Pharmacokinetics, pharmacodynamics, and safety of inhaled cyclosporin A (ADI628) after single and repeated administration in healthy male and female subjects and asthmatic patients

Severe asthmatics treated with oral/inhaled corticosteroids are at risk of side effects (adrenal suppression). Oral cyclosporin A has been effective in asthma treatment, and nebulized cyclosporin A has been administered for approximately 6 months with no nephrotoxicity or hepatotoxicity, suggesting a wider therapeutic margin for an inhaled cyclosporin A for treatment of asthma. Single- and repeated-dose studies in healthy and asthmatic male and female subjects were conducted to determine the pharmacokinetics, pharmacodynamics, and safety of a new formulation of inhaled cyclosporin A (ADI628) metered-dose inhaler (MDI). ADI628 had roughly dose-linear increases in blood concentrations with moderate variability after single and multiple administration in healthy subjects. Steady-state ADI628 concentrations reflected an effective half-life of 7.0 to 12.5 hours. No overt gender-related differences were observed after single inhaled 10 mg ADI628 dose. However, asthmatics and females (20 mg dose group) had lower ADI628 concentrations as compared to healthy males, probably due to lower inspiratory flow rates and probably not due to disease- or gender-related differences in metabolism/elimination of ADI628. Renal excretion was a minor route of elimination for ADI628 with no dose- or gender-related differences. The blood ADI628 exposure in humans was 1/3- to 1/6-fold lower than the no-effect dose in dogs. Also, the blood ADI628 exposure after the highest inhaled dose was much lower than after the administration of the efficacious oral cyclosporin A dose (3 mg/kg) for treating asthma. The highest steady-state dose (10 mg bid) resulted in ADI628 concentrations that are not typically associated with systemic nephrotoxicity or immunosuppression. Furthermore, repeated inhaled doses of ADI628 were safe and generally well tolerated with no apparent systemic immunosuppressive activity in healthy and asthmatic subjects.     

Pharmacokinetics, pharmacodynamics, and safety of a platelet GPIIb/IIIa antagonist, RGD891, following intravenous administration in healthy male volunteers

The pharmacokinetics (PK), pharmacodynamics (PD), and safety of a platelet GPIIb/IIIa receptor antagonist, RGD891, and its active metabolite, RGD039, were evaluated after administration of various intravenous regimens of RGD891 to healthy male volunteers in two Phase I studies. Plasma and urine concentrations of RGD891 and RGD039 were measured by validated LC/MS/MS methods with minimum quantifiable limit (MQL) of 1 ng/mL and 10 ng/mL, respectively. PD activity was assessed by percent inhibition of ADP (20 microM)-induced platelet aggregation. Following intravenous dosing, the RGD891 was the predominant compound in plasma. The PK of RGD891 was dose independent associated with modest between-subject variability. RGD891 was rapidly cleared (Cl, 11.2-15.5 L/h), exhibited a restricted distribution (Vss, 23.0-25.9 L) and a short terminal t1/2 lambda z (1.2-2.1 h). Plasma concentrations of the metabolite (RGD039) increased with dose but were variable. RGD039 had longer t1/2 lambda z of 4.5 to 6.6 hours. Renal excretion of unchanged drug played an important role in the elimination of the parent compound. Both RGD891 and RGD039 exhibited renal clearance values that were comparable to the glomerular filtration rate. Intravenous administration of RGD891 effectively inhibited platelet aggregation in a dose-dependent and reversible manner. At the highest dose (60 micrograms/kg bolus dose + 336 micrograms/kg 8-h infusion) > 90% inhibition of platelet aggregation was achieved. PD activity was primarily attributed to the parent compound. Inhibition of platelet aggregation was dependent on the anticoagulant present, with samples containing PPACK showing 20% to 30% lower activity as compared to citrate. RGD891 was safe and well tolerated across the various regimens studies.     

Risk factors for parvovirus B19 infection in pregnancy

Context  Parvovirus B19 infection during pregnancy has been associated with fetal death. However, the incidence of and risk factors for infection in pregnant women have not been well studied. Objectives  To estimate a pregnant woman's risk of infection with parvovirus B19 in epidemic and endemic situations and to study risk factors for infection. Design  Population-based cohort study conducted between November 1992 and June 1994. Setting  Three regions in Denmark. Participants  A total of 30,946 pregnant women from a consecutive and population-based screening. Main Outcome Measures  Specific IgG antibodies in serum samples obtained in the first trimester of pregnancy and from the newborn infant to assess past infection and seroconversion. Information on family structure, educational background, socioeconomic status, and pregnancy outcome was obtained from national registers. Results  Based on 30,946 serum samples, 65.0% of pregnant women had evidence of past infection. Annual seroconversion rates among susceptible women during endemic and epidemic periods were 1.5% (95% confidence interval [CI], 0.2%-1.9%) and 13.0% (95% CI, 8.7%-23.1%), respectively. Baseline seropositivity was significantly correlated with increasing number of siblings, having a sibling of the same age, number of own children, and occupational exposure to children. Risk of acute infection increased with the number of children in the household as follows: 0 children odds ratio (OR), 1 (reference); 1 child OR, 3.17 (95% CI, 2.24-4.49); 2 children OR, 5.47 (95% CI, 3.55-8.45); 3 or more children OR, 7.54 (95% CI, 3.80-14.94). Having children aged 6 to 7 years resulted in the highest rate of seroconversion among mothers (6.8%; OR, 4.07; 95% CI, 1.89-8.73). Compared with other pregnant women, nursery school teachers had a 3-fold increased risk of acute infection (OR, 3.09; 95% CI, 1.62-5.89). Population-attributable risk of seroconversion was 55.4% for number of own children and 6.0% for occupational exposure. Conclusions  The risk of infection is high for susceptible pregnant women during epidemics and associated with the level of contact with children. Nursery school teachers have the highest occupational risk, but most infections seem to be the result of exposure to the woman's own children.      

Lack of pancreatic body and tail in HNF1B mutation carriers

Aims Hepatocyte nuclear factor 1B (HNF1B) gene mutation carriers have a systemic disease characterized by congenital malformations in the urogenital tract, diabetes mellitus of maturity‐onset diabetes of the young type and dysfunction of the liver and exocrine pancreas. We aimed to investigate pancreatic structure and exocrine function in carriers of HNF1B mutations. Methods We studied five subjects from two families with the previously reported mutation R137_K161del and the novel mutation F148L in HNF1B. All patients underwent computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP). We measured faecal elastase and serum vitamins D and E. Results One of the mutation carriers reported abdominal symptoms. All five subjects had faecal elastase deficiency, three had vitamin D deficiency and two had vitamin E deficiency. Neither CT nor MRCP depicted tissue corresponding to the pancreatic body and tail in the five mutation carriers, indicating agenesis of the dorsal pancreas. The head of the pancreas was slightly atrophic but had normal X‐ray attenuation at CT in all patients. Conclusions Agenesis of the pancreatic body and tail and pancreatic exocrine dysfunction are parts of the phenotype in HNF1B mutation carriers. This strengthens the evidence for a critical role of HNF1B in development and differentiation of at least the dorsal pancreas.     

Cunninghamella bertholletiae infection in a bone marrow transplant patient: amphotericin lung penetration, MIC determinations, and review of the literature.

Infections caused by Cunninghamella bertholletiae, an opportunistic fungal organism, have an extremely high mortality rate. A fatal case of C. bertholletiae fungal pneumonia occurred in a man who had received an allogeneic bone marrow transplant. Aggressive debridement and high-dose liposomal amphotericin B failed to eradicate the infection. Right lung tissue samples obtained during lobectomy were assayed for amphotericin B concentrations by high-performance liquid chromatography, and minimum inhibitory concentration (MIC) determinations of amphotericin B against C. bertholletiae were determined by the macrobroth dilution method. The MIC for the isolate of C. bertholletiae was 4 microg/ml. Amphotericin B lung concentrations averaged 9.5 microg/ml (range 3.7-13.8 microg/ml), with a corresponding serum trough concentration of 0.9 microg/ml. To our knowledge, this is the first reported case of amphotericin B concentrations measured at the site of infection in a patient with a pulmonary Cunninghamella infection, together with a corresponding MIC of the organism. The patient's death, which occurred despite aggressive debridement and high amphotericin B lung concentrations, highlights the need for novel strategies to treat infections caused by invasive molds such as C. bertholletiae.     

Age‐related changes in brain energetics and phospholipid metabolism

Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus (³¹P) MRS. ³¹P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21–84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (?0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p = 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using ³¹P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non‐demented and psychiatrically stable older adults and specifically analyzed gray‐white matter differences in brain metabolism. Copyright © 2009 John Wiley & Sons, Ltd.     

The role of hypertension in the development of nephropathy in type 1 (insulin-dependent) diabetes mellitus

Summary Which comes first when developing clinical diabetic nephropathy, the blood pressure rise or the increasing urinary albumin excretion? This issue is discussed based on recent literature of studies in humans with Type 1 (insulin-dependent) diabetes mellitus. We conclude that hypertension has a central role in the progression of diabetic nephropathy and has deleterious effects on the life expectancy of patients who already have signs of diabetic renal disease in terms of elevated urinary albumin excretion. However, blood pressure is preceded by small increments of urinary albumin excretion rates, an indicator of a universally increased vascular leakiness, and thus does not seem to be the cause of diabetic nephropathy.     

Nephrotoxicity of cyclosporin A in patients with newly diagnosed type 1 diabetes mellitus

Renal function was studied in 18 patients with Type 1 diabetes mellitus. All were participating in the Canadian-European randomized placebo-controlled cyclosporin trial in newly diagnosed Type 1 diabetic patients, nine being randomized to placebo, and nine to cyclosporin A. During treatment for 12 to 18 months, cyclosporin A caused significant reductions in the glomerular filtration rate (before drug withdrawal, cyclosporin 97 +/- 18 vs placebo 125 +/- 16 ml min-1 1.73-m-2, p less than 0.05), renal plasma flow (454 +/- 83 vs 536 +/- 70 ml min-1 1.73-m-2, p less than 0.05), and lithium clearance (17 +/- 3 vs 28 +/- 5 ml min-1 1.73-m-2, p less than 0.05). The fractional proximal reabsorption was increased (0.82 +/- 0.03 vs 0.78 +/- 0.03, p less than 0.05), and the fractional distal sodium reabsorption reduced (0.88 +/- 0.03 vs 0.94 +/- 0.02, p less than 0.05). These results are in accordance with the hypothesis that the nephrotoxic effect of cyclosporin A results from a preferential constriction of afferent glomerular vessels. One year after withdrawal of the drug, all variables were similar in the two groups, except for blood glucose control which was worse in the cyclosporin A treated group. When corrected for differences in blood glucose control it appeared that in three out of nine patients glomerular filtration rate had not completely returned to the reference range of the placebo group. We conclude that the nephrotoxic side-effects of cyclosporin A treatment for 1 year are reversible. There are, however, signs of minor and perhaps chronic renal injury.     

Rapid MR assessment of left ventricular systolic function after acute myocardial infarction using single breath-hold cine imaging with the temporal parallel acquisition technique (TPAT) and 4D guide-point modelling analysis of left ventricular function

We compared four-dimensional guide-point modelling left ventricular function analysis (4DVF) results of cine images in four short-axis and two long-axis slices acquired in a single breath-hold, obtained with the temporal parallel acquisition technique (TPAT), with standard left ventricular function (LVF) analysis results determined by the summation of discs method, in patients who had recently suffered myocardial infarction. Despite wall motion abnormalities, 4DVF yields results for left ventricular ejection fractions and end-diastolic and end-systolic volumes that are in excellent agreement with standard LVF analysis results in these patients. A shortened cardiac magnetic resonance (CMR) protocol using single breath-hold cine image acquisition could facilitate the assessment of left ventricular function soon after myocardial infarction in critically ill patients who are unable to comply with the multiple breath-holds required for standard LVF analysis.