Sympathetic reinnervation after heart transplantation, assessed by iodine-123 metaiodobenzylguanidine imaging, and heart rate variability.

OBJECTIVE: Complete allograft denervation occurs during heart transplantation. Partial ventricular sympathetic reinnervation may develop one year or later after transplantation and can be measured with iodine-123-meta-iodobenziylguanidine (MIBG) uptake. Aim of this study was to assess sinus node sympathetic reinnervation measured with heart rate variability and ventricular sympathetic reinnervation evaluated with MIBG. METHODS: Twelve patients and 14 healthy controls were included. In patients, MIBG scintigraphy with early and late imaging was performed. Heart to mediastinum ratio (HMR) was calculated and patients were divided in groups with (HMR>1.3) and without left ventricular reinnervation (HMR<1.3). Bipolar ECG with high sampling rate and resolution was recorded over 8.5 min in supine position and in upright position after 10 min interval. R-R intervals in time domain and heart rate variability in frequency domain through spectral power analysis of R-R intervals were analysed to evaluate sinus node reinnervation. Spectral power in low frequency range (0.04-0.15 Hz) above 4.5 ms(2) was considered as sinus node sympathetic reinnervation. RESULTS: Six (50%) patients had evidence of left ventricular sympathetic reinnervation on scintigraphy. Sinus node sympathetic reinnervation based on heart rate variability was detected in 6 (50%) patients in supine, and in 4 (33%) patients in upright body position. Four patients groups were discerned: (1) with ventricular and sinus node sympathetic reinnervation, (2) with sinus node sympathetic reinnervation, (3) with ventricular sympathetic reinnervation and (4) without atrial or ventricular sympathetic reinnervation. Ventricular reinnervation process was time dependent and sinus node reinnervation was not. CONCLUSIONS: Simultaneous ventricular sympathetic reinnervation assessed by MIBG and sinus node sympathetic reinnervation assessed by heart rate variability in supine as in upright position were detected only in two patients (17%). The results of our study show that eventual sinus node sympathetic reinnervation and left ventricular sympathetic reinnervation do not occur simultaneously.     

Dose-dependent Inhibition of Platelet Function by Acetaminophen in Healthy Volunteers

Background: Acetaminophen (paracetamol) is widely used for postoperative analgesia. Its mechanism of action is inhibition of prostaglandin synthesis in the central nervous system, and acetaminophen is traditionally not considered to influence platelet function. The authors studied the dose-dependent inhibition of platelet function by acetaminophen in healthy volunteers.

Methods: Thirteen healthy male volunteers (aged 19-26 yr) were given placebo or 15, 22.5, or 30 mg/kg acetaminophen intravenously in a double-blind, crossover study. Ten and 90 min after infusion, platelet function was assessed by photometric aggregometry and by measuring release of thromboxane B2, analgesia by cold pressor test, and plasma acetaminophen concentrations by high-performance liquid chromatography.

Results: When triggered with 500 [mu]m arachidonic acid, median platelet aggregation (area under the curve) was 25.7, 22.8, 4.1, or 3.6 x 103 area units (P < 0.001) 10 min after placebo or 15, 22.5, or 30 mg/kg acetaminophen, respectively. An increasing concentration of arachidonic acid attenuated the antiaggregatory effect. After 90 min, platelet function was recovering. Release of thromboxane B2 was also dose-dependently inhibited by acetaminophen. Although plasma concentration of acetaminophen increased linearly with the dose, no analgesic effect was detected in the cold pressor test.     

Synthesis of a new hydroxyethylene dipeptide isostere Phe ψ[CH2CH(OH)]Phe as HIV-1 protease inhibitor

A new type of pseudodipeptide isostere exampled by Phe ψ[CH2CH(OH)]Phe was synthesized from phenylalanine. The H]V protease inhibitory activity (IC50) of Noa-His-Pheψ[CH2CH(OH)]Phe-Ile-Amp was 0. 8 pmol·L-1.     

Hydroxypropyl-β-Cyclodextrin Increases the Aqueous Solubility and Stability of Pilocarpine Prodrugs

Purpose. The effects of 2-hydroxypropyl--cyclodextrin (HP--CD) on the aqueous solubility and stability of two lipophilic bispilocarpine prodrugs were investigated at pH 7.4. Methods. The solubility of prodrugs was studied by phase-solubility method (0–72.5 mM HP--CD). The stability of one of the prodrugs was investigated as a function of temperature (40°C–70°C) and HP--CD concentration (0–72.5 mM). The apparent rate constants (k ₁, k ₂) for degradation of prodrug in 1:1 and 1:2 inclusion complexes and apparent stability constants (K _1:1, K _l:2) were calculated by the curve-fitting method. Results. The phase-solubility diagrams were classified as A_p-type and the apparent stability constants (K _l:l, K _l:2) for 1:1- and 1:2-inclusion complexes were calculated to be 143–815 M^–l and 29–825 M^–1, respectively. The stability of prodrug increased as a function of HP--CD concentration over the studied temperature range. The shelf-life (t _90%, calculated by the Arrhenius equation) of the prodrug in 72.5 mM HP--CD solution increased 5.1-fold and 6.1-fold at 25°C and 4°C, respectively. Conclusions. The solubility of the prodrugs was shown to increase markedly in phase-solubility studies. The degradation rate of prodrug in stability studies was shown to be slower in the l:2-complex than in the l:l-complex and the relative amounts of complex species were found to be dependent on CD concentration.     

Improved Corneal Pilocarpine Permeability with O,O′-(l,4-Xylylene) Bispilocarpic Acid Ester Double Prodrugs

0,0-(l,4-Xylylene) bispilocarpic acid esters are pilocarpine pro-drugs containing two pilocarpic acid monoesters linked with one pro-moiety. Each mole of prodrug forms two pilocarpine moles in the presence of esterases. Corneal uptake and permeability of various bispilocarpic acid diesters were investigated in vitro using isolated albino rabbit corneas. The permeability coefficient of pilocarpine was 2.8 × 10 ^–6 cm/sec, whereas for bispilocarpic acid diesters, despite their large molecular weights (between 638 and 722), permeability coefficients were 6.5–20.2 × 10 ^–6 cm/sec. Only pilocarpine, and no intact prodrug, was observed at the endothelial side. Corneal uptake was increased with increasing lipophilicity, but a parabolic relationship between the logarithm of the apparent partition coefficient (1-octanol–pH 7.4 phosphate buffer) (log PC) and the corneal permeability was noticed. Corneal permeability and the rate of enzymatic hydrolysis of the compounds correlated well. The corneal permeability of pilocarpine given as lipophilic bispilocarpic acid diester (log PC 3) prodrugs seems to be controlled by the formation of pilocarpine in the corneal epithelium rather than by the absorption of prodrugs into the epithelium or their epithelium–stroma transport rate.     

Anandamide prodrugs. 1. Water-soluble phosphate esters of arachidonylethanolamide and R-methanandamide.

Phosphate esters of arachidonylethanolamide (AEA) and R-methanandamide were synthesized and evaluated as water-soluble prodrugs. Various physicochemical properties (pK(a), partition coefficient, aqueous solubility) were determined for the synthesized phosphate esters. The chemical stability of phosphate esters was determined at pH 7.4. In vitro enzymatic hydrolysis rates were determined in 10% liver homogenate, and in a pure enzyme-containing (alkaline phosphatase) solution at pH 7.4. The intraocular pressure (IOP) lowering properties of R-methanandamide phosphate ester were tested on normotensive rabbits. The phosphate promoiety increased the aqueous solubility of the parent compounds by more than 16500-fold at pH 7.4. Phosphate esters were stable in buffer solutions, but rapidly hydrolyzed to their parent compounds in alkaline phosphatase solution (t(1/2)<15 s) and liver homogenate (t(1/2)=8-9 min). The phosphate ester of R-methanandamide reduced IOP in rabbits. These results indicate that the phosphate esters of AEA and R-methanandamide are useful water-soluble prodrugs.     

Inefficient central nervous system delivery limits the use of ibuprofen in neurodegenerative diseases.

Chronic use of non-steroidal anti-inflammatory drugs may reduce the risk or delay the onset of Alzheimer's disease. To date, only limited information exists on the brain distribution of these drugs. The objective of this study was to determine the absolute brain delivery of ibuprofen by using constant in vivo infusion in rats. Ibuprofen was infused to steady-state concentrations both in plasma and brain tissue. Ibuprofen levels in plasma and brain tissue were measured by RP-HPLC after the plasma and the brain samples were purified by protein precipitation and solid phase extraction, respectively. Results indicate that both plasma and brain concentrations reached steady-state within 6h, and that the brain to plasma ratio of ibuprofen was only 0.02. Thus, limited brain penetration prevents the possible use of ibuprofen in treating or preventing neurodegenerative disorders such as Alzheimer's disease.     

Retaining Mechanical Properties of GMA-Welded Joints of 9%Ni Steel Using Experimentally Produced Matching Ferritic Filler Metal

Motivated by the loss of tensile strength in 9%Ni steel arc-welded joints performed using commercially available Ni-based austenitic filler metals, the viability of retaining tensile strength using an experimentally produced matching ferritic filler metal was confirmed. Compared to the austenitic Ni-based filler metal (685 MPa), higher tensile strength in gas metal arc (GMA) welded joints was achieved using a ferritic filler metal (749 MPa) due to its microstructure being similar to the base metal (645 MPa). The microstructure of hard martensite resulted in an impact energy of 71 J (−196 °C), which was two times higher than the specified minimum value of ≥34 J. The tensile and impact strength of the welded joint is affected not only by its microstructure, but also by the degree of its mechanical mismatch depending on the type of filler metal. Welds with a harder microstructure and less mechanical mismatch are important for achieving an adequate combination of tensile strength and notched impact strength. This is achievable with the cost-effective ferritic filler metal. A more desirable combination of mechanical properties is guaranteed by applying low preheating temperature (200 °C), which is a more practicable and economical solution compared to the high post-weld heat treatment (PWHT) temperature (580 °C) suggested by other research.