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At least 469 records · Page 26Linked to original sources

PubMed1996

[Intubation requirements after rocuronium and succinylcholine].

OBJECTIVE: Rocuronium is a new non-depolarising steroidal muscle relaxant with a short onset time. The present study was undertaken to compare intubating conditions as well as onset and clinical duration of a single dose of 0.6 mg/kg (2 x ED95) with a single dose of 1 mg/kg suxamethonium (3 x ED95). METHODS: After obtaining informed consent and approval of the Ethics Committee, 40 adult patients (ASA I-III) participated in this study. After premedication with oxazepam, anaesthesia was induced with fentanyl and propofol and maintained with propofol, N2O and supplements of fentanyl as needed. Muscular relaxation was assessed by EMG recording of adductor pollicis muscle after supramaximal single twitch stimulation of the ulnar nerve every 10 s. Patients were allocated randomly to receive either rocuronium 0.6 mg/kg or suxamethonium 1 mg/kg. The following parameters were measured: intubating conditions 60 s after injection, onset time and clinical duration of neuromuscular block, % block at intubation, heart rate, blood pressure and arterial oxygen saturation. RESULTS: (mean +/- SD). Intubating conditions after rocuronium and suxamethonium were found to be clinically acceptable (excellent or good) in 90% of patients, though there was only a partial blockade of the adductor pollicis muscle with rocuronium (71 +/- 23%) compared to suxamethonium (95 +/- 14%) (p < 0.05). The onset time and clinical duration of relaxation was shorter after suxamethonium (p < 0.05) and occurred at 0.8 +/- 0.2, 7 +/- 2.1 and 3.2 +/- 1.3, 29 +/- 11 min after suxamethonium and rocuronium respectively. CONCLUSION: At a dosage of 0.6 mg/kg, rocuronium has an onset time of about 3 min and a clinical duration of relaxation of nearly half an hour. These data are supported by various studies, while others show shorter times, probably due to different monitoring techniques. In spite of the pharmacodynamic differences between suxamethonium and rocuronium, the intubating conditions after administration of both compounds are comparable and develop at the same rate.

Adolescent↗

PubMed1992

The influence of implant design, application, and site on clinical performance and crestal bone: a multicenter, multidisciplinary clinical study. Dental Implant Clinical Research Group (Planning Committee).

This investigation is designed to provide scientific data that is directly relevant to the placement of dental implants. The study is concerned with the influence of implant design, application, and location on long-term clinical performance and crestal bone response over 5 years of function. It involves approximately 700 patients at 30 Veterans Administration Medical Centers from various geographic regions. Patients are being entered into the study over an 18-month period and monitored (post-loading) over 5 years. The participating centers were randomly assigned to one of two separate, independent study groups. Complications and adverse responses associated with the placement and use of the implants will be evaluated and all failures thoroughly documented. The experimental design and sample size are based on the primary hypothesis that an implant-supported prosthesis will be successful/functional over a 5-year period in at least 90 percent of the cases treated. Secondary hypotheses to be tested are (1) the success rate among implant designs are the same over a 5-year period; (2) the success rate among implant applications are the same over a 5-year period; (3) the success rate of individual implants are the same with regard to jaw location over a 5-year period; (4) the loss of crestal bone at the individual implant sites are the same among the implant designs over a 5-year period; and (5) the complications and adverse responses experienced with the different implant designs are the same over a 5-year period. The experimental design of this multicenter, multidisciplinary, randomized investigation is a cooperative effort of the Department of Veterans Affairs and several United States dental schools.

Alveolar Bone Loss↗

PubMed2004

Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand.

BACKGROUND: Although zidovudine prophylaxis decreases the rate of transmission of the human immunodeficiency virus (HIV) type 1 substantially, a large number of infants still become infected. We hypothesized that the administration, in addition to zidovudine, of a single dose of oral nevirapine to mothers during labor and to neonates would further reduce transmission of HIV. METHODS: We conducted a randomized, double-blind trial of three treatment regimens in Thai women who were receiving zidovudine therapy during the third trimester of pregnancy. In one group, mothers and infants received a single dose of nevirapine (nevirapine-nevirapine regimen); in another, mothers and infants received nevirapine and placebo, respectively (nevirapine-placebo regimen); and in the last, mothers and infants received placebo (placebo-placebo regimen). The infants also received one week of zidovudine therapy and were formula-fed. The end point of the study was infection with HIV in the infants, established by virologic testing. RESULTS: Between January 15, 2001, and February 28, 2003, a total of 1844 Thai women were enrolled. At the first interim analysis, the independent data monitoring committee stopped enrollment in the placebo-placebo group. Among women who delivered before the interim analysis, the as-randomized Kaplan-Meier estimates of the transmission rates were 1.1 percent (95 percent confidence interval, 0.3 to 2.2) in the nevirapine-nevirapine group and 6.3 percent (95 percent confidence interval, 3.8 to 8.9) in the placebo-placebo group (P<0.001). The final per-protocol transmission rate in the nevirapine-nevirapine group, 1.9 percent (95 percent confidence interval, 0.9 to 3.0), was not significantly inferior to the rate in the nevirapine-placebo group (2.8 percent; 95 percent confidence interval, 1.5 to 4.1). Nevirapine had an effect within subgroups defined by known risk factors such as viral load and CD4 count. No serious adverse effects were associated with nevirapine therapy. CONCLUSIONS: A single dose of nevirapine to the mother, with or without a dose of nevirapine to the infant, added to oral zidovudine prophylaxis starting at 28 weeks' gestation, is highly effective in reducing mother-to-child transmission of HIV.

Adult↗

PubMed1998

Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study.

BACKGROUND: Tamoxifen is a candidate chemopreventive agent in breast cancer, although the drug may be associated with the development of endometrial cancer. Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive. METHODS: In October, 1992, we started a double-blind placebo-controlled, randomised trial of tamoxifen in women (mainly in Italy) who did not have breast cancer and who had had a hysterectomy. Women were randomised to receive tamoxifen 20 mg per day or placebo, both orally for 5 years. The original plan was to follow the intervention phase by 5 years' follow-up. In June, 1997, the trialists and the data-monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study. Recruitment ended on July 11, 1997, and the study will continue as planned. The primary endpoints are the occurrence of and deaths from breast cancer. This preliminary interim analysis is based on intention-to-treat. FINDINGS: 5408 women were randomised; participating women have a median follow-up of 46 months for major endpoints. 41 cases of breast cancer occurred so far; there have been no deaths from breast cancer. There is no difference in breast-cancer frequency between the placebo (22 cases) and tamoxifen (19) arms. There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial: among 390 women on such therapy and allocated to placebo, we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen. Compared with the placebo group, there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen. INTERPRETATION: Although this preliminary analysis has low power, in this cohort of women at low-to-normal risk of breast cancer, the postulated protective effects of tamoxifen are not yet apparent. Women using hormone-replacement therapy appear to have benefited from use of tamoxifen. There were no deaths from breast cancer recorded in women in the study. It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy.

Adult↗

PubMed2004

Guidelines for vaginal birth after previous Caesarean birth.

OBJECTIVE: To provide evidence-based guidelines for the provision of a trial of labour (TOL) after Caesarean section. OUTCOME: Fetal and maternal morbidity and mortality associated with vaginal birth after Caesarean (VBAC) and repeat Caesarean section. EVIDENCE: MEDLINE database was searched for articles published from January 1995 to February 2004, using the key words "vaginal birth after Caesarean (Cesarean) section." The quality of evidence is described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam. RECOMMENDATIONS: 1. Provided there are no contraindications, a woman with 1 previous transverse low-segment Caesarean section should be offered a trial of labour after Caesarean with appropriate discussion of maternal and perinatal risks and benefits. The process of informed consent with appropriate documentation should be an important part of the birth plan in a woman with a previous Caesarean section. (II-2B) 2. The intention of a woman undergoing a TOL after Caesarean should be clearly stated and documentation of the previous uterine scar should be clearly marked on the prenatal record. (II-2B) 3. For a safe labour after Caesarean section, the woman should deliver in a hospital where an immediate Caesarean section is available. The woman and her health-care provider must be aware of the hospital resources and the availability of obstetric, anaesthesia, pediatric, and operating-room staff. (II-2A) 4. Each hospital should have a written policy in place regarding the notification and/or consultation for the physicians responsible for a possible immediate Caesarean. (III B) 5. Continuous electronic fetal monitoring of women attempting a TOL after Caesarean is recommended. (II-2A) 6. Suspected uterine rupture requires urgent attention and expedited laparotomy in order to attempt to decrease maternal and perinatal morbidity and mortality. (II-2A) 7. Oxytocin augmentation is not contraindicated in women undergoing a TOL after Caesarean. (II-2A) 8. Medical induction of labour with oxytocin may be associated with an increased risk of uterine rupture and should be used carefully after appropriate counselling. (II-2B)9. Medical induction of labour with prostaglandin E2 (dinoprostone) is associated with an increased risk of uterine rupture and should not be used except in rare circumstances after appropriate counselling. (II-2B) 10. Prostaglandin E1 (misoprostol) is associated with a high risk of uterine rupture and should not be used as part of a TOL after Caesarean. (II-2A) 11. A foley catheter may be used safely to ripen the cervix in a woman planning a TOL after Caesarean. (II-2A) 12. The available data suggest that a trial of labour in women with more than one previous Caesarean section is likely to be successful but is associated with a higher risk of uterine rupture. (II-2B) 13. Multiple gestation is not a contraindication to a TOL after Caesarean. (II-2B) 14. Diabetes mellitus is not a contraindication to TOL after Caesarean. (II-2B) 15. Suspected fetal macrosomia is not a contraindication to a TOL after Caesarean. (II-2B) 16. Women delivering within 18 to 24 months of a Caesarean section should be counselled about an increased risk of uterine rupture in labour. (II-2B) 17. Postdatism is not a contraindication to a TOL after Caesarean. (II-2B) 18. Every effort should be made to obtain the previous Caesarean section operative report to determine the type of uterine incision used. In situations where the scar is unknown, information concerning the circumstances of the previous delivery is helpful in determining the likelihood of a low transverse incision. If the likelihood of a lower transverse incision is high, TOL after Caesarean can be offered. (II-2B) VALIDATION: These guidelines were approved by the Clinical Practice Obstetrics and Executive Committees of the Society of Obstetricians and Gynaecologists of Canada.

Female↗

PubMed1993

Multicenter evaluation of ondansetron use in hospitalized oncology patients.

An evaluation of ondansetron use in oncology patients in three hospitals is described. Criteria for the use of ondansetron were developed and approved by each hospital's pharmacy and therapeutics committee or medical staff executive committee. Ondansetron use was concurrently monitored in adult inpatients for four months. Nursing and physician notes were reviewed, and the patients were interviewed. Data were collected on patient demographics, medical history, dosage of ondansetron, outcome, adverse effects, and concurrent medications. The approved criteria were used to evaluate the appropriateness, effectiveness, and safety of ondansetron therapy. A total of 262 oncology patients were evaluated. Of these, 223 (85%) received ondansetron appropriately based on the emetic potential of their antineoplastic drug regimen. Ondansetron was correctly prescribed for acute-phase prophylaxis of nausea and vomiting in 252 patients (96%). Only 117 (45%) of the patients met the criterion for appropriate dosage. The mean +/- S.D. dose of ondansetron was 11.7 +/- 3.22 mg, and the mean +/- S.D. number of doses received per patient was 4.4 +/- 3.23. Of the 135 patients who received an inappropriate dosage, 106 (79%) were given a dose larger than currently recommended by the manufacturer. Positive outcomes, defined as no more than two episodes of vomiting, no more than two episodes of retching, and no more than two p.r.n. doses of antiemetics, were observed in 97%, 99.6%, and 94% of the 248 patients included in the outcome analysis, respectively. Chemotherapy was completed on schedule in all the patients, and there were no complications due to excessive vomiting or retching. Adverse reactions were reported by 21 patients (8%).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed2004

ABI 007.

ABI 007 [Abraxane] is an albumin-stabilised nanoparticle formulation of paclitaxel designed to overcome insolubility problems encountered with paclitaxel. This then eliminates the need for toxic solvents like cremophor, which limits the dose of paclitaxel that can be administered and hence affect overall drug efficacy. Studies have shown that the albumin receptor-mediated paclitaxel-transport mechanism is analogous to the opening of a 'trapdoor' on the endothelial cell wall within blood vessels. This facilitates the passage of ABI 007 from the bloodstream via the blood vessels to the underlying tumour tissue. ABI 007 is being developed for the treatment of a variety of tumour types by American Pharmaceutical Partners. In addition to the standard infusion formulation of ABI 007, oral and pulmonary delivery formulations are also being investigated. American Pharmaceutical Partners, a subsidiary of American BioScience, secured exclusive North American marketing and manufacturing rights to ABI 007 from American BioScience in November 2001. In anticipation of product launch within the fourth quarter of 2004, the company formed Abraxis Oncology and recruited an experienced sales and marketing team. The company has also accumulated approximately 28 million US dollars of paclitaxel inventory. As such, American Pharmaceutical Partners anticipates pre-launch expenses to cost approximately 40 million US dollars, incurred over 2004. In addition, the company expects to make two milestone payments worth 10 million US dollars as well as 15 million US dollars, based upon US FDA acceptance of NDA filing in the second quarter of 2004 and subsequent US FDA approval, respectively. The milestone for US FDA approval would be capitalised and amortised over the estimated life of the product.Previously, American Pharmaceutical Partners reported that its rolling NDA submission for ABI 007 commenced in May 2003. In July 2003, the company announced that this was progressing on schedule and expected to have completed its entire NDA submission by the end of 2003. The company also began preparations to form a sales and marketing group in anticipation of product launch. In addition, production of commercial quantities of ABI 007 was expected to begin in the second half of 2003. The US FDA granted fast-track status to ABI 007 for this indication in January 2003. The decision for NDA filing was based on the successful completion of a phase III trial evaluating ABI 007 versus standard paclitaxel among 460 patients with metastatic breast cancer in the US. In September 2003, American Pharmaceutical Partners and American BioScience jointly announced positive interim results from the trial, which shows that the primary efficacy objective had been exceeded. American BioScience completed this phase III trial in early 2003 with the results unblinded in mid-2003. The phase III study directly compared the efficacy of ABI 007 260 mg/m(2) versus paclitaxel 175 mg/m(2). Both agents were administered every 3 weeks. ABI 007 was administered as a 30-minute infusion without steroid pretreatment. Paclitaxel-treated patients received steroid pretreatment and the drug was administered over 3 hours. Enrollment was completed in December 2002 with 460 first- and second-line metastatic breast cancer patients enrolled. A Data Monitoring Committee concluded in October 2002 that a sample-size adjustment of the phase III trial was not required and that the study could be continued to completion. A phase II trial of ABI 007 was also underway in metastatic breast cancer patients who have failed taxane therapy. The trial was evaluating a weekly rather than 3-weekly regimen of ABI 007. Also in February 2004, American BioScience initiated a multicentre phase II trial in patients with metastatic melanoma. The trial will evaluate both chemotherapy-naive patients (at a dose of 150 mg/m(2) administered weekly) and patients who have previously received chemotherapy (at a dose of 100 mg/m(2) administered weekly) as treatment for metastatic disease. In May 2003, American Pharmaceutical Partners reported that ABI 007 is also being evaluated for the treatment of non-small cell lung cancer, ovarian cancer, melanoma and cervical cancers. Phase I/II trials have also been conducted in other solid tumours, including squamous cell cancer of the head and neck, and pelvis. Phase I trials have also been conducted in patients with solid tumours to evaluate the administration of ABI 007 on a weekly schedule. In September 2003, American BioScience was issued US patent No. 6,506,405, which has 89 claims covering compositions of matter and unit dosage forms. In addition, the patent covers methods of use without the requirement for pretreatment with steroid therapy or growth factor support. In July 2003, the US Court of Appeals for the Federal Circuit in Washington DC unanimously ruled that American BioScience is the true and rightful owner of patent No. 5,780,653. This patent covers three next-generation taxane anticancer compounds. This ruling overturned a lower court decision in a lawsuit brought in 1998 by Florida State University (FSU) and FSU Prof. Robert Holton's privately held company, Taxolog. In the lawsuit, FSU and Taxolog alleged that Prof. Holton and others at FSU were the true inventors of the compounds claimed under American BioScience's patent.

Albumin-Bound Paclitaxel↗

PubMed2005

SOGC clinical practice guidelines. Guidelines for vaginal birth after previous caesarean birth. Number 155 (Replaces guideline Number 147), February 2005.

OBJECTIVE: To provide evidence-based guidelines for the provision of a trial of labor (TOL) after Caesarean section. OUTCOME: Fetal and maternal morbidity and mortality associated with vaginal birth after Caesarean (VBAC) and repeat Caesarean section. EVIDENCE: MEDLINE database was searched for articles published from January 1, 1995, to February 28, 2004, using the key words "vaginal birth after Caesarean (Cesarean) section". The quality of evidence is described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on the Periodic Health Exam. RECOMMENDATIONS: 1. Provided there are no contraindications, a woman with 1 previous transverse low-segment Caesarean section should be offered a trial of labor (TOL) with appropriate discussion of maternal and perinatal risks and benefits. The process of informed consent with appropriate documentation should be an important part of the birth plan in a woman with a previous Caesarean section (II-2B). 2. The intention of a woman undergoing a TOL after Caesarean section should be clearly stated, and documentation of the previous uterine scar should be clearly marked on the prenatal record (II-2B). 3. For a safe labor after Caesarean section, a woman should deliver in a hospital where a timely Caesarean section is available. The woman and her health care provider must be aware of the hospital resources and the availability of obstetric, anesthetic, pediatric, and operating-room staff (II-2A). 4. Each hospital should have a written policy in place regarding the notification and (or) consultation for the physicians responsible for a possible timely Caesarean section (III-B). 5. In the case of a TOL after Caesarean, an approximate time frame of 30 min should be considered adequate in the set-up of an urgent laparotomy (IIIC). 6. Continuous electronic fetal monitoring of women attempting a TOL after Caesarean section is recommended (II-2A). 7. Suspected uterine rupture requires urgent attention and expedited laparotomy to attempt to decrease maternal and perinatal morbidity and mortality (II-2A). 8. Oxytocin augmentation is not contraindicated in women undergoing a TOL after Caesarean section (II-2A). 9. Medical induction of labor with oxytocin may be associated with an increased risk of uterine rupture and should be used carefully after appropriate counseling (II-2B). 10. Medical induction of labor with prostaglandin E2 (dinoprostone) is associated with an increased risk of uterine rupture and should not be used except in rare circumstances and after appropriate counseling (II-2B). 11. Prostaglandin E1 (misoprostol) is associated with a high risk of uterine rupture and should not be used as part of a TOL after Caesarean section (II-2A). 12. A foley catheter may be safely used to ripen the cervix in a woman planning a TOL after Caesarean section (II-2A). 13. The available data suggest that a trial of labor in women with more than 1 previous Caesarean section is likely to be successful but is associated with a higher risk of uterine rupture (II-2B). 14. Multiple gestation is not a contraindication to TOL after Caesarean section (II-2B). 15. Diabetes mellitus is not a contraindication to TOL after Caesarean section (II-2B). 16. Suspected fetal macrosomia is not a contraindication to TOL after Caesarean section (II-2B). 17. Women delivering within 18-24 months of a Caesarean section should be counseled about an increased risk of uterine rupture in labor (II-2B). 18. Postdatism is not a contraindication to a TOL after Caesarean section (II-2B). 19. Every effort should be made to obtain the previous Caesarean section operative report to determine the type of uterine incision used. In situations where the scar is unknown, information concerning the circumstances of the previous delivery is helpful in determining the likelihood of a low transverse incision. If the likelihood of a lower transverse incision is high, a TOL after Caesarean section can be offered (II-2B). VALIDATION: These guidelines were approved by the Clinical Practice Obstetrics and Executive Committees of the Society of Obstetricians and Gynaecologists of Canada.

Cervical Ripening↗

PubMed2005

A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome.

BACKGROUND: Available therapeutic surfactants are either animal-derived or non-protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non-protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. OBJECTIVE: We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. METHODS: A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. RESULTS: The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: -7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, -7.3%, being greater than the prespecified noninferiority margin of -14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1-46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8-41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0-17.6%] vs 16.1% [95% CI: 9.7-22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). CONCLUSIONS: Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.

Biological Products↗

PubMed1995

Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial.

BACKGROUND AND PURPOSE: CGS 19755 is a competitive N-methyl-D-aspartate (NMDA) receptor antagonist that limits neuronal damage in animal stroke models. The objectives of this multicenter (7 centers), randomized, double-blind, placebo-controlled, ascending-dose phase IIa study were to evaluate the safety and tolerability of CGS 19755 and obtain pharmacokinetic and preliminary data on its efficacious dose range in patients treated within 12 hours of hemispheric ischemic stroke. METHODS: At each dose level, 6 patients were randomized to one or two intravenous bolus doses of CGS 19755, and 2 patients were randomized to placebo. An unblinded safety and monitoring committee-evaluated results at each dose before ascending to the next level. All patients at the first level (1 mg/kg) received two doses separated by 12 hours. The first 2 patients at 2 mg/kg received two doses, but adverse experiences occurred in both; subsequent patient groups received single doses of 2.0, 1.75, or 1.5 mg/kg. RESULTS: Adverse experiences (agitation, hallucinations, confusion, paranoia, and delirium) occurred in all 6 patients treated with 2 mg/kg, and in 3 of 5 at 1.75 mg/kg. Similar but milder adverse experiences were noted in 4 of 7 patients at 1.5 mg/kg and 1 of 6 patients at 1.0 mg/kg. Adverse experiences began between 20 minutes and 22 hours (mean, 8 hours) after treatment and lasted 2 to 60 hours (mean, 24 hours). Mortality was 1 of 8 in patients receiving placebo and 3 of 24 in treated patients. In treated survivors, median and mean percent improvement in National Institutes of Health Stroke Scale scores from baseline to terminal visit (mean, 86 days) was comparable at all doses, and 95% of treated patients had Barthel Index scores of > or = 70 at the terminal visit. CONCLUSIONS: We conclude that a single intravenous dose of 1.5 mg/kg CGS 19755 is safe and tolerable in patients with acute ischemic stroke. An efficacy trial is indicated.

Acute Disease↗

PubMed2001

Wavelet analysis of middle latency auditory evoked responses: calculation of an index for detection of awareness during propofol administration.

BACKGROUND: Middle latency auditory evoked responses (MLAER) as a measure of depth of sedation are critically dependent on data quality and the analysis technique used. Manual peak labeling is subject to observer bias. This study investigated whether a user-independent index based on wavelet transform can be derived to discriminate between awake and unresponsive states during propofol sedation. METHODS: After obtaining ethics committee approval and written informed consent, 13 volunteers and 40 patients were studied. In all subjects, propofol was titrated to loss of response to verbal command. The volunteers were allowed to recover, then propofol was titrated again to the same end point, and subjects were finally allowed to recover. From three MLAER waveforms at each stage, latencies and amplitudes of peaks Pa and Nb were measured manually. In addition, wavelet transform for analysis of MLAER was applied. Wavelet transform gives both frequency and time information by calculation of coefficients related to different frequency contents of the signal. Three coefficients of the so-called wavelet detail level 4 were transformed into a single index (Db3d4) using logistic regression analysis, which was also used for calculation of indices for Pa, Nb, and Pa/Nb latencies. Prediction probabilities for discrimination between awake and unresponsive states were calculated for all MLAER indices. RESULTS: During propofol infusion, subjects were unresponsive, and MLAER components were significantly depressed when compared with the awake states (P < 0.001). The wavelet index Db3d4 was positive for awake and negative for unresponsive subjects with a prediction probability of 0.92. CONCLUSION: These data show that automated wavelet analysis may be used to differentiate between awake and unresponsive states. The threshold value for the wavelet index allows easy recognition of awake versus unresponsive subjects. In addition, it is independent of subjective peak identification and offers the advantage of easy implementation into monitoring devices.

Adult↗

PubMed1999

The scope for cardiovascular disease risk factor intervention among people with diabetes mellitus in England: a population-based analysis from the Health Surveys for England 1991-94.

AIMS: To examine the scope for cardiovascular disease risk factor intervention among diabetic patients in England was examined using data from the Health Surveys for England 1991-94. This evaluation included calculating the proportion who require lipid lowering therapy according to the Standing Medical Advisory Committee (SMAC) guidelines. METHODS: The Health Survey for England is an annual, nationwide household-based in which anthropomorphic data, blood pressure, lipids and details of cardiovascular risk factors are collected from households after random stratification for geographical and socio-economic factors within a population sample of 39639 adults, 970 (2.3%) diabetic subjects were identified. RESULTS: Overall, 51% of those with diabetes had hypertension (systolic blood pressure > or = 160 mmHg or a diastolic BP > or = 95 mmHg or being on antihypertensive therapy), 27% were obese (body mass index > or = 30 kg/m2) and 19% were current smokers. One-third of those with hypertension were untreated and less than one-half of those on treatment had their hypertension controlled to below 160/ 95 mmHg. More than one-quarter had poor glycaemic control (glycated Hb>11% or an HbA1c>7.5%). Of those aged <70 years, 29% required lipid lowering therapy according to the SMAC guidelines and almost all (94%) of these were not on treatment. An analysis showed that, because the SMAC guidelines do not require high density lipoprotein (HDL) cholesterol to be measured, their use is likely to result in substantial underestimation of the need for lipid lowering, particularly in diabetic women. CONCLUSION: In England, among those with diabetes there is considerable unmet need for cardiovascular risk factor intervention, particularly for hypertension and raised cholesterol. With this baseline established, future improvements can be monitored.

Adult↗

PubMed1998

Single centre open study to compare patient recording of PRN salbutamol use on a daily diary card with actual use as recorded by the MDI compliance monitor.

The aim of this study was to assess the patients' use of inhaled short acting bronchodilators as rescue therapy during a 4-week study period. In this study an electronic metered-dose inhaler compliance monitor (MDI-CM) was used to measure the time and date of actuations of the device and this information was then compared with the patients' self reporting diary card (DC). Salbutamol canisters were used in the compliance monitor. The study was approved by the local ethics committee, and written informed consent was obtained from all patients. Patients aged 18 years and over who were either receiving, or in the investigators opinion required, inhaled salbutamol on a PRN basis were enrolled for a 4-week monitoring phase during which all rescue salbutamol used was obtained from the MDI-CM. Patients were recording their use of salbutamol in the DC each morning and evening. There was a 2-week follow-up period following completion of the monitoring phase or withdrawal from the study. Forty-four patients were enrolled and 35 patients completed the study. The mean age (range) was 43 (20-76) years and mean FEV1 2.32 (0.7-4.0) 1, with male:female ratio of 19:25. Comparison of MDI-CM and DC recordings showed patients fell into three categories: (1) patients who used rescue salbutamol appropriately and whose MDI-CM and DC recordings matched closely; (2) patients who used rescue salbutamol for acute relief but whose MDI-CM and DC recordings did not correlate and (3) patients whose use of rescue salbutamol was inappropriate or erratic according to the MDI-CM but whose DC indicated good compliance. This category of patients include those who 'dumped' all their salbutamol before attending clinic appointments. There was no significant difference in the demographic details or the severity of disease in the three groups. Recorded use of 'rescue' bronchodilator is frequently used as an indicator of efficacy for new anti-asthma therapies. This study comparing electronic data monitoring and remembered rescue salbutamol highlights the potential errors that can occur without accurate recording systems.

Adrenergic beta-Agonists↗

PubMedDate not supplied

Safety assessment of biotechnology-derived pharmaceuticals: ICH and beyond.

Many scientific discussions, especially in the past 8 yr, have focused on definition of criteria for the optimal assessment of the preclinical toxicity of pharmaceuticals. With the current overlap of responsibility among centers within the Food and Drug Administration (FDA), uniformity of testing standards, when appropriate, would be desirable. These discussions have extended beyond the boundaries of the FDA and have culminated in the acceptance of formalized, internationally recognized guidances. The work of the International Committee on Harmonisation (ICH) and the initiatives developed by the FDA are important because they (a) represent a consensus scientific opinion, (b) promote consistency, (c) improve the quality of the studies performed, (d) assist the public sector in determining what may be generally acceptable to prepare product development plans, and (e) provide guidance for the sponsors in the design of preclinical toxicity studies. Disadvantages associated with such initiatives include (a) the establishment of a historical database that is difficult to relinquish, (b) the promotion of a check-the-box approach, i.e., a tendancy to perform only the minimum evaluation required by the guidelines, (c) the creation of a disincentive for industry to develop and validate new models, and (d) the creation of state-of-the-art guidances that may not allow for appropriate evaluation of novel therapies. The introduction of biotechnology-derived pharmaceuticals for clinical use has often required the application of unique approaches to assessing their safety in preclinical studies. There is much diversity among these products, which include the gene and cellular therapies, monoclonal antibodies, human-derived recombinant regulatory proteins, blood products, and vaccines. For many of the biological therapies, there will be unique product issues that may require specific modifications to protocol design and may raise additional safety concerns (e.g., immunogenicity). Guidances concerning the design of preclinical studies for such therapies are generally based on the clinical indication. Risk versus benefit decisions are made with an understanding of the nature of the patient population, the severity of disease, and the availability of alternative therapies. Key components of protocol design for preclinical studies addressing the risks of these agents include (a) a safe starting dose in humans, (b) identification of potential target organs, (c) identification of clinical parameters that should be monitored in humans, and (d) identification of at-risk populations. One of the distinct aspects of the safety evaluation of biotechnology-derived pharmaceuticals is the use of relevant and often nontraditional species and the use of animal models of disease in preclinical safety evaluation. Extensive contributions were made by the Center for Biologics Evaluation and Research to the ICH document on the safety of biotherapeutics, which is intended to provide worldwide guidance for a framework approach to the design and review of preclinical programs. Rational, scientifically sound study design and early identification of the potential safety concerns that may be anticipated in the clinical trial can result in preclinical data that facilitate use of these novel therapies for use in humans without duplication of effort or the unnecessary use of animals.

Animals↗

PubMed2005

Ventilatory and hemodynamic changes during retroperitoneal and transperitoneal laparoscopic nephrectomy: a prospective real-time comparison.

PURPOSE: Nephrectomies are currently performed via the transperitoneal or retroperitoneal laparoscopic approach. We compared the ventilatory and hemodynamic effects of these approaches. MATERIALS AND METHODS: After institutional ethics committee approval was obtained patients requiring nephrectomy in a 9-month period were prospectively allocated to the retroperitoneal (24) or transperitoneal (15) approach. All were initially ventilated in the volume controlled mode (10 ml kg tidal volume). Intraoperative fingertip, pulse derived arterial oxygen saturation less than 97%, end tidal CO2 partial pressure greater than 40 mm Hg and peak inspiratory pressure greater than 36 cm H2O necessitated changes in ventilatory parameters, as deemed necessary by the anesthetist. If tidal volume decreased greater than 25% of baseline, pressure controlled ventilation was begun instead. RESULTS: Peak inspiratory and plateau pressures increased for the transperitoneal approach by approximately 30% more than in the retroperitoneal group (p <0.05). Volume controlled ventilation was changed to pressure controlled ventilation in 8 transperitoneal vs zero retroperitoneal cases (p <0.05). Heart rate, and systolic and diastolic blood pressure increased by approximately 13% more in the transperitoneal than in the retroperitoneal group (p <0.05). CONCLUSIONS: Nephrectomy via the retroperitoneal laparoscopic approach interferes with ventilatory and hemodynamic functions less than nephrectomy via the transperitoneal approach.

Adult↗

PubMedDate not supplied

[Ambulatory monitoring of arterial pressure in the treatment of mild-moderate arterial hypertension with lisinopril vs. enalapril].

OBJECTIVE: To compare the antihypertensive efficacy of lisinopril (L) versus enalapril (E) given 20 mg once daily for the treatment of mild to moderate arterial hypertension (diastolic blood pressure between 90-114 mm Hg) using ambulatory blood pressure monitoring (ABPM). This study also investigated the tolerance and changes in haematological or biochemical parameters with both drugs. METHODS: One hundred patients (men and women) with a range of age between 18 to 75 years were included in this open, randomised study to assess the hypotensive efficacy of L versus E after 2 months of treatment, using ambulatory blood pressure monitoring. To study data obtained from ABPM Mc Call curves were used and statistical analysis was made using SPSS program. Covariance and Chi-square test were used for the comparative analysis of different variables, considering as significant value p < 0.05. Graphics were made using HG 3.0 version. All patients gave their informed consent to participate in the study. The protocol was approved by the Ethical Committee of the Clinic Hospital. RESULTS: Systolic blood pressure (SBP) decreased from 179.00 to 156.96 mm Hg in the Lisinopril group (p < 0.001) and from 176.65 to 149.20 mm Hg in the Enalapril group (p < 0.001). Diastolic blood pressure (DBP) decreased from 104.96 to 89.94 mm Hg in the L group (p < 0.001) and from 104.16 to 86.20 mm Hg in the E group (p < 0.001). Using ABPM mean SBP daily decreased from 163.86 to 132.26 mm Hg with L (p < 0.001) and from 156.65 to 136.18 mm Hg with E (p < 0.001). Mean DBP daily decreased from 99.23 to 87.51 mm Hg with L (p < 0.001) and from 96.55 to 87.24 with E (p < 0.001). Decreases were found from total cholesterol in both groups (from 218.46 to 207.29 mg/dl with L and from 220.59 to 205.19 mg/dl with E) (p < 0.05) and Cholesterol-LDL in the E group (150.44 to 138.88) (p < 0.05). CONCLUSIONS: Both drugs produce a fall of blood pressure in mild-to-moderate hypertension, although using ABPM this fall is more significant with. According to McCall index 73.45% of patients in the Lisinopril group and 69.26% of Enalapril group controlled their hypertension, there was a difference found between BP values obtained in the clinic and those obtained using ABPM.

Adolescent↗

PubMed2002

[Rapid sequence intubation in emergency: is there any place for fentanyl?].

OBJECTIVES: Rapid sequence intubation (RSI) with the association of etomidate and succinylcholine is the French "Gold standard" for urgent "full stomach" endotracheal intubations. The aim of this study is to assess the fentanyl as a co-induction agent to take over the sedation between the RSI and the keeping of sedation, which is a critical period in which harmful neuro-vegetatives events, and awakening signs are frequently seen. STUDY DESIGN: Randomized, double blind controlled prospective study, after acceptation by the local ethical committee. PATIENTS AND METHODS: Three groups of patients undergoing RSI in the intensive care unit and by the out-of-hospital medical team were compared: group A patients received fentanyl 3 micrograms kg-1 during RSI, before paralysis was induced. Group B patients received the same dose of fentanyl immediately after endotracheal intubation. Group C patients did not received fentanyl (control group). Outcome measures were awakening signs arrival (respiratory movements, eyes opening, spontaneous limb movements), Ramsay score assessment, and haemody namics. Attempt at intubation and vomiting incident were also measured. Discrete data were compared by chi-2 analysis, continuous data were compared with two-way analysis of variance. A p value < 0.05 was the significant threshold. RESULTS: Thirty-six patients were enrolled and completed the study. All the included patients presented awakening signs. The use of fentanyl did not prevent the recourse of other sedative medications. Ten minutes after endotracheal intubation, significant differences has been noticed for the awakening signs arrival between fentanyl groups (A: 42% and B: 36%) and control group (C: 77%). The Ramsay score evolution follows the same variation. All the patients were intubated on the first attempt, there was no vomiting incident noticed. CONCLUSION: The use of fentanyl, as a co-induction agent with etomidate and succinylcholine during RSI, allows a significant delay of the awakening signs arrival and attenuate the neurovegetative response during the minutes after endotracheal intubation after RSI, without deleterious haemodynamic effects.

Anesthesia, Intravenous↗

PubMed2002

[Preoxygenation with the NasOral((R)) system or the standard face mask?].

INTRODUCTION: Adequate preoxygenation of patients before onset of apnea for orotracheal intubation is of major importance in general anaesthesia. Various preoxygenation techniques are available but a face mask providing an oxygen supply via the circle absorber system of a mechanical respirator is most frequently used. Recently, a new device for preoxygenation - the NasOral((R)) system - has become available. The aim of the present study was to compare the efficacy of intrapulmonary oxygen storage with either the NasOral((R)) device or the standard face mask. METHODS: After informed and written consent and ethics committee approval was obtained, 40 elective patients (ASA I and II) undergoing surgical procedures of the neck and mouth area, were enrolled in this randomized, prospective study. In group A ( n=20), preoxygenation was performed using the NasOral((R)) system. Patients inhaled 100% oxygen through the nose and exhaled orally through unidirectional valves. In group B ( n=20), a conventional face mask with an O(2) flow of 15 l/min and an open airway pressure release valve was used for preoxygenation. In both groups preoxygenation lasted for 2.5 min. Induction of general anaesthesia was performed in a standardized manner. After intubation patients were not ventilated until the O(2) saturation in pulse oximetry (psaO(2)) dropped to 95%. This time of apnea was recorded in both groups and we determined the hemoglobin concentration (cHb) after beginning of ventilation. RESULTS: There were no significant differences with regard to demographic data and cHb. Time of apnea leading to a O(2) saturation of 95% was 6.0+/-2.1 min in group A and 6.3+/-2.1 min in group B (mean+/-SD, p>0.05). CONCLUSIONS: Both the NasOral((R)) system and the face mask are effective for intrapulmonary oxygen storage. In both systems the O(2) flow has to be adequately high and the masks have to be held tightly in order to avoid any contamination of the inhaled oxygen with nitrogen. Due to its unidirectional flow, the NasOral((R)) system additionally requires the patient to be cooperative. As the NasOral((R)) system is more expensive and has no clinical advantages without apneic oxygenation, we prefer the standard face mask for patient preoxygenation.

Adolescent↗