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PubMed1994

Cyclosporine in common clinical practice: an estimation of the benefit/risk ratio in patients with rheumatoid arthritis.

OBJECTIVE: To investigate in common clinical practice the toxicity/efficacy ratio of low dose cyclosporine A (CsA) in patients with advanced rheumatoid arthritis (RA) after 12 months CsA administration. METHODS: One hundred and two patients with RA were included in the study. The initial dose of CsA was 2.5 mg/kg/day, the mean maximum dose was 3.2 mg/kg/day and the dose at 12 months was 2.8 mg/kg/day. RESULTS: Sixty-nine (68%) patients completed 12 months of treatment. Seventeen (17%) patients discontinued for lack of efficacy and 16 (16%) for toxicity (of which 50% for gastrointestinal intolerance). The clinical efficacy variables improved significantly by 36-42% between entry and Month 6 and remained stable thereafter. The C-reactive protein decreased from 43 U/ml at entry to 22 U/ml (p < 0.0001) at 12 months. Forty-four percent of the patients and 47% of the physicians judged the efficacy as good or very good. The median number of adverse events/patient was 3 but most adverse events were either not clinically important or disappeared after dose reduction. Gastrointestinal (GI) intolerance and nephrotoxicity (> 30% increase in serum creatinine) each occurred in 50% of the patients. GI intolerance was transient in 80% of the patients but accounted for 50% of the premature discontinuations for toxicity. Nephrotoxicity persisted in the 50% of the patients in whom it occurred, despite dose reduction. The mean serum creatinine rose from 70 (13) mumol/l at entry to 86 (23) mumol/l at 12 months (23% increase; p < 0.0001), and this increase had been entirely reached after 3 months. Variables that could significantly predict the occurrence of nephrotoxicity could not be identified. CONCLUSION: CsA can be safely and effectively administered to patients with RA for a duration of at least 12 months. An acceptable renal function at entry, close monitoring of the serum creatinine concentration and dose reductions when appropriate are prerequisities.

Adolescent↗
PubMed1980

Dose-dependent reduction of hereditary obesity in the non-diabetic mouse by polymeric prostaglandin PGBx.

Mice genetically obese but not diabetic show large reductions of excessive body weight and excessive food intake when treated with polymeric prostaglandin PGBx. Larger doses of PGBx produce greater reduction of both body weight and food consumption, in agreement with dose-dependent effects of PGBx observed previously in the genetically diabetic mouse. Only minor effects of PGBx on blood glucose were observed. This suggests that PGBx effects on obesity and appetite are not mediated through a blood glucose mechanism.

Age Factors↗
PubMed1988

Interaction of sympathomimetics and insulin with hepatic glucose production by isolated perfused rat livers: effects of continuous versus pulsatile infusion.

To elucidate the efficacy of continuous vs. intermittent exposure to epinephrine, phenylephrine, and insulin, hepatic glucose production was monitored in isolated perfused rat livers (means +/- SE, n = 6 each). To this end livers of fed rats were perfused with 5 mM glucose Krebs-Ringer buffer in a nonrecirculating system. Using this model it was shown that intermittent exposure (3 min on/off period, dose reduction -50%) to epinephrine (0.4 microM, alpha + beta-agonist) and phenylephrine (5 microM, alpha-agonist) elicited an almost identical rise in hepatic glucose production [epinephrine: 0.72 +/- 0.08 mmol/(86 min X 100 g BW); phenylephrine: 0.68 +/- 0.07 mmol/(86 min X 100 g BW) as their continuous administration (epinephrine: 0.78 +/- 0.06 mmol/(86 min X 100 g BW); phenylephrine: 0.74 +/- 0.09 mmol/(86 min X 100 g BW)]. Inhibition by insulin (100 mU/liter) given either continuously or intermittently (3 min on/off intervals; dose reduction -50%) was equipotent for epinephrine- and phenylephrine-stimulated hepatic glucose production. When the off period was doubled to 6 min, thereby reducing the total insulin dose to 33%, no significant suppression of epinephrine- and phenylephrine-stimulated hepatic glucose production was observed. From this we conclude that 1) the effect on hepatic glucose production of pulsatile (3 min on/off, dose reduction 50%) and continuous administration is equipotent for the respective action of epinephrine, phenylephrine as well as of insulin; and 2) insulin is more effective (P less than 0.02) in inhibiting hepatic glucose production stimulated by an alpha-agonist (phenylephrine; 5.0 microM) than in counteracting alpha + beta-agonist action (epinephrine; 0.4 microM). The characteristics of hepatic glucose release as stimulated by alpha- and/or beta-adrenergic agonists and its inhibition by continuously or intermittently infused insulin were simulated and described by a computer model. Thereby, no qualitative difference could be demonstrated in alpha- vs. beta-adrenergic agonists action on stimulated hepatic glucose production.

Animals↗
PubMed2003

Amorphous silicon, flat-panel, x-ray detector versus storage phosphor-based computed radiography: contrast-detail phantom study at different tube voltages and detector entrance doses.

RATIONALE AND OBJECTIVES: Evaluation of the contrast-detail performance of an active-matrix flat-panel x-ray detector in comparison with a storage phosphor system with special regard to the potential of dose reduction. METHODS: A digital x-ray detector based on cesium iodide (CsI) and amorphous silicon (a-Si) technology was compared with a fifth-generation storage phosphor system. A lucite plate with 36 drilled holes of varying diameters and depths was used as contrast-detail phantom. At 45 kVp, 70 kVp, and 113 kVp, images at 8 different detector entrance doses ranging between 0.3 microGy and 40 microGy were obtained. On soft-copy displays, 3 masked observers evaluated the detectability of each aperture in each image according to a 5-point scale. The mean sum scores of corresponding images were compared. RESULTS: For all tube voltages and detector entrance doses, the images obtained with the CsI/a-Si detector resulted in better observer contrast-detail performance as compared with the images of the storage phosphor system. The CsI/a-Si system allowed a calculated dose reduction of 39% at 45 kVp, 68% at 70 kVp, and 81% at 113 kVp as compared with the storage phosphor system, without loss of contrast-detail detectability. CONCLUSIONS: Under the conditions of the chosen experimental design, the CsI/a-Si system provided a superior contrast-detail performance as compared with the storage phosphor system. The potential of dose reduction increased with rising tube voltage.

Cesium↗
PubMed1985

Temocillin pharmacokinetics in normal and impaired renal function.

In 18 healthy volunteers and 18 patients with varying degrees of impaired renal function, the plasma concentrations after intravenous administration of temocillin 0.5, 1, and 2g were determined. Another group of 6 patients received temocillin 0.5 g intramuscularly. Surprisingly, it was found that with higher doses, the plasma concentrations, and consequently the area under the plasma concentration/time curve (AUC), did not increase proportionately. Instead, the renal and, to a greater extent, the total clearance of temocillin increased. The plasma concentrations in patients with impaired renal function were clearly higher than in the subjects with normal renal function. Dose-reduction factors were derived which allowed the determination of the dosing regimen necessary to achieve approximately the same high plasma concentrations (and the same AUCs) in patients with impaired renal function as in healthy subjects. However, these dose-reduction factors could only be determined for certain doses because of the specific behaviour of temocillin.

Glomerular Filtration Rate↗
PubMed2001

Interferon-alpha2a/ribaviran versus interferon-alpha2a alone for the retreatment of hepatitis C patients who relapse after a standard course of interferon.

AIM: To compare the efficacy of a descalating dose of interferon (48 weeks) versus a combination therapy of interferon and ribavirin (24 weeks) in hepatitis C positive subjects who relapsed within six months of cessation of a standard six month course of interferon three million units thrice weekly. METHODS: All 32 subjects had biopsy proven chronic hepatitis C, were PCR positive and had elevated transaminase enzymes at least one and a half times the upper limit of normal. Subjects were randomly assigned to either a descalating dose of interferon-alpha-2a; six million units thrice weekly for 24 weeks followed by 3 MIU 3x for 24 weeks or interferon three million units thrice weekly for 24 weeks plus ribavirin 1,000 mg/day for 12 weeks. A complete virological response was defined as a negative PCR for HCV RNA at 24 weeks after cessation of therapy. RESULTS: Sixteen patients were assigned to each arm and the sustained virological response was 50% for both the interferon and combination therapy arm (pNS). The biochemical response correlated with the virological response; 7/8 virological responders in the interferon alone had normalisation of transaminase 24 weeks post treatment as did 8/8 of those in the combination arm. One patient withdrew from treatment in the descalating interferon group and three required dose reduction. No subjects in the combination arm discontinued therapy but dose reduction was required in three subjects. CONCLUSION: High dose descalating interferon-alpha 2a and a combination of interferon-alpha 2a and ribavirin were effective in achieving a sustained virological response in 50% of subjects who had relapsed after a standard six month course of interferon.

Adult↗
PubMed1994

Incidence of neutropenic fever in patients treated with standard-dose combination chemotherapy for small-cell lung cancer and the cost impact of treatment with granulocyte colony-stimulating factor.

PURPOSE: We sought to determine the incidence of neutropenic fever associated with the use of standard-dose combination chemotherapy for small-cell lung cancer (SCLC) and to use these data as a template to analyze the costs and benefits of the routine use of granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: We retrospectively reviewed records of 137 consecutive, unselected patients with SCLC treated with combination chemotherapy from January 1987 to March 1992. Admission criteria for neutropenic fever were temperature > or = 38.5 degrees C and an absolute neutrophil count < or = 500/microL. Neutropenic fevers were managed with a 25% dose reduction of the myelosuppressive drugs in subsequent cycles. Charge estimates for hospitalization ($1,244 per day) and G-CSF use ($2,027 per course) were estimated by reviewing charges to patients at Indiana University hospitalized for neutropenic fever or treated with outpatient G-CSF. We imposed assumptions from the Neupogen (filgrastim; Amgen Inc, Thousand Oaks, CA) licensing trial regarding the effectiveness of G-CSF and the Indiana University charge estimates on three models of G-CSF use: (1) preemptive--with all courses of chemotherapy, (2) reactive--with all cycles of chemotherapy following a neutropenic fever, and (3) dose reduction only (no G-CSF)--to derive charge estimates for G-CSF use. RESULTS: Records of 137 patients with SCLC were identified and reviewed. The incidence of neutropenic fever was 12% in the first cycle of chemotherapy, and 18% overall, compared with the placebo- and G-CSF-treated arms of the Neupogen licensing trial, in which the incidence of neutropenic fever was 77% and 40%, respectively. Other therapeutic outcomes, such as neutropenic septic deaths, response rates, and survival, were comparable. We derived the following charge estimates for the three models of G-CSF: (1) preemptive--total charges = $1,287,481; (2) reactive--total charges = $276,154; and (3) dose reduction only--total charges = $192,820. CONCLUSION: The incidence of neutropenic fever with standard-dose chemotherapy for SCLC was 18%. Routine use of G-CSF in SCLC patients treated with standard-dose chemotherapy appears to be expensive and is not associated with an obvious therapeutic benefit or cost savings. We suggest that careful analysis of the incidence of infectious complications, rather than granulocyte nadir and duration, be performed, and that clinical guidelines for the use of these effective, but expensive, products be developed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Dose comparison between conventional and quasi-monochromatic systems for diagnostic radiology.

Several techniques have been introduced in the last year to reduce the dose to the patient by minimizing the risk of tumour induced by radiation. In this work the radiological potential of dose reduction in quasi-monochromatic spectra produced via mosaic crystal Bragg diffraction has been evaluated, and a comparison with conventional spectra has been performed for four standard examinations: head, chest, abdomen and lumbar sacral spine. We have simulated quasi-monochromatic x-rays with the Shadow code, and conventional spectra with the Spectrum Processor. By means of the PCXMC software, we have simulated four examinations according to parameters established by the European Guidelines, and calculated absorbed dose for principal organs and the effective dose. Simulations of quasi-monochromatic laminar beams have been performed without anti-scatter grid, because of their inherent scatter geometry, and compared with simulations with conventional beams with anti-scatter grids. Results have shown that the dose reduction due to the introduction of quasi-monochromatic x-rays depends on different parameters related to the quality of the beam, the organ composition and the anti-scatter grid. With parameters chosen in this study a significant dose reduction can be achieved for two out of four kinds of examination.

Algorithms↗
PubMed2005

Undertreatment of obese women receiving breast cancer chemotherapy.

BACKGROUND: Systematic undertreatment of breast cancer in overweight and obese women may contribute to the poorer prognosis in these women. The objective of this study was to investigate treatment patterns in overweight and obese women undergoing breast cancer adjuvant chemotherapy. METHODS: We performed a retrospective cohort study of 9672 women treated with doxorubicin hydrochloride and cyclophosphamide between 1990 and 2001. The main outcome measure was the quality of chemotherapy as measured by the use of reduced doses for the first treatment (compared with standard doses), the overall dose proportion (actual-expected dose ratio), and relative dose intensity. RESULTS: First-cycle dose reductions (defined as a dose proportion of <0.9 compared with standard published doses) were administered to 9% of the healthy weight, 11% of the overweight, 20% of the obese, and 37% of the severely obese women (P<.001). First-cycle reduction was independently associated with being overweight (P = .03), obese (P<.001), severely obese (P<.001), older than 60 years (P<.001), and having a serious comorbid condition (P = .03). Practices varied greatly in the use of dose reductions in overweight and obese patients. Severe obesity was independently associated with a lower likelihood of admission for febrile neutropenia, even among those subjects given full weight-based doses (odds ratio, 0.61; 95% confidence interval, 0.38-0.97). CONCLUSIONS: Overweight and obese women with breast cancer often receive intentionally reduced doses of adjuvant chemotherapy. Administration of initial and overall full weight-based doses of adjuvant chemotherapy in overweight and obese women is likely to improve outcomes in this group of patients.

Aged↗
PubMed1999

Effect of mycophenolate mofetil on erythropoiesis in stable renal transplant patients is correlated with mycophenolic acid trough levels.

BACKGROUND: Both mycophenolate mofetil (MMF) and azathioprine (AZA) are immunosuppressive drugs that inhibit purine synthesis. In theory, MMF selectively inhibits lymphocyte proliferation, while AZA has well-known effects on red blood cells and thrombocytes as well. In renal transplant recipients we replaced CsA therapy by MMF in an attempt to reduce the immunosuppressive load 1 year after kidney transplantation. During this study we observed the effect of MMF on haematological parameters such as haemoglobin (Hb), leukocytes, and thrombocytes. METHODS: One year after kidney transplantation 26 stable patients were converted from cyclosporin A (CsA) to MMF (2 g/day). Thereafter, these patients were tapered twice in their MMF dose from 2 g to 1.5 g (4 months after conversion) and from 1.5 to 1 g (8 months after conversion) per day. The Hb levels, leukocyte and thrombocyte counts, and mycophenolic acid (MPA) trough levels were routinely measured. RESULTS: After conversion from CsA to MMF not only creatinine levels and the number of leukocytes, but also the haemoglobin (Hb) level significantly decreased in 21/26 patients (P=0.0004). In eight patients the Hb level dropped more than 1 mmol/l (=1.61 g/dl). Only in two of eight patients was an explanation for blood loss found. The effect on Hb level did not ameliorate after the first MMF dose reduction to 1.5 g/day. After tapering the MMF dose to 1 g/day, the Hb approached the pre-conversion level. Not only the MMF dose but also the mycophenolic acid (MPA) trough level correlated with the Hb level. CONCLUSIONS: After conversion from CsA to MMF 1 year after kidney transplantation, a decrease in Hb level and leukocyte count was observed. The MPA trough level correlated also with the Hb level. The effect on the Hb level was reversible after dose reduction. This finding suggests that MMF exerts a negative effect on erythropoietic cells.

Blood Cell Count↗
PubMed2001

Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages.

PURPOSE: The aim of this study was to evaluate the relative activity and tolerance of liposomal doxorubicin in recurrent ovarian, peritoneal, and tubal carcinoma at an initial dose of 40 or 50 mg/m(2) every 4 weeks. METHODS: A retrospective single-institution study was performed on patients who received liposomal doxorubicin from 1/97 to 12/00. Demographic data, liposomal doxorubicin dose, dose reductions, response, and progression-free and overall survival were recorded. RESULTS: Seventy-eight patients, 38 treated at 40 mg/m(2) and 40 treated at 50 mg/m(2), were identified. There was no difference with respect to patient age, performance status, percentage of patients who were platinum resistant or paclitaxel resistant, or tumor bulk. The response rate in this highly resistant population was 13.5 and 7.7% for liposomal doxorubicin at 40 and 50 mg/m(2) every 4 weeks, respectively. Stable disease was observed in 49 and 51% of patients treated with liposomal doxorubicin at a dose of 40 and 50 mg/m(2) every 4 weeks, respectively. The progression-free survival for patients with responding and stable disease was similar. Dose reductions were required in 27.5% of patients treated at 50 mg/m(2) versus no patients treated at 40 mg/m(2) (P < 0.001). Treatment delays due to toxicity were required in 32.5% of patients treated at 50 mg/m(2) versus 16% of patients treated at 40 mg/m(2) (P = 0.14). CONCLUSION: Liposomal doxorubicin at a dose of 40 mg/m(2) appears to be as active as liposomal doxorubicin at a dose of 50 mg/m(2) in ovarian, peritoneal, and tubal carcinoma and is better tolerated based on the frequency of dose reductions and treatment delays.

Adult↗
PubMed2004

Use of the rectal retractor to reduce the rectal dose in high dose rate intracavitary brachytherapy for a carcinoma of the uterine cervix.

Commercially available rectal retractors can be used in high dose rate intracavitary brachytherapy (HDR ICR) as one of the methods for reducing the rectal dose in radiotherapy for a uterine cervical cancer. However, the extent of the rectal protection achieved using these rectal retractors has not been reported. The aim of the study was to examine the effect of a rectal retractor on reducing the rectal dose in HDR ICR. Thirty patients were treated with HDR ICR using rectal retractors. Tandem and ovoids were applied in 15 patients and ovoids only were used in the other 15 patients. During the simulation, the rectum was filled with barium, and anteroposterior and lateral radiographs were then taken with and without the rectal retractor. Along the anterior rectal wall outlined, 4 to 8 points (median 6) were chosen to calculate the dose for each patient including the rectal point (RP), which is an author-defined rectal point modified from the definition of the rectal reference point in the ICRU report 38. The length of the measured rectum was 3-7 cm (median 5 cm). The bladder point (BP) dose was measured as recommended by the ICRU. The prescription doses to point A varied from 3.5 to 5 Gy (median 4 Gy). Paired comparisons were made on the individual patients by calculating the normalized mean doses of the RP, the maximal point (MP), and the longitudinal average (LA) with and without the rectal retractor. The doses to the bladder points (BP) were also calculated in parallel to the rectal points. The anterior rectal walls were displaced posteriorly after inserting the rectal retractor. In the tandem and ovoids group, the number of patients with a reduced dose in the RP, MP and LA were 14 (93.3%), 12 (80.0%) and 13 (86.7%), respectively. In the ovoids only group, the corresponding figures were 14 (93.3%), 14 (93.3%) and 14 (93.3%). In the tandem and ovoids group, the reduced dose in the RP, MP, and LA dose were 0.52 Gy (13.0%), 0.50 Gy (12.5%), and 0.39 Gy (9.8%), respectively (p < 0.05). In the ovoids only group, the RP, MP, and LA dose were reduced by 0.62 Gy (15.5%), 0.92 Gy (23.0%), and 0.54 Gy(13.5%), respectively (p < 0.05). There was no significant change in the bladder point doses when the rectal retractor was applied, although the mean BP dose were 0.27 Gy and 0.09 Gy lower for the tandem and ovoids group and for ovoids only group, respectively (p > 0.05). The mean RP, MP, and LA dose reduction rates of the patient subgroup where the RP dose was < 70% of the prescription dose were compared with the subgroup where the RP dose was > 70%. The effect of the rectal dose reduction was significant only in the subgroup of patients who received > 70% of the prescription dose (p < 0.05). The use of the rectal retractor was a simple and an effective method for reducing the rectal dose. It was also considered to be a highly reproducible method, which can replace the time-consuming vaginal gauze packing in HDR-ICR.

Brachytherapy↗
PubMed2006

Due to low infection rates no routine anti-infective prophylaxis is required in younger patients with chronic lymphocytic leukaemia during fludarabine-based first line therapy.

The impact of the combination therapy fludarabine plus cyclophosphamide (FC) in comparison with fludarabine alone regarding the incidence and severity of infections among previously untreated patients with chronic lymphocytic leukaemia (CLL) was evaluated within a multicentre phase III study. A total of 375 patients, up to 65 years old, were randomised between fludarabine or FC for first line therapy. No routine anti-infective prophylaxis was provided. A total of 196 infectious episodes, including 33 severe infections, were documented. In the fludarabine arm, 32.9% of the patients developed an infectious complication compared with 39.9% in the FC arm (P = 0.2). No difference was observed in the rate of severe infections (Common Toxicity Criteria grades III and IV) between both treatment arms. Dose reductions were performed more frequently in FC-treated patients. Granulocyte colony-stimulating factor (G-CSF) was administered due to leucopenia in 5% of all patients. A multivariate regression model identified only elevated thymidine kinase, but not the treatment arm, as a statistically independent risk factor for infections. In summary, FC was not associated with a higher rate of infections compared with fludarabine alone. No routine antibiotic or virostatic prophylaxis, or preemptive treatment with G-CSF, is necessary in first line therapy with fludarabine-based regimens in younger patients with CLL, if adequate dose reduction is performed. The combination therapy FC is not associated with a higher rate of infections compared with fludarabine alone. No routine antibiotic or virostatic prophylaxis as well as preemptive treatment with G-CSF is necessary in first line therapy with fludarabine-based regimen in younger patients with CLL, if adequate dose reductions due to cytopenia or previous infections are performed.

Anti-Infective Agents↗
PubMed1991

Dose-related reduction of intestinal cytochrome a,a3 induced by endotoxin in rats.

Dose-related, endotoxin-induced changes in oxidative metabolism were investigated in vivo using near-infrared spectrophotometry. Sixty fasted male Sprague-Dawley rats were randomly allocated to groups (N = 10 each) receiving saline, 0.08, 0.3, 1.25, 5, or 20 mg/kg Escherichia coli endotoxin by i.v. bolus (1 ml/kg volume). Isoflurane anesthesia with controlled ventilation was used for surgery and the subsequent collection of hemodynamic and metabolic data. Approximately half the length of the small intestine was exteriorized for continuous spectrophotometric monitoring of tissue oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and mitochondrial cytochrome a,a3 (AA3) redox state. Hemodynamic parameters included arterial and central venous pressures, cardiac output, and superior mesenteric artery blood flow (SMAF). Intestinal AA3 exhibited a marked and sustained shift toward reduction in those groups (1.25, 5, and 20 mg/kg) which developed significant blood pressure and blood flow decreases. However, the AA3 reduction did not seem to reflect tissue hypoxia, since 1) the simultaneously measured tissue HbO2 levels remained essentially constant, 2) the AA3 redox shift did not reverse upon recovery of intestinal blood flow in the 1.25 mg/kg group, which exhibited only a transient decrease in SMAF, and 3) systemic oxygen consumption was unchanged in any group. Endotoxin-induced lethality was tested in six separate groups (N = 10 each) and was significant (60%) only in the 20 mg/kg group. These results suggest that endotoxin may induce a direct (or rapidly mediated indirect) impairment of cellular oxidative phosphorylation.

Animals↗
PubMed2001

Treatment of progressive hepatitis C recurrence after liver transplantation with combination interferon plus ribavirin.

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is common, although the majority of cases are mild. A subset of transplant recipients develops progressive allograft injury, including cirrhosis and allograft failure. Minimal data are available on the safety and efficacy of antiviral treatment in this group of patients. The aim of this study is to review our experience in the treatment of moderate to severe HCV recurrence with combination interferon-alpha2b and ribavirin (IFN/RIB). Between October 1993 and October 1999, a total of 197 patients underwent OLT for HCV-related liver failure. This study describes 12 transplant recipients with moderate to severe recurrence treated with IFN/RIB. All patients met at least 1 of the following inclusion criteria: (1) moderate to severe inflammation (grade III to IV) on allograft biopsy, (2) bridging fibrosis on allograft biopsy, or (3) severe cholestasis attributable solely to HCV recurrence. Two patients had undergone re-OLT for allograft cirrhosis secondary to HCV recurrence and now had evidence of progressive HCV in their second allografts. Appropriate dose reductions of both IFN and RIB, as well as initiation of granulocyte colony-stimulating factor (G-CSF), for marked leukopenia were recorded. IFN/RIB therapy was started 60 to 647 days post-OLT, and duration of therapy ranged from 39 to 515 days. Seven patients were administered G-CSF to successfully treat leukopenia. Six of the 12 patients (50%) became HCV RNA negative by polymerase chain reaction. One of these 6 patients (no. 1) was HCV RNA negative at 6 months but chose to discontinue therapy because of intolerable side effects, experienced a relapse, and was HCV RNA positive at 12 months. Two of the remaining 5 patients were HCV RNA negative at 2 and 9 months off therapy. For the entire group, there was a statistically significant decrease in serum biochemical indices assessed at initiation of therapy and 1, 3, and 6 months into therapy. Most patients required dose reductions of both IFN and RIB. Five patients died; 3 patients died of liver-related complications that included severe intrahepatic biliary cholestasis, severe HCV recurrence, and chronic rejection with profound cholestasis. In the subset of HCV-positive liver transplant recipients with moderate to severe recurrence, combination IFN/RIB therapy resulted in complete virological response (serum RNA negative) in 6 of 12 patients ( approximately 50%). However, only 1 of 12 patients (8.3%) had sustained virological clearance after cessation of IFN/RIB therapy. Dose reductions of both IFN and RIB were required in most patients. The use of G-CSF (sometimes preemptively) allowed correction of leukopenia and full-dose antiviral therapy. Multicenter trials using combination therapy to identify factors predictive of response are needed in the subset of patients with progressive allograft injury.

Adult↗
PubMed1998

Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder.

OBJECTIVE: To compare the efficacy and tolerability of tolterodine with that of oxybutynin in patients with an overactive bladder. PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled, parallel group, multinational phase-III study was conducted in urology and gynaecology clinics in the UK, Republic of Ireland and Sweden. The study enrolled 293 patients with urodynamically confirmed bladder overactivity, increased frequency of micturition (> or = micturitions/24 h) and symptoms of urgency and/or urge incontinence (> or = 1 episode/24 h). Patients received either tolterodine (2 mg twice daily) or oxybutynin (5 mg three times daily) or placebo. Doses could be reduced, to prevent withdrawal, to 1 mg or 2.5 mg, respectively. The main outcome measures were the mean change from baseline in frequency of micturition/24 h, the number of incontinent episodes/24 h and volume voided per micturition. RESULTS: After 12 weeks' treatment, the mean frequency of micturition decreased by 21% and 19.5% in those receiving tolterodine (n = 118) and oxybutynin (n = 118), respectively, and by 10.5% in those on placebo (n = 57). Among those with urge incontinence at baseline (75% of patients), the mean number of incontinent episodes decreased by 47%, 71% and 19%, respectively, in those receiving tolterodine, oxybutynin and placebo. The effect of tolterodine and oxybutynin on these two micturition variables was statistically equivalent. There was also a comparable increase in mean volume voided per micturition in the tolterodine (27%) and oxybutynin groups (31%), compared with 7% in the placebo group. Dry mouth was the most common adverse event and was reported with greater frequency and intensity among patients receiving oxybutynin than among those receiving either tolterodine or placebo. In the oxybutynin group, more patients also withdrew because of adverse events and a greater proportion required dose reduction as a result of adverse events. Despite dose reduction, the frequency of adverse events and the intensity of dry mouth remained higher among those receiving oxybutynin (2.5 mg three times daily) than in patients who remained on tolterodine 2 mg twice daily. CONCLUSION: Tolterodine 2 mg twice daily is effective and well tolerated in the treatment of bladder overactivity. Tolterodine was better tolerated than oxybutynin, particularly with respect to the frequency and intensity of dry mouth, but had comparable clinical efficacy. The superior tolerability of tolterodine therefore allows more patients to remain on effective therapy than the current most commonly prescribed agent for the treatment of the overactive bladder.

Adult↗
PubMed2005

Treating HCV with ribavirin analogues and ribavirin-like molecules.

Nucleos(t)ide analogues have proven useful in the treatment of viral infections. Ribavirin is a nucleoside, guanosine analogue, whose mechanisms of action include inhibition of inosine monophosphate dehydrogenase (IMPDH), which is the key step in de novo guanine synthesis, a requirement for viral replication. In combination with pegylated interferon alfa, ribavirin is the standard of care for the treatment of chronic hepatitis C today. However, the medication is associated with significant haemolytic anaemia, which may require dose reduction, discontinuation or treatment with recombinant human erythropoietin. Dose reduction also appears to decrease sustained viral clearance rates. Newer IMPDH inhibitors are in various stages of development. Viramidine, a liver-targeting prodrug of ribavirin, has demonstrated significant antiviral activity and erythrocyte-sparing properties. It is currently in Phase 3 trials. Clinical trials of merimepodib, another investigational IMPDH inhibitor, have completed enrolment for a Phase 2b study as a third medication for administration with pegylated interferon plus ribavirin. Although other IMDPH inhibitors also have antiviral activity, these medications appear best suited as immunosuppressive medications at this time.

Antiviral Agents↗
PubMed1998

Optimization of acid suppression for patients with peptic ulcer bleeding: an intragastric pH-metry study with omeprazole.

OBJECTIVE: To study whether an intravenous infusion dose of omeprazole (80 mg + 8 mg/h) during 24 h can be subsequently reduced with maintained effect. Second, to study the effect of oral omeprazole 20 mg given once or twice daily up to day 10, after cessation of a 3-day intravenous infusion (80 mg + 8 mg/h). DESIGN: Prospective, randomized, partly blinded study. METHODS: Twelve Helicobacter pylori(+) patients and 12 H. pylori(-) subjects were included. In part I the patients received omeprazole, 80 mg + 8 mg/h, during 24 h followed by 8, 4 or 2 mg/h. In part II the subjects received 80 mg + 8 mg/h during 3 days followed by 20 mg omeprazole orally, once or twice daily until day 10. Intragastric pH was measured. RESULTS: All H. pylori(+) patients showed a rapid increase of intragastric pH with a mean intragastric pH of 6.7 during the second half of the first day. After the subsequent dose reduction, the mean pH decreased to 6.1-6.2. Patients continuing on 8 mg/h showed the best results. Likewise, all H. pylori(-) subjects showed a rapid and sustained reduction of intragastric acidity during the infusion. Subsequent dose reduction to 20 mg once daily led to a stable fraction of time with pH > 3 of 72%. CONCLUSIONS: Omeprazole given as a continuous infusion of 80 mg + 8 mg/h for 72 h followed by omeprazole 20 mg once daily raised the intragastric pH to and above levels alleged to allow haemostasis in patients with peptic ulcer bleeding and subsequent healing of the ulcer.

Adult↗