Plasma and erythrocyte amino acid levels of adult humans given 100 mg/kg body weight aspartame

Blood amino acid and methanol levels were measured in 6 fasting adult subjects (3 male, 3 female) administered an abuse dose of aspartame (100 mg/kg body wt) in both solution and slurry form. A randomized cross-over design was used. Greater variation in blood aspartate, phenylalanine and methanol levels was noted when aspartame was administered in slurry form. Blood aspartate, phenylalanine and methanol levels did not exceed those associated with toxic findings in any case. Plasma aspartate levels increased from mean (± S.D.) baseline levels of 0.16 ± 0.05 μmol/dl to peak values of 0.43 ± 0.23 (P = 0.02) 30 min after administration in solution. Plasma aspartate levels increased to peak values of 3.6 and 5.8 μmol/dl at 30–45 min in 2 of 6 subjects given aspartame in slurry form, while levels in the other 4 subjects were unchanged from baseline values. Erythrocyte aspartate levels were unchanged in all subjects. Plasma and erythrocyte phenylalanine levels increased significantly (P = 0.001) after both solution and slurry administration. Plasma phenylalanine levels reached mean (± S.D.) peak values of 20.3 ± 2.05 and 26.0 ± 18.9 μmol/dl respectively 45 min after loading. The higher variation after slurry administration reflected 2 subjects with peak values of 45.8 and 51.3 μmol/dl. Blood methanol levels increased after both solution and slurry administration, reaching mean (± S.D.) levels of 1.16 ± 0.47 and 1.27 ± 0.48 mg/dl respectively 60–90 min after loading.     

Aspartame and sucrose produce a similar increase in the plasma phenylalanine to large neutral amino acid ratio in healthy subjects.

Aspartame (L-aspartyl-L-phenylalanine methyl ester) consumption has been postulated to increase brain phenylalanine levels by increasing the molar ratio of the plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids (Phe/LNAA). Dietary manipulations with carbohydrate or protein can also produce changes in the Phe/LNAA value. To compare the effects of aspartame and carbohydrate on Phe/LNAA, beverages sweetened with aspartame, sucrose, and aspartame plus sucrose, and unsweetened beverage were ingested by 8 healthy, fasted subjects in a randomized, four-way crossover design. The beverages were sweetened with an amount of aspartame (500 mg) and/or sucrose (100 g) approximately equivalent to that used to sweeten 1 liter of soft drink. The baseline-corrected plasma Phe/LNAA values did not differ significantly following ingestion of aspartame or sucrose. Following aspartame alone, the high mean ratio increased 26% over baseline 1 h after ingestion. Following sucrose alone, the high mean ratio increased 19% at 2.5 h. Sucrose increased the Phe/LNAA value due to an insulin-mediated decrease in the plasma LNAA, while aspartame increased the ratio by increasing the plasma Phe concentration. These findings indicate that similar increases in plasma Phe/LNAA occur when healthy, fasting subjects ingest amounts of equivalent sweetness of sucrose or aspartame.     

The phenylalanine and tyrosine contnet of maternal and fetal body fluids from rabbits fed aspartame.

The methyl ester of aspartylphenylalanine (aspartame; SC-18862; 3-amino-N-(α-carboxyphenethyl)-succinamic acid, methyl ester) is a sweetening agent which organoleptically has about 180 times the sweetness of sugar. Since this compounds is a food additive its metabolism in pregnancy has been evaluated. Pregnant female rabbits were fed aspartame at a level of 6% in the diet beginning on day 6 of pregnancy. Maternal plasma samples taken at days 6, 9, 16, and 20 were analyzed for phenylalanine and tyrosine. Fetal amniotic fluids were similarly analyzed on days 16 and 20 as were fetal plasma samples at day 20. Maternal plasma phenylalanine and tyrosine increased as a result of the treatment, reaching a peak on day 9. These values returned toward normal levels by day 20. The ratios of fetal/maternal plasma phenylalanine and tyrosine concentrations were unaffected by the treatment. No evidence of substrate inhibition of phenylalanine hydroxylase was seen in maternal or fetal plasma analyses or in in vitro studies of maternal liver homogenates. Tyrosine concentrations in maternal and fetal plasma rose higher with treatment than phenylalanine concentrations. Both amino acids accumulated in the amniotic fluid in amounts greater than, but proportional to, plasma concentrations.     

Effects of Ni(II) upon plasma glucagon and glucose in rats.

Plasma glucagon and glucose concentrations were measured in fasting Fischer rats after administration of Ni(II) as NiCl₂ in ip dosage of 34 or 68 μmol/kg. Injection of Ni(II) produced prompt increases in plasma glucagon and glucose concentrations. Thus, at 0.5 hr after Ni(II) (68 μmol/kg), plasma glucagon concentrations averaged 0.75 ± 0.24 ng/ml (vs 0.20 ± 0.05 in control rats, p < 0.001), and plasma glucose concentrations averaged 236 ± 17 mg/dl (vs 137 ± 11 in control rats, p < 0.001). Plasma concentrations of glucagon and glucose in Ni(II)-treated rats returned to control values within 2–4 hr following the ip injection. These findings suggest that hyperglucagonemia may be responsible for the acute hyperglycemic response to Ni(II).     

The influence of telmisartan on metformin pharmacokinetics and pharmacodynamics

Metformin is the most widely used drug among type 2 diabetes mellitus patients. However, drug interaction on metformin will influence its glucose-lowering effect or increase its side effect of lactic acidosis. In this study, a randomized, two-stage, crossover study was conducted to unveil the potential drug interaction between metformin and the anti-hypertension drug, telmisartan. Totally, 16 healthy Chinese male volunteers were enrolled. Blood samples from various time-points after drug adminstration were analyzed for metformin quantification. Oral glucose tolerance test (OGTT) was conducted 2 h after metformin administration. The AUC_0-12 and Cmax of metformin in subjects co-administrated with telmisartan were significantly lower than with placebo. The geometric mean ratios (value of metformin plus telmisartan phase/value of metformin plus placebo phase) for Cmax and AUC_0-12 is 0.7972 (90%CI: 0.7202–0.8824) and 0.8336 (90%CI: 0.7696–0.9028), respectively. Moreover, telmisartan co-administration significantly increased the plasma concentrations of both glucose and insulin at 0.5 h since OGTT (7.64 ± 1.86 mmol/l·min vs 6.77 ± 0.83 mmol/l·min, P = 0.040; 72.91 ± 31.98 μIU/ml·min vs 60.20 ± 24.20 μIU/ml·min, P = 0.037), though the AUC of glucose and insulin after OGTT showed no significant difference. These findings suggested that telmisartan had a significant influence on the Pharmacokinetics of metformin in healthy groups, though the influence on glucose-lowering effect was moderate.     

Bioavailability of progesterone from rectal dosage forms in rabbits

The systemic availability of progesterone in two rectal dosage forms was investigated in rabbits. The progesterone plasma concentration was determined as total radioactivity (progesterone and its metabolites) after a single dose of 5 mg/kg [³H]-labelled progesterone in an adeps solidus suppository (1) and in a propylene glycol enema (2) given in a randomized cross-over fashion. The equivalent dose was given intravenously (3) to the same rabbits.The maximum plasma concentration (C_max) after (1) was 0.82 ± 0.43 μg/ml and significantly lower than after (2), which was 3.81 ± 1.08 μg/ml (mean ± S.E.; P < 0.05). The time to reach the maximum plasma concentration (T_max) was for (1) 1.75 ± 0.25 h and for (2) 0.56 ± 0.32 h (mean ± S.E.; P < 0.05). The mean plasma concentration vs time curve after (3) indicates that a muhicompartment system is involved in the disposition of progesterone. The plasma half-life (t_{$\text{1}\text{2}$}) estimated from 0–6 h was 5.10 ± 1.12 (mean ± S.E.).The systemic availability (F%) of (1) from 0–6 h (AUC_0–6h) was 14 ± 8% and significantly lower than that of (2), which was 44 ± 10% (mean ± S.E.; P < 0.05).The results indicate a delayed and possibly lower absorption of progesterone from the suppositories as compared to the enema.     

GENOTYPIC INFLUENCE ON PLASMA DIPEPTIDYL CARBOXYPEPTIDASE-1 ACTIVITY IN HYPERTENSIVES

1. Plasma dipeptidyl carboxypeptidase-1 (DCP1; angiotensin I-converting enzyme, kininase II; EC 3.4.15.1) tracks with the deletion allele in genotypes of a 287 bp insertion/deletion (I/D) polymorphism of its gene, DCP1, in healthy Caucasian populations. The aim of the present study was to see whether genotype has a similar influence on plasma DCP1 in hypertensives. 2. The study involved 35 Caucasian patients with severe, familial essential hypertension, who were not being treated with DCP1 inhibitors, and 94 normotensives. Genotyping for the I/D polymorphism was performed by polymerase chain reaction and plasma DCP1 activity was measured by rate of hydrolysis of both [³H]-Hip-Gly-Gly and Hip-His-Leu. 3. Plasma DCP1 activity (nmol Gly-Gly/min per mL; mean ± s.e.m.) was 67 ± 2, 82 ± 4 and 91 ± 6 in II, ID and DD hypertensives, respectively, which was similar to values of 68 ± 4, 82 ± 3 and 94 ± 3 in normotensives (P= 0.0001 by one-way analysis of variance). Results for the His-Leu assay indicated similar tracking with genotype. 4. The Michaelis constant (μmol Hip-Gly-Gly/mL; mean ± s.e.m., n= 10) for DD subjects was the same as for II subjects (10.6 ± 1.6 vs 11.1 ± 2.3; P = 0.86). 5. In conclusion, in severely hypertensive Caucasian subjects, plasma DCP1 activity is subject to a similar genotypic influence in hypertensives as has been reported previously in normotensives. Furthermore, the plasma DCP1 enzyme itself appears to be functionally similar for each genotype.     

Detoxification/toxification of cadmium in scorpionfish (Scorpaena guttata): Acute exposure

Scorpionfish were exposed to sea water (control), sea water dosed with 25 mg Cd/l (0.4 96-h LC₅₀), and 50 mg Cd/l (0.8 96-h LC₅₀) as CdCl₂ for 96 h. These fish were then analyzed to determine the effects of near-lethal Cd exposure on mechanisms of detoxification by metallothionein and the potential for toxification of enzymes in several tissues. In scorpionfish exposed to 50 mg Cd/l, the highest concentrations of metallothionein pool Cd occurred in liver ($\text{532 ± 68 μ}\text{mol/wet}\text{kg; mean}\text{±}\text{sd}\text{; n=3}$) followed by intestine (151 ± 55 μmol/wet kg), gills (27.1 ± 9.6 μmol/wet kg) and then kidney (26.8 ± 6.1 μmol/wet kg). In these same fish, the highest concentrations of enzyme pool Cd occurred in kidney (65 ± 41 μmol/wet kg), followed by gills (33.4 ± 2.2 μmol/wet kg), intestine (21 ± 12 μmol/wet kg) and then liver (3.9 ± 1.6 μmol/wet kg). Based upon this partitioning of Cd, the order of sensitivity of tissues, at near-lethal Cd concentrations, would appear to be kidney > gills > intestine > liver.     

Aspartame: review of recent experimental and observational data

In this report the neurotoxicity of aspartame and its constituent amino acids aspartic acid and phenylalanine is reviewed. The adverse reactions ascribed to the consumption of aspartame-containing products, as reported in the U.S.A., are discussed and placed in perspective with the results of recent behavioural studies in humans and animals. The issue of common intake levels associated with proposed uses of aspartame is addressed. In brief, the following conclusions can be drawn: When aspartame is consumed at levels within the ADI-limit of 40 mg/kg body wt, there is no significant risk for an aspartate-induced neurotoxic effect in the brain. When aspartame is consumed at levels within the ADI-limit by normal subjects or persons heterozygous for phenylketonuria (PKU) the resultant plasma phenylalanine concentrations are practically always within the normal postprandial range; elevation to plasma concentrations commonly associated with adverse effects has not been observed. Persons suffering from phenylketonuria (PKU-homozygotes) on a phenylalanine-restricted diet should avoid consumption of aspartame. PKU-homozygotes on the (less strict) phenylalanine-liberalized diet should be made aware of the phenylalanine content of aspartame. In the available behavioural studies in humans with acute dosing, no adverse effects were observed. Long-term studies on behaviour and cognitive function in (sensitive) humans are lacking. Analyses of adverse reaction reports made by consumers in the U.S.A. have not yielded a specific constellation of symptoms clearly related to aspartame that would suggest a widespread public health hazard associated with aspartame use. Focussed clinical studies are now being carried out in the U.S.A.; the results should provide additional evidence concerning the interpretation of the reports on adverse reactions ascribed to aspartame. In the regulation of admitted uses for aspartame the possibility of intake levels exceeding the ADI-limit in some groups of consumers should be a point of attention.     

Systemic absorption of ocular pilocarpine is modified by polymer matrices

Systemic absorption of ocularly applied pilocarpine (1.2 mg) was studied after administration in aqueous solution, in hydroxypropylcellulose (HPC) matrix, and in a matrix of n-butyl half-ester of poly(methyl vinyl ether/maleic anhydride) (PVM/MA). In vitro release of pilocarpine from the HPC-matrix deviated slightly and positively from the diffusional square root of time dependence. The rate of drug release was independent of the phosphate buffer concentration of the dissolution medium with an initial pH of 7.4; the rate of release was 10.91 ± 0.59% min^?0.5 in 1.3 mM buffer and 9.91 ±0.37% min^?0.5 in 66.7 mM buffer. A matrix of n-butyl half-ester of PVM/MA released pilocarpine according to zero-order kinetics. The rate of drug release was 0.22 ± 0.02% min^?1 in 1.3 mM phosphate buffer and 0.95 ± 0.06% min^?1 in 66.7 mM phosphate buffer. From the 2% aqueous solution, pilocarpine was absorbed efficiently into the plasma (t_max = 3.6 ± 0.9 min, c_max = 0.384 ± 0.024 μg/ml). Pharmacokinetic analysis of data for drug absorption revealed that the conjunctiva of the eye was the most important site for systemic absorption of pilocarpine. Both the HPC matrix (t_max = 35.0 ± 7.9 min, c_max = 0.256 ± 0.022 μg/ml) and the matrix of n-butyl half-ester of PVM/MA (t_max = 204 ± 17.5 min, c_max = 0.112 ± 0.014 μg/ml) delayed and decreased the peak concentrations of pilocarpine in general circulation. (AUC_{0–6 h}/AUC_{0–6 h,i,v.}) values were 0.72 ± 0.08, 0.67 ± 0.16, and 0.41 ± 0.05 for the aqueous solution, HPC matrix, and n-butyl half-ester of PVM/MA matrix, respectively. During the in vivo study, HPC matrices dissolved in 7–12 min in the tear fluid. n-Butyl half-ester of PVM/MA neither dissolved totally nor released all the drug from the matrix in the tear fluid during 8 h. Besides improving ocular drug absorption, as shown in earlier studies, the pilocarpine concentrations in systemic circulation can be decreased by administering the drug in polymer matrices.     

Urate and antioxidants inhibit Na+-adenosine transport in rat renal brush border membranes

The effects of urate and antioxidants were evaluated on sodium-dependent [³H]adenosine transport (Na⁺/ADO) in rat renal brush border membrane vesicles (BBMV). Na⁺/ADO was estimated for a range of adenosine concentrations of 1–10 μmol/l in BBMV preincubated with urate (0.5–50 μmol/l). Michaelis-Menten kinetics showed a significant increase in K_m values from 2.48±0.49 μmol/l in control to 20.58±4.56 μmol/l with 50 μmol/l urate; V_max (243±15 pmol/mg protein×min) was not modified. Menadione (10 μmol/l) significantly increased the Na⁺/ADO activity, from 17.57±5.50 in the control, to 27.70±7.60 pmol/mg prot.×min (a 1.60 times increase, p<0.05). This stimulation was prevented when BBMV were preincubated with either 1 μmol/l α-tocopherol (trolox) or urate. Similarly conjugated dienes and malonaldehyde were stimulated in a dose-dependent fashion by menadione and the effect was inhibited with 10 μmol/l trolox. The antioxidants probucol, captopril and allopurinol inhibited in a concentration-dependent manner the Na⁺/ADO (IC₅₀ were 79±8, 100±9 and 89±9 nM, respectively). This effect might be specific on K_m of the Na⁺/ADO, since 1 μmol/l trolox (IC₅₀=1000±20 nM), inhibited V_max but not K_m of the Na⁺/glucose transport. Our results suggest that the Na⁺/ADO in BBMV is modified by agents that affect the redox status of the membranes.     

A comparative pharmacokinetic study of valpromide and valproic acid after intravenous administration in humans

The pharmacokinetics of valpromide and valproic acid were investigated comparatively in 6 healthy subjects after intravenous administration of the two drugs. Valpromide was very rapidly and almost completely biotransformed to valproic acid (f_m = 81.2 ± 10.5%; mean ± S.D.; n = 6). Relative to valproic acid valpromide has a very short half-life (0.84 ± 0.33 h) a high-clearance value (70 ± 30.5 l/h) and a large volume of distribution (V_β = 75.3 ± 12.7 l). The results of this study showed that there was no significant difference between the biotransformation of valpromide to valproic acid after intravenous administration and that obtained after oral administration of valpromide. Therefore, in humans, valpromide appears to be a prodrug of valproic acid after intravenous as well as oral administration.     

Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers

Purpose

Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers.

Methods

In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600?mg of icotinib. Plasma was sampled for up to 72?h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS).

Results

Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC_0-∞ and C_max (14.56 ±5.31?h?mg/L and 2.32?±?0.49?μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7?±?6.11 and 3.28?±?0.48, P?=?0.046 and 0.047). The mean CL/F (44.18?±?12.17?L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42?±?9.23?L/h, P?=?0.013).

Conclusions

The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.     

beta-adrenergic receptors of human leukocytes: studies with intact mononuclear and polymorphonuclear cells and membranes comparing two radioligands in the presence and absence of chloroquine

Owing to the large differences in reported values for β-adrenergic receptor numbers and binding affinity in normal leukocytes, we undertook a systematic re-examination of the binding of two widely used beta antagonists, (-)-[³H]dihydroalprenolol (DHA) and $\text{(±)-}\text{[}{}^{125}\text{I]iodohydroxybenzylpindolol}$ (HYP), to intact normal mononuclear (MN) leukocytes and polymorphonuclear (PMN) leukocytes and membrane preparations. Assays were conducted in the presence and absence of chloroquine, which has been proposed recently to eliminate ligand uptake into a non-receptor cell compartment such as lysosomes. The binding curves relating radioligand concentration to specific sitesper intact cell were biphasic. At high (10–24 nM) (-)-DHA ligand concentration in the absence of chloroquine, a large number (20,000–60,000 sites/cell) of low affinity (K_d 12–15 nM) stereospecific binding sites were detected in both cell types. This class of binding sites was eliminated by 10 ,μM chloroquine not only in PMN cells but also in the lysome-poor MN cells (? 90% lymphocytes), leaving 2000–3000 specific high affinity (-)-DHA sites/cell. In the absence of chloroquine, comparably low numbers of specific high affinity binding sites/cell were also obtained by the use of appropriately low concentrations of (-)-DHA or (±)-HYP (800 pM or less). However, even at these low radioligand concentrations chosen to measure high affinity specific binding, the addition of 10 μM chloroquine produced a moderate reduction in the number of sites/cell, without a detectable change in the apparent K_d. Mean (± S.E.M.) site numbers obtained in the presence of chloroquine were: 1331 ± 100 sites/MN cell and 1135 ±129 sites/PMN cell (K_d 143–153 pM) using (-)-DHA; and 1487 ± 210 sites/MN cell and 1065 ± 69 sites/PMN cell [avg. K_d(±) 224–274 pM] using (±)-HYP. Chloroquine had no effect on agonist-stimulated cAMP production but produced an apparent increase in the effectiveness of (-)-propranolol as an inhibitor of DHA binding. Competition studies on the binding of DHA and HYP with zinterol and practolol confirmed that the receptor was of the β₂-subtype for both MN and PMN cells. The detection of a moderately larger number of high affinity binding sites at saturation (Scatchard analysis) by (±)-HYP than by (-)-DHA was a consistent finding with either intact cells or membranes, with or without chloroquine. The possible overestimation of receptor numbers by a racemic ligand such as (±)-HYP is discussed and leads us to favor the use of a pure stereoisomer such as (-)-DHA. A system employing 800 pM (-)-[³H]DHA, 1 ,μM (-)-propranolol and 10, μM chloroquine with intact MN and PMN cells yielded reproducible and plausible results. Our values for β-adrenergic receptor numbers of intact MN and PMN cells and membranes are compared to others in the literature.     

那格列奈片治疗2型糖尿病安全性和有效性的临床观察

目的评价那格列奈片治疗2型糖尿病的有效性和安全性。方法 2型糖尿病患者未使用促胰岛素分泌剂以及胰岛素的患者,已经使用二甲双胍和葡萄糖苷酶抑制剂者剂量不变。采用5个中心、随机、双盲、瑞格列奈片对照研究,计划入选240例患者(1:1随机,每组120例),完成研究的2型糖尿病患者231例,那格列奈组115例,对照药物瑞格列奈116例。观察时间12周,治疗前后观察指标包括标准餐(0、60、120分)取血测定血糖和血清胰岛素水平、HbAlc和安全性指标(肝肾功能、血尿常规)。结果与瑞格列奈片相比,那格列奈片治疗2型糖尿病患者 HbAlc下降水平相似,治疗前后HbAlc的变化那格列奈片为(-0．95±1．32)％,瑞格列奈片为(-1．22±1．23)％, 两组之间没有统计学差异,但是每组治疗前后相比均具有统计学差异。标准餐后1h和2h血糖两组较治疗前相比均有统计学意义的下降,餐后2h血糖那格列奈组治疗前后分别为12．72±3．84mmol／L和10．93±3．59mmol／L(P <0．05),瑞格列奈组治疗前后分别为13．28±2．80mmol／L和11．09±3．24mmol／L(P<0．05),但两组之间比较没有统计学差异。使用那格列奈治疗12周后标准餐1h血清胰岛素水平显著升高,治疗前后的水平分别为21．89± 14．01μIU／mL和22．41±13．93μIU／mL(P<0．05),瑞格列奈组治疗前后分别为22．77±17．14μIU／mL和23.06± 17．29μIU／mL(P<0．05),两组之间比较和0分及2h治疗前后均没有差别。两组安全性方面没有差别。结论那格列奈和瑞格列奈一样是安全有效的降血糖药物。     

Decreased natural killer (NK) cell activity in zinc-deficient rats

• 1.1. In the study, the effect of zinc deficiency, a natural killer (NK), and lipopolysaccharide (LPS) activated NK cell activity were investigated.
• 2.2. Rats were fed with zinc-deficient and normal diet for 3 weeks.
• 3.3. NK and LPS activated NK cell activity was 7.2 ± 1.8%/10⁶ cells (n = 10) and 9.5 ± 4.3%/10⁶ cells (n = 10), respectively, in the zinc deficient group. In the control group fed with normal diet, NK and LPS activated NK cell activity was 22.2 ± 3.3%/10⁶ cells (n = 10) and 32.5 ± 3.5%/10⁶ cells (n = 10), respectively.
• 4.4. Plasma zinc concentration was 131.7 ± 8.8 μg/dl in the zinc-deficient group and 206 ± 17.7 μg/dl in the control group.
• 5.5. The results suggest that decreased NK and LPS activated NK cell activity is associated with zinc deficiency.

     

Higher rate of hyperglycemia than hypoglycemia during Ramadan fasting in patients with uncontrolled type 1 diabetes: Insight from continuous glucose monitoring system

Background

Patients with uncontrolled type 1 diabetes mellitus (T1DM) are at a high risk for Ramadan fasting and are exempt from fasting; however, most still insist on fasting. The aim of this study was to examine glucose level fluctuations in those patients during Ramadan fasting using a real-time continuous glucose monitoring system (RT-CGMS).

Population pharmacokinetics of recombinant factor VIII:C (ReFacto®) in adult HIV-negative and HIV-positive haemophilia patients

Purpose

The aim of this study was to explore possible differences in the pharmacokinetics (PK) of recombinant factor VIII:C (ReFacto® - ReFacto ) in HIV+ vs. HIV– patients and also differences in the chromogenic substrate bioassay (CHS) and one-stage clotting (OSC) methods.

Methods

Twenty-eight haemophilia A adults (20 HIV– and eight HIV+) were assayed with both the CHS and OSC methods. An average of two and six samples were collected per patient for HIV–/+, respectively, after one, and occasionally two more, prophylactic doses (mean 2,003 IU; range 1,000–4,300 IU). The observations were analysed with the mixed-effects (population) compartmental PK modelling package NONMEM (nonlinear mixed-effects modelling) and the FOCE (first-order conditional estimation) method. Base modelling was performed independently for the CHS and OSC bioassays for comparison, and covariate models and simulation tests were done only for the commonly used OSC bioassay. The final covariate model was validated using the bootstrap method. Monte Carlo simulations were used to estimate the expected probability of exceeding 20%, 40% or 60% of normal factor VIII:C in plasma after a single dose, corresponding to required levels for preventing mild, moderate and life-threatening haemorrhages.

Results

One-compartment base-model population PK parameters were [mean parameter (interpatient variability %)] for CHS: clearance (CL)?=?2.56 dl h^?1 (33.2%); volume of distribution (V)?=?34.8 dl (12.8%); and for OSC: CL?=?3.83 dl h^?1 (47.8%), V?=?53.7 dl (22.4%). The volumes differed significantly between the CHS and OSC methods (p?1/2?=?l n (2) × V/CL) were similar for CHS and OSC, [(mean ± standard deviation (SD)], 9.5 ± 3 h and 10.2 ± 4 h, respectively. In covariate modelling with the OSC-derived model, HIV status (VIR) was a significant categorical predictor (p?

Conclusions

Both HIV– and HIV+ patients showed 100% success with the 20% threshold at doses >20 IU/kg. HIV– patients receiving >50 IU/kg had a 100% expected chance of success for all thresholds. HIV+ patients for moderate or life-threatening haemorrhage treatment need 10 IU/kg more than the HIV– patient equivalent to have the same probability of success.

     

Serum Iron Concentrations and Symptoms of Acute Iron Poisoning in Children

Study Objective . To determine whether serum iron concentrations correlate with the development of symptoms of iron poisoning in children. Design . A retrospective study of medical records from January 1976 through June 1992. Setting . A tertiary care children's medical center. Patients . Criteria for patient selection included an acute ingestion of iron-containing drugs, measurement of serum iron prior to deferoxamine administration, and a serum iron concentration (obtained within 2–9 hours of exposure) that was greater than 150 μg/dl (27 μmol/L). Of the 128 children who were hospitalized for acute iron poisoning, 92 patients (mean age 2.3 ± 2.2 years) met the selection criteria. Interventions . None. Measurements and Main Results . The mean (± SD) serum iron concentrations (μg/dl) of patients who exhibited cardiovascular instability (725 ± 555, n = 6; p < 0.001) differed from those categorized with central nervous system changes (373 ± 77, n = 30), gastrointestinal symptoms (334 ± 83, n = 44), and no symptoms (368 ± 102, n = 12). Serum iron concentrations in patients with cardiovascular instability ranged from 205–500 μg/dl (37–269 μmol/L), whereas those with no symptoms ranged from 170–513 μg/dl (30 to 92 μmol/L) demonstrating considerable overlap of ranges. Conclusions . Serum iron concentrations do not necessarily relate to acute toxicity, and further study is needed to demonstrate the value of serum iron concentrations and to identify alternative strategies in the emergency assessment of the acutely poisoned child.     

Pharmacokinetics and Safety of Concentration-Controlled Oral Zidovudine Therapy

Study Objective . To evaluate the pharmacokinetics, safety, and feasibility of concentration-controlled oral zidovudine therapy. Design . Randomized, crossover, open-label study. Setting . University-affiliated general clinical research center. Patients . Eight individuals infected with the human immunodeficiency virus with CD4₊ lymphocyte counts of 100 cells/μl or greater. Intervention . During the 24-week study, patients received oral zidovudine regimens that consisted of a standard fixed dose of 500 mg/day and a concentration-controlled regimen designed to maintain a steady-state plasma concentration (C_ss) of 0.187 ± 0.04 mg/L (0.7 ± 0.14 μM). Measurements and Main Results . The mean C_ss during standard therapy was 0.170 ± 0.024 mg/L versus 0.205 ± 0.021 mg/L with the concentration-controlled regimen (p=0.025). Respective mean changes in hemoglobin were −0.02 g/dl (range −0.9–0.9 g/dl) and −0.30 g/dl (range −1.5–0.4 g/dl, p=0.67). The absolute neutrophil count decreased 0.90 × 10⁹/L during standard therapy and increased 0.40 × 10⁹/L during concentration-controlled therapy (p=0.07). The regimens did not differ in toxicity. Conclusion . Concentration-controlled oral antiretroviral therapy with zidovudine is feasible and safe, and provides pharmacologic data to determine the regimen's virologic and immunologic benefits.