (ISIS 22023) inhibitor of mouse Fas expression. In tissue culture, this oligonucleotide induced a reduction in Fas mRNA expression that was both concentration- and sequence-specific. In Balb/c mice, dosing with ISIS 22023 reduced Fas mRNA and protein expressions in liver by 90%. The ID50 for this response was 8-10 mg kg-1 daily dosing, and the reduction was highly dependent on oligonucleotide sequence, oligonucleotide concentration in liver, and treatment time. Pretreatment with ISIS 22023 completely protected mice from fulminant hepatitis induced by agonistic Fas antibody, by a mechanism entirely consistent with an oligonucleotide antisense mechanism of action. In addition, oligonucleotide-mediated suppression of Fas expression reduced the severity of acetaminophen-mediated fulminant hepatitis, but was without effect on concanavalin A-mediated hepatitis. Our results demonstrate that 2'-O-(2-methoxy)ethyl containing antisense oligonucleotides targeting Fas can exert in vivo pharmacological activity in liver, and suggest that oligonucleotide inhibitors of Fas may be useful in the treatment of human liver disease.
Animals↗
The lateral femoral cutaneous nerve block.
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Femoral Nerve↗
Sternal instability after midline sternotomy.
The purpose of this paper is to discuss sternal instability a problem occasionally associated with midline sternotomy, including the etiology, predisposing conditions, diagnosis and management. Among the methods of repair, sternal weaving and pectoralis muscle advancement are thought to be especially effective.
Bone Wires↗
Exhaled nitric oxide levels correlate with measures of disease control in asthma.
BACKGROUND: Asthma guidelines emphasize maintaining disease control. However, objective measures of asthma disease control are lacking. OBJECTIVE: We sought to examine the relationship between exhaled nitric oxide (NO) levels and measures of asthma disease control versus asthma disease severity. METHODS: We performed a cross-sectional study of 100 patients (age range, 7-80 years) with asthma. We administered a questionnaire to identify characteristics of asthma, performed spirometric testing before and after administration of a bronchodilator, and measured exhaled NO levels in all participants. RESULTS: Exhaled NO was significantly correlated with the following markers of asthma disease control: asthma symptoms within the past 2 weeks (P =.02), dyspnea score (P =. 02), daily use of rescue medications (P =.01), and reversibility of airflow obstruction (P =.02). Exhaled NO levels were not correlated with the following markers of asthma disease severity: history of respiratory failure (P =.20), health care use (P =.08), fixed airflow obstruction (P =.91), or a validated asthma severity score (P =.19). Markers with relevance to both disease control and severity showed either a weak correlation (FEV(1) and FEV(1) percent predicted) or no correlation (controller drug use) with exhaled NO. CONCLUSION: We conclude that exhaled NO levels are correlated predominantly with markers of asthma control rather than asthma severity. Monitoring of exhaled NO may be useful in outpatient asthma management.
Adult↗
Primary closure for midline defects of the nose: a simple approach for reconstruction.
We present a modification of the standard linear closure for small to medium-sized defects of the lower nose that avoids many of the limitations of flap or graft reconstruction. The surgical technique detailed yields predictable functional and cosmetic reconstruction with very few complications. The dermatologic surgeon should consider this option when reconstructing defects of the lower nose.
Adult↗
A strategic approach to falls prevention.
As part of the Trust's clinical governance arrangements and to facilitate a systematic approach to clinical governance a risk assessment was conducted. This assessment identified that falls were a significant risk of patients, both during episodes of in-patient care and in their own homes. There is little evidence nationally to guide good practice; therefore a multidisciplinary steering group was set up to develop a comprehensive approach to falls prevention. This resulted in the development of evidence based falls prediction tools, Trust policy and guidelines and extensive staff training programmes. Information leaflets have been provided to patients and additional services such as falls groups have been developed.
Accidental Falls↗
Impact of population pharmacokinetic-pharmacodynamic analyses on the drug development process: experience at Parke-Davis.
BACKGROUND: Continued scepticism about the benefits of population pharmacokinetics and/or population pharmacodynamics, here referred to collectively as the population approach, hampers its widespread application in drug development. At the same time the sources of this scepticism have not been clearly defined. In an attempt to capture and clearly define these concerns and to help communicate the value of the population approach in drug development at Parke-Davis we conducted a survey of customers within the company. The results of this survey are presented here. METHODS: All drug development programmes conducted over the past 10 years that included a population approach in data analysis and interpretation were identified. A brief description of the population analysis was prepared together with a brief description of how the resulting information was used in each drug development programme. These synopses were forwarded to relevant members of each drug development team together with a survey designed to solicit opinions as to the relevance and impact of these analyses. RESULTS: The most frequent use of information derived from population-based analysis was in labelling. In all cases of drugs making to New Drug Application (NDA) submission the analyses resulted in information that was included in approved or proposed labelling. In almost half of the cases summarised here (5 of 12), population-based analysis was perceived to have resulted in information that influenced the direction of individual development programmes. In many of these cases the information was serendipitous. It is also noted that most of these analyses were not the result of clearly defined objectives and prospective analysis plans. CONCLUSIONS: Use of the population approach, even when applied retrospectively, may have value in complementing or supporting interpretation of other data collected during the course of a trial. Atypical systemic exposure is quickly and easily assessed for correlation with adverse events or exceptional efficacy in retrospective or ad hoc evaluation. Although we know of no direct evidence, it is possible that such use of population pharmacokinetic data has facilitated NDA review and approval by providing insight into the role of atypical systemic drug exposure in otherwise spurious events.
Data Collection↗
Modeling the long-term outcomes and costs of HIV antiretroviral therapy using HIV RNA levels: application to a clinical trial.
A model was developed to gain insight into the potential clinical and economic impact of antiretroviral therapy for HIV-infected patients. Observed HIV RNA levels and CD4 cell counts are used in the model to estimate the probability that an individual progresses from asymptomatic infection to the first AIDS-defining illness and death and to estimate the total net cost of care and long-term cost-effectiveness of antiretroviral therapy. The model was applied to patients in a clinical trial (Merck protocol 035) that compared the surrogate marker response to triple therapy with indinavir (IDV; 800 mg every 8 hr) plus zidovudine (ZDV; 200 mg every 8 hr) plus lamivudine (3TC; 150 mg twice a day) to double therapy with ZDV+3TC. The model projected that for an individual without AIDS who received triple therapy the progression to AIDS and death would be delayed more than for a patient who received double therapy with ZDV+3TC if no other treatment options were offered. Because of this delay in disease progression, the total discounted cost over the initial 5-year period was projected to be $5100 lower for patients who received triple therapy compared with double therapy if suppression with triple therapy lasts up to 3 years. If suppression with triple therapy lasts up to 5 years, costs were projected to be higher with the triple combination, but 81% of the cost is offset by lower disease costs as a result of fewer patients progressing to AIDS. Over 20 years, total discounted cost was projected to be higher for the triple-therapy regimen primarily because of a longer estimated survival time. At 20 years, the incremental cost per life-year gained by adding IDV to a ZDV+3TC regimen was estimated at $13,229, which is well within the range of other widely accepted medical interventions.
Anti-HIV Agents↗
Validation of an assay for the determination of cotinine and 3-hydroxycotinine in human saliva using automated solid-phase extraction and liquid chromatography with tandem mass spectrometric detection.
The validation of a high-performance liquid chromatographic method for the simultaneous determination of low level cotinine and 3-hydroxycotinine in human saliva is reported. Analytes and deuterated internal standards were extracted from saliva samples using automated solid-phase extraction, the columns containing a hyper cross-linked styrene-divinylbenzene copolymer sorbent, and analysed by reversed-phase liquid chromatography with tandem mass spectrometric detection (LC-MS-MS). Lower limits of quantitation of 0.05 and 0.10 ng/ml for cotinine and 3-hydroxycotinine, respectively, were achieved. Intra- and inter-batch precision and accuracy values fell within +/-17% for all quality control samples, with the exception of quality control samples prepared at 0.30 ng/ml for 3-hydroxycotinine (inter-day precision 21.1%). Results from the analysis of saliva samples using this assay were consistent with subjects' self-reported environmental tobacco smoke (ETS) exposures, enhancing the applicability of cotinine as a biomarker for the assessment of low level ETS exposure.
Chromatography, High Pressure Liquid↗
Decreased expression of the pro-apoptotic protein Par-4 in renal cell carcinoma.
Par-4 is a widely expressed leucine zipper protein that confers sensitization to apoptosis induced by exogenous insults. Because the expression of genes that promote apoptosis may be down-regulated during tumorigenesis, we sought to examine the expression of Par-4 in human tumors. We present here evidence that Par-4 protein levels were severely decreased in human renal cell carcinoma specimens relative to normal tubular cells. Replenishment of Par-4 protein levels in renal cell carcinoma cell lines conferred sensitivity to apoptosis. Because apoptosis may serve as a defense mechanism against malignant transformation or progression, decreased expression of Par-4 may contribute to the pathophysiology of renal cell carcinoma.
Apoptosis↗
Detection of intracellular tumor necrosis factor alpha in stimulated fetal cells.
BACKGROUND: It is unknown if immature fetal cells produce tumor necrosis factor (TNF) alpha in the same manner that adult cells do. The aim of this study was to determine the feasibility of early detection of intracellular TNF produced by circulating human monocytes (Mo) and lymphocytes (Ly) using flow cytometry and to compare the stimulation profiles of mature and fetal cells. MATERIAL AND METHODS: Fetal umbilical cord blood (n = 10) and adult volunteer blood (n = 10) were obtained. In vitro stimulation with endotoxin (LPS) and ionomycin-PMA was performed. Brefeldin A was added to prevent extracellular transport of TNF. Cell type was determined by using CD-14 marker separating monocyte and lymphocyte populations. Anti-human TNF monoclonal antibody was used to detect intracellular TNF by flow cytometry analysis. RESULTS: Thirty to sixty thousand cells were analyzed per sample. Average TNF expression of stimulated fetal Mo was 28.2%, and that of fetal Ly was only 1.1%. Adult stimulated Ly had an average TNF expression of 31.9%, and adult Mo, 29.6% (P < 0.05 for adult Ly vs fetal Ly). CONCLUSION: TNF flow cytometry analysis allows assessment of individual cell types and their ability to produce that cytokine. Fetal cells are able to produce TNF when stimulated, but the stimulation profile of Ly differs from that of adult samples. This observation may be of clinical importance in evaluating the response of immature cells to a septic stimulus. Flow cytometry is reliable, reproducible, quick, and easily obtained from a small sample of peripheral blood. Clinical use will be applicable once appropriate controls are developed, as reported in this study.
Adult↗
The philosophy of change and adaptation of radiology to the information age.
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Diagnostic Imaging↗
Global nail dystrophy associated with human papillomavirus type 57 infection.
Verrucae vulgares frequently induce nail dystrophy when infection of the nail matrix occurs. Classic periungual warts are easily recognized by the experienced physician. We report a very unusual presentation of human papillomavirus (HPV) infection of the nail matrix and nail bed involving all 20 nails in an otherwise immunocompetent patient. Viral typing by in situ hybridization revealed HPV type 57. To our knowledge, this is the first association between dystrophy of all 20 nails and HPV infection. However, as the ease of HPV typing improves, a variety of previously unrecognized cutaneous lesions is likely to be associated with HPV infection.
Aged↗