Minimum effective drug concentrations of a transdermal patch system containing procyclidine and physostigmine for prophylaxis against soman poisoning in rhesus monkeys

A transdermal patch system containing procyclidine, an N-methyl-d-aspartate receptor antagonist possessing anticholinergic action, and physostigmine, a reversible cholinesterase inhibitor, was developed, and its prophylactic efficacy against soman intoxication was investigated. Male rhesus monkeys were shaved on the dorsal area, attached with a matrix-type patch with various sizes (2 × 2 to 7 × 7 cm) for 24 or 72 h, and challenged with 2 × LD₅₀ doses (13 μg/kg) of soman. The smallest patch size for the protection against lethality induced by soman intoxication was 3 × 3 cm, resulting in blood procyclidine concentration of 10.8 ng/ml, blood physostigmine concentration of 0.54 ng/ml, which are much lower concentrations than maximum sign-free doses, and blood cholinesterase inhibition of 42%. The drug concentrations and enzyme inhibition rate corresponding to a diverging point of survivability were presumably estimated to be around 7 ng/ml for procyclidine, 0.35 ng/ml for physostigmine, and 37% of enzyme inhibition. Separately, in combination with the patch treatment, the post treatment consisting of atropine (0.5 mg/kg) plus 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 50 mg/kg) exerted protection against 5 × LD₅₀ challenge of soman, which means the posttreatment remarkably augmented the efficacy of the patch. Additionally, it was found that brain injuries induced by soman toxicity were effectively prevented by the patch treatment according to histopathological examinations. These results suggest that the patch system could be an effective alternative for diazepam, an anticonvulsant, and the current pyridostigmine pretreatment, and especially in combination with atropine plus HI-6, could be a choice for quality survival from nerve-agent poisoning.     

Protection by sustained release of physostigmine and procyclidine of soman poisoning in rats

The efficacy of a combinational prophylactic regimen on the lethality, convulsions, and loss of morphological and functional integrities of the brain induced by an organophosphate soman was investigated in rats. The rats were implanted subcutaneously with osmotic minipumps containing the combinational prophylactic regimen composed of physostigmine, a reversible cholinesterase inhibitor, and procyclidine, an N-methyl-D-aspartate antagonist possessing anticholinergic action, for 3 days, and intoxicated subcutaneously with soman (160 microg/kg, 1.3 LD50). The doses of combinational regimen in minipumps were optimized to achieve 30-35% inhibition of blood cholinesterase activity by physostigmine and 50-100 ng/ml of blood concentrations of procyclidine as clinically available doses, respectively. In comparison, 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 125 mg/kg) was administered intraperitoneally 30 min prior to the soman challenge in control groups to reduce mortality of rats without affecting convulsions. Soman induced profound limbic convulsions and 30% mortality, leading to increased blood-brain barrier permeability, neural injuries, learning and memory impairments, and physical incapacitation of survived rats pretreated with HI-6. The combinational regimen, at optimal doses without adverse effects on passive avoidance performances (72 microg/kg/h of physostigmine plus 432 microg/kg/h of procyclidine), exerted full protective effects against lethality, convulsions, blood-brain barrier opening, brain injuries, learning and memory impairments, and physical incapacitation induced by soman. Taken together, it is suggested that the combination of physostigmine and procyclidine, at adequate doses, could be a choice to provide the victims of organophosphate poisoning with chance of intensive care for survival and neuroprotection.     

Protection of mice against soman by pretreatment with eptastigmine and physostigmine

Organophosphate (OP) compounds such as the nerve agents sarin, soman and VX are powerful inhibitors of acetylcholinesterases (AChEs), butyrylcholinesterases (BChEs), and carboxylesterases (CaEs) The acute toxicity of OPs is the result of their irreversible binding with AChEs in the nervous system, which elevates the acetylcholine (ACh) levels. In this study the protective actions of intravenously (i.v.), administered eptastigmine and physostigmine in acute soman intoxication were studied in mice. The mice received eptastigmine (0.9 mg/kg body weight) or physostigmine (0.1 mg/kg body weight) 10 min prior to the intraperitoneal (i.p.) administration of soman. To avoid possible signs of poisoning, the animals received atropine 37.5 mg/kg body weight subcutaneously (s.c.) in saline immediately after soman injection. Eptastigmine was the most effective carbamate against soman intoxication. The LD50 value of soman was 0.44 mg/kg, and the protective ratios of eptastigmine and physostigmine were 2.1- and 1.3-fold, respectively. Both eptastigmine and physostigmine had protected AChEs when measured 24 h after soman exposure. In this study, there was no inhibition of microsomal CaEs in soman treated mice. Nonetheless, the role of microsomal CaEs might be more important with prophylaxis at multiple LD50s of soman. In conclusion, these results indicate that eptastigmine treatment given i.v. protects better than physostigmine against soman exposure.     

Scopolamine augments the efficacy of physostigmine against soman poisoning in guinea pigs

The efficacy of the subchronically administered cholinesterase-inhibitor physostigmine (PHY) (0.025 mg/kg/h) either with or without the muscarinergic receptor antagonist scopolamine (SCO) (0.018 mg/kg/h) in counteracting soman-induced lethality and incapacitation were determined in guinea pigs. This was tested in animals that either received atropine sulphate (AS, 17.4 mg/kg i.m.) or no postintoxication therapy. Behavioral and neurophysiological readout systems were used to measure postintoxication incapacitation. Only the pretreatment with PHY alone did not offer any protection against 2x LD50 soman intoxication. Animals that received the complete treatment (PHY + SCO + AS) did not show any abberations in the performance of learned behavior. The use of AS after soman intoxication resulted in an increase of the startle response, whereas the addition of SCO to the pretreatment led to a more persistent duration of the effect in time. In case one has to rely completely on the pretreatment, the addition of SCO to PHY is life-saving. However, some postintoxication incapacitation is still present. Therefore, the pretreatment regime may perhaps further be improved by the addition of a nicotinic antagonist.     

Formulation and biopharmaceutical evaluation of a transdermal patch containing aceclofenac

To reduce the adverse effects of aceclofenac that accompanied with oral administration of this drug, transdermal patches in the form of drug-in-adhesive (DIA) patches, containing aceclofenac, were formulated. The effect of formulation factors on the skin permeation of the drug and physical properties of the patch were evaluated using excised rat skins. The optimized patch contained 12 % aceclofenac and 20 % lauryl alcohol in DT-2852 as a pressure-sensitive adhesive. The pharmacokinetic characteristics of the DIA patch were determined after application of the transdermal patches to human volunteers. The calculated relative bioavailability of the aceclofenac DIA patch was 18.2 % compared to oral administration of the drug. The findings of this study suggest that transdermal application of aceclofenac can substitute for oral administration of the drug.     

Acetylcholinesterase inhibition by (+)physostigmine and efficacy against lethality induced by soman

The optical isomer (+)Physostigmine [(+)Phy] is a very weak anticholinesterase. In a recent report, pretreatment with (+)Phy, at a dose which failed to inhibit acetylcholinesterase (AChE), and atropine provided efficacy against a lethal dose of sarin (SYNAPSE:2, 139, 1988). It was of interest to see whether (+)Phy could protect against soman at a dose which caused only marginal inhibition of the whole blood (WB) AChE in guinea pigs (GPs). (-)Phy (0.15 mg/kg, im) and (+)Phy (10.0 mg/kg, im) produced nearly 70% inhibition of WB AChE at 30 min whereas (+)Phy (0.15 mg/kg, im) caused only marginal inhibition. Groups of guinea pigs (20/group) were dosed, im, with (-)Phy (0.15 mg/kg), (+)Phy (0.15 mg/kg), (+)Phy (10.0 mg/kg) or vehicle (0.5 ml/kg) respectively in one thigh while the mild anticholinergic trihexyphenidyl (THP), 2.0 mg/kg, was injected into the other thigh of 10 animals from each of the respective groups. Thirty min after pretreatment, all animals were challenged with soman (60 micrograms/kg, sc; 2 LD50s); this dose of soman is lethal in unprotected animals. (-)Phy or (+)Phy (10 mg/kg) alone protected nearly 50% from soman lethality, and in combination with THP, all animals survived. In contrast, (+)Phy (0.15 mg/kg; alone or together with THP) was completely ineffective against a 2 LD50 challenge of soman. These data support the hypothesis that protection against soman-induced lethality is related to the degree of carbamylation of the AChE just prior to challenge.     

Protection of guinea pigs against soman poisoning with ferrocene carbamate

The protective effect of ferrocene carbamate pretreatment against soman poisoning was studied in guinea pigs. At doses corresponding to 1/20 x and 1/10 × LD₅₀ of this carbamate a 20% and 45% decrease of the acetylcholinesterase in blood and brain, respectively, was obtained. In combination with additional pretreatment, diazepam, and therapy, HI-6 and atropine, the protective ratios (LD₅₀ of soman in treated animals/LD₅₀ of soman in untreated animals) were around 20 and 40, respectively. Animals pretreated with the high dose of the ferrocene carbamate that survived 10 x and 15xLD_50s of soman showed no remaining signs of poisoning after 24 h. Thus, the ferrocene carbamate afforded a better protection against soman than physostigmine. The explanation for this could be due to the properties of the ferrocene carbamate, not correlated to its cholinesterase inhibiting activity. This hypothesis is discussed.     

特立氟胺经皮吸收贴剂的处方筛选和体内外相关性评价

目的制备特立氟胺经皮吸收贴剂,评价其体内外经皮透过行为。方法有机溶媒挥散法制备特立氟胺压敏胶分散型贴剂;采用水平双室扩散池,以离体兔皮为通透屏障,单因素考察法筛选贴剂系统中的压敏胶、载药量及促透剂;以家兔为实验动物,考察特立氟胺经皮吸收贴剂及注射液在体内的药动学行为,用HPLC法测定血药浓度,Win Nonlin软件求算药物动力学参数并进行体内外相关性评价。结果特立氟胺贴剂最优处方为DURO-TAK1压敏胶,质量分数为10%的氮酮和2.75%的特立氟胺。体内结果表明血药浓度在(12.92±3.95)h达到峰值,达峰质量浓度为(5.44±1.36)mg·L-1,MRT(mean retention time,MRT)达(16.30±3.70)h,血药浓度可长时间维持;体内外相关系数为0.9822。结论所制备的特立氟胺贴剂体内药物浓度平缓,体内外相关性良好。     

Nasal absorption of procyclidine in rats and dogs

Nasal absorption of procyclidine, a synthetic anticholinergic compound, was investigated in Wistar rats and Beagle dogs. The dosing solution was prepared by dissolving 14C-procyclidine in 50% ethanolic saline. The dosing solution was administered intravenously and intranasally to rats at a dose of 0.6 mg/kg (i.e., 60 microl/kg in the form of a 1% w/v solution), and intravenously, orally and intranasally to dogs at a dose of 0.3 mg/kg (i.e., 6 microl/kg in the form of a 5% w/v solution). Blood samples were taken from an artery of the animals through the catheter for periods of 1200 (for rats) and 1,440 min (for dogs), and the radioactivity in the samples was determined by liquid scintillation counting. The nasal bioavailability of procyclidine in rats and dogs, based on the radioactivity, was calculated to be 81.1 and 98.6%, respectively. In both rats and dogs, the plasma profiles of procyclidine following nasal administration were very close to those following intravenous administration, leading to nearly superimposable profiles between the two protocols. In dogs, nasal administration resulted in significantly higher plasma concentrations during the first 30 min period compared to oral administration, suggesting the superiority of the nasal route over the oral route in terms of a prompt expression of the pharmacological effect of the drug. The results obtained in this study indicate that procyclidine is rapidly and nearly completely absorbed via the nasal route. In conclusion, nasal administration represents a viable alternative to intravenous administration in the case of procyclidine.     

Subchronic physostigmine pretreatment in marmosets: absence of side effects and effectiveness against soman poisoning with negligible postintoxication incapacitation.

Subchronic pretreatment with physostigmine (PHY) (0.0125 mg/kg/h) leading to a blood acetylcholinesterase inhibition of about 30% caused no side effects when applied to marmoset monkeys. This was evident on behavioral parameters and on EEG and cortical visual evoked response. Furthermore, this treatment regime, followed by atropine as postintoxication therapy, protected the marmosets against lethality after a 2 x LD50 dose of soman with negligible postintoxication incapacitation. These findings suggest that a symptom-free pretreatment with subchronic PHY could protect man sufficiently against severe soman intoxication.     

Rivastigmine exposure provided by a transdermal patch versus capsules

ABSTRACT

Objectives: The rivastigmine transdermal patch is the first transdermal treatment for Alzheimer's disease (AD) and dementia associated with Parkinson's disease. The objective of this study was to evaluate the pharmacokinetics of rivastigmine following transdermal delivery by a patch versus oral delivery with conventional capsules in a population of AD patients.

Methods: Both non-compartmental and compartmental analyses were performed on the same database showing relatively large inter-patient variations in pharmacokinetic parameters (up to 73% for the capsule group). The compartmental analysis provided model-based predictions of pharmacokinetic parameters, with the aim of comparing the two modes of administration when adjusting for confounding factors such as patient body weight and gender.

Results: According to both non-compartmental and compartmental analyses, the patch provided significantly lower peak rivastigmine plasma concentrations (C_max) and slower times to C_max (t_max), compared with capsules. However, drug exposure (area under the curve; AUC) was not significantly different between the 4.6?mg/24 hour (5?cm²) patch and 3?mg BID (6?mg/day) capsule doses, or between the 9.5?mg/24 hour (10?cm²) patch and 6?mg BID (12?mg/day) capsule doses, according to both analyses. This suggests comparable exposure from these two rivastigmine delivery systems.

Conclusion: The analyses were consistent with previous reports of a markedly less fluctuating, more continuous drug delivery with the rivastigmine patch. This characteristic delivery profile is associated with similar efficacy yet improved tolerability, compared with capsules.     

梭曼和毒扁豆碱引起大鼠脑电癫痫波的M和N胆碱能成分

在加拉碘铵麻痹, 人工呼吸维持和甲基阿托品预防的大鼠上, 梭曼0.1 mg·kg^-1 im (n=24)或毒扁豆碱30.0 mg·kg^-1 iv (n=18)使全部大鼠脑电图(EEG)上出现早期持续很短的紧张性癫痫波和随后持续很长的阵挛性癫痫波. 中枢N受体激动剂烟碱1.0 mg·kg^-1 iv (n=38)和中枢M受体激动剂槟榔碱150 mg·kg^-1 iv (n=46)或匹鲁卡品380 mg·kg^-1 iv (n=24)能分别在EEG癫痫波的特征, 出现时间和持续时间上模拟出上述早期紧张性癫痫波和随后的阵挛性癫痫波. 预先小剂量iv烟碱使中枢N受体脱敏或给小剂量N受体拮抗剂美加明保护中枢N受体后, 梭曼只能引起潜伏 期较长且持续很久的阵挛性癫痫波. 胆碱酯酶抑制剂梭曼和毒扁豆碱较大剂量引起大鼠EEG癫痫波可能的机理是过量的乙酰胆碱作用于潜伏期短, 容易脱敏的N受体出现早期持续很短的EEG紧张性癫痫波, 又作用于潜伏期较长, 不容易脱敏的M受体, 出现稍后的EEG阵挛性癫痫波.     

盐酸格拉司琼透皮贴剂对化疗药物致犬呕吐的预防作用

目的:观察盐酸格拉司琼透皮贴剂(GH透皮贴剂)对化疗药物诱导的犬呕吐的拮抗作用。方法:30只比格犬按体重随机分为5组,每组6只,分别为模型组、盐酸格拉司琼片剂组(0.1 mg.kg-1)、GH透皮贴剂0.150,.30和0.60 mg.kg-1组。GH透皮贴剂组给药24 h后以及片剂组给药1 h后,静脉注射顺铂3.0 mg.kg-1或环磷酰胺70 mg.kg-1诱导犬呕吐,观察呕吐和干呕次数、呕吐潜伏期和持续时间。结果:GH透皮贴剂0.15,0.30和0.60 mg.kg-1给药24 h后,均能显著减少顺铂和环磷酰胺引起的犬干呕及呕吐的次数,明显延长呕吐反应的潜伏期及缩短持续时间,剂量关系明确。结论:GH透皮贴剂对顺铂和环磷酰胺所致的犬呕吐有明显的拮抗作用。     

Design and evaluation of a novel transdermal patch containing diclofenac and teriflunomide for rheumatoid arthritis therapy

The aim of this study was to design a compound transdermal patch containing diclofenac (DA) and teriflunomide (TEF) for the treatment of rheumatoid arthritis (RA). The various organic amines salts of DA were prepared and their forming was confirmed using DSC and FTIR. The percutaneous permeation of organic amines salt of DA was investigated in vitro using a two-chamber diffusion cell with excised rabbit skin as transdermal barrier. The formulation of the patch was optimized in terms of the concentration of percutaneous permeation enhancer and the loading dose of drugs. The pharmacokinetic behavior of the optimal formulation was studies in rabbits and the anti-inflammatory and analgesic effects of the optimal patch were evaluated with the adjuvant arthritis model in rats and the pain model in mice, respectively. The result showed that skin penetration of diclofenac-triethylamine (DA-TEtA) salt was better than other organic amine salts. Based on previous study of our laboratory, teriflunomide-triethylamine (TEF-TEtA) significantly enhanced the skin permeation of TEF. 10% of azone (AZ) was the best enhancer for the two drugs. The optimal patch formulation was composed of 2% of TEF-TEtA, 6% of DA-TEtA and 10% of AZ. The cumulative permeated amount of DA-TEtA in vitro was comparable with that of the commercial diclofenac-diethylamine (DA-DEtA) patch. The absolute bioavailability of TEF-TEtA was 42%, which could achieve the therapeutic drug levels. In animal study, the optimized compound patch containing DA-TEtA and TEF-TEtA displayed significant anti-inflammatory and analgesic effect, which indicated the potential of the compound patch.     

Toxicity of anticholinesterases: interactions of pyridostigmine and physostigmine with soman

This investigation was conducted to assess the potential of carbamate pretreatment to exacerbate the ill effects of low doses of soman. Ambulatory Activity in a photocell cage (AA) and performance time on an accelerating rotarod (ARR) were used to test for interactions between pyridostigmine or physostigmine and soman. ED50s (i.e., dosages sufficient to reduce ARR time and AA to 50% of control level) of each carbamate (IM) and soman (SC) were determined. The ED50 values (mg/kg) in the ARR test were 3.2, 0.21, and 0.072 for pyridostigmine, physostigmine and soman, respectively, while in the AA test the corresponding values were 1.8, 0.072 and 0.060. The matrix of 16 combinations of 0, 1, 2/3, and 1/3 ED50 each of carbamate and soman was studied in each test system, as well as the effect of behavioral deficit free (BDF) dosages of each carbamate on the ED50s of soman. In both the AA and ARR tests the matrix of combinations of pyridostigmine and soman indicated an additive effect. In contrast, physostigmine produced one instance of potentiation in each test system and anatagonism in two combinations in the AA procedure. A BDF dosage of each carbamate (0.056 mg/kg of pyridostigmine and 0.026 mg/kg of physostigmine) gave no evidence of adding to the deficit in AA induced by soman. In the ARR test, the ED50 of soman was lower by 11% with pyridostigmine pretreatment and by 14% with physostigmine; the latter just reached statistical significance (p less than 0.05). Although additivity was most often found at higher dosages of pyridostigmine and physostigmine, at the BDF dosages little or no adverse interaction was found between Pyridostigmine or Physostigmine and low levels of soman.     

梭曼和毒扁豆碱引起大鼠脑电癫痫波的M和N胆碱能成分

在加拉碘铵麻痹，人工呼吸维持和甲基阿托品预防的大鼠上，梭曼ＦＳ０．１ｍｇ·ｋｇ－１ｉｍ（ｎ＝２４）或毒扁豆碱３０．０ｍｇ·ｋｇ－１ｉｖ（ｎ＝１８）使全部大鼠脑电图（ＥＥＧ）上出现早期持续很短的紧张性癫痫波和随后持续很长的阵挛性癫痫波．中枢＃ＦＳＮ＃ＦＫ受体激动剂烟碱１．０ｍｇ·ｋｇ－１ｉｖ（ｎ＝３８）和中枢Ｍ受体激动剂槟榔碱１５０ｍｇ·ｋｇ－１ｉｖ（ｎ＝４６）或匹鲁卡品３８０ｍｇ·ｋｇ－１ｉｖ（ｎ＝２４）能分别在ＥＥＧ癫痫波的特征，出现时间和持续时间上模拟出上述早期紧张性癫痫波和随后的阵挛性癫痫波．预先小剂量ｉｖ烟碱使中枢Ｎ受体脱敏或给小剂量Ｎ受体拮抗剂美加明保护中枢Ｎ受体后，梭曼只能引起潜伏期较长且持续很久的阵挛性癫痫波．胆碱酯酶抑制剂梭曼和毒扁豆碱较大剂量引起大鼠ＥＥＧ癫痫波可能的机理是过量的乙酰胆碱作用于潜伏期短，容易脱敏的Ｎ受体出现早期持续很短的ＥＥＧ紧张性癫痫波，又作用于潜伏期较长，不容易脱敏的Ｍ受体，出现稍后的ＥＥＧ阵挛性癫痫波     

Effectiveness of procyclidine in combination with carbamate prophylactics against diisopropylfluorophosphate poisoning

The protective effect of cholinolytics such as procyclidine and atropine, in combination with carbamate prophylactics, against diisopropylfluorophosphate poisoning was examined in mice. Doses of carbamates were optimized, based on the maximum sign-free dose, the time course of cholinesterase inhibition and the protective potential against diisopropylfluorophosphate poisoning. Centrally-active physostigmine was more toxic than centrally-inactive pyridostigmine and the toxic signs of carbamates appeared to be closely related to the level of inhibition of brain cholinesterase activity. In combination with atropine, physostigmine was more effective than pyridostigmine in protecting mice intoxicated with diisopropylfluorophosphate. Moreover, centrally-active atropine sulfate was a more effective co-antidote to carbamates than centrally-inactive atropine methylnitrate. The most prominent protection was achieved with the combination of carbamates and procyclidine, a centrally-active cholinolytic showing anticonvulsion, which was also observed to prevent diisopropylfluorophosphate-induced convulsions (Kim et al., 1997). Taken together, it is suggested that procyclidine could be a possible substitute for atropine as an antidote to diisopropylfluorophosphate poisoning.     

Inhibition of salivary secretion by tolterodine transdermal patch

Tolterodine, a nonselective muscarinic antagonist available only as immediate release (IR) or extended release (ER) oral formulations, is used for the treatment of overactive bladder (OAB). This study aimed to compare the efficacy and extent of dry mouth adverse effects of tolterodine transdermal patch to the oral formulation. The two formulations have been examined through the muscarinic receptor binding tests conducted in bladder and salivary gland tissues and the salivary secretion tests conducted in rats. Comparable average tolterodine blood concentration levels were obtained 3 h after oral administration of tolterodine 25 mg/kg and 12 h after transdermal application of tolterodine patch 6 mg/8 cm². While K_d in the bladder tissue increased to a similar degree in both formulations of tolterodine, K_d in the salivary gland increased to a greater degree in the oral formulation. These results indicate that similar degree of inhibitory effects were observed in the bladder for both formulations while less inhibitory effects were observed in the salivary gland with tolterodine transdermal formulation compared to the oral formulation. For assessment of salivary secretion, tolterodine transdermal patch 6 mg/8 cm² application resulted in significantly less inhibitory effects than oral tolterodine 25 mg/kg. Therefore, this study suggests that tolterodine transdermal patch could be a useful formulation that provides uniform and consistent inhibitory effects to effectively control OAB symptoms with reduced severity of dry mouth in comparison to the oral formulation.     

Pharmacokinetics of physostigmine in man following a single application of a transdermal system.

1. The pharmacokinetics of physostigmine were investigated in a three-way cross-over design in six healthy, male volunteers comparing a physostigmine transdermal system (PTS), an oral solution and an i.v. infusion. 2. A single application of the patch over 24 h produced detectable plasma drug concentrations after a mean lag-time of 4 h. Thereafter, the drug was absorbed continuously from the PTS and putative therapeutic plasma concentrations were measured over approximately 18 h. 3. A mean absolute bioavailability of 36% was determined for the transdermal system and 3% for the oral solution. In comparison with the oral solution, interindividual variability of pharmacokinetics was less with the PTS. 4. The mean amount of physostigmine released from the transdermal system after 24 h was 5.7 mg. Because of extensive metabolism, only 2.2 mg of physostigmine were detected systemically. 5. After removing the PTS, the mean apparent half-life of elimination was 4.9 h, compared with 0.5 h for the i.v. infusion. This indicates continued drug absorption from a skin depot. 6. Physostigmine was well tolerated by the volunteers. With the PTS, a mild erythema was observed at the area of application, disappearing within a few hours.