Seven Japanese Herbals Prolonged Cardiac Allograft Survival.

Japanese herbal medicines have long been used as alternative therapy because of their immunomodulatory effects. In recent years, use herbal medicines is rapidly increasing worldwide. In this study, we investigated the effect of 17 components of traditional Japanese herbal medicines on alloimmune responses in a murine model of cardiac allograft transplantation. Fully vascularized heterotopic hearts from C57BL/6 donors were transplanted into CBA mice by using microsurgical techniques. Artemisiae capillaris herba (Inchinko) was given to CBA recipients at a dosage of 1 g/kg/day from the day of transplantation until 7 days afterward. The other 16 components were given at a dosage of 2 g/kg/day for the same time period. Naïve CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST] of 7 days). CBA transplant recipients given 2 g/kg/day of Glycyrrhizae radix (Kanzou), Poria sclerotium (Bukuryo), Pinellia tuber (Hange), Cnidii rhizome (Senkyu), Paeoniae radix (Shakuyaku), and Scutellariae radix (Ogon) had prolonged C57BL/6 allograft survival significantly (MSTs were 18, 18, 17, 14, 12, and 12 days, respectively). Moreover, CBA transplant recipients given 1g/kg/day of Artemisiae capillaris herba had prolonged C57BL/6 allograft survival (MST >100 days); however, none of other 10 components prolonged allograft survival. In conclusion, administration of 7 components of traditional Japanese herbal medicines might induce prolongation of fully major histocompatibility complex-mismatched cardiac allografts.

The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood-brain barrier of neonatal rats: a critical period for efficacy.

Proinflammatory cytokines circulating in the periphery of early postnatal animals exert marked influences on their subsequent cognitive and behavioral traits and are therefore implicated in developmental psychiatric diseases such as schizophrenia. Here we examined the relationship between the permeability of the blood-brain barrier to interleukin-1 alpha (IL-1 alpha) in neonatal and juvenile rats and their later behavioral performance. Following s.c. injection of IL-1 alpha into rat neonates, IL-1 alpha immunoreactivity was first detected in the choroid plexus, brain microvessels, and olfactory cortex, and later diffused to many brain regions such as neocortex and hippocampus. In agreement, IL-1 alpha administration to the periphery resulted in a marked increase in brain IL-1 alpha content of neonates. Repeatedly injecting IL-1 alpha to neonates triggered astrocyte proliferation and microglial activation, followed by behavioral abnormalities in startle response and putative prepulse inhibition at the adult stage. Analysis of covariance with a covariate of startle amplitude suggested that IL-1 alpha administration may influence prepulse inhibition. However, adult rats treated with IL-1 alpha as neonates exhibited normal learning ability as measured by contextual fear conditioning, two-way passive shock avoidance, and a radial maze task and had no apparent sign of structural abnormality in the brain. In comparison, when IL-1 alpha was administered to juveniles, the blood-brain barrier permeation was limited. The increases in brain IL-1 alpha content and immunoreactivity were less pronounced following IL-1 alpha administration and behavioral abnormalities were not manifested at the adult stage. During early development, therefore, circulating IL-1 alpha efficiently crosses the blood-brain barrier to induce inflammatory reactions in the brain and influences later behavioral traits.

Prediction of anti-tumour effect of thermochemotherapy with in vitro thermochemosensitivity testing for non-small cell lung cancer.

PURPOSE: We investigated whether it is possible to predict the antitumour effects of thermochemotherapy from the results of anticancer agent sensitivity testing. MATERIALS AND METHODS: We produced a nude mouse cancer model using 4 lung cancer cell lines. Animals were divided into 4 groups: Thermotherapy (HT group), chemotherapy (CT group), thermochemotherapy (HT+CT group), and no therapy (NT group). Comparison of in vivo and in vitro effects were performed using cisplatin (CDDP), doxorubicin (ADR) and vinorelbine (NVB). In vivo thermotherapy was performed using the Thermotron RF IV, and radiofrequency (RF) capacitative hyperthermia device that induces a localised temperature of 42.0 degrees C for 45 min. The collagen gel embedded culture drug sensitivity test (CD-DST) was used for in vitro chemosensitivity analysis of the anticancer agents. In vitro thermochemotherapy was performed using a modified CD-DST method, with the incubator set at 42.0 degrees for the first hour of the 24 hours drug exposure period. RESULTS: A good correlation was seen between in vivo and in vitro treated/control ratios (T/C%) in the HT group (R = 0.91, p = 0.09). Good correlations were also seen between in vivo and in vitro T/C in all cell lines in the CT group (R = 0.759, p = 0.09) and the HT+CT group (R = 0.65, p = 0.02). True positive rate was 87.5% (7/8), and true negative rate was 100% (4/4). Sensitivity, specificity and accuracy were 100% (7/7), 80% (4/5), and 91.7% (11/12) respectively. CONCLUSION: A modified CD-DST using an exposure temperature of 42 degrees C can be used to predict the antitumour effect of thermochemotherapy.

IL-12 Production Induced by Agaricus blazei Fraction H (ABH) Involves Toll-like Receptor (TLR).

Agaricus blazei Murill is an edible fungus used in traditional medicine, which has various well-documented medicinal properties. In the present study, we investigated the effects of hemicellulase-derived mycelia extract (Agaricus blazei fraction H: ABH) on the immune system. First, we examined the cytokine-inducing activity of ABH on human peripheral mononuclear cells (PBMC). The results indicated that ABH induced expression of IL-12, a cytokine known to be a critical regulator of cellular immune responses. Flow cytometric analysis demonstrated the induction of IL-12 production by the CD14-positive cell population, consisting of monocytes/macrophages (Mo/Mphi). Furthermore, the elimination of Mo/Mphi attenuated IL-12 production in PBMC. ABH-induced IL-12 production was inhibited by anti-CD14 and anti-TLR4 antibodies but not by anti-TLR2 antibody. The activity of ABH was not inhibited by polymyxin B, while the activity of lipopolysaccharide used as a reference was inhibited. Oral administration of ABH enhanced natural killer (NK) activity in the spleen. These findings suggest that ABH activated Mo/Mphi in a manner dependent on CD14/TLR4 and NK activity.

Down-regulation of GABA-transporter function by hippocampal translation products: its possible role in epilepsy.

The genetically epileptic mouse strain (El) is used as a model for human temporal lobe epilepsy. To address the question of whether altered function of the neuronal GABA transporter GAT1 is involved in the pathology of epilepsy of El mice, we expressed in Xenopus oocytes cloned GAT1 of mouse brain by injection of complementary ribonucleic acid (cRNA) and co-injected messenger ribonucleic acid (mRNA) isolated from the hippocampus of non-epileptic control mother strain (ddY) mice and from El mice. GABA transporter activity was investigated by measurements of [(3)H]-GABA uptake as well as by steady-state and transient current measurements under voltage clamp.Co-injection of hippocampal mRNA into oocytes reduced GAT1-mediated transport. This effect was more pronounced for mRNA from ddY mice than for that from El mice that never experienced seizures, El(-), and being absent for mRNA from El mice that have had high seizure experience, El(+). The pronounced inhibition of GABA transport after injection of mRNA from the ddY strain results from reduced expression of functional GAT1, but to about one third also from a reduced GABA translocation rate. The reduced translocation can be attributed to a reduced forward rate of a step associated with extracellular Na(+) binding. If the results can be applied to the mouse brain, we may hypothesise that in ddY mice some GAT down-regulating factor translated from hippocampal mRNA may be involved to keep GAT1 activity low, and hence GABA concentration in synaptic cleft high. In El(-) mice such regulatory mechanism may be reduced or counteracted by another unknown factor present in El(-) brain. The repeated seizure experience in El(+) mice enhances this compensatory effect.

3-(Arylacetylamino)-N-methylbenzamides: a novel class of selective anti-Helicobacter pylori agents.

After chemical modification preceded by the random screening of our chemical library, a novel class of selective anti-Helicobacter pylori agents was generated. Consequently, the 3-(arylacetylamino)-N-methylbenzamides, which were quite easy to prepare, showed potent inhibitory activity against Helicobacter pylori but exhibited no inhibitory activity against other sorts of bacteria and fungi, e.g., Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Bacteroides fragilis, and Candida albicans. These compounds showed potent anti-H. pylori activity under acidic conditions, whereas amoxicillin and clarithromycin decreased activity. The 3-(3-arylpropionylamino)-N-methylbenzamides, 3-(aryloxyacetylamino)-N-methylbenzamides, and (3-methylcarbamoylphenyl)carbamic acid 1-arylmethyl esters also exhibited potent anti-H. pylori activity. Finally, we selected 7n (BAS-118) as a candidate compound for further evaluation.

Low power diode laser treatment using indocyanine green for eradication of esophageal varices.

BACKGROUND AND STUDY AIMS: Endoscopic variceal ligation (EVL) is an alternative to sclerotherapy for the treatment of esophageal varices, but is associated with higher rates of recurrence and subsequent bleeding than sclerotherapy. To prevent recurrence of varices after EVL, we have developed a low-dose diode laser therapy combined with the injection of indocyanine green, which allows enhanced tissue absorption of the laser beam selectively around varices. In this study we investigated the efficacy and safety of this technique. PATIENTS AND METHODS: Eight patients with F2 or F3 esophageal varices were enrolled. At 1 week after EVL, indocyanine green solution (1 mg/ml) was injected submucosally around the remaining varices. A diode laser (power 10 watts) was applied to the surface from the esophagogastric junction to 5 cm above it. The spot size was kept to 5 mm in diameter. RESULTS: Laser irradiation was performed safely, without bleeding from the varices, or perforation. There were no major complications. Endoscopy 1 month later showed F0 forms in seven patients, F1 in one patient, and no red color sign in any patient. No recurrence of varices has been observed in any of the patients during the follow-up period of at least 12 months. CONCLUSION: This technique may provide a simple, safe and effective procedure, as an additional treatment to EVL, for the prevention of recurrence of esophageal varices.

Potent dibasic GPIIb/IIIa antagonists with reduced prolongation of bleeding time: synthesis and pharmacological evaluation of 2-oxopiperazine derivatives.

A series of 2-oxopiperazine derivatives, possessing basic moieties at the 3- and the 4-positions, were synthesized and evaluated for their abilities to inhibit platelet aggregation and for their effects on bleeding time. Among the compounds, 2-[(3S)-4-[2-[(4-guanidinobenzoyl)amino]acetyl]-3-[3-[(4-guanidinobenzoyl)amino]propyl]-2-oxopiperazinyl]acetic acid (12c) showed a potent inhibitory effect on platelet aggregation and good dissociation between the efficacy and the bleeding side effect. Intravenous infusion of compound 12c at 1.6 microg/mL/min completely prevented arterial thrombus formation induced by endothelial injury in guinea pigs. The dose of 12c that prolonged the bleeding time to three times the control value was 5.8 microg/mL/min. These results suggest that compound 12c might be useful in the clinical treatment of thrombotic diseases, and we selected 12c (TAK-024) as a candidate for the clinical trials.

The functional unit of Na,K-ATPase is a monomeric alphabeta protomer.

The ouabain-resistant and ouabain-sensitive alpha-subunit cRNAs in various molar ratios were injected into Xenopus oocytes together with cRNA for the beta-subunit. The ouabain-resistant ATPase activity, as well as ouabain-resistant Rb+ uptake, of the injected oocytes increased linearly with increasing the amount of cRNA for the ouabain-resistant alpha-subunit. When a functionless mutant was used instead of the ouabain-sensitive alpha-subunit, similar results were obtained in ATPase activity and Rb+ uptake. These results indicate that a monomeric alphabeta protomer is a functional unit of membrane-bound Na,K-ATPase, even if the enzyme exists structurally as a diprotomer or higher oligomers in membranes.

Ibotenic acid-induced lesions of the medial septum increase hippocampal membrane associated protein kinase c activity and reduce acetylcholine synthesis: prevention by a phosphatidylcholine/vitamin B12 diet.

Ibotenic acid infusion into the medial septum (MS) results in biochemical alterations in the hippocampus. The biochemical events involved in this neuronal lesion are poorly understood. We investigated the effect of a purified diet supplemented with egg phosphatidylcholine (PC) and vitamin B(12) on ibotenic acid-medicated biochemical changes in the rat hippocampus and crude synaptosomal membranes. Male Wistar rats with this MS lesion were fed a purified diet (control diet) or a purified diet supplemented with 5.7 g PC and 125 microg vitamin B(12) per 100 g (experimental diet) for 18 days. Sham-operated rats were fed the control diet. Compared with the sham-operated rats, MS-lesioned rats fed the control diet showed increased activity of membrane-bound protein kinase C (PKC), decreased activity of choline acetyltransferase, and decreased concentrations of acetylcholine in the hippocampus. The ratio of cholesterol to phospholipid in the crude synaptic membrane was lower in the lesioned rats than in the sham-operated rats, but this was not accompanied by any alteration in membrane lipid fluidity. MS-lesioned rats fed the experimental diet showed lowered PKC activity and elevated acetylcholine concentrations than did rats fed the control diet, but there were no significant effects on choline acetyltransferase activity and the lipid ratio. The ibotenic acid-mediated elevation of PKC activity was observed as early as 2 days postinjury in the control diet-fed rats but not in the experimental diet-fed rats. We propose that ibotenic acid mediates pathophysiologic actions through the activation of PKC and that PC combined with vitamin B(12) ameliorates the second messenger-mediated injury.

Microanalysis of a selective potent anti-Helicobacter pylori compound in a Brazilian medicinal plant, Myroxylon peruiferum and the activity of analogues.

A selective potent anti-Helicobacter pylori isoflavone was isolated from a Brazilian Medicinal Plant, Myroxylon peruiferum. The isolation bioassay-guided and the characterization of an active anti-H. pylori constituent was performed using the methanol extract of plant of minute amount. The active compound was identified as cabreuvin (1), an isoflavone derivative. The structure-activity relationships of several related compounds were also investigated.

Management of acute metabolic decompensation in maple syrup urine disease: a multi-center study.

BACKGROUND: Therapeutic modalities in acute metabolic decompensation in maple syrup urine disease (MSUD) are variable, and outcomes of each therapeutic measure have been known only individually. Factors that affect neurological outcome are not clear. METHODS: A questionnaire was sent throughout Japan to each pediatrician treating any of the 42 MSUD patients. RESULTS: Necessary information was available for 13 patients through the questionnaire, and through a publication for one patient. In nine of the 14 patients episodes of metabolic decompensation developed in the neonatal period. In the other five, the onset of disease was delayed until infancy or later. In the nine patients with neonatal onset, a pretreatment level of plasma leucine greater than 40 mg/100 mL or a duration of altered level of alertness longer than 10 days was associated with a poor neurological outcome. The therapeutic measures employed included intravenous infusion of glucose and electrolyte solution or hypertonic glucose and electrolyte solution, exchange transfusion, peritoneal dialysis, a large dose of thiamine and intravenous hyperalimentation. All patients had survived the episodes and were alive at the time of the survey. Five of the nine patients with neonatal onset have developed neurological sequelae to varying degrees. Episodes of metabolic decompensation in infancy or thereafter did not affect, or only minimally affected, the neurological outcome. CONCLUSION: Therapeutic goals to improve neurological outcome are to shorten the duration of the altered level of consciousness, and to minimize the peak plasma leucine level as much as possible.

Effectiveness of 1,25-dihydroxyvitamin D supplementation on blood pressure reduction in a pseudohypoparathyroidism patient with high renin activity.

A 42-year-old man had biochemical and somatic abnormalities compatible with pseudohypoparathyroidism type I (PsHP) and also had high plasma renin activity (PRA). After 1,25-dihydroxyvitamin D (calcitriol) supplementation the systolic/diastolic blood pressure, assessed by 24-hour non-invasive ambulatory blood pressure monitoring, was reduced from 145/96 mm Hg to 128/85 mm Hg with normalization of the serum calcium level and its related hormones, as well as decreased PRA. Calcitriol supplementation successfully reduced the blood pressure in this patient with PsHP and a high PRA, suggesting that calcium-related hormones and/or the renin-angiotensin system were involved in lowering the blood pressure.

[Thermoradiotherapy combined with daily administration of low dose cisplatin for locally advanced laryngeal carcinoma].

We applied thermoradiotherapy combined with daily administration of low dose cisplatin (CDDP) to five patients with locally advanced laryngeal carcinoma. The total response rate (CR + PR) was 100% after irradiation of 30 or 40 Gy. One case showed CR, and the larynx could be preserved by adding a full dose of irradiation. CDDP administration was discontinued in two cases due to renal dysfunction or thrombopenia, but other cases tolerated the therapy without severe side effects. Total laryngectomy and bilateral neck dissection was carried out in four cases after irradiation of 30 or 40 Gy. Removed larynxes were prepared for light microscopic observations of the serial sections. One of the four specimens revealed a CR histologically. The combination of thermoradiotherapy with low dose CDDP showed a remarkable effect on reduction of tumor size and cytotoxicity of tumor cells. This might contribute to saving the larynx of patients with locally advanced laryngeal carcinoma.

New serine protease inhibitors with leukotriene B4 (LTB4) receptor binding affinity.

A series of new trypsin-like serine protease inhibitors, 1, 2 and 7-23, containing amidinobenzene moiety was found to show potent LTB4-receptor affinity. Among them, compounds 1 and 2 were found to be LTB4 receptor antagonists based on an inhibition assay of human polymorphonuclear neutrophil (PMN) intracellular calcium mobilization induced by LTB4. Compounds 1 and 2, which satisfy the reported structural requirements for good oral activity, are expected to show a balanced dual mode of action, i.e., protease inhibitory activity and LTB4 receptor antagonist activity, in vivo.

Effects of low-dose phenytoin administered to newborn mice on developing cerebellum.

To examine correlations between dose levels of phenytoin (PHT) and neurotoxic effects on cerebellar development, we administered 10, 17.5, 25, and 35 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2-4 and determined plasma PHT concentrations during the administration period. Mortality rates were 12.5% and 35.2% in males and 15.3% and 33.3% in females for the 25 and 35 mg/kg PHT-treated groups during the PHT treatment, respectively. In the 25 and 35 mg/kg PHT-treated groups, total brain weight, the size of the cerebellum, and cerebellar weight were significantly reduced on postnatal day 21. However, in the 10 and 17.5 mg/kg PHT-treated groups, total brain weight and the size and weight of the cerebellum did not differ from those of the control group. Histologically, the number of pyknotic cells in the external granular layer (EGL) in the 25 and 35 mg/kg PHT-treated groups was increased on postnatal day 5, and the EGL was thicker than in the control group on postnatal day 14. Some of the Purkinje cells in the 35 mg/kg PHT-treated group showed degeneration. Plasma PHT levels were 10.7 +/- 2.2 and 24.6 +/- 2.6 micrograms/ml in the 25 and 35 mg/kg PHT groups on the third day of PHT treatment, respectively. In the 25 mg/kg PHT group, plasma PHT level was found to be in the therapeutic range for humans, 10-20 micrograms/ml. Accordingly, during pregnancy, epileptic women should be carefully given PHT at the lowest effective dose while plasma PHT levels are monitored properly. These findings emphasize the importance of pharmacokinetics in evaluating of phenytoin-induced developmental neurotoxicity.

Assembly of the chimeric Na+/K+-ATPase and H+/K+-ATPase beta-subunit with the Na+/K+-ATPase alpha-subunit.

Two sets of chimeric beta-subunits were constructed from subunits of Torpedo californica Na+/K+-ATPase and pig gastric H+/K+-ATPase. Five unique restriction sites (SnaBI, EcoRV, MunI, SphI and EcoT22I) were created at equivalent positions of the respective cDNAs and were used as joining points for the construction. One set of chimeras (HxN series) was made by exchanging the 5' portion of the Na+/K+-ATPase beta-subunit cDNA with the corresponding portion of the H+/K+-ATPase beta-subunit cDNA at the respective joining point. Complementary constructs were also prepared (NxH series). In the HxN series, the chimera joined at the SnaBI site formed a stable trypsin resistant complex with the Na+/K+-ATPase alpha-subunit, which was functional with respect to ATP hydrolysis and pump current generation, although the activities were less than those of the complex with the Na+/K+-ATPase beta-subunit. Trypsin resistance decreased for the complex of the chimera joined at the EcoRV site. In the NxH series, the chimeras joined at the SnaBI site and the EcoRV site formed rather trypsin-resistant complexes, but the expressions of the alpha-subunits were below 50% of the control. The chimeras joined at the MunI, SphI and EcoT22I site formed complexes susceptible to tryptic digestion. None of the chimeras in the NxH series were functional. These results suggest that at least two regions of the Na+/K+-ATPase beta-subunit [SnaBI site(Tyr40) to EcoRV site(Ile89) and EcoT22I site(Cys176) to C-terminus)] are involved in stable assembly with the Na+/K+-ATPase alpha-subunit and that the cytoplasmic domain [N-terminus to SnaBI site(Tyr40)] is functionally replaceable with the corresponding domain of the H+/K+-ATPase beta-subunit.

Nafamostat mesilate reduces blood-foreign surface reactions similar to biocompatible materials.

BACKGROUND: Nafamostat mesilate (FUT-175) is a synthetic serine protease inhibitor that inactivates coagulation, fibrinolysis, and platelet aggregation. Nafamostat mesilate may suppress the blood-foreign surface reaction similar to biocompatible materials by blocking factor XIIa. METHODS: We performed an in vitro study of cardiopulmonary bypass (CPB) with fresh human blood among the following three groups: standard CPB sets (C), biocompatible CPB sets (B), and standard CPB sets with FUT-175 (10 mg/L) (F). A clinical study using these same CPB groups also was performed in 45 patients undergoing aortocoronary bypass operations (15 patients each). We injected FUT-175 at 40 mg/h during CPB. RESULTS: In the in vitro study, both groups B and F showed significantly lower levels of coagulation factors, thrombin-antithrombin III complex, fibrinopeptide A, beta-thromboglobulin, complement C3a, granulocyte elastase, and free hemoglobin than group C at the conclusion of the study. Thrombin-antithrombin III complex and free hemoglobin in group F also were lower than in group B. The platelet count remained at a higher level in group F than in the other groups. Separation of bradykinin was suppressed most significantly in group F. In the clinical study, group F also showed significantly lower levels of alpha 2-plasmin inhibitor plasmin complex and C3a than both groups C and B. There were minimal levels of free hemoglobin in group F. CONCLUSIONS: Nafamostat mesilate may contribute major beneficial effects toward conservation of blood during CPB and prevention of coagulopathy after CPB.

Increased migration of neutrophils to granulocyte-colony stimulating factor in rat carrageenin-induced pleurisy: roles of complement, bradykinin, and inducible cyclooxygenase-2.

Administration of human recombinant granulocyte colony-stimulating factor (G-CSF, 100 micrograms/kg/day, s.c) to rats for 4 days significantly increased circulating neutrophil counts (by 1130%), together with an increase in mononuclear leukocyte counts (by 119%). Infiltrated pleural neutrophil counts in G-CSF-treated rats (G-CSF-r) 5 h after the intrapleural injection of zymosan-activated serum were significantly higher (by 155%) than those in control rats (Vehicle-r). In carrageenin-induced pleurisy, counts of infiltrated pleural neutrophils in G-CSF-r 5 and 7 h after carrageenin were significantly higher (by 119% and 116%) than those in Vehicle-r. G-CSF treatment increased the volume of pleural exudate and the plasma exudation rate by 122% and 226%, compared to values in Vehicle-r 5 h after carrageenin. Cobra venom factor (75 micrograms/kg, i.v.) significantly reduced pleural neutrophil migration in G-CSF-r (by 53%) and Vehicle-r (by 49%). Bromelain (10 mg/kg, i.v.) and aspirin (100 mg/kg, p.o.) reduced pleural neutrophil migration and reduced exudate volume and plasma exudation. Intrapleural bradykinin-(1-5) and prostaglandin E2 levels were significantly higher in G-CSF-r than in Vehicle-r. The increased neutrophil migration in G-CSF-r may be attributed to enhanced activation of the complement system facilitated by increased plasma exudation due to bradykinin and prostaglandins.

Soft drugs. 21. Design and evaluation of soft analogs of propantheline.

The soft drug approach was applied to synthesize seven soft analogs of propantheline, which by design display predictable and controllable decomposition to inactive metabolites. Their synthesis involved the quatemization of several different amine groups with the chloromethyl ester of 9-methylxanthene-9-carboxylic acid. The rates of disappearance were measured for all of the compounds and were found to be more rapid than that of propantheline bromide in a variety of chemical and biological media under in vitro conditions. One of the soft analogs was found to be equipotent with propantheline in an in vitro assay. This soft analog was found to be equipotent with propantheline, in vivo, in protecting the rats against indomethacin-induced gastric ulceration and in inducing mydriasis in rabbits on intravenous administration. The pupil sizes returned faster to predrug levels with the soft analog than with propantheline, indicating increased metabolic lability of the soft analog. The equipotency of this soft analog coupled with increased metabolic lability proves the rationality of the soft drug approach for the design of safer therapeutic agents with higher therapeutic indices.