Drug-incorporating calcium carbonate nanoparticles for a new delivery system.

We devised a simple method for incorporating drugs into solid calcium carbonate nanoparticles (nano-CaCO3). The size of nano-CaCO3 was controlled by mixing speed. Washing the nanoparticles released little incorporated drug but much drug that was adsorbed on the surface. In an in vitro releasing test, granulocyte colony-stimulating factor incorporated in nano-CaCO3 was chemically stable and released very slowly. Subcutaneous injection of nano-CaCO3 incorporating betamethasone phosphate (BP) resulted in a smaller initial increase in plasma concentration and a subsequent sustained release in compared with betamethasone phosphate solution. Nano-CaCO3 may be useful to deliver hydrophilic drugs and bioactive proteins.

The role of cholinergic and noncholinergic mechanisms in the cardiorespiratory failure produced by N-methylcarbamate cholinesterase inhibitors in rabbits.

We investigated the relative contribution of several cardiorespiratory components to acute lethality produced by N-methylcarbamate cholinesterase (ChE) inhibitors physostigmine, 2-sec-butylphenyl methylcarbamate (BPMC), and 2-isopropoxyphenyl methylcarbamate (PHC) in halothane-anesthetized rabbits. Intravenous injection of these compounds produced dose-dependent pressor and/or depressor responses related to each compound. A lethal dose of physostigmine resulted in cardiovascular collapse after a pressor response. That of PHC produced cardiovascular collapse after biphasic effects on blood pressure, a transient decrease followed by an increase. Unlike these compounds, BPMC elicited a rapidly developing depressor response followed by cardiovascular collapse. Artificial ventilation prevented cardiovascular collapse and lethal actions to physostigmine and PHC, but not BPMC. A degree of acute lethality to physostigmine and PHC depended on their anti-ChE activity, whereas BPMC exhibited a low degree of lethality relative to its anti-ChE activity. While the pressor response to physostigmine and PHC was ascribed to an atropine-sensitive increase in cardiac contractility, the depressor response to PHC and BPMC was attributed to an atropine-insensitive decrease in cardiac contractility and/or vascular resistance. Similar to the order for eliciting the depressor response in vivo, all three compounds inhibited contraction of the isolated cardiac and aortic smooth muscles with the order of their inhibition in terms of anti-ChE activity, i.e., BPMC > PHC > physostigmine. Thus, the primary cause of death with physostigmine and PHC is respiratory arrest subsequent to ChE inhibition, whereas BPMC exhibiting the low degree of lethality causes cardiovascular collapse mediated through direct inhibitory effects on cardiac and vascular smooth muscle contraction.

Pharmacological analysis of noncholinergic action of 2-sec-butylphenyl N-methylcarbamate insecticide on the isolated rabbit aorta.

We investigated noncholinergic actions of 2-sec-butylphenyl N-methylcarbamate (BPMC) on the isolated rabbit thoracic aorta to help determine the mechanisms responsible for its unique toxicological properties, which are characterized by cardiovascular collapse and low lethality compared to its anticholinesterase (anti-ChE) activity. BPMC inhibited K(+)-induced contraction more effectively than it did norepinephrine (NE)-induced contraction. The inhibitory effect on K(+)-induced contraction was not altered by changing the external K(+) concentration, but it was decreased by adding an L-type Ca(2+) channel agonist, BAY K 8644. Simultaneous measurement of tension and cytosolic Ca(2+) levels elevated by K(+) stimulation revealed that BPMC decreased the Ca(2+) levels prior to and parallel to the tension. The magnitude of the inhibitory effect on Ca(2+) levels was increased by treating BPMC before Ca(2+) application in the depolarized preparation. However, BPMC did not inhibit caffeine- or NE-induced transient contraction in Ca(2+)-free medium. On the other hand, BPMC produced tonic contraction in the resting aorta. The contraction to BPMC did not develop after removing the adventitia. The contraction was inhibited by phentolamine or guanethidine but not by atropine or tetrodotoxin. These results suggest that BPMC inhibits depolarization- or agonist-induced contraction by inhibiting Ca(2+) entry through L-type Ca(2+) channels, whereas it produces vascular contraction in the resting state by releasing NE from sympathetic nerve terminals. These apparently opposing mechanisms may contribute to the unique noncholinergic toxicological properties of BPMC.

Cardiovascular collapse through non-cholinergic mechanism after intravenous injection of N-methylcarbamate insecticide in rabbits.

This study was undertaken to investigate whether cholinesterase (ChE) inhibitor exerts cardiovascular collapse through non-cholinergic mechanism in halothane-anesthetized rabbits. Physostigmine and N-methylcarbamate insecticides (BPMC = 2-sec-butylphenyl methylcarbamate and PHC = propoxur = 2-isopropoxyphenyl methylcarbamate) were employed as ChE inhibitors. Intravenous injection of physostigmine produced a dose-related pressor response a few minutes after the injection. In contrast, the injection of BPMC elicited a dose-related depressor response during the injection. PHC produced a slight depressor response during the injection followed by a dose-dependent pressor response. Norepinephrine (NE)-induced pressor response was inhibited by the ChE inhibitors with the same order and magnitude as the depressor response. ECG of physostigmine or PHC was characterized by an increase in QRS voltage and a sinus bradycardia, and that of BPMC by a decrease in QRS voltage. Atropine pretreatment inhibited the pressor response, the increase in QRS voltage and the sinus bradycardia, but not the depressor response and the decrease in QRS voltage. From these observations, it is suggested that the pressor response is ascribed to the cholinergic mechanism (acetylcholine accumulation through ChE inhibition), but the depressor response may result from a non-cholinergic mechanism. It is also suggested that the difference in the cardiovascular response is determined by a balance between cholinergic and non-cholinergic activity of each ChE inhibitor.

Non-cholinergic lethality following intravenous injection of carbamate insecticide in rabbits.

This study was undertaken to investigate the possibility that non-cholinergic mechanism accounts for acute lethality of cholinesterase (ChE) inhibitor. Physostigmine and carbamate insecticides (2-s-butylphenyl methylcarbamate (BPMC); isoprocarb, 2-isopropylphenyl methylcarbamate (MIPC); and propoxur, 2-isopropoxyphenyl methylcarbamate (PHC)) were employed as ChE inhibitors. Rabbits intravenously given any of the ChE inhibitors showed typical signs of anti-ChE poisoning, a marked inhibition of systemic ChE activity, and an increase in RR interval on an ECG. Injection of physostigmine or PHC at a lethal dose produced a pressor response before cessation of spontaneous breathing. In contrast, injection of MIPC or BPMC primarily elicited a cardiovascular collapse, characterized by a rapid and progressive decrease in blood pressure and a decrease in QRS amplitude of ECG, before cessation of spontaneous breathing. The atropine pretreatment inhibited the pressor response, but not the depressor response and the QRS change. The pretreatment antagonized acute lethality of the ChE inhibitors except BPMC. It is suggested that the mode of lethality for intravenous ChE inhibitor could be determined by a balance between anti-ChE activity and some mechanism other than ChE inhibition. BPMC produced acute lethality through the latter mechanism rather than the former one.

A novel second-generation polyolefin container for storage of single-donor apheresis platelets.

A non-blow-molded LE-2 polyolefin (PO) container was developed to store single-donor apheresis platelet concentrates (PCs) processed by the Haemonetics Plasma Collecting System (PCS) at 22 degrees C for over 1 day. We molded PO containers with heat-sealing of light-weight polymer alloy films with a thickness of 0.25 mm. The film was made of polymer blends consisting of polypropylene, styrene ethylene butylene styrene-block copolymer, and ethylene ethylacrylate copolymer. The PO container with enough strength and flexibility in routine practice has 2 and 1.6 times higher oxygen and carbon dioxide gas transfer properties than standard polyvinyl chloride (PVC) plastic containers. PCs (1-1.9 x 10(11) platelets) processed from 450 ml platelet-rich plasma were stored in 0.6-liter PO containers at 22 degrees C with flatbed agitation for up to 6 days. The pH of PCs was well maintained at the mean values of 7.0 in PO containers after 6 days in the well-oxygenated condition. The energy metabolism of stored platelets was determined. Oxygen consumption rates of platelets stored in PO containers averaged 1.5 nmol/min/10(9) platelets. The rates of glucose consumption and lactate production were 0.4 and 0.8 nmol/min/10(11) platelets, respectively. The rates of adenosine triphosphate (ATP) generation of platelets, 9.7 nmol/min/10(9) platelets, in PO containers did not differ from those in the PVC containers. Aggregation responses to adenosine diphosphate and hypotonic shock response of platelets were better maintained in PO containers. The morphological changes into sphere forms with projections and the appearance of unclassified forms were more frequently observed in PO than in PVC containers.(ABSTRACT TRUNCATED AT 250 WORDS)