ABSTRACT
We describe a new method to broaden the frequency spectrum of a femtosecond oscillator in the continuous-wave (CW) domain. The method relies on modulating the femtosecond laser using four-wave mixing inside a Raman-based optical modulator. We prepare the modulator by placing deuterium molecules inside a high-finesse cavity and driving their fundamental vibrational transition using intense pump and Stokes lasers that are locked to the cavity modes. With the molecules prepared, any laser within the optical region of the spectrum can pass through the system and be modulated in a single pass. This constitutes a CW optical modulator at a frequency of 90 THz with a steady-state single-pass efficiency of â¼10-6 and transient (10 µs-time-scale) single-pass efficiency of â¼10-4. Using our modulator, we broaden the initial Ti:sapphire spectrum centered at 800 nm and produce upshifted and downshifted sidebands centered at wavelengths of 650 nm and 1.04 µm, respectively.
Subject(s)
Drug-Related Side Effects and Adverse Reactions/mortality , Drug-Related Side Effects and Adverse Reactions/prevention & control , Methadone/therapeutic use , Opiate Substitution Treatment/mortality , Opioid-Related Disorders/mortality , Analgesics, Opioid/therapeutic use , Comorbidity , Germany/epidemiology , Prevalence , Risk Assessment , Survival Analysis , Survival Rate , Treatment OutcomeABSTRACT
A multidisciplinary German expert group met in 2012 to discuss the current status and prospects of health care of geriatric patients with urinary incontinence in Germany. The purpose of this position paper is to raise awareness among health care providers for the challenges associated with adequate management of urinary incontinence in frail elderly. The experts agree that a multidisciplinary collaboration is essential for the successful treatment of urinary incontinence symptoms which are often associated with loss of autonomy and social isolation. For most geriatric patients, usually the general practitioner is the first contact when seeking help. Hence, the general practitioner plays a crucial role in the coordination of diagnosis and treatment. The involved health care providers should have adequate education and training in their respective disciplines and should be networked allowing quick turnaround times. Non-pharmacological treatments (e.g. behavioural interventions) should have been tried before any pharmacotherapy is initiated. If pharmacological treatment of urinary incontinence involves the use of anticholinergic agents, cognitive performance should be monitored regularly. If indicated, anticholinergic agents with a documented efficacy and safety profile, explicitly assessed in the elderly population, should be preferred.
Subject(s)
Behavior Therapy/methods , Cholinergic Antagonists/therapeutic use , Practice Guidelines as Topic , Quality Improvement/standards , Urinary Incontinence/diagnosis , Urinary Incontinence/therapy , Urology/standards , Aged, 80 and over , Female , Frail Elderly , Geriatric Assessment/methods , Germany , Humans , MaleSubject(s)
Antimalarials/therapeutic use , Endemic Diseases/prevention & control , Malaria/prevention & control , Travel , Animals , Anopheles/parasitology , Antimalarials/adverse effects , Child , Emergencies , Female , Humans , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/drug therapy , Infant , Infant, Newborn , Malaria/transmission , Malaria, Falciparum/prevention & control , Malaria, Falciparum/transmission , Mosquito Control , Pregnancy , Risk Factors , Self Medication , Tropical ClimateABSTRACT
Despite limited evidence from clinical studies, anticoagulant drugs such as vitamin K antagonists (VKA) (e.g., warfarin or phenprocoumon) are widely used in the background treatment of patients with pulmonary arterial hypertension (PAH). According to current guidelines, they are generally accepted as efficacious drugs, although their efficacy is neither supported by randomised controlled trials, nor formally approved by regulatory agencies for use in the specific PAH indication. The use of these drugs is not without problems, as a paradoxical situation has to be managed in the treatment of this condition. On one hand, thrombosis is one of the key pathophysiologic features of PAH (besides vasoconstriction, proliferation and inflammation). On the other hand, the incidence of bleeding events is increased in PAH patients. This applies particularly to PAH that is related to connective tissue diseases, congenital heart disease and chronic thromboembolic pulmonary hypertension. In patients receiving VKA, caution must be observed in particular when concomitantly using prostanoids or sildenafil. Similarly, VKA doses have to be adjusted according to the labelling when using sitaxentan concomitantly. Regular International Normalized Ratio monitoring contributes to the safety of PAH patients on VKA.
Subject(s)
Hemorrhage/etiology , Hypertension, Pulmonary/complications , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Antihypertensive Agents/therapeutic use , Endothelin Receptor Antagonists , Humans , Hypertension, Pulmonary/drug therapy , Thrombosis/etiology , Vitamin K/antagonists & inhibitorsSubject(s)
Drug Therapy/trends , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Anticholesteremic Agents/adverse effects , Anticholesteremic Agents/pharmacology , Anticholesteremic Agents/therapeutic use , Anticoagulants/adverse effects , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Azetidines/adverse effects , Azetidines/pharmacology , Azetidines/therapeutic use , Body Weight/drug effects , Cannabinoid Receptor Antagonists , Cetuximab , Ezetimibe , Fondaparinux , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Insulin/adverse effects , Insulin/pharmacology , Insulin/therapeutic use , Osteoporosis, Postmenopausal/drug therapy , Piperidines/adverse effects , Piperidines/pharmacology , Piperidines/therapeutic use , Polysaccharides/adverse effects , Polysaccharides/pharmacology , Polysaccharides/therapeutic use , Pyrazoles/adverse effects , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Rimonabant , Smoking Cessation , Teriparatide/adverse effects , Teriparatide/pharmacology , Teriparatide/therapeutic use , Thromboembolism/prevention & controlABSTRACT
OBJECTIVES: To investigate the clinical efficacy and safety of a newly developed diclofenac patch in the topical treatment of blunt impact injuries. METHODS: This was a randomised, placebo controlled, double blind, multicentre study in 120 patients with traumatic blunt soft tissue injury. Within 3 h of the injury participants of sport competitions and training camps were enrolled and treated twice daily with the diclofenac or a placebo patch over a period of 7 days. Patients were randomised (1:1) to two parallel groups. Tenderness produced by pressure was measured twice daily during the first 3 days after enrollment as well as at day 7. Tenderness was defined as the amount of pressure (measured by a calibrated caliper at the centre of the injury) that first produced a pain reaction as reported by the patient. RESULTS: The primary efficacy variable was the area under the curve for tenderness over the first 3 days. The diclofenac patch was significantly more effective than placebo (p<0.0001). The treatment effect was 64.7 kp h/cm2 (95% confidence interval 48.7 to 80.9) between diclofenac and placebo patches. These results were supported by all secondary efficacy variables. The diclofenac patch produced rapid pain relief as reflected by the time to reach resolution of pain at the injured site which was significantly shorter compared to placebo (p<0.0001). The diclofenac patch was well tolerated. The most frequently observed adverse events were local cutaneous adverse reactions (pruritus, rash) of minor severity occurring with the same frequency as in the placebo group. CONCLUSIONS: A newly developed diclofenac patch is effective and safe for the treatment of blunt impact injuries.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Athletic Injuries/drug therapy , Diclofenac/administration & dosage , Wounds, Nonpenetrating/drug therapy , Acute Disease , Administration, Topical , Adult , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Area Under Curve , Diclofenac/adverse effects , Double-Blind Method , Female , Humans , Male , Pain Measurement/methods , Time Factors , Treatment OutcomeABSTRACT
The combination of artesunate and mefloquine is currently one of the most effective treatments against multidrug-resistant Plasmodium falciparum malaria. To improve patient compliance to such a combination, the two agents have been combined in a prepacked single blister. Patients were instructed to simultaneously co-administer the drugs once a day for three days. In the present randomized, double-blind, parallel group, comparative, single center study in Thailand, this concept was investigated in 204 adults and children with acute, uncomplicated P. falciparum malaria. Patients were randomized into two treatment groups and received once a day over a three-day period the following: Group A received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg, approximately 8.5 mg/kg/day, simultaneously. Group B received artesunate, 4-5 mg/kg/day, and mefloquine, total dose = 25 mg/kg, sequentially (i.e., no mefloquine dose on the first day, 15 mg/kg on the second day, and 10 mg/kg on the third day). Both treatment groups showed no relevant differences in baseline demographic and clinical characteristics. Intent-to-treat analysis revealed a cure rate at day 28 (primary endpoint) of 100% in group A and 99% in group B (difference not significant). The secondary endpoints of mean time to fever clearance (group A = 34 hours, group B = 31 hours) and mean time to parasite clearance (group A = 44 hours group B = 48 hours) were similar between groups (both differences not significant). Tolerability was good in both treatment groups, with no difference in the overall incidence of adverse events. There was a low incidence of nausea/vomiting (4.9% in both groups) and central nervous system side effects (4.9% in group A versus 8.8% in group B). These were comparable between groups and generally of a mild nature. The three-day combination of artesunate and mefloquine (Artequin, Mepha, Ltd., Aesch, Switzerland) with the introduction of mefloquine on day 1 offers a practical dosing regimen that is highly effective and well tolerated in patients of different ages with uncomplicated P. falciparum malaria. It is likely that the prepacked blister approach translates clinically into a better patient compliance, thereby contributing to limit the development of drug resistance.
Subject(s)
Artemisinins/administration & dosage , Artemisinins/therapeutic use , Drug Packaging , Drug Therapy, Combination , Malaria, Falciparum/drug therapy , Mefloquine/administration & dosage , Mefloquine/therapeutic use , Plasmodium falciparum/drug effects , Sesquiterpenes/administration & dosage , Sesquiterpenes/therapeutic use , Adolescent , Adult , Animals , Antimalarials/administration & dosage , Antimalarials/adverse effects , Antimalarials/therapeutic use , Artemisinins/adverse effects , Artesunate , Central Nervous System Diseases/chemically induced , Child , Double-Blind Method , Drug Administration Schedule , Drug Resistance , Female , Fever/chemically induced , Humans , Male , Mefloquine/adverse effects , Nausea/chemically induced , Sesquiterpenes/adverse effects , Thailand , Treatment OutcomeABSTRACT
A randomized, double-blind, parallel-group study in 104 hospitalized patients with acute, uncomplicated Plasmodium falciparum malaria was performed in West and Central Africa from March to July 2001. Patients were randomized to receive simultaneous dosing (artesunate 200 mg/d plus mefloquine 250 mg/d from the first to the third day [investigational group]) or sequential dosing (artesunate 200 mg/d for 3 d plus mefloquine 250 mg on the second and 500 mg on the third day [reference group]). Patients were followed-up for 28 d, and clinical and parasitological outcomes were assessed. The 14-d cure rate was 100% in the investigational group and 98% in the reference group with no recrudescence until day 28. Mean times to fever and parasite clearance were similar between the 2 groups (32 h vs. 26 h and 45 h vs. 48 h) and tolerability was good in both groups. The number of patients with vomiting was statistically significantly lower in the investigational group compared to the reference group (3.8% vs. 19.2%, P = 0.014). A 3-d once-daily co-administration of artesunate and mefloquine starting on day one offers a practical dosing regimen, which is highly effective and well tolerated in patients with uncomplicated P. falciparum malaria.
Subject(s)
Antimalarials/therapeutic use , Artemisinins/therapeutic use , Malaria, Falciparum/drug therapy , Mefloquine/therapeutic use , Sesquiterpenes/therapeutic use , Adolescent , Adult , Africa, Central , Africa, Western , Antimalarials/adverse effects , Artemisinins/adverse effects , Artesunate , Child , Double-Blind Method , Drug Resistance , Drug Therapy, Combination , Female , Humans , Male , Mefloquine/adverse effects , Middle Aged , Sesquiterpenes/adverse effects , Treatment OutcomeABSTRACT
Analyses of eight widely used memory measures (Word List Acquisition and Recall used in the Alzheimer's Disease Assessment Scale and the Consortium to Establish a Registry for Alzheimer's Disease neuropsychology battery, Wechsler Memory Scale-Revised [WMS-R] Logical Memory I and II, WMS-R Visual Reproduction I and II, the memory scores from the Neurobehavioral Cognitive Status Examination [NCSE], memory scores from the Mini-Mental State Examination [MMSE]), and the MMSE total score showed each to have moderate predictive power in differentiating between patients with mild dementia and healthy normal controls. When these instruments were combined in a logistic regression analysis, three of them had substantial predictive power. Together, the Word List Acquisition, WMS-R Logical Memory II, and WMS-R Visual Reproduction II were 97.26% accurate (100% sensitive and 94.59% specific) in distinguishing these two groups. The Word List Acquisition is a brief test that alone had high accuracy (92%). These memory tests are highly useful in the diagnosis of mild dementia.
Subject(s)
Dementia/diagnosis , Dementia/psychology , Memory , Neuropsychological Tests/standards , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Logistic Models , Male , Predictive Value of Tests , ROC Curve , Sensitivity and SpecificityABSTRACT
BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.
Subject(s)
Cyclosporine/administration & dosage , Cyclosporine/pharmacokinetics , Heart Transplantation/immunology , Adolescent , Adult , Aged , Chemistry, Pharmaceutical , Emulsions/administration & dosage , Humans , Maximum Tolerated Dose , Middle Aged , Oils/administration & dosage , Therapeutic Equivalency , Time FactorsABSTRACT
BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.
Subject(s)
Cyclosporine/administration & dosage , Heart Transplantation , Immunosuppressive Agents/administration & dosage , Adolescent , Adult , Aged , Cyclosporine/adverse effects , Cyclosporine/therapeutic use , Double-Blind Method , Emulsions , Female , Graft Rejection/physiopathology , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Oils , Postoperative Complications , Safety , Time Factors , Treatment OutcomeABSTRACT
STUDY OBJECTIVE: To assess the potential for a drug-drug interaction between valspodar, a P-glycoprotein (mdrl) modulator used as a chemotherapy adjunct, and dexamethasone, widely included in oncology antiemetic regimens. DESIGN: Randomized, open-label, three-period crossover study. SETTING: Clinical pharmacology research center. SUBJECTS: Eighteen healthy men volunteers (age 25.8+/-3.5 yrs, weight 71.6+/-10.3 kg). INTERVENTIONS: Subjects received single fasting oral doses of valspodar 400 mg, dexamethasone 8 mg, and both drugs concomitantly with 2- to 3-week washout phases between administrations. MEASUREMENTS AND MAIN RESULTS: Lack of a pharmacokinetic drug-drug interaction with respect to valspodar was conclusively demonstrated for both Cmax,b (2.3+/-0.4 vs 2.4+/-0.5 microg/ml) and AUCb (19.8+/-4.8 vs 19.6+/-4.9 microg x hr/ml) inasmuch as bioequivalence criteria were satisfied when comparing administration alone with coadministration, respectively. Although no changes in the rate of dexamethasone absorption were noted on coadministration with valspodar (Cmax 88+/-23 vs 91+/-20 ng/ml), overall exposure was significantly increased by 24% on average (AUC 400+/-87 vs 494+/-90 ng x hr/ml). Regression analysis of valspodar Cmax,b and AUCb during coadministration versus the extent of the interaction (percentage increase in dexamethasone AUC) did not reveal a concentration-effect relationship (p=0.7299 and 0.9718, respectively). CONCLUSION: Given dexamethasone's wide therapeutic index and the short duration of coadministration foreseen for these drugs in a clinical setting (maximum 1 wk/chemotherapy cycle), the 24% increase in dexamethasone's AUC is unlikely to be relevant. Thus no alterations in valspodar or dexamethasone dosages appear warranted when the two drugs are coadministered. Multiple-dose experience in patients would be desirable to confirm these conclusions.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Antiemetics/pharmacokinetics , Cyclosporins/pharmacokinetics , Dexamethasone/pharmacokinetics , Adult , Antiemetics/adverse effects , Area Under Curve , Cross-Over Studies , Cyclosporins/adverse effects , Dexamethasone/adverse effects , Drug Interactions , Extremities , Humans , Linear Models , Male , Paresthesia/chemically inducedABSTRACT
OBJECTIVE: To determine which brain regions lose volume with aging over time in healthy, nondemented elderly. BACKGROUND: Cross-sectional studies suggest widespread loss of brain volume with aging. These studies may be biased by significant numbers of preclinically demented elderly in the oldest comparison groups. Longitudinal studies may allow closer determination of the effect of aging unaffected by dementia. METHODS: Quantitative volumetric MRI was performed annually on 46 healthy subjects older than age 65 who had maintained cognitive health a mean of 5 years. Comparisons (analysis of variance) were made of rates of volume loss (slopes) divided into 11 young-old (mean age, 70 years), 15 middle-old (mean age, 81 years), and 20 oldest-old (mean age, 87 years) subjects. Regions of interest included CSF spaces, lobar regions, and limbic-subcortical regions. RESULTS: There were significant differences between groups in intracranial, total brain, left hemisphere, right hemisphere, temporal lobe, basilar-subcortical region, and hippocampus volumes, with oldest-old subjects showing the smallest volumes, followed by middle-old and young-old subjects. Oldest-old subjects had significantly greater subarachnoid volumes than the younger groups. There were no significant differences in rates of change of regions of interest across age groups. CONCLUSIONS: After age 65 there is minimal brain volume loss observed over time in healthy elderly. Brain volume differences seen cross-sectionally, at any age, likely reflect small, constant rates of volume loss with healthy aging. Healthy oldest-old subjects do not show greater rates of brain loss compared with younger elderly, suggesting that large changes seen in cross-sectional studies reflect the presence of preclinical dementia in older groups.
Subject(s)
Aging/pathology , Brain/pathology , Aged , Aged, 80 and over , Atrophy , Female , Humans , Male , Mental Status Schedule , Neuropsychological Tests , Organ SizeSubject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Aryl Hydrocarbon Hydroxylases , Cyclosporine/pharmacokinetics , Cytochrome P-450 Enzyme Inhibitors , Immunosuppressive Agents/pharmacokinetics , Oxidoreductases, N-Demethylating/antagonists & inhibitors , Administration, Oral , Biological Availability , Biotransformation , Cross-Over Studies , Cyclosporine/administration & dosage , Cyclosporine/blood , Cytochrome P-450 CYP3A , Dosage Forms , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Male , Metabolic Clearance Rate/drug effects , Protein Synthesis Inhibitors/pharmacologySubject(s)
Autoimmune Diseases/immunology , Cyclosporine/pharmacokinetics , Immunosuppressive Agents/pharmacokinetics , Intestinal Absorption , Liver Transplantation/immunology , Transplantation Immunology , Administration, Oral , Chromatography, High Pressure Liquid , Cross-Over Studies , Cyclosporine/administration & dosage , Cyclosporine/blood , Cyclosporine/therapeutic use , Drug Monitoring , Emulsions , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Liver Transplantation/physiologySubject(s)
Cyclosporine/pharmacokinetics , Cyclosporine/therapeutic use , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Transplantation Immunology , Administration, Oral , Adult , Blood Pressure/drug effects , Child , Creatinine/blood , Cyclosporine/pharmacology , Emulsions , Graft Rejection/epidemiology , Graft Rejection/prevention & control , Humans , Immunosuppressive Agents/pharmacology , Kidney Transplantation/immunology , Randomized Controlled Trials as Topic , Regression AnalysisSubject(s)
Cyclosporine/pharmacokinetics , Cyclosporine/therapeutic use , Heart Transplantation/immunology , Immunosuppressive Agents/pharmacokinetics , Immunosuppressive Agents/therapeutic use , Administration, Oral , Biological Availability , Cyclosporine/administration & dosage , Cyclosporine/blood , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Heart Transplantation/physiology , Humans , Immunosuppressive Agents/administration & dosage , Infusions, Intravenous , Male , Metabolic Clearance Rate , Middle Aged , Time FactorsABSTRACT
The recent introduction of a cyclosporine microemulsion demonstrating less pharmacokinetic variability than the conventional formulation offers the potential for accurately and precisely predicting area under the curve (AUC) with a limited-sampling monitoring strategy. This was studied based on the pharmacokinetic profiles from 55 stable patients with renal transplants who were observed on two occasions at steady state on both formulations. Multiple linear regression analyses were performed on a training dataset from 27 patients, in which combinations of cyclosporine concentrations drawn from 0 to 4 hours postdose were regressed against the full AUC over the dosing interval. Predictor regression equations used concentration combinations ranging from one-point (concentrations at 0, 1, 2, 3, or 4 hours) through five-points (all five concentrations 0 to 4 hours). The predictive performance of these equations was then assessed in the training group with data from a subsequent profiling occasion and in the remaining 28 patients who constituted an independent test group. Prediction bias (mean prediction error) and prediction precision (absolute prediction error) were quantified and compared between formulations. Correlations between predicted and actual AUC were consistently stronger for the microemulsion, suggesting the possibility of more accurate and precise predictions of exposure than from the conventional formulation. For both formulations, the one-point predictors rendered the lowest prediction precision, and predictive performance improved considerably when multiple-point predictors were used. Significantly higher precision and lower variability were observed with the microemulsion for most predictors in the both training and test groups. For the microemulsion, two-point (C0 + C1 or C0 + C2) and three-point (C0 + C1 + C2) predictors yielded relatively unbiased and precise exposure predictions, inasmuch as mean absolute prediction error was less than 10% and 5%, respectively. Hence, a two- or three-point method may provide a clinically important improvement over the use of trough levels in monitoring cyclosporine therapy in patients with renal transplants.