Anders Lindholm - Academia.edu (original) (raw)
Papers by Anders Lindholm
Therapeutic drug monitoring, 1992
In order to study the performance of a specific fluorescence polarization immunoassay (FPIA) for ... more In order to study the performance of a specific fluorescence polarization immunoassay (FPIA) for monitoring of the area under the concentration time curve (AUC) of cyclosporine (CsA), a total of 170 24-h CsA AUC studies were prospectively collected from 40 consecutive adult renal transplant recipients during the first 6 months after transplantation. Each AUC study included whole blood samples that had been collected at 0, 2, 4, 6, 10, 14, and 24 h after CsA administration. Each sample was subjected to CsA analysis in whole blood using a 3H-tracer specific monoclonal radioimmunoassay (wb-sRIA), specific FPIA (wb-sFPIA), and polyclonal FPIA (wb-pcFPIA). Furthermore, the performance of the specific assays was assessed against high-performance liquid chromatography (HPLC). Correlations between HPLC and specific assays were good, namely correlation coefficients of 0.94. Contrariwise, correlations between specific and nonspecific assay were poorer. As compared to HPLC, wb-sRIA overestimat...
Clinical Pharmacology and Therapeutics, 1992
The impact of several demographic and blood biochemistry factors on the pharmacokinetics of the i... more The impact of several demographic and blood biochemistry factors on the pharmacokinetics of the immunosuppressive drug cyclosporine were studied in 187 patients with uremia. All patients underwent a pharmacolcinetic evaluation including a 3 mg/kg intravenous dose of cyclosporine and a 14 mg/kg oral dose of cyclosporine. Cyclosporine was analyzed by specific monoclonal radioimmunoassay on whole blood samples. Statistical analysis included univariate analyses and stepwise multiple regression analysis.
Clinical Pharmacokinetics, 2001
Transplantation, 1992
A randomized trial was performed with the aim to compare two immunosuppressive treatment schedule... more A randomized trial was performed with the aim to compare two immunosuppressive treatment schedules in adult recipients of first cadaveric renal transplants. A total of 229 patients were randomized to double therapy with cyclosporine and prednisolone and 234 patients were randomized to triple therapy with cyclosporine, azathioprine, and prednisolone. Minimum follow-up was 4 years. The actuarial 5-year patient survival was 79.8% in the double therapy group and 82.3% in the triple therapy group (n.s.). The corresponding graft survival figures were 54.4% and 59.6% in the two groups, respectively (n.s.). There were no differences between the groups regarding cause of death or cause of graft loss. Renal function as determined by serum creatinine did not differ between the groups and was stable throughout the observation period. Azathioprine was instituted in a total of 51 patients randomized to double therapy. This subgroup of patients had a patient and graft survival not different from the remaining patients randomized to double therapy or from the patients randomized to triple therapy. There were no differences between the double and triple therapy groups regarding incidence and timing of acute rejection or infections. The incidence of other medical diseases and adverse events such as nephrotoxicity or malignancy did not differ between the groups. Azathioprine-induced leukopenia was uncommon (19 episodes in the triple therapy group). In a multivariate analysis of the whole series the only covariates that significantly influenced graft survival were age of recipient and occurrence of acute rejection, while among other factors treatment schedule did not. Thus this prospective study, in accordance with previous such studies, failed to find support for the use of triple therapy as first choice immunosuppression in first cadaveric renal transplantation. However, the study could not rule out the possibility that some patients at risk for the development of irreversible rejection or nephrotoxicity of CsA might benefit from the addition of azathioprine to the treatment schedule.
European Journal of Clinical Pharmacology, 1999
Objective: The pharmacokinetics of a new insulin analogue, insulin aspart, were compared with unm... more Objective: The pharmacokinetics of a new insulin analogue, insulin aspart, were compared with unmodified human insulin in a double-blind crossover study of 25 fasting healthy men following a single subcutaneous dose. Methods: Either insulin aspart or human insulin, 0.1 U kg-body-weight−1, was injected subcutaneously and followed by determination of 8-h profiles of serum insulin and plasma glucose concentrations. Results: The absorption of
Transplantation, 1993
The influence of cyclosporine pharmacokinetic parameters on clinical events and outcome after tra... more The influence of cyclosporine pharmacokinetic parameters on clinical events and outcome after transplantation was studied in 100 renal transplant recipients who underwent a pre- as well as posttransplant CsA pharmacokinetic evaluation. Among the patients, 30 were black and 50 were white. Black recipients had significantly lower bioavailability (F) pre- as well as posttransplantation than white recipients, the posttransplant mean F values being 25.8 +/- 9.0% and 38.1 +/- 16.7%, respectively (P < 0.002). The posttransplant CsA clearance rate (CL) and oral clearance (clearance/bioavailability; CLoral) were significantly higher in patients who had acute rejection than in those who did not, with CL mean values of 425 +/- 141 ml/min and 359 +/- 131 ml/min, respectively (P < 0.02). The initial posttransplant F was significantly lower, and the CLoral higher in patients who eventually lost their grafts than in those who did not, the mean F values being 26.5 +/- 12.8% and 38.7 +/- 17.5%, respectively (P < 0.002). Thus, several important relationships between CsA pharmacokinetic parameters and clinical events following renal transplantation were documented. The CLoral decreased during the first 3 months after transplantation (P < 0.0001), but it was stable thereafter. Neither the bioavailability nor the clearance of CsA showed a correlation with administered dose. These results indicate that certain recipient groups, such as black patients, and individuals with rapid CL, may benefit from larger CsA doses and/or shorter dosage intervals, in order to compensate for these interpatient variabilities.
Transplantation, 1993
To characterize factors of importance for the occurrence of acute rejection as well as study the ... more To characterize factors of importance for the occurrence of acute rejection as well as study the impact of these episodes on long-term renal survival and function, a total of 819 acute rejection episodes were studied in 951 primary cadaveric donor kidney recipients (CD) and in 396 primary living donor kidney recipients (LD). The patients were treated by three immunosuppressive schedules, namely, CsA given in a high dose, a medium dose, or a low dose. Additionally, all patients received PRED and patients in the low-dose group received AZA. The incidence of acute rejection was higher and occurred earlier after transplantation in the CsA medium dose and low dose groups than in the CsA high dose group (P < 0.05 and P < 0.01, respectively). Although the incidence of first acute rejection was similar in CD and LD patients, 59.1% vs. 60.6%, it was successfully reversed by antirejection treatment in a higher percentage in LD patients. The estimated graft half-life was shorter in patients who had acute rejection episodes than those who did not, 6.6 years vs. 12.5 years in CD patients (P < 0.0001). Renal function at 1-5 years after transplantation was stable, but significantly poorer in CD patients who had experienced acute rejection than in patients who had not, with the mean creatinine clearance rates in the ranges 45-47 vs. 54-60 ml/min in the other groups (P < 0.0001). In a stepwise Cox regression analysis in CD recipients, risk factors for acute rejection were CsA (low dose) treatment schedule, immunization as displayed by presence of panel-reactive antibodies and positive B cell cross-match, young recipient age, disease of diabetes mellitus, and HLA-DR mismatching. In LD recipients, the corresponding risk factors were treatment schedule, young recipient, HLA mismatching, and transplantation from parent to child. Thus, the study has demonstrated some factors of importance for acute rejection episodes in CsA-treated patients as well as showing the detrimental effect of these episodes on long-term graft survival and renal function. These results suggest that a primary aim of future treatment strategies should be to reduce the incidence of these episodes.
Transplantation, 1995
Causes of graft loss and death were studied in 1347 recipients of primary renal transplants follo... more Causes of graft loss and death were studied in 1347 recipients of primary renal transplants followed for 5 years after transplantation irrespective of graft function. Immunosuppression consisted of high or medium dose CsA and prednisolone or low dose CsA and prednisolone and azathioprine. In recipients of cadaver grafts, death with a functioning transplant was more common than graft rejection after the first posttransplant year, accounting for 49% and 41% of the graft losses, respectively. Of deaths with a functioning graft, 53% were due to ischemic heart disease (IHD) and 10% were due to other vascular disease. In the 55- to 64-year-old age group, the risk of death from IHD was 6.4 times higher in the transplanted nondiabetic patients, 8.6 times higher in the dialysis patients (European Dialysis and Transplant Association figures), and 20.8 times higher in the transplanted diabetic patients than in the general population (national figures). A multivariate Cox regression analysis showed that old age, diabetes mellitus, occurrence of acute rejection, pretransplant transfusions, delayed onset of graft function, and male gender were significant for death in IHD. We conclude that, in comparison to reports from other regions, Scandinavian renal transplant recipients are at high risk of dying of IHD. Future advances in long-term renal graft survival will depend largely on the success of preventing myocardial infarction and death in this patient population.
Therapeutic Drug Monitoring, 1995
Search by Subject Search using Medical Subject Headings (< b> MeSH</b>), a controlled... more Search by Subject Search using Medical Subject Headings (< b> MeSH</b>), a controlled vocabulary for indexing life sciences content.< br/> Note that some records do not have MeSH. These include Patents and the latest PubMed and PubMed Central records.
Nephron, 1988
To study a possible relationship between ciclosporin-induced hypertrichosis and sex hormone patte... more To study a possible relationship between ciclosporin-induced hypertrichosis and sex hormone pattern, the hair growth in different areas of the body was graded and hormone levels were assayed before and up to 6 months after kidney transplantation. Increased hair growth was observed in 100% (23/23) of the patients in skin areas connected with androgen action and in 78% of the patients in androgen-insensitive areas. After renal transplantation the pituitary, testicular and adrenal hormone levels normalized. The posttransplantation levels of these hormones would not explain the observation of increased hairgrowth. Thus, ciclosporin induces hypertrichosis via a mechanism independent of sex hormones.
Pharmacogenomics, 2008
Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event asso... more Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele. To confirm a possible association of HLA-DRB1*9 and Ab-positive PRCA, we performed a pharmacogenomic analysis using subjects from an earlier case-control study of risk factors associated with Ab-positive PRCA, which had been performed using subjects from Europe or Canada. The primary goal of the analysis was to test the association between HLA-DRB1*9 and Ab-positive PRCA. A secondary goal was to perform an exploratory analysis in order to identify additional HLA alleles potentially associated with Ab-positive PRCA. Subjects were taken from a case-control study of Ab-positive PRCA in chronic kidney disease patients treated in Europe or Canada. Ab-positive PRCA cases (n=24) were matched to controls (n=81) by timing of treatment exposure and, when possible, by location. The allele frequency of HLA-DRB1*9 was 12.5% in cases vs 1.2% in controls (p=0.002). The frequency of the HLA-DRB1*9/other genotype was 25.0% in cases vs 2.5% in controls (p=0.004; OR: 10.8 [95% CI: 2.2-53.7]). Within the exploratory analysis, six additional HLA alleles (HLA-A*25, HLA-B*53, HLA-C*12, HLA-DQB1*3, HLA-DQB1*6 and HLA-DRB1*4) were also found to be associated with Ab-positive PRCA. This study confirmed that HLA-DRB1*9 occurs at a significantly higher frequency in Ab-positive PRCA cases than in controls; however, within this sample set, carrying the *9 allele was neither necessary nor sufficient to cause Ab-positive PRCA.
Immunology and Cell Biology, 1994
The effect of HLA-A matching on long-term cadaver kidney graft survival was analysed, on average,... more The effect of HLA-A matching on long-term cadaver kidney graft survival was analysed, on average, 6 years after transplantation in a total of 1085 cyclosporine (CyA)-treated patients.
Expert Opinion on Pharmacotherapy, 2002
The novel, rapid-acting insulin analogue insulin aspart (IAsp; Novo Nordisk) has been shown in pr... more The novel, rapid-acting insulin analogue insulin aspart (IAsp; Novo Nordisk) has been shown in preclinical studies to be more rapidly absorbed than human insulin (HI) when administered subcutaneously. IAsp reaches higher peak serum concentrations in a shorter time than HI, whilst maintaining a similar receptor binding and safety profile. The physiological pharmacokinetic profile of IAsp compared to that of HI has been demonstrated in both adult and paediatric populations and was accompanied by small but statistically significant reductions in HbA(1c), lower postprandial glucose excursions and a reduced risk of late postprandial and major nocturnal hypoglycaemia. Benefits may be maximised by dose optimisation, using bolus doses that result in effective postprandial glucose reduction, as well as higher and multiple basal insulin doses. The safety profile, including cardiovascular risk, is equivalent to HI.
Expert Opinion on Investigational Drugs, 1999
In order to improve therapy and increase the quality of life for diabetic patients, it has been o... more In order to improve therapy and increase the quality of life for diabetic patients, it has been of significant interest to develop rapid-acting insulin preparations that mimic the physiological meal-time profile of insulin more closely than soluble human insulin. Insulin aspart (B28Asp human insulin) is a novel rapid-acting insulin analogue that fulfils this criterion. The B28Asp modification weakens the self-association of the insulin molecule and provides a more rapid absorption from the sc. injection site. The preclinical evaluation in vitro and in vivo demonstrates that apart from the more rapid absorption, insulin aspart is equivalent to human insulin. Thus, insulin aspart is equivalent to human insulin on key in vitro parameters such as insulin receptor affinity, insulin receptor dissociation rate, insulin receptor tyrosine kinase activation, IGF-I receptor binding affinity, metabolic and mitogenic potency. In accordance with the equivalent in vitro profiles, the toxico-pharmacological properties of insulin aspart and human insulin are also identical. The available data for insulin aspart and other rapid-acting insulin analogues supports that in vitro assays are sensitive and valuable in the preclinical evaluation of insulin analogues. Clinical studies demonstrate that insulin aspart has a pharmacokinetic and pharmacodynamic profile superior to that of soluble human insulin. In Type 1 diabetic patients on a basal-bolus injection regimen, insulin aspart given immediately before the meals provides an improved postprandial glycaemic control and an improved long-term metabolic control, as compared to soluble human insulin given 30 min before the meals, without increasing the risk of hypoglycaemia. Taken together, the data support the hope that insulin aspart will allow the diabetic patient to combine a more flexible lifestyle with better glycaemic control, without any increased safety risk.
European Journal of Pediatrics, 2000
The pharmacokinetics of the novel, rapid-acting insulin aspart were compared with those of solubl... more The pharmacokinetics of the novel, rapid-acting insulin aspart were compared with those of soluble human insulin following subcutaneous administration in nine children (aged 6±12 years) and nine adolescents (aged 13±17 years) with stable type 1 diabetes. The study had a randomised, double-blind, two-period crossover design. Each patient received a single subcutaneous dose of insulin aspart or human insulin (0.15 IU/kg body weight) 5 min before breakfast and the plasma insulin and glucose concentrations were measured at intervals during the following 5 h. The pharmacokinetic pro®le of insulin aspart diered signi®cantly from that of human insulin with a higher mean maximum serum insulin (C max ins ), 881 321 (SD) pmol/l versus 422 193 pmol/l for human insulin (P < 0.001); and with a shorter median serum insulin t max ins , 40.0 min (interquartile range: 40±50 min) versus 75.0 min (interquartile range: 60±120 min) for human insulin, (P < 0.001). An age-related eect on C max ins and area under the curve (AUC 0±5h ins ) was observed with higher values in adolescents than in children for both insulin aspart and human insulin. Postprandial glycaemic control was improved with insulin aspart; the baseline-adjusted DC max glu being lower for insulin aspart compared with human insulin (increase of 7.6 5.1 versus 9.4 4.4 mmol/l respectively, P < 0.05). The incidence of adverse events was similar for the two insulin types. Conclusion The more rapid onset of action of insulin aspart versus human insulin, previously observed in adults, is con®rmed in a paediatric population with type 1 diabetes.
European Journal of Clinical Pharmacology, 1993
The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokineti... more The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period.
European Journal of Clinical Pharmacology, 1988
We have measured total and unbound plasma concentrations of cyclosporin A in seven healthy men af... more We have measured total and unbound plasma concentrations of cyclosporin A in seven healthy men after single oral doses (12 mg per kg body weight) on two occasions at least two weeks apart. There was an up to two-fold intraindividual and a more than three-fold interindividual variation in the AUCs of both total and unbound drug. The intraindividual variability in the AUC of cyclosporin is similar to that of many other drugs and needs to be taken into account in the planning of pharmacokinetic studies.
Drug and Alcohol Dependence, 2009
The development and implementation of programs in the U.S. to minimize risks and assess unintende... more The development and implementation of programs in the U.S. to minimize risks and assess unintended consequences of new medications has been increasingly required by the Food and Drug Administration (FDA) since the mid 1990s. This paper provides four case histories of risk management and post-marketing surveillance programs utilized recently to address problems associated with possible abuse, dependence and diversion. The pharmaceutical sponsors of each of these drugs were invited to present their programs and followed a similar template for their summaries that are included in this article. The drugs and presenting companies were OxyContin, an analgesic marketed by Purdue Pharma L.P., Daytrana and Vyvanse, ADHD medications marketed by Shire Pharmaceuticals, Xyrem for narcolepsy marketed by Jazz Pharmaceuticals, and Subutex and Suboxone for opioid dependence marketed by Reckitt Benckiser Pharmaceuticals Inc. These case histories and subsequent discussions provide invaluable real-world examples and illustrate both the promise of risk management programs in providing a path to market and/or for keeping on the market drugs with serious potential risks. They also illustrate the limitations of such programs in actually controlling unintended consequences, as well as the challenge of finding the right balance of reducing risks without posing undue barriers to patient access. These experiences are highly relevant as the FDA increasingly requires pharmaceutical sponsors to develop and implement the more formalized and enforceable versions of the risk management term Risk Evaluation and Mitigation Strategies (REMS).
Diabetic Medicine, 2003
Insulin aspart has been shown to improve post-prandial and overall glycaemic control in people wi... more Insulin aspart has been shown to improve post-prandial and overall glycaemic control in people with Type 1 diabetes. We hypothesized that insulin aspart with intensified basal NPH insulin supplementation would result in better overall glycaemic control than human regular insulin with standard basal NPH insulin.
Diabetic Medicine, 2000
Aims To compare the ef®cacy of insulin aspart, a rapid-acting insulin analogue, with that of unmo... more Aims To compare the ef®cacy of insulin aspart, a rapid-acting insulin analogue, with that of unmodi®ed human insulin on long-term blood glucose control in Type 1 diabetes mellitus.
Therapeutic drug monitoring, 1992
In order to study the performance of a specific fluorescence polarization immunoassay (FPIA) for ... more In order to study the performance of a specific fluorescence polarization immunoassay (FPIA) for monitoring of the area under the concentration time curve (AUC) of cyclosporine (CsA), a total of 170 24-h CsA AUC studies were prospectively collected from 40 consecutive adult renal transplant recipients during the first 6 months after transplantation. Each AUC study included whole blood samples that had been collected at 0, 2, 4, 6, 10, 14, and 24 h after CsA administration. Each sample was subjected to CsA analysis in whole blood using a 3H-tracer specific monoclonal radioimmunoassay (wb-sRIA), specific FPIA (wb-sFPIA), and polyclonal FPIA (wb-pcFPIA). Furthermore, the performance of the specific assays was assessed against high-performance liquid chromatography (HPLC). Correlations between HPLC and specific assays were good, namely correlation coefficients of 0.94. Contrariwise, correlations between specific and nonspecific assay were poorer. As compared to HPLC, wb-sRIA overestimat...
Clinical Pharmacology and Therapeutics, 1992
The impact of several demographic and blood biochemistry factors on the pharmacokinetics of the i... more The impact of several demographic and blood biochemistry factors on the pharmacokinetics of the immunosuppressive drug cyclosporine were studied in 187 patients with uremia. All patients underwent a pharmacolcinetic evaluation including a 3 mg/kg intravenous dose of cyclosporine and a 14 mg/kg oral dose of cyclosporine. Cyclosporine was analyzed by specific monoclonal radioimmunoassay on whole blood samples. Statistical analysis included univariate analyses and stepwise multiple regression analysis.
Clinical Pharmacokinetics, 2001
Transplantation, 1992
A randomized trial was performed with the aim to compare two immunosuppressive treatment schedule... more A randomized trial was performed with the aim to compare two immunosuppressive treatment schedules in adult recipients of first cadaveric renal transplants. A total of 229 patients were randomized to double therapy with cyclosporine and prednisolone and 234 patients were randomized to triple therapy with cyclosporine, azathioprine, and prednisolone. Minimum follow-up was 4 years. The actuarial 5-year patient survival was 79.8% in the double therapy group and 82.3% in the triple therapy group (n.s.). The corresponding graft survival figures were 54.4% and 59.6% in the two groups, respectively (n.s.). There were no differences between the groups regarding cause of death or cause of graft loss. Renal function as determined by serum creatinine did not differ between the groups and was stable throughout the observation period. Azathioprine was instituted in a total of 51 patients randomized to double therapy. This subgroup of patients had a patient and graft survival not different from the remaining patients randomized to double therapy or from the patients randomized to triple therapy. There were no differences between the double and triple therapy groups regarding incidence and timing of acute rejection or infections. The incidence of other medical diseases and adverse events such as nephrotoxicity or malignancy did not differ between the groups. Azathioprine-induced leukopenia was uncommon (19 episodes in the triple therapy group). In a multivariate analysis of the whole series the only covariates that significantly influenced graft survival were age of recipient and occurrence of acute rejection, while among other factors treatment schedule did not. Thus this prospective study, in accordance with previous such studies, failed to find support for the use of triple therapy as first choice immunosuppression in first cadaveric renal transplantation. However, the study could not rule out the possibility that some patients at risk for the development of irreversible rejection or nephrotoxicity of CsA might benefit from the addition of azathioprine to the treatment schedule.
European Journal of Clinical Pharmacology, 1999
Objective: The pharmacokinetics of a new insulin analogue, insulin aspart, were compared with unm... more Objective: The pharmacokinetics of a new insulin analogue, insulin aspart, were compared with unmodified human insulin in a double-blind crossover study of 25 fasting healthy men following a single subcutaneous dose. Methods: Either insulin aspart or human insulin, 0.1 U kg-body-weight−1, was injected subcutaneously and followed by determination of 8-h profiles of serum insulin and plasma glucose concentrations. Results: The absorption of
Transplantation, 1993
The influence of cyclosporine pharmacokinetic parameters on clinical events and outcome after tra... more The influence of cyclosporine pharmacokinetic parameters on clinical events and outcome after transplantation was studied in 100 renal transplant recipients who underwent a pre- as well as posttransplant CsA pharmacokinetic evaluation. Among the patients, 30 were black and 50 were white. Black recipients had significantly lower bioavailability (F) pre- as well as posttransplantation than white recipients, the posttransplant mean F values being 25.8 +/- 9.0% and 38.1 +/- 16.7%, respectively (P < 0.002). The posttransplant CsA clearance rate (CL) and oral clearance (clearance/bioavailability; CLoral) were significantly higher in patients who had acute rejection than in those who did not, with CL mean values of 425 +/- 141 ml/min and 359 +/- 131 ml/min, respectively (P < 0.02). The initial posttransplant F was significantly lower, and the CLoral higher in patients who eventually lost their grafts than in those who did not, the mean F values being 26.5 +/- 12.8% and 38.7 +/- 17.5%, respectively (P < 0.002). Thus, several important relationships between CsA pharmacokinetic parameters and clinical events following renal transplantation were documented. The CLoral decreased during the first 3 months after transplantation (P < 0.0001), but it was stable thereafter. Neither the bioavailability nor the clearance of CsA showed a correlation with administered dose. These results indicate that certain recipient groups, such as black patients, and individuals with rapid CL, may benefit from larger CsA doses and/or shorter dosage intervals, in order to compensate for these interpatient variabilities.
Transplantation, 1993
To characterize factors of importance for the occurrence of acute rejection as well as study the ... more To characterize factors of importance for the occurrence of acute rejection as well as study the impact of these episodes on long-term renal survival and function, a total of 819 acute rejection episodes were studied in 951 primary cadaveric donor kidney recipients (CD) and in 396 primary living donor kidney recipients (LD). The patients were treated by three immunosuppressive schedules, namely, CsA given in a high dose, a medium dose, or a low dose. Additionally, all patients received PRED and patients in the low-dose group received AZA. The incidence of acute rejection was higher and occurred earlier after transplantation in the CsA medium dose and low dose groups than in the CsA high dose group (P < 0.05 and P < 0.01, respectively). Although the incidence of first acute rejection was similar in CD and LD patients, 59.1% vs. 60.6%, it was successfully reversed by antirejection treatment in a higher percentage in LD patients. The estimated graft half-life was shorter in patients who had acute rejection episodes than those who did not, 6.6 years vs. 12.5 years in CD patients (P < 0.0001). Renal function at 1-5 years after transplantation was stable, but significantly poorer in CD patients who had experienced acute rejection than in patients who had not, with the mean creatinine clearance rates in the ranges 45-47 vs. 54-60 ml/min in the other groups (P < 0.0001). In a stepwise Cox regression analysis in CD recipients, risk factors for acute rejection were CsA (low dose) treatment schedule, immunization as displayed by presence of panel-reactive antibodies and positive B cell cross-match, young recipient age, disease of diabetes mellitus, and HLA-DR mismatching. In LD recipients, the corresponding risk factors were treatment schedule, young recipient, HLA mismatching, and transplantation from parent to child. Thus, the study has demonstrated some factors of importance for acute rejection episodes in CsA-treated patients as well as showing the detrimental effect of these episodes on long-term graft survival and renal function. These results suggest that a primary aim of future treatment strategies should be to reduce the incidence of these episodes.
Transplantation, 1995
Causes of graft loss and death were studied in 1347 recipients of primary renal transplants follo... more Causes of graft loss and death were studied in 1347 recipients of primary renal transplants followed for 5 years after transplantation irrespective of graft function. Immunosuppression consisted of high or medium dose CsA and prednisolone or low dose CsA and prednisolone and azathioprine. In recipients of cadaver grafts, death with a functioning transplant was more common than graft rejection after the first posttransplant year, accounting for 49% and 41% of the graft losses, respectively. Of deaths with a functioning graft, 53% were due to ischemic heart disease (IHD) and 10% were due to other vascular disease. In the 55- to 64-year-old age group, the risk of death from IHD was 6.4 times higher in the transplanted nondiabetic patients, 8.6 times higher in the dialysis patients (European Dialysis and Transplant Association figures), and 20.8 times higher in the transplanted diabetic patients than in the general population (national figures). A multivariate Cox regression analysis showed that old age, diabetes mellitus, occurrence of acute rejection, pretransplant transfusions, delayed onset of graft function, and male gender were significant for death in IHD. We conclude that, in comparison to reports from other regions, Scandinavian renal transplant recipients are at high risk of dying of IHD. Future advances in long-term renal graft survival will depend largely on the success of preventing myocardial infarction and death in this patient population.
Therapeutic Drug Monitoring, 1995
Search by Subject Search using Medical Subject Headings (< b> MeSH</b>), a controlled... more Search by Subject Search using Medical Subject Headings (< b> MeSH</b>), a controlled vocabulary for indexing life sciences content.< br/> Note that some records do not have MeSH. These include Patents and the latest PubMed and PubMed Central records.
Nephron, 1988
To study a possible relationship between ciclosporin-induced hypertrichosis and sex hormone patte... more To study a possible relationship between ciclosporin-induced hypertrichosis and sex hormone pattern, the hair growth in different areas of the body was graded and hormone levels were assayed before and up to 6 months after kidney transplantation. Increased hair growth was observed in 100% (23/23) of the patients in skin areas connected with androgen action and in 78% of the patients in androgen-insensitive areas. After renal transplantation the pituitary, testicular and adrenal hormone levels normalized. The posttransplantation levels of these hormones would not explain the observation of increased hairgrowth. Thus, ciclosporin induces hypertrichosis via a mechanism independent of sex hormones.
Pharmacogenomics, 2008
Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event asso... more Antibody (Ab)-positive pure red-cell aplasia (PRCA) is a very rare but serious adverse event associated with recombinant human erythropoietin treatment (4.1 reports per 100,000 patient-years) in which patients produce antibodies to recombinant and endogenous erythropoietin, halting red blood cell production. In a previous case series, four Thai subjects with chronic kidney disease and Ab-positive PRCA were reported to have the HLA-DRB1*9 allele. To confirm a possible association of HLA-DRB1*9 and Ab-positive PRCA, we performed a pharmacogenomic analysis using subjects from an earlier case-control study of risk factors associated with Ab-positive PRCA, which had been performed using subjects from Europe or Canada. The primary goal of the analysis was to test the association between HLA-DRB1*9 and Ab-positive PRCA. A secondary goal was to perform an exploratory analysis in order to identify additional HLA alleles potentially associated with Ab-positive PRCA. Subjects were taken from a case-control study of Ab-positive PRCA in chronic kidney disease patients treated in Europe or Canada. Ab-positive PRCA cases (n=24) were matched to controls (n=81) by timing of treatment exposure and, when possible, by location. The allele frequency of HLA-DRB1*9 was 12.5% in cases vs 1.2% in controls (p=0.002). The frequency of the HLA-DRB1*9/other genotype was 25.0% in cases vs 2.5% in controls (p=0.004; OR: 10.8 [95% CI: 2.2-53.7]). Within the exploratory analysis, six additional HLA alleles (HLA-A*25, HLA-B*53, HLA-C*12, HLA-DQB1*3, HLA-DQB1*6 and HLA-DRB1*4) were also found to be associated with Ab-positive PRCA. This study confirmed that HLA-DRB1*9 occurs at a significantly higher frequency in Ab-positive PRCA cases than in controls; however, within this sample set, carrying the *9 allele was neither necessary nor sufficient to cause Ab-positive PRCA.
Immunology and Cell Biology, 1994
The effect of HLA-A matching on long-term cadaver kidney graft survival was analysed, on average,... more The effect of HLA-A matching on long-term cadaver kidney graft survival was analysed, on average, 6 years after transplantation in a total of 1085 cyclosporine (CyA)-treated patients.
Expert Opinion on Pharmacotherapy, 2002
The novel, rapid-acting insulin analogue insulin aspart (IAsp; Novo Nordisk) has been shown in pr... more The novel, rapid-acting insulin analogue insulin aspart (IAsp; Novo Nordisk) has been shown in preclinical studies to be more rapidly absorbed than human insulin (HI) when administered subcutaneously. IAsp reaches higher peak serum concentrations in a shorter time than HI, whilst maintaining a similar receptor binding and safety profile. The physiological pharmacokinetic profile of IAsp compared to that of HI has been demonstrated in both adult and paediatric populations and was accompanied by small but statistically significant reductions in HbA(1c), lower postprandial glucose excursions and a reduced risk of late postprandial and major nocturnal hypoglycaemia. Benefits may be maximised by dose optimisation, using bolus doses that result in effective postprandial glucose reduction, as well as higher and multiple basal insulin doses. The safety profile, including cardiovascular risk, is equivalent to HI.
Expert Opinion on Investigational Drugs, 1999
In order to improve therapy and increase the quality of life for diabetic patients, it has been o... more In order to improve therapy and increase the quality of life for diabetic patients, it has been of significant interest to develop rapid-acting insulin preparations that mimic the physiological meal-time profile of insulin more closely than soluble human insulin. Insulin aspart (B28Asp human insulin) is a novel rapid-acting insulin analogue that fulfils this criterion. The B28Asp modification weakens the self-association of the insulin molecule and provides a more rapid absorption from the sc. injection site. The preclinical evaluation in vitro and in vivo demonstrates that apart from the more rapid absorption, insulin aspart is equivalent to human insulin. Thus, insulin aspart is equivalent to human insulin on key in vitro parameters such as insulin receptor affinity, insulin receptor dissociation rate, insulin receptor tyrosine kinase activation, IGF-I receptor binding affinity, metabolic and mitogenic potency. In accordance with the equivalent in vitro profiles, the toxico-pharmacological properties of insulin aspart and human insulin are also identical. The available data for insulin aspart and other rapid-acting insulin analogues supports that in vitro assays are sensitive and valuable in the preclinical evaluation of insulin analogues. Clinical studies demonstrate that insulin aspart has a pharmacokinetic and pharmacodynamic profile superior to that of soluble human insulin. In Type 1 diabetic patients on a basal-bolus injection regimen, insulin aspart given immediately before the meals provides an improved postprandial glycaemic control and an improved long-term metabolic control, as compared to soluble human insulin given 30 min before the meals, without increasing the risk of hypoglycaemia. Taken together, the data support the hope that insulin aspart will allow the diabetic patient to combine a more flexible lifestyle with better glycaemic control, without any increased safety risk.
European Journal of Pediatrics, 2000
The pharmacokinetics of the novel, rapid-acting insulin aspart were compared with those of solubl... more The pharmacokinetics of the novel, rapid-acting insulin aspart were compared with those of soluble human insulin following subcutaneous administration in nine children (aged 6±12 years) and nine adolescents (aged 13±17 years) with stable type 1 diabetes. The study had a randomised, double-blind, two-period crossover design. Each patient received a single subcutaneous dose of insulin aspart or human insulin (0.15 IU/kg body weight) 5 min before breakfast and the plasma insulin and glucose concentrations were measured at intervals during the following 5 h. The pharmacokinetic pro®le of insulin aspart diered signi®cantly from that of human insulin with a higher mean maximum serum insulin (C max ins ), 881 321 (SD) pmol/l versus 422 193 pmol/l for human insulin (P < 0.001); and with a shorter median serum insulin t max ins , 40.0 min (interquartile range: 40±50 min) versus 75.0 min (interquartile range: 60±120 min) for human insulin, (P < 0.001). An age-related eect on C max ins and area under the curve (AUC 0±5h ins ) was observed with higher values in adolescents than in children for both insulin aspart and human insulin. Postprandial glycaemic control was improved with insulin aspart; the baseline-adjusted DC max glu being lower for insulin aspart compared with human insulin (increase of 7.6 5.1 versus 9.4 4.4 mmol/l respectively, P < 0.05). The incidence of adverse events was similar for the two insulin types. Conclusion The more rapid onset of action of insulin aspart versus human insulin, previously observed in adults, is con®rmed in a paediatric population with type 1 diabetes.
European Journal of Clinical Pharmacology, 1993
The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokineti... more The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period.
European Journal of Clinical Pharmacology, 1988
We have measured total and unbound plasma concentrations of cyclosporin A in seven healthy men af... more We have measured total and unbound plasma concentrations of cyclosporin A in seven healthy men after single oral doses (12 mg per kg body weight) on two occasions at least two weeks apart. There was an up to two-fold intraindividual and a more than three-fold interindividual variation in the AUCs of both total and unbound drug. The intraindividual variability in the AUC of cyclosporin is similar to that of many other drugs and needs to be taken into account in the planning of pharmacokinetic studies.
Drug and Alcohol Dependence, 2009
The development and implementation of programs in the U.S. to minimize risks and assess unintende... more The development and implementation of programs in the U.S. to minimize risks and assess unintended consequences of new medications has been increasingly required by the Food and Drug Administration (FDA) since the mid 1990s. This paper provides four case histories of risk management and post-marketing surveillance programs utilized recently to address problems associated with possible abuse, dependence and diversion. The pharmaceutical sponsors of each of these drugs were invited to present their programs and followed a similar template for their summaries that are included in this article. The drugs and presenting companies were OxyContin, an analgesic marketed by Purdue Pharma L.P., Daytrana and Vyvanse, ADHD medications marketed by Shire Pharmaceuticals, Xyrem for narcolepsy marketed by Jazz Pharmaceuticals, and Subutex and Suboxone for opioid dependence marketed by Reckitt Benckiser Pharmaceuticals Inc. These case histories and subsequent discussions provide invaluable real-world examples and illustrate both the promise of risk management programs in providing a path to market and/or for keeping on the market drugs with serious potential risks. They also illustrate the limitations of such programs in actually controlling unintended consequences, as well as the challenge of finding the right balance of reducing risks without posing undue barriers to patient access. These experiences are highly relevant as the FDA increasingly requires pharmaceutical sponsors to develop and implement the more formalized and enforceable versions of the risk management term Risk Evaluation and Mitigation Strategies (REMS).
Diabetic Medicine, 2003
Insulin aspart has been shown to improve post-prandial and overall glycaemic control in people wi... more Insulin aspart has been shown to improve post-prandial and overall glycaemic control in people with Type 1 diabetes. We hypothesized that insulin aspart with intensified basal NPH insulin supplementation would result in better overall glycaemic control than human regular insulin with standard basal NPH insulin.
Diabetic Medicine, 2000
Aims To compare the ef®cacy of insulin aspart, a rapid-acting insulin analogue, with that of unmo... more Aims To compare the ef®cacy of insulin aspart, a rapid-acting insulin analogue, with that of unmodi®ed human insulin on long-term blood glucose control in Type 1 diabetes mellitus.