Community pharmacists' measurement of health-related quality of life in outpatients taking high-risk drugs.

Patients experiencing severe side effects when taking high-risk drugs may have a significantly reduced health-related quality of life (QOL); therefore, it is important to identify changes in the health-related QOL in these patients. This study aimed to determine the health-related QOL in community pharmacy outpatients taking high-risk drugs. This prospective observational study was conducted in 29 community pharmacies with 71 pharmacists in 12 regions and cities in Japan from October to December 2020 and 760 patients were enrolled. Using descriptive questionnaires of EuroQOL-5-dimensions-5-levels (EQ-5D-5L), community pharmacists obtained health-related QOL data from outpatients taking high-risk drugs. The mean health-related QOL of all outpatients was 0.869. The health-related QOL decreased with increasing age. The outpatient health-related QOL was 0.700, 0.763, 0.785, and 0.817 when taking antiepileptic, antidepressant, digitalis, and antiarrhythmic drugs, respectively, which was lower than the average health-related QOL of all outpatients. Mobility and pain/ discomfort accounted for a large proportion of the decline in the health-related QOL with increasing age. There were no significant differences in personal care with increasing age; however, the number of outpatients with mobility, normal activity, and pain challenges decreased with age. In contrast, outpatients aged <65 years with anxiety/depression showed a lower than overall average health-related QOL. To the best of our knowledge, this is the first study in Japan to report an investigation by community pharmacists regarding health-related QOL assessment in outpatients taking high-risk drugs.

In vitro release of Tacrolimus from Tacrolimus ointment and its speculated mechanism.

The in vitro release profiles and the bleeding phenomenon of Tacrolimus and propylene carbonate (PC) as a dispersing solvent for Tacrolimus drug substance in Tacrolimus ointment were investigated when changing concentrations of Tacrolimus and PC in the ointment were used, respectively. The bleeding test result indicated that Tacrolimus was in equilibrium between inside and outside of PC droplets in intact ointment base. A cumulative release amount of Tacrolimus from ointment, plotted against the square root of time, showed a straight line initially with a slope of q1 followed to change a slope to be q2 at a certain time, where the relation of these slopes being q1

Potential role of the anterior spinal artery in preventing propagation of thrombus in a therapeutically occluded vertebral artery: angiographic studies before and after endovascular treatment.

Therapeutic occlusion of the vertebral artery (VA) is one of the treatments for unclippable aneurysms and other lesions, although controversy still surrounds the appropriate site for occlusion to attain selective thrombosis of the lesion while avoiding ischaemic complications. The lower two-thirds of the lateral medulla are supplied by perforating branches of both the VA and the posterior inferior cerebellar artery (PICA). However, in patients without a PICA or in whom the origin of the PICA is low (at or below the foramen magnum), the VA is usually the only source of perforating vessels. We retrospectively studied the results of VA occlusion on such anatomically high-risk patients, and propose a safer procedure. Five high-risk patients underwent therapeutic occlusion of the VA for dissecting aneurysms or arteriovenous fistula. A lateral medullary syndrome developed due to propagation of thrombus after the procedure in two patients in whom angiography did not demonstrate the anterior spinal artery (ASA) within the stump of the VA. Ischaemic signs did not develop in the other three patients, in whom the ASA was visible, and retrograde flow was observed proximal to the origin of the ASA. This suggests that the ASA may play a role in preventing propagation of thrombus in the VA distal to the site of occlusion and supply blood to its perforating arteries in high-risk patients. Angiographic assessment of the ASA may be useful for predicting the likelihood of the lateral medullary syndrome developing with therapeutic occlusion of the VA in patients without a PICA or with one whose origin is low.

Facilitation of passive avoidance response by newly synthesized cationized arginine vasopressin fragment 4-9 in rats.

The effects of a newly synthesized cationized arginine vasopressin fragment 4-9 analogue (C-AVP-(4-9)) on learning and memory in rats were studied by the passive avoidance test. C-AVP-(4-9) and its parent peptide, arginine vasopressin fragment 4-9 (AVP-(4-9)), a well known potent neuropeptide, were subcutaneously injected 1.5 hr prior to the retention test. The most effective doses of C-AVP-(4-9) and AVP-(4-9) were 8.6 x 10(-2) and 1.3 nmol/kg, respectively. To evaluate the distribution of C-AVP-(4-9) in the control nervous system (CNS), apparent tissue-plasma concentration rations (Kp.app) of intravenously administered radioiodinated C-AVP-(4-9) (125I-C-AVP-(4-9)) in the CNS in mice were determined. At the apparent steady state of plasma concentration of 125I-C-AVP-(4-9), the Kp.app values of the 125I-C-AVP-(4-9) in the cerebrum, cerebellum and spinal cord were over 12 times higher than that of the vascular space marker which slightly penetrates the BBB. Moreover, the rat cerebral homogenate converted C-AVP-(4-9) into its parent peptide AVP-(4-9). These results suggest that the potent effects of C-AVP-(4-9) on learning and memory may be due to AVP-(4-9) generated as a result of distribution and metabolism of peripherally administered C-AVP-(4-9) in the CNS.

Synthesis of Didocosahexaenoylphosphatidylserine.

1,2-Di-O-isopropylideneglycerophosphorochloridate prepared from isopropylindene glycerol and phosphorus oxychloride, was allowed to react with Z-l-serine-N-phthalimidomethyl ester to obtain a derivative of phosphatidylserine. Then, after the isopropylidene group was removed by Amberlite IR-120 (H(+)), and the phosphate group was also blocked as a Ba-salt, this derivative was coupled with docosahexaenoic acid, applying the method of activated ester. Removal of both protective groups of serine was finally done by dry hydrogen chloride in chloroform.

Mechanism of mobilization of cadmium by dithiocarbamates in rat primary hepatocyte cultures.

The mechanism of mobilization of cadmium (Cd) by N-benzyl-D-glucamine dithiocarbamate (BGD) and N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD) in rat primary hepatocyte cultures was studied. Probenecid pretreatment increased Cd efflux from the hepatocytes by BGD, but did not affect Cd efflux by HBGD. p-Aminohippurate treatment had no effect on Cd efflux by the chelating agents. These results suggest that an enhancing effect of probenecid on the BGD-induced Cd mobilization is due to its inhibitory effect on the glucuronidation of BGD and not its specific action on BGD transport. Verapamil and nicardipine had no effect on the chelating agent-induced Cd mobilization. Phlorizin did not affect Cd efflux by BGD or HBGD. Phloretin and cytochalasin B inhibited Cd efflux by the chelating agents. These results seem to be evidence that BGD and HBGD may be transported by a facilitated diffusion system in the hepatocytes.

Uses of Grafton for reconstructive foot and ankle surgery.

Grafton is a demineralized allogenic bone grafting substance supplied in gel form. The gel consistency allows simple application of this osteoinductive substance. Possible applications and cases are presented.

CPT-11 converting enzyme from rat serum: purification and some properties.

A rat serum enzyme that catalyzes the conversion of a pro-drug, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), to an anticancer drug, 7-ethyl-10-hydroxycamptothecin (SN-38), was purified and its properties were characterized. The enzyme was purified by column chromatography on diethylaminoethyl Toyopearl 650M, QAE-Sephadex, Sephadex G-150, Con A-Sepharose and high performance liquid chromatography with an ion-exchanger column. It was most active at pH 7.5 and was stable at pH 4-9 for 1 h at 30 degrees C. The molecular weight was estimated to be 60 and 57 kDa by gel filtration and sodium dodecylsulfate-polyacrylamide gel electrophoresis methods, respectively, and the isoelectric point was 4.6, as determined by isoelectric focusing. The Km value for CPT-11 was 0.28 microM. This enzyme was inhibited by diisopropyl phosphorofluoridate (DFP) and phenylmethanesulfonyl fluoride (PMSF) but insensitive to eserine, p-chloromercuribenzoate (PCMB) and ethylenediaminetetraacetate (EDTA). The enzyme also hydrolyzed p-nitrophenylacetate (p-NPA), a commonly used substrate for esterases, but was not active toward acetylcholine, suggesting that the enzyme is a carboxylesterase[EC 3.1.1.1]. During the hydrolyses of CPT-11 and p-NPA, an initial burst phenomenon similar to that found in the alpha-chymotrypsin-catalyzed hydrolysis of p-NPA was observed. Kinetic analysis revealed that the deacylation of the enzyme is the rate-limiting step in substrate hydrolysis. This enzyme was found to also split other ester derivatives of SN-38 besides CPT-11.

Aneurysmal bone cyst of the cuboid.

Aneurysmal bone cysts are a rare entity encountered in podiatric medicine. The frequency of aneurysmal bone cysts distal to the ankle joint is low. The authors present a literature review of the etiologies and possible treatments of an aneurysmal bone cyst. An unusual case of an aneurysmal bone cyst in the cuboid is also presented. Only one other documented case of an aneurysmal bone cyst in the cuboid has been reported since 1967.

Specific inhibitors for prolyl endopeptidase and their anti-amnesic effect.

Several peptides and peptide derivatives were tested for their inhibitory effect on prolyl endopeptidase and possible properties as anti-amnesic agents. Among the compounds tested, Z-Gly-Pro-CH2Cl, Z-Val-prolinal, Boc-Pro-prolinal, Z-Pro-prolinal, aniracetam and pramiracetam inhibited the enzyme activities at Ki values in the order of nM to microM, and the effect of the prolinal-containing peptide derivatives was specific for prolyl endopeptidase. Z-Pro-prolinal was the most effective inhibitor in vitro (Ki = 5 nM) and in vivo (50 to 70% inhibition in various organs of rat at a dose of 1 mumol/animal i.p.). Regional differences were observed in the effect of inhibitors on the brain enzyme activities: most active in mesencephalon, followed by striatum, cerebellum, hippocampus, hypothalamus; and inactive in cerebral cortex and medulla oblongata. In the passive avoidance learning test using rats, pretreatment with Z-Pro-prolinal prevented the induction of amnesia by scopolamine at the dose of 1 mumol/animal, i.p. Z-Val-prolinal, Z-Pyr-prolinal and Z-Gly-Pro-CH2Cl were also effective in the retention test at 24 and 48 h after the training trial. The antiamnesic effect of these compounds was approximately parallel to the in vitro inhibitory activities on prolyl endopeptidase. These results suggest the possibility that the inhibitors exhibit their anti-amnesic effect through the regulation of the enzyme activity in the brain.

Comparison of inhibitory effects of prolinal-containing peptide derivatives on prolyl endopeptidases from bovine brain and Flavobacterium.

The inhibitory effects of proline-containing peptides and their derivatives on prolyl endopeptidases from Flavobacterium meningosepticum and bovine brain were compared. Replacement of the carboxyl terminal proline in N-blocked peptides with prolinal resulted in remarkable decreases in Ki values for both prolyl endopeptidases. Further reduction of the prolinal to prolinol led to a decrease in their inhibitory effects. Z-Pro-, Z-Val-, and Suc-Pro-prolinals were similarly inhibitory for both the enzymes with Ki values of nM order. However, the inhibitory effects of Z-Pyr-prolinal and Boc-Pro-prolinal on these enzymes were significantly distinguished: they strongly inhibited the mammalian prolyl endopeptidase with Ki values of nM order, while the Ki values of these compounds for the microbial enzyme were only of microM order. These results suggest that there are some structural differences in the S2 and S3 subsites between the two enzymes, though their substrate specificities are apparently indistinguishable.

Spontaneous rupture of the common carotid artery.

A spontaneous rupture of the common carotid artery occurred in a 56-year-old, apparently healthy, man. The patient suffered a sudden, painful swelling on the left side of the neck and bulge of the tonsillar fossa simulating a parapharyngeal abscess. Emergency surgical exploration of the neck revealed a 5-mm rent in the common carotid artery 15 mm proximal from the bifurcation. Such abnormalities as aneurysm, thickness, or thinness of the arterial wall were not detected. The rent was closed by sutures during temporal ligation of the carotid artery. The duration of the temporal interruption of the bloodstream was not longer than three minutes. Postoperative examinations did not indicate atherosclerosis or syphilis. There are several possible causes of this rupture.

Characteristic biotransformation of aminopyrine in rat when administered with barbital.

After the administration of aminopyrine with or without barbital to rats, aminopyrine and its main metabolites were detected in plasma and the brain by means of gas chromatography-mass spectrometry. It was clarified that a marked increase of 4-monomethylaminoantipyrine was observed in the case of coadministration of aminopyrine and barbital, while the plasma level of aminopyrine decreased significantly compared with single administration.

Purification and characterization of L-pyrrolidonecarboxylate peptidase from Bacillus amyloiliquefaciens.

Microorganisms capable of producing L-pyrrolidonecarboxylate peptidase [L-pyrrolidonyl peptidase, EC 3.4.11.8] were screened and a strain of Bacillus amyloliquefaciens was chosen as one of the most potent producers of the enzyme. The enzyme was purified from lysozyme-lysate of the bacterial cells by salting out with ammonium sulfate, adsorption on DEAE-cellulose, covalent chromatography on PCMB-Sepharose and by gel filtration on Sephadex G-150. By these procedures, the enzyme was purified about 800-fold with an activity recovery of 9%, and the preparation was electrophoretically homogenous. The enzyme was most active and stable at pH 7-8. The presence of 2-mercaptoethanol and EDTA was effective for stabilizing the enzyme. The molecular weight was estimated to be 72,000 by the gel filtration method and to be 24,000 by SDS-polyacrylamide gel electrophoresis, suggesting that the enzyme is a subunit oligomer, presumably trimer. The enzyme was inactivated by the addition of PCMB, sodium tetrathionate, Hg2+ and Cu2+, but the activity lost was restored by the addition of 2-mercaptoethanol and EDTA. The purified enzyme split amide and ester linkages in L-pyroglutamyl derivatives of L-alanine, beta-naphthylamine, alpha-naphthol, and 4-methylumbelliferone, but was completely inert towards various peptides and esters used as substrates for usual amino- and carboxy-peptidases, and for endopeptidases such as trypsin, subtilisin and alpha-chymotrypsin.

Interaction of porcine alpha2-macroglobulin with chemically modified proteinases.

The interactions of porcine alpha2-macroglobulin (alpha2M) with native proteinases, their zymogens and the chemically-modified enzymes were compared. The alpha2M did not bind to chymotrypsinogen, or to most of the chemically modified derivatives of alpha-chymotrypsin, trypsinogen, DIP- and PMS-trypsins, but it could interact with anhydrotrypsin, PMS-subtilisin, and O-acetylated neutral subtilopeptidase. Anhydrotrypsin appeared to bind very tightly to alpha2M, as does native trypsin, whereas the binding of PMS-subtilisin to alpha2M was weaker than that of the native enzyme, judging from exchange experiments with labeled enzyme and from competitive enzyme assay. There are, however, some differences in the mode of interaction with alpha2M between native and anhydrotrypsins. (1) The shape and the magnitude of ultraviolet difference spectra caused by the interaction with alpha2M were significantly different. (2) The interaction of alpha2M with active proteinase led to the formation of new amino-terminal amino acids, while that with anhydrotrypsin did not. (3) In vivo experiments showed that radioactivity of 3H-labeled trypsin-alpha2M complex was rapidly cleared from the plasma of rats, whereas the anhydrotrypsin-alpah2M complex was cleared very slowly. These results suggest that the proteolytic activity of the enzyme is not obligatory for the first phase of alpha2M-proteinase interaction (formation of Michaelis-type complex), but only the proteolytically modified complex is cleared rapidly from the blood circulation system.