300-mg Group Research Articles

Cyclosporine does not enhance the development of accelerated coronary artery disease: experimental study in a rat cardiac transplant model

Background Among other factors, cyclosporine (CsA) is linked with the development of accelerated coronary artery disease (ACAD) after transplantation. The objective of this study was to assess the influence of different CsA regimens on ACAD after rat heart transplantation. Methods After heterotopic cardiac transplantation (Lewis to Fisher), animals were treated with 3 or 12 mg/kg per day of CsA, administered subcutaneously. The control group received no therapy. CsA blood levels were determined every 10 days. Twenty and 80 days after grafting, the incidence of ACAD was determined and the extent of ACAD was assessed as mean vessel occlusion (mvo). Results In the 12-mg group, CsA levels were nearly 10-fold higher than in the 3-mg group. Only in the 12-mg CsA group was the incidence of ACAD significantly reduced at Days 20 and 80 when compared with controls. Continuous therapy with 3 mg and 12 mg of CsA significantly reduced the mvo at Days 20 and 80 when compared with control animals ( p < .05). However, comparing the two dosages, there were no significant differences. When the 20-day-limited course of CsA application was used we did not observe significant differences in mvo at Day 80 upon comparison of 3-mg and 12-mg CsA treatment versus untreated animals. Conclusions Despite the excessive increase in CsA blood levels we observed neither a further reduction nor an increase of ACAD in the high-dose group compared with the low-dose group. Therefore, CsA did not enhance the development of chronic rejection in this experiment.

Analysis of Recent Papers in Hypertension

Analysis of Recent Papers in Hypertension

Pharmacodynamics of abacavir in an in vitro hollow-fiber model system.

Abacavir is a potent new carbocyclic nucleoside analogue. We employed our hollow-fiber pharmacodynamic modeling system to examine the antiretroviral effects of different abacavir exposures, as well as the impact of the schedule of drug administration on efficacy. Dose ranging of abacavir revealed that a concentration of four times the 50% effective concentration (EC(50)) (approximately the EC(95)) was required to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) (strain MN) either in a continuous-infusion hollow-fiber experiment or in a classical tissue culture flask experiment. In contrast to earlier work with another drug class (HIV-1 protease inhibitors), addition of physiological amounts of the human drug binding proteins albumin and alpha(1) acid glycoprotein revealed that there was little impact on the antiviral effect of the drug. Comparison of equivalent exposures (an area under the concentration-time curve [AUC] developed by approximately 500 mg per day of orally administered abacavir), either in a continuous-infusion mode or as a single oral dose of abacavir, demonstrated no difference in the ability to suppress either strain III(B) or strain MN. Comparison of administration of 250 mg every 12 h (q12h) versus once-daily administration of 500 mg for strain MN again showed no significant difference in suppressive effect. These experiments were carried out over 8 to 15 days. Because of these promising initial results, we extended the experiment to 30 days and examined three different schedules of administration that generated the same AUC at 24 h (AUC(24)): 300 mg q12h, 600 mg q24h, and 1,200 mg q48h. The aim of the last of these regimens was to definitively demonstrate schedule failure. There was little difference between the 1,200-mg q48h treatment group and the untreated control at 30 days. Likewise, there was little difference between the 600-mg q24h and 300-mg q12h treatment groups. However, at circa day 18 of the experiment, there was a small increase in viral output of p24 in the once-daily dosing unit. Examination of virus from all groups demonstrated no phenotypic or genotypic differences. The small difference in hollow-fiber unit p24 in the once-daily dosing group was not due to emergence of resistance over the 30-day single-drug exposure. We conclude that the dose of abacavir currently being studied in clinical trials (300 mg orally q12h) will be efficacious for the majority of sensitive clinical isolates of HIV-1. These in vitro data also suggest that this drug may be able to be administered to patients on a once-daily basis at a dose of 600 mg.

Hyperbaric Spinal Levobupivacaine: A Comparison to Racemic Bupivacaine in Volunteers

Levobupivacaine is the isolated S-enantiomer of bupivacaine and may be a favorable alternative to spinal bupivacaine. However, its clinical efficacy relative to bupivacaine and its dose-response characteristics, in spinal anesthesia, must first be known. This double-blinded, randomized, cross-over study was designed to compare the clinical efficacy of hyperbaric levobupivacaine and bupivacaine for spinal anesthesia. Eighteen healthy volunteers were randomized into three equal groups to receive two spinal anesthetics, one with bupivacaine and the other with levobupivacaine, of equal-milligram doses (4, 8, or 12 mg). We assessed blockade quality and duration with pinprick, transcutaneous electrical stimulation, thigh tourniquet, abdominal and quadriceps muscle strength, modified Bromage scale, and time until achievement of discharge criteria. Sensory and motor block were similar between the same doses of levobupivacaine and bupivacaine (P > 0.56 to 0.86). For example, in the 12-mg groups of levobupivacaine versus bupivacaine, mean duration of tolerance to transcutaneous electrical stimulation at T12 was 100 min for both. The duration of motor block at the quadriceps was 71 versus 73 min, and time until achievement of discharge criteria was 164 min for both. Hyperbaric spinal levobupivacaine has equivalent clinical efficacy to racemic bupivacaine for spinal anesthesia in doses from 4 to 12 mg.

Pregabalin in patients with postoperative dental pain

Pregabalin is an analogue of the inhibitory neurotransmitter gamma-aminobutyric acid. In preclinical models, it has shown activity as an analgesic agent. A randomized, double-blind, placebo-controlled, parallel-group trial was undertaken to compare pregabalin to placebo and 400 mg of ibuprofen using a dental pain model. Study medication was administered postoperatively to patients who had undergone elective surgery to remove one or two third molars, at least one of which was mandibular and fully or partially impacted in bone. The study was conducted in the UK at a single centre and evaluated pregabalin at doses of 50 and 300 mg. Primary efficacy parameters included pain relief (PR), pain intensity difference (PID), pain relief intensity difference (PRID), time to onset of analgesia, and duration of analgesia. The patient’s global impression of the study medication was used as a secondary efficacy parameter. Efficacy data were evaluated for the intent-to-treat (ITT) population, defined as all randomized patients who took study medication. Results showed that there were statistically significant differences in PR, PID, and PRID between the 300-mg pregabalin group and placebo. In addition, the 300-mg pregabalin group had a significantly longer duration of analgesia than the ibuprofen group and had the highest score on the patient global impression of study medication. Adverse events were reported more frequently in the pregabalin 300-mg group.Pregabalin appears to have significant analgesic properties in the third molar extraction model. Further research is needed to confirm these findings.

Bupivacaine-sparing effect of fentanyl in spinal anesthesia for cesarean delivery

Background and Objectives: Visceral pain decreases in cesarean patients under spinal anesthesia when the dose of local anesthetic is increased. However, larger doses of local anesthetic are associated with higher sensory blocks. We hypothesized that the addition of fentanyl could reduce the dose of bupivacaine necessary to achieve adequate surgical anesthesia. Methods: Two double-blinded, sequential, prospective studies were performed on 120 patients. In the preliminary study, the patients received 8, 10, or 12 mg of 0.5% hyperbaric bupivacaine intrathecally. In the second, main study, they received each bupivacaine dose with 10 μg of fentanyl. Each group consisted of 20 patients, and the groups were identified as B8, B10, B12, BF8, BF10, and BF12. Sensory and motor block, intraoperative pain defined by visual analogue scale (VAS), muscle relaxation, and side effects were assessed. We also measured the sensory and motor recovery and the onset of pain in the postanesthesia care unit (PACU). Results: Maximal block level and incidence of high block (≥T1) were higher in the 12-mg groups. There was intraoperative pain in 35% of the B8 patients and 20% of the B10 patients, but none in the B12 patients and all fentanyl groups. Incidences of other side effects were not different. The addition of fentanyl to bupivacaine significantly delayed the onset of postoperative pain and sensory recovery, but motor recovery time did not change with additional fentanyl. Conclusions: The optimal dose of hyperbaric bupivacaine to produce surgical anesthesia was 12 mg, which was accompanied by high sensory block. With the addition of 10 μg of fentanyl, the dose of bupivacaine could be reduced to 8 mg in spinal anesthesia for cesarean delivery. Reg Anesth Pain Med 2000;25:240–245

Metabolic effects of vanadyl sulfate in humans with non—insulin-dependent diabetes mellitus: In vivo and in vitro studies

To investigate the efficacy and mechanism of action of vanadium salts as oral hypoglycemic agents, 16 type 2 diabetic patients were studied before and after 6 weeks of vanadyl sulfate (VOSO4) treatment at three doses. Glucose metabolism during a euglycemic insulin clamp did not increase at 75 mg/d, but improved in 3 of 5 subjects receiving 150 mg VOSO4 and 4 of 8 subjects receiving 300 mg VOSO4. Basal hepatic glucose production (HGP) and suppression of HGP by insulin were unchanged at all doses. Fasting glucose and hemoglobin A1c (HbA1c) decreased significantly in the 150- and 300-mg VOSO4 groups. At the highest dose, total cholesterol decreased, associated with a decrease in high-density lipoprotein (HDL). There was no change in systolic, diastolic, or mean arterial blood pressure on 24-hour ambulatory monitors at any dose. There was no apparent correlation between the clinical response and peak serum level of vanadium. The 150- and 300-mg vanadyl doses caused some gastrointestinal intolerance but did not increase tissue oxidative stress as assessed by thiobarbituric acid-reactive substances (TBARS). In muscle obtained during clamp studies prior to vanadium therapy, insulin stimulated the tyrosine phosphorylation of the insulin receptor, insulin receptor substrate-1 (IRS-1), and Shc proteins by 2- to 3-fold, while phosphatidylinositol 3-kinase (PI 3-kinase) activity associated with IRS-1 increased 4.7-fold during insulin stimulation (P = .02). Following vanadium, there was a consistent trend for increased basal levels of insulin receptor, Shc, and IRS-1 protein tyrosine phosphorylation and IRS-1-associated PI 3-kinase, but no further increase with insulin. There was no discernible correlation between tyrosine phosphorylation patterns and glucose disposal responses to vanadyl. While glycogen synthase fractional activity increased 1.5-fold following insulin infusion, there was no change in basal or insulin-stimulated activity after vanadyl. There was no increase in the protein phosphatase activity of muscle homogenates to exogenous substrate after vanadyl. Vanadyl sulfate appears safe at these doses for 6 weeks, but at the tolerated doses, it does not dramatically improve insulin sensitivity or glycemic control. Vanadyl modifies proteins in human skeletal muscle involved in early insulin signaling, including basal insulin receptor and substrate tyrosine phosphorylation and activation of PI 3-kinase, and is not additive or synergistic with insulin at these steps. Vanadyl sulfate does not modify the action of insulin to stimulate glycogen synthesis. Since glucose utilization is improved in some patients, vanadyl must also act at other steps of insulin action.

A Dose-Dependent Increase in Mortality with Vesnarinone Among Patients with Severe Heart Failure

Background Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity. Methods We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days. Results There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had ...

The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase (COX)-1 and COX-2 isoenzymes and are effective in the treatment of inflammatory disorders. This 8-week, double-masked, placebo-controlled trial was undertaken to assess the safety profile, tolerability, and effective dose range of once-daily rofecoxib, a COX-2-specific inhibitor, in the treatment of rheumatoid arthritis (RA). After a 3- to 15-day washout of prior NSAID therapy, 658 patients were randomly allocated to receive placebo or rofecoxib 5 mg, 25 mg, or 50 mg once daily. Safety profile, tolerability, and efficacy were evaluated after 2, 4, and 8 weeks of therapy. Six hundred fifty-eight patients (168, 158, 171, and 161 in the placebo and 5-mg, 25-mg, and 50-mg rofecoxib groups, respectively) were enrolled at 79 clinical centers in the United States. Mean age was 55 years, mean duration of RA was 10 years, and 506 (77%) of the 658 patients were female. All groups had similar baseline demographic characteristics. Patients taking rofecoxib 25 and 50 mg showed significant clinical improvement compared with those taking placebo; 43.9% in the rofecoxib 25-mg group and 49.7% in the rofecoxib 50-mg group completed the treatment period and achieved an American College of Rheumatology 20 response ( P = 0.025 and 0.001 vs placebo, respectively). The 5-mg dose of rofecoxib did not differ significantly from placebo. Patients in the rofecoxib 25- and 50-mg groups showed significant improvement in key individual efficacy measurements, including patient global assessment of pain, patient and investigator global assessment of disease activity, and Stanford Health Assessment Questionnaire Disability Index ( P < 0.05 vs placebo). Compared with placebo, significantly fewer patients in the 25-mg and 50-mg rofecoxib groups discontinued therapy because of lack of efficacy ( P = 0.02 and P = 0.032, respectively). Our results show that rofecoxib 25 and 50 mg once daily was effective and generally welltolerated in patients with RA.

Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women

Objective: To investigate the long-term effects of raloxifene on fasting plasma homocysteine levels in postmenopausal women compared with conjugated equine estrogen (CEE). Design: Randomized, double-blind, placebo-controlled study. Setting: Outpatient department of a university hospital. Patient(s): Fifty-two hysterectomized, healthy postmenopausal women. Intervention(s): Oral raloxifene in two dosages (60 mg/d [n = 13] and 150 mg/d [n = 13]), oral CEE (0.625 mg/d [n = 13], and placebo (n = 13) were given for 24 months. Main Outcome Measure(s): Fasting plasma homocysteine concentrations. Result(s): Plasma homocysteine levels were not altered in the placebo group. After 12 months, a significant reduction versus baseline in the mean plasma homocysteine level (−16%) was found only in the raloxifene 150-mg group. The mean change in plasma homocysteine levels within this group also was significantly different from the changes versus baseline found in the placebo group (+2%) and the raloxifene 60-mg group (−2%), but not different from those found in the CEE group (−8%). After 24 months, plasma homocysteine levels were decreased significantly in the raloxifene 150-mg and CEE groups compared with both baseline (−13% and −10%, respectively) and placebo values (−15% and −11%, respectively). No significant change in plasma homocysteine levels was observed in the raloxifene 60-mg group. Conclusion(s): Raloxifene has a favorable, dose-related effect on plasma homocysteine levels in postmenopausal women.

A multicenter evaluation of the efficacy and safety of 150 and 300 mg/d sustained-release bupropion tablets versus placebo in depressed outpatients

This multicenter, randomized, double-masked, placebo-controlled, parallel-group study compared the antidepressant efficacy and safety of bupropion sustained-release (SR) tablets (150 mg QD or 150 mg BID) with placebo in outpatients with moderate-to-severe depression. The study consisted of a 1-week placebo phase followed by 8 weeks of active treatment with bupropion SR 150 mg/d (150 mg QD, n = 121) or 300 mg/d (150 mg BID, n = 120) or placebo (n = 121). Efficacy was measured by changes in scores on the 17-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions for Severity of Illness (CGI-S) and Clinical Global Impressions for Improvement of Illness (CGI-I) scales. Safety was monitored by regular assessment of vital signs and adverse events as well as by pretreatment and posttreatment physical and clinical laboratory examinations. By day 56, both bupropion SR treatments were more effective in relieving the symptoms of depression than was placebo. Compared with those receiving placebo, patients in the bupropion SR 150- and 300-mg/d groups had significantly reduced symptoms by treatment day 56, as measured on the 17-item HAM-D, CGI-S, and CGI-I scales ( P < 0.05). Bupropion SR was well tolerated, with no serious adverse events reported by bupropion-treated patients; 95% of all reported adverse events were of mild or moderate intensity. No clinically significant changes in vital signs, laboratory test results, or physical findings were observed. A greater mean weight loss was observed at the end of treatment in both the bupropion SR 150-mg (0.5 kg) and bupropion SR 300-mg (1.0 kg) group compared with placebo (0.2 kg). We found that bupropion SR 150 mg administered either once or twice daily was more effective than placebo in treating depression and that once-daily dosing appears to be at least as effective as twice-daily dosing. Should this prove true, depressed patients may be able to benefit from the convenience and improved tolerability associated with once-daily dosing.

Bolus Administration of Saruplase in Europe (BASE), a Pilot Study in Patients with Acute Myocardial Infarction.

To study the safety and efficacy of the thrombolytic agent saruplase as a bolus, the angiographic and clinical outcomes of three bolus regimens were investigated in a pilot study conducted in 192 patients with an acute myocardial infarction and were compared with the standard regimen. Fifty-two patients received a double bolus of 40 mg and 40 mg after 30 minutes, 51 patients a bolus of 80 mg, and 36 patients a bolus of 60 mg. Fifty-three patients received the standard regimen (a bolus of 20 mg and 60 mg IV infusion over 1 hour). At 60 minutes TIMI 2 and 3 flow were, respectively, 9.6% and 61.5% with the 40/40-mg bolus, 15.7% and 51.0% with the 80-mg bolus, 16.7% and 30.6% with the 60-mg bolus, and 7.5% and 54.7% with the standard 20/60-mg infusion. At 90 minutes TIMI 2 and 3 flow improved to 9.6% and 73.1%, 15.7% and 56.9%, 13.9% and 36.1%, and 5.7% and 71.7%, respectively. The primary endpoint, persistent patency (TIMI 2 + 3) at 24-45 hours, was seen in 69.2%, 64.7%, 44.4%, and 67.9% of patients who had no rescue PTCA, respectively. Inclusion in the 60-mg bolus group was prematurely stopped because of their low patency rates. The 40/40-mg bolus group had the highest mortality rate (13.5%), whereas the 60-mg bolus group had no deaths. Other adverse event rates were similar in the four groups. This clinical outcome is highly influenced by rescue PTCA of patients with insufficient TIMI flow. This pilot study indicates that in patients with an acute myocardial infarction, a double bolus of 40/40 mg resulted in the highest patency but also had the highest complication rate. The 80-mg single bolus is an attractive alternative for further evaluation because of its acceptable patency and event profile, and its easy form of administration.

Single-dose pharmacokinetics of thalidomide in human immunodeficiency virus-infected patients

The pharmacokinetics of thalidomide in nine human immunodeficiency virus-infected patients were studied. Single doses of thalidomide were well absorbed, with mean peak concentrations (+/- standard deviations) of 1.17 +/- 0.21 and 3.47 +/- 1.14 microg/ml in the 100- and 300-mg dosing groups, respectively, and the mean elimination half-life was approximately 6 h. Adverse effects were mild, with drowsiness being reported for seven of nine patients.

Nifedipine gastrointestinal therapeutic system (GITS) for hypertensive patients in a primary care setting: results of the Extended Release Adalat Canadian Trial (EXACT)

Nifedipine gastrointestinal therapeutic system (GITS) is an extended-release dosage formulation that provides sustained blood concentrations of nifedipine over 24 hours. A 20-week, postmarketing surveillance study of the effectiveness and patient tolerability of nifedipine GITS 30 or 60 mg was conducted in the offices of 187 Canadian general practitioners from September 1992 to March 1994. A total of 1700 patients previously or newly diagnosed with mild-to-moderate essential hypertension (sitting diastolic blood pressure, 95 to 114 mm Hg) were included. The 20-week treatment period was completed by 1326 patients. Patients received nifedipine GITS 30 mg initially; the dose could be titrated upward to 60 mg after 3 and 6 weeks. Of all patients entered, 605 (35.6%) reported one or more adverse events. The three most frequently occurring adverse events were headache (12.2%), peripheral edema (8.1%), and dizziness (2.9%). The frequency of adverse events was highest in the first 3 weeks and decreased subsequently. The overall incidence of adverse events was 29.8% in patients receiving 30 mg of nifedipine GITS and 25.3% in those receiving 60 mg; adverse events were the cause of study discontinuation in 12.3% of patients. The overall health status of patients as measured by the SF-36 questionnaire was comparable to that previously reported for healthy individuals. At baseline, mean (±SE) systolic/diastolic blood pressure values for all patients were 160.1 ± 0.4/97.4 ± 0.2 mm Hg. Final blood pressure readings after 20 weeks of treatment in the 30-mg group (141.5 ± 0.4/84.8 ± 0.2 mm Hg) and the 60-mg group (146.6 ± 0.8/88.8 ± 0.4 mm Hg) were significantly decreased from baseline. At week 20, the 30-mg dose was sufficient to maintain blood pressure in 74.5% of patients; 25.5% of patients required 60 mg. Subgroup analysis revealed similar responses in patients who had received blood pressure medication before study initiation and those who had not. Response was also independent of age and type of previous antihypertensive therapy. In general medical practice, the 30-mg and 60-mg doses of nifedipine GITS were both effective and well tolerated and had minimal or no negative effects on the overall health status of treated individuals.

An open assessment of the acceptability, efficacy, and tolerance of venlafaxine in usual care settings

An open-label study in 518 outpatients with major depression was performed by a collaborative group involving 105 psychiatrists in 22 cities in Mexico. The objectives of this study were to assess the tolerance and efficacy of venlafaxine, a new antidepressive drug, in outpatients in usual care settings. The two largest psychiatric medical associations approved the proposed protocol, and their chairmen coordinated the study. Patients had to comply with the diagnostic criteria for major depression as stated in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised. The Hamilton Depression rating scale (21 items) and the Clinical Global Impressions (CGI) rating scale were used to assess a patient's clinical response to drug, which was prescribed in different doses (37.5 to 75 mg, 100 to 150 mg, and 175 to 300 mg) according to a patient's status at enrollment. Patients were followed for 6 weeks. A total of 435 patients (84%) completed the study. After 7 days of treatment with venlafaxine, there was a statistically significant improvement in patients with mild-to-moderate depression—those in the 37.5- to 75- mg group (mean CGI improvement, 3.8% to 38.2%) and in the 100- to 150-mg group (mean CGI improvement, 1.3% to 16.7%)—and by day 14 in patients with severe depression—those in the 175- to 300-mg group (mean CGI improvement at day 14, 1.8% to 20.0%). The efficacy of venlafaxine was assessed in all three groups by day 42, with statistically significant improvement observed after treatment with venlafaxine as compared with baseline. The adverse events most frequently associated with the use of venlafaxine were nausea (35.13%) and headache (17.95%), which did not differ in nature and intensity from that reported by other investigators. A total of 83 patients withdrew from the study; 50 of these dropped out due to an adverse event. Although the study design weakened the conclusions drawn from this study, in this 6-week, open-label, uncontrolled trial, venlafaxine appeared to be an efficacious, well-tolerated antidepressant in patients with major depression, with improvement generally detected in about 1 week.

Assessment of different markers of bone resorption in postmenopausal osteoporotic women treated with pamidronate

The aim of this study was to evaluate the different bone resorption markers, total pyridinoline (Pyr) and total deoxypyridinoline (Dpyr), assessed by a HPLC method, free Dpyr, assessed by a new immunoassay, and urinary excretion of hydroxyproline (OH-proline), in postmenopausal osteoporotic women during long-term treatment with pamidronate.A total of 60 postmenopausal women with previous distal forearm fracture were included in this 12-month placebo-controlled and double-blind study, where intermittent oral pamidronate, 75 or 150 mg, or placebo were given daily for 4 weeks, every 16 weeks. After 1 week a significant reduction in urinary excretion of total Dpyr was observed in the group treated with 150 mg pamidronate compared to the placebo (p<0.01) and to the 75-mg group (p<0.001). A maximal 50.4% decrease in total Dpyr, (p<0.0001 compared to the placebo group, p<<0.01 compared to the 75-mg group), was observed after 3 weeks of treatment with 150 mg pamidronate, and this decrease persisted to week 52. After 4 weeks of treatment with 150 mg pamidronate the maximal decrease in free Dpyr was only 26.5%, which persisted during 12 months of treatment. Decreases in urinary excretion of total Pyr and OH-proline were less than the decreases in total DpyrThe correlation between total Dpyr (HPLC method) and free Dpyr (Pyrilinks-D assay) at baseline was r=0.91. Total Dpyr assessed by the HPLC method reflects the pamidronate-induced decrease in bone resorption, and the changes in this resorption marker were more pronounced than changes in free Dpyr, total Pyr and OH-proline. In this study free Dpyr analysis was less suitable for reflecting bone resorption during bisphosphonate therapy.

Combined Spinal-Epidural Anesthesia for Outpatient Surgery

Background : Combined spinal-epidural anesthesia (CSE) may offer theoretic advantages for outpatient surgery, because it produces the rapid onset of spinal anesthesia, with the option to extend the blockade with an epidural catheter. In this study, the authors attempted to determine an appropriate initial dose of a short-acting local anesthetic, 2% lidocaine, to administer for outpatient knee arthroscopy using CSE. Methods : Data were collected from 90 patients undergoing outpatient knee arthroscopy. Using a double-blinded, prospective study design, patients were randomly assigned to receive CSE with an initial dose of intrathecal 2% lidocaine of 40, 60, or 80 mg. A 27-G 4 11/16-inch Whitacre needle was placed through a 17-G Weiss needle. Onset and regression of sensory anesthesia and motor blockade were measured by a blinded observer at frequent intervals. Results : All 90 patients had adequate anesthesia. Durations of thoracic and lumbar sensory and lower limb motor blockade were significantly shorter in the 40-mg group compared with the 60- or 80-mg groups (P < 0.0002 Mantel-Cox, Survivorship Analysis). Indices of neural blockade resolved 30-40 min more rapidly in the 40-mg group than in either the 60- or 80-mg group. Times to urinate, sit upright in a chair, take oral fluids, and be discharged were all significantly shorter (between 30 and 60 min) in the 40-mg group compared with the 60- and 80-mg groups (P < 0.01). Seven patients required intraoperative epidural supplementation : three in the 40-mg group, three in the 60-mg group, and one in the 80-mg group. Conclusions : Combined spinal-epidural anesthesia with a 40-mg initial intrathecal dose of lidocaine provided reliable anesthesia for knee arthroscopy. Duration of spinal anesthesia with lidocaine was dose related.

Combined Spinal-Epidural Anesthesia for Outpatient Surgery

Combined spinal-epidural anesthesia (CSE) may offer theoretic advantages for outpatient surgery, because it produces the rapid onset of spinal anesthesia, with the option to extend the blockade with an epidural catheter. In this study, the authors attempted to determine an appropriate initial dose of a short-acting local anesthetic, 2% lidocaine, to administer for outpatient knee arthroscopy using CSE. Data were collected from 90 patients undergoing outpatient knee arthroscopy. Using a double-blinded, prospective study design, patients were randomly assigned to receive CSE with an initial dose of intrathecal 2% lidocaine of 40, 60, or 80 mg. A 27-G 4 11/16-inch Whitacre needle was placed through a 17-G Weiss needle. Onset and regression of sensory anesthesia and motor blockade were measured by a blinded observer at frequent intervals. All 90 patients had adequate anesthesia. Durations of thoracic and lumbar sensory and lower limb motor blockade were significantly shorter in the 40-mg group compared with the 60- or 80-mg groups (P < 0.0002 Mantel-Cox, Survivorship Analysis). Indices of neural blockade resolved 30-40 min more rapidly in the 40-mg group than in either the 60- or 80-mg group. Times to urinate, site upright in a chair, take oral fluids, and be discharged were all significantly shorter (between 30 and 60 min) in the 40-mg group compared with the 60- and 80-mg groups (P < 0.01). Seven patients required intraoperative epidural supplementation: three in the 40-mg group, three in the 60-mg group, and one in the 80-mg group. Combined spinal-epidural anesthesia with a 40-mg initial intrathecal dose of lidocaine provided reliable anesthesia for knee arthroscopy. Duration of spinal anesthesia with lidocaine was dose related.

単回療法による女子急性単純性膀胱炎の治療成績

Female acute uncomplicated cystitis responds relatively well to antimicrobial chemotherapy. In particular, new quinolones are suited for use as antimicrobial agents in single-dose therapy of female acute uncomplicated cystitis since they have a long serum half-life and express potent antimicrobial activity against the causative microbes of this infection. Lomefloxacin (LFLX) is one such new quinolone which shows a long serum half-life, expresses potent antimicrobial activity against Escherichia coli (E. coli) and maintains an effective urinary drug concentration for approximately three days after a single administration. The authors carried out a comparative investigation of the clinical efficacy of single doses of 100 mg and 300 mg of LFLX in the treatment of female acute uncomplicated cystitis. The clinical efficacy rates with these doses, evaluated on the 3rd day after administration, were 98.2% (56/57 cases) for the 100mg-LFLX dose and 100% (62/62 cases) for the 300-mg LFLX dose. When the evaluation was performed on the 7th day after administration, the clinical efficacy rates were 91.3% (42/46 cases) for the 100-mg LFLX dose and 95.8% (46/48 cases) for the 300-mg LFLX dose. In addition, the microbial eradication rates were 73.7% (42/57 cases) for the 100-mg LFLX group and 75.8% (47/62 cases) for the 300-mg LFLX group on the 3rd day after administration, and 71.7% (33/46 cases) for the 100-mg LFLX group and 83.3% (40/48 cases) for the 300-mg LFLX group on the 7th day after administration. Although there were no statistically significant differences between the two LFLX dosage groups for these parameters at either of the evaluation times, the rates for the 300-mg LFLX dose were slightly superior. The investigators judged the efficacy of the LFLX treatment as having been insufficient in 12 patients, and urological examinations performed on six of those cases determined that there were mild underlying diseases in four cases, such as stenosis of the urethral meatus. On the basis of the findings described above, it is clear that a single 100-mg dose of LFLX provided sufficient clinical efficacy in the treatment of female acute uncomplicated cystitis, but the efficacy of the 300-mg dose of LFLX was even better. In addition, it was surmised that performance of detailed urological examinations provides an opportunity to detect mild underlying diseases that may be the cause of the intractability in female acute uncomplicated cystitis cases showing an insufficient response to treatment with antimicrobial agents such as LFLX.

Ursodeoxycholic acid therapy for chronic type C hepatitis: A multicenter, dose-finding trial

Ursodeoxycholic acid (UDCA) was administered orally for 12 weeks to 40 patients with chronic type C hepatitis. Patients were randomly assigned to receive UDCA 150 mg/day (n = 20) or 450 mg/day (n = 20). In the 450-mg group, alanine aminotransferase (ALT) decreased significantly ( P < 0.05) during treatment but increased ( P < 0.05) 4 weeks after the drug was withdrawn. In contrast, in the 150-mg group, ALT showed no significant decrease during treatment. In the 450-mg group, aspartate aminotransferase (AST) at weeks 8 and 12 and ALT at week 12 were significantly decreased compared with the 150-mg dose group ( P < 0.01). No significant difference between groups was observed in gamma-glutamyltransferase (GGT) levels, although in both groups GGT significantly decreased ( P < 0.05). The UDCA fraction to serum bile acid ratio increased to 29 mol% in the 150-mg group and to 47 mol% in the 450-mg group. There was a good correlation between the increase in the serum UDCA fraction and the decrease in ALT and GGT levels. These results suggest that in chronic type C hepatitis, UDCA at a dose of 450 mg/day significantly improves AST, ALT, and GGT levels and that these improvements are associated with an increase in the serum UDCA fraction.