Paradoxical antagonism of neuromuscular block by vecuronium metabolites.

Vecuronium is hydrolyzed in the body to 3-deacetyl (ORG 7268), 17-deacetyl (ORG NC58), and 3, 17-bis-deacetyl (ORG 7402) derivatives. Interactions of vecuronium and these metabolites were studied in phrenic nerve-hemidiaphragm preparations of rats. As already reported, ORG 7268 had a potent neuromuscular blocking action, and ORG NC58 and ORG 7402 had a weak neuromuscular blocking action. As expected, ORG 7268 increased the degree of neuromuscular block by vecuronium. However, a low concentration (10 microM) of ORG NC58 and ORG 7402 reversed the block by vecuronium. At a high concentration (50 microM), ORG NC58 and ORG 7402 increased the degree of block by vecuronium. Although we do not have enough data to explain these paradoxical reversal of neuromuscular block at this moment, we postulate that these results reflect the interaction between &#34;slow&#34; and &#34;fast&#34; competitive antagonists. Regardless of the mechanism, it should be emphasized that the concentrations of ORG NC58 and ORG 7402 which are necessary to reverse the block are much lower than those which facilitate the block. It is conceivable that this paradoxical reversal of the block occurs in experimental and clinical situations. Therefore, in determining the neuromuscular blocking action of a compound, the &#34;antagonistic&#34; effect of its metabolites should also be considered.</p

A Prototype Model Using Clinical Document Architecture (CDA) with a Japanese Local Standard : Designing and Implementing a Referral Letter System

Since clinical document architecture (CDA) became an American National Standards Institute (ANSI)-approved health level seven (HL7) Standard, many countries have begun making an eff ort to make local standards conform to CDA. In order to make CDA compatible with the many diff erent local standards existing in diff erent countries, we designed a prototype model using HL7 CDA R2 with medical markup language (MML), a Japanese medical data exchange standard. Furthermore, a referral letter system based on this model was developed. Archetypes were used to express medical concepts in a formal manner and to make 2 diff erent standards work collaboratively. We share herein the experience gathered in designing and implementing a referral letter system based on HL7 CDA, Release 2 (CDA R2). We also outline the challenges encountered in our project and the opportunities to widen the scope of this approach to other clinical documents.</p

前立腺癌に対するPepleomycin(Bleomycin Derivative, NK-631)の効果

未治療の前立腺腺癌2症例に本剤を投与し，その効果を検討した。症例1： 71歳， 排尿困難，左大腿部痛を主訴として1978年6月15日当科受診。前立腺は超鶏卵大，石様硬，表面不整，骨盤へ浸潤。左ソケイ部にくるみ大の硬いリンパ腺を触知。骨シンチで多数の転移を認めた。 前立腺の針生検組織像は分化型腺癌であった。pepleomycin 200 mg (1回10mg，静注， 週3回)の投与により前立腺癌，左ソケイ部リンパ腺の著明な縮小がみられ，血清酸ホスファターゼ値が治療前6.5K.A.U.から9.5K.A.U まで低下した。治療終了後の生検組織像は癌細胞の変性，壊死組織の線維化が目立った。　　症例2: 74歳，排尿困難で1978年8月19日当科受診。前立腺は鶏卵大，硬，周囲に浸潤。骨シンチで転移巣が多数あり，前立腺生検組織像は未分化型腺癌であった。 pepleomycin投与で自覚症状は症例1ほどの改善はみられず，前立腺癌そのものもあまり縮小しなかったが，残尿は80mlから10mlへ減少した。治療後の前立腺生検所見でも癌細胞の空胞化が著明に認められた。なお副作用としては症例1では著明な皮膚変化がみられたが，症例2でぎ軽度の口内炎を認めるにとどまった。NK 631 投与前後で血中FSH，LH，testosteroneを測定したところ，両症例ともに投与終了後FSH，LH，t estosterone値は投与前値の約1/2となっていた (Table 2)。 つまり， NK 631 の抗腫瘍作用はDNA合成抑制によるということになっているが，前立腺癌に対する抗腫聖書効果はNK631 の下重体抑制による睾丸のLeydig cellよりのandrogen分泌抑制も関与している可能性があることが示唆された。本剤の下垂体抑制効果については今後検討されるべき課題であると考える。Since the new bleomycin derivative-pepleomycin was reported to be effective for experimentally induced adenocarcinoma of stomach in rats, it was administered in two cases of prostatic cancer. Satisfactory response was obtained in well differentiated carcinoma, meanwhile only histological effect was observed in undifferentiated one. It seems that the effect of pepleomycin on prostatic cancer was brought about by the suppression of DNA synthesis of tumor and also of pituitary function resulting in decreased androgen secretion from Leydig cells

Interaction of Sevoflurane, Isoflurane, Enflurane and Halothane with Non-Depolarizing Muscle Relaxants and their Prejunctional Effects at the Neuromuscular Junction

The interaction of four inhalational anesthetics (sevoflurane, isoflurane, enflurane and halothane) with pancuronium and vecuronium and also their prejunctional actions at the neuromuscular junction were quantitatively studied using rat phrenic nerve-hemidiaphragm preparations. To investigate the prejunctional effects of inhalational anesthetics, a train-of-four ratio (T4/T1) and the tetanus ratio (the ratio of the final response to the initial response during tetanus) were evaluated. All four inhalational anesthetics markedly potentiated the neuromuscular blockade of twitch response caused by either pancuronium or vecuronium with halothane and enflurane being the most potent both on a % concentration basis and on a MAC (minimum alveolar concentration) basis. Although none of the four inhalational anesthetics had any effects on the T4/T1 ratio, they produced variable effects on the tetanus ratio. Sevoflurane had little effect on the tetanus ratio, whereas 1 and 2% isoflurane and 1, 2 and 3% enflurane increased the tetanus ratio and 5% halothane and 5% enflurane significantly reduced the tetanus ratio. Halothane and enflurane had the most potent depressant action of the four inhalational anesthetics both on the % concentration basis and on the MAC basis. These results indicate that the main site of action of inhalational anesthetics is a postjunctional site at the neuromuscular junction and that they do not seem to act on prejunctional sites at the concentrations used in clinical situations

Clinical and Pathological Improvement in Stroke-Prone Spontaneous Hypertensive Rats Related to the Pleiotropic Effect of Cilostazol

Background and Purpose-Cerebral infarction is a major cause of death or decreasing activities of daily living. This study aimed to investigate the efficacy of commonly used antiplatelet drugs on stroke and motor and cognitive functions in relation to oxidative stress markers and insulin-like growth factor 1 receptor (IGF-1R). Methods-Stroke-prone spontaneously hypertensive rats were treated with vehicle, aspirin, clopidogrel, and cilostazol from 8 to 10 weeks of age. Physiological parameters, regional cerebral blood flow, and serum lipids were examined. Motor and cognitive functions were evaluated weekly by the Rotorod and water maze task. Spontaneous infarct volume, oxidative stress markers for lipid, protein, and DNA at the ischemic boundary zone of spontaneous infarction, and the IGF-1R-positive cell ratio in the hippocampus were immunohistochemically examined in brain sections. IGF-1R beta expression in the hippocampus was assessed by Western blotting. Results-The antiplatelet drugs, cilostazol and clopidogrel, reduced the spontaneous infarct volume more than aspirin. Only cilostazol improved motor and cognitive functions with a significant increase (P<0.05) in the memory-related IGF-1R-positive ratio and IGF-1R beta expression in the hippocampus. Cilostazol reduced the 4 oxidative stress markers in affected neurons in stroke-prone spontaneously hypertensive rats regardless of blood pressure, regional cerebral blood flow, or serum lipid levels. Conclusions-The present results suggest that a possible pleiotropic effect of cilostazol resulted in the reduction of spontaneous infarct volume and preservation of motor and spatial cognitive functions. The increase of IGF-1R-positive cells in the hippocampal CA1 region could partly explain the preservation of spatial cognitive function in stroke-prone spontaneously hypertensive rats

Additive Intraocular Pressure-Lowering Effects of Ripasudil with Glaucoma Therapeutic Agents in Rabbits and Monkeys

Ripasudil hydrochloride hydrate (K-115), a specific Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, is developed for the treatment of glaucoma and ocular hypertension. Topical administration of ripasudil decreases intraocular pressure (IOP) by increasing conventional outflow through the trabeculae to Schlemm’s canal, which is different from existing agents that suppress aqueous humor production or promote uveoscleral outflow. In this study, we demonstrated that ripasudil significantly lowered IOP in combined regimens with other glaucoma therapeutic agents in rabbits and monkeys. Ripasudil showed additional effects on maximum IOP lowering or prolonged the duration of IOP-lowering effects with combined administration of timolol, nipradilol, brimonidine, brinzolamide, latanoprost, latanoprost/timolol fixed combination, and dorzolamide/timolol fixed combination. These results indicate that facilitation of conventional outflow by ripasudil provides additive IOP-lowering effect with other classes of antiglaucoma agents. Ripasudil is expected to have substantial utility in combined regimens with existing agents for glaucoma treatment

Dark Rearing Promotes the Recovery of Visual Cortical Responses but Not the Morphology of Geniculocortical Axons in Amblyopic Cat

Monocular deprivation (MD) of vision during early postnatal life induces amblyopia, and most neurons in the primary visual cortex lose their responses to the closed eye. Anatomically, the somata of neurons in the closed-eye recipient layer of the lateral geniculate nucleus (LGN) shrink and their axons projecting to the visual cortex retract. Although it has been difficult to restore visual acuity after maturation, recent studies in rodents and cats showed that a period of exposure to complete darkness could promote recovery from amblyopia induced by prior MD. However, in cats, which have an organization of central visual pathways similar to humans, the effect of dark rearing only improves monocular vision and does not restore binocular depth perception. To determine whether dark rearing can completely restore the visual pathway, we examined its effect on the three major concomitants of MD in individual visual neurons, eye preference of visual cortical neurons and soma size and axon morphology of LGN neurons. Dark rearing improved the recovery of visual cortical responses to the closed eye compared with the recovery under binocular conditions. However, geniculocortical axons serving the closed eye remained retracted after dark rearing, whereas reopening the closed eye restored the soma size of LGN neurons. These results indicate that dark rearing incompletely restores the visual pathway, and thus exerts a limited restorative effect on visual function