Search

Background: This prospective, randomised, observer-blinded study has been conducted in patients undergoing procedures of the lower extremities to evaluate the time to complete block resolution of 2-chloroprocaine 1% at three intrathecal doses (30, 40 and 50 mg)., Methods: After informed consent, we enrolled 45 male and female patients, aged 18-65 years, ASA score I-II, BMI 18-32 kg/m 2 , undergoing elective lower limb procedures lasting ≤40 min and with a requested dermatomeric level of sensory block ≥ T12. The patients were randomised in a 1:1:1 ratio to receive Chloroprocaine HCl 1% at one of the three different intrathecal doses (Group 30 = 30 mg, Group 40 = 40 mg or Group 50 = 50 mg). The progression and regression of both sensory and motor blocks were evaluated blindly. Urine and venous blood samples were collected for pharmacokinetic analysis., Results: Times to regression of spinal blocks were 1.76 ± 0.35 h, 2.13 ± 0.46 h and 2.23 ± 0.38 h, in Group 30, 40 and 50 respectively: the 30 mg dose showed a significantly faster resolution of spinal block than the 40 mg (p = 0.034) and the 50 mg (p = 0.006). Time to readiness for surgery was significantly reduced with the dose of 50 mg when compared to dose of 30 mg (p = 0.0259)., Conclusions: The doses of 50 mg and 40 mg yielded a longer resolution of spinal block than the dose of 30 mg. Nevertheless, the dose of 30 mg resulted in a higher secondary failure rate., Trial Registration: Registration of clinical trial: clinicaltrials.gov ( NCT02481505 ).

Study Objective: Spinal anesthesia is well suited for day-care surgery, however a persisting motor block after surgery can delay discharge. Among the new drugs available, chloroprocaine has been associated with a short onset time, and motor block duration and a quicker discharge. However, it is not clear if those outcomes are clinically significantly superior compared to those associated with the use of low-dose hyperbaric bupivacaine., Design: Aim of the study was to determine if spinal 2-chloroprocaine was superior to low-dose spinal bupivacaine regarding the following outcomes: onset time, block duration, time to ambulation and time to discharge., Patients/interventions: We performed a systematic literature search of the last 30 years using PubMed Embase and the Cochrane Controlled Trials Register. We included only blinded, prospective trials comparing chloroprocaine with a low dose of bupivacaine for spinal anesthesia. Low dose bupivacaine was defined as a dose of 10 mg or less. Outcomes of interest were time to motor block regression (primary outcome), time to ambulation and time to discharge (secondary outcomes), as indirect indicators of a complete recovery after spinal anesthesia., Main Results: Compared to a low dose bupivacaine, spinal 2-chloroprocaine was associated with significantly faster motor and sensory block regression (pMD = -57 min-140.3 min; P = 0.015 and <0.001 respectively), a significantly shorter time to ambulation and an earlier discharge (pMD = -84.6 min; P < 0.001 and pMD = -88.6 min and <0.001 respectively). Onset time did not differ between the two drugs (pMD = -1.1 min; P = 0.118)., Conclusions: Spinal 2-chloroprocaine has a shorter motor block duration, a significantly quicker time to ambulation and time to discharge compared to low dose hyperbaric bupivacaine and may be advantageous when spinal anesthesia is performed for day case surgery., (Copyright © 2018. Published by Elsevier Inc.)

A methodology that employs confocal Raman microscopy (CRM) on ex vivo skin samples is proposed for the investigation of drug content and distribution in the skin. To this end, the influence of the penetration enhancers propylene glycol and polyoxyethylene-23-lauryl ether on the penetration and permeation of procaine as a model substance was investigated. The drug content of skin samples that had been incubated with semisolid formulations containing one of these enhancers was examined after skin segmentation. The experiments showed that propylene glycol did not affect the procaine content that was delivered to the skin, whereas polyoxyethylene-23-lauryl ether led to higher procaine contents and deeper penetration. Neither substance was found to influence the permeation rate of procaine. It is thereby shown that CRM can provide additional information on drug penetration and permeation. Furthermore, the method was found to enhance the depth from which Raman spectra can be collected and to improve the depth resolution compared to previously proposed methods.

Background: This prospective, observer-blinded, randomised, multicentre study aimed at determining the non-inferiority of 50 mg of plain 1% 2-chloroprocaine vs. 10 mg of 0.5% plain bupivacaine in terms of sensory block onset time at T10 after spinal injection. The study hypothesis was that the difference in onset times of sensory block to T10 between the two drugs is ≤ 4 min., Methods: One hundred and thirty patients undergoing lower abdominal or lower limb procedures (≤ 40 min) were randomised to receive one of two treatments: 50 mg of plain 1% 2-chloroprocaine (Group C, n = 66) or 10 mg of plain 0.5% bupivacaine (Group B, n = 64). Times to sensory and motor block onsets, maximum sensory block level, readiness for surgery, regression of sensory and motor blocks, first analgesic requirements, unassisted ambulation, home discharge, and side effects after 24 h and 7 days were registered blindly., Results: Chloroprocaine was comparable with plain 0.5% bupivacaine in terms of time to sensory block at T10 level. Group C showed faster onsets of motor block (5 vs. 6 min), maximum sensory block level (8.5 vs. 14 min), resolution of sensory (105 vs. 225 min) and motor (100 vs. 210 min) blocks, unassisted ambulation (142.5 vs. 290.5 min), first analgesic requirement (120 vs. 293.5 min), and home discharge (150 vs. 325 min) (all comparisons, P < 0.05). No chloroprocaine patient developed transient neurological symptoms., Conclusion: Spinal anaesthesia with 50 mg of plain 1% 2-chloroprocaine is similar to 10 mg of plain 0.5% bupivacaine in terms of onset of sensory block at T10 but shows quicker recovery from anaesthesia than with 0.5% bupivacaine., (© 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Nicotinic acetylcholine receptors (nAChRs) have been studied in detail with regard to their interaction with therapeutic and drug addiction-related compounds. Using a structure-activity approach, we have examined the relationship among the molecular features of a set of eight para-R-substituted N,N-[(dimethylamino)ethyl] benzoate hydrochlorides, structurally related to procaine and their affinity for the α(3)β(4) nAChR heterologously expressed in KXα3β4R2 cells. Affinity values (log[1/IC50]) of these compounds for the α(3)β(4) nAChR were determined by their competition with [(3)H]TCP binding. Log(1/IC50) values were analyzed considering different hydrophobic and electronic parameters and those related to molar refractivity. These have been experimentally determined or were taken from published literature. In accordance with literature observations, the generated cross-validated quantitative structure-activity relationship (QSAR) equations indicated a significant contribution of hydrophobic term to binding affinity of procaine analogs to the receptor and predicted affinity values for several local anesthetics (LAs) sets taken from the literature. The predicted values by using the QSAR model correlated well with the published values both for neuronal and for electroplaque nAChRs. Our work also reveals the general structure features of LAs that are important for interaction with nAChRs as well as the structural modifications that could be made to enhance binding affinity., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The efficacy and duration of epidural morphine analgesia is diminished when administered after 2-chloroprocaine compared with lidocaine. The mechanism of the interaction between 2-chloroprocaine and morphine is unknown. Possible explanations include differences in the latency and duration of action of the two drugs or opioid receptor antagonism. We hypothesized that administration of epidural morphine 30 min before the initiation of 2-chloroprocaine anesthesia would result in postoperative analgesia of similar duration and quality to that achieved by epidural morphine after the initiation of lidocaine anesthesia in patients undergoing postpartum tubal ligation., Methods: Subjects undergoing bilateral postpartum tubal ligation after vaginal delivery with epidural analgesia were randomized to one of three groups. Subjects received epidural morphine or saline 30 min before the initiation of analgesia with 3% 2-chloroprocaine (two groups) or 2% lidocaine (one group), and at the time of surgical incision, they received either epidural saline or morphine. The duration of analgesia was defined as the time from morphine administration until the first request for supplemental analgesia. Duration of epidural morphine analgesia was compared among groups using Kaplan-Meier survival analysis and the log-rank test., Results: Administration of epidural morphine 30 min before the initiation of 2-chloroprocaine anesthesia (n = 29) resulted in a longer median duration of analgesia (28.6 h [95% CI 4.4-52.7]) compared with the administration of morphine after 2-chloroprocaine anesthesia (n = 30) (2.2 h [95% CI 0-4.8]) (P = 0.006). The median duration of analgesia observed when morphine was administered before 2-chloroprocaine was similar to that observed when morphine was administered after initiation of lidocaine anesthesia (n = 28) (25.8 h [95% CI 10.7-40.9]) (P = 0.83). Pain scores were not different in the postanesthesia care unit, but were higher on admission to the postpartum unit in the subjects receiving morphine after 2-chloroprocaine. Supplemental morphine equivalents administered in the first 48 h were similar among groups and there were no differences in opioid-related side effects., Discussion: This study demonstrates that administration of epidural morphine 30 min before epidural anesthesia with 2-chloroprocaine provides a similar duration of analgesia as epidural morphine after epidural lidocaine anesthesia. This suggests that the observed interaction between epidural morphine and 2-chloroprocaine is a result of differences in latency and duration of action of the two drugs, or that the administration of morphine before 2-chloroprocaine effectively blocks a receptor site antagonism.

The capacity of human, minipig, and rat skin and liver subcellular fractions to hydrolyze the anesthetic ester procaine was compared with carboxylesterase substrates 4-methylumbelliferyl-acetate, phenylvalerate, and para-nitrophenylacetate and the arylesterase substrate phenylacetate. Rates of procaine hydrolysis by minipig and human skin microsomal and cytosolic fractions were similar, with rat displaying higher activity. Loperamide inhibited procaine hydrolysis by human skin, suggesting involvement of human carboxylesterase hCE2. The esterase activity and inhibition profiles in the skin were similar for minipig and human, whereas rat had a higher capacity to metabolize esters and a different inhibition profile. Minipig and human liver and skin esterase activity was inhibited principally by paraoxon and bis-nitrophenyl phosphate, classical carboxylesterase inhibitors. Rat skin and liver esterase activity was inhibited additionally by phenylmethylsulfonyl fluoride and the arylesterase inhibitor mercuric chloride, indicating a different esterase profile. These results have highlighted the potential of skin to hydrolyze procaine following topical application, which possibly limits its pharmacological effect. Skin from minipig used as an animal model for assessing transdermal drug preparations had similar capacity to hydrolyze esters to human skin.

The colloidal phenomenon of soft particles is becoming an important field of research due to the growing interest in using polymeric system in drug delivery. Previous studies have focused on techniques that require intermediate process step such as dialysis or centrifugation, which introduces additional errors in obtaining the diffusion kinetic data. In this study, a drug selective electrode was used to directly measure the concentration of procaine hydrochloride (PrHy) released from methacrylic acid-ethyl acrylate (MAA-EA) microgel, thereby eliminating the intermediate process step. PrHy selective membrane constructed using a modified poly (vinyl chloride) (PVC) membrane and poly (ethylene-co-vinyl acetate-co-carbon monoxide) as plasticizer exhibited excellent reproducibility and stability. The response was reproducible at pH of between 3 to 8.5 and the selectivity coefficients against various organic and inorganic cations were evaluated. Drug release was conducted using the drug electrode under different pHs and the release rate increased with pH. The release behavior of the system under different pH exhibited obvious gradient release characteristics.

A method for the extraction and quantitation of procaine in equine plasma was developed for use with liquid chromatography-mass spectrometry (LC-MS). Procaine was isolated from equine plasma by liquid-liquid extraction at pH 11 with dichloromethane using procaine-d10 as an internal standard. Quantitation was achieved by LC-MS using a 3-microm C-18 column coupled to an electrospray ionization source on a linear ion-trap mass spectrometer. The limit of detection and limit of quantitation was determined to be 50 and 200 pg/mL, respectively. The lowest limit of detection determined by previous methods was 1 ng/mL. Administration samples were obtained as part of a larger study to determine a regulatory limit for procaine in racehorses and procaine concentrations were determined using this method.

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a monofunctional Pt triamine complex synthesized starting from cisplatin and procaine hydrochloride, characterized by a good antitumor activity coupled with low toxic effects and able to impair prenatal development of mice but at doses outside or just in the upper range of therapeutic doses. In the present paper the transplacental passage of DPR-derived Pt was investigated in CD1 mice on days 9, 13, 16 and 18 of pregnancy, 24 h after ip administration of 21 mg/kg DPR. For comparison, groups of mice were treated with an equivalent Pt-containing dose of cisplatin (10.7 mg/kg). Similarly to cisplatin, small amounts of Pt were detected in fetuses on day 9. From day 13 of gestation the concentration of DPR- and cisplatin-derived Pt increased up to the highest fetal concentrations detected on day 16. On day 18 the concentration of Pt decreased. Most importantly, on days 13-18 of pregnancy cisplatin-derived Pt was always significantly higher than that assayed after DPR administration. In addition, on day 13 of pregnancy Pt exposure of fetuses was significantly higher when dams were treated with cisplatin (AUC(0.5-24)= 3.40 vs. 4.95 microg.h/g). Finally, it is worth noting that serum decay of Pt after DPR or cisplatin administration in adult female mice was similar with AUC0.13-2h s of 7.5 and 6.6 microg.h/ml, respectively. When we determined the concentration of Pt into the main organs of fetuses from dams treated with either DPR or cisplatin on day 18 of gestation, we observed a different organ distribution. In fact, while the concentration of DPR-derived Pt was greater in the heart (1.08+/-0.30 vs. 0.78 +/- 0.35 microg/g, p <0.10), an opposite situation was found in the kidney (0.51+/-0.20 vs. 0.69 +/- 0.22 microg/g, p <0.05). In conclusion, our data show that DPR may pass through the placenta with an efficiency significantly lower than that of cisplatin. This finding may represent one of the possible causes of the lower embryotoxic/teratogenic effect of DPR as compared to cisplatin.

In order for a drug to be effective, enough of the active form must reach the target to elicit the desired effect. The first-pass effect for drugs taken orally is well known but the metabolism of drugs in plasma must also be considered during the drug discovery and development process. For instance, hydrolysis of a compound by plasma enzymes can significantly alter the bioavailability of the active compound. This unit describes methods for the determination of the stability of compounds in plasma.

Vetramycin is an injectable veterinary compound for animal use only. In veterinary medicine, it has been used for a long time as a bactericidal beta-lactam and aminglycoside antibiotics combination, extending the bactericidal spectrum of these substances. This compound, in addition to bactericidal procaine penicillin and dihydrostreptomycin (DHS), contains also prednisolone acetate and procaine hydrochloride, two biologically active substances. Prednisolone, a glucocorticoide, has an antiinflammatory, antiallergic, antiitchical and analgesic effect. Procaine hydrochloride, in turn, has a local anaesthetic effect and attenuates pain caused by irritable properties of antibiotics at the injection sites. The average dosage of, respectively, procaine benzylpenicillin (I.U./kg(-1) b.w.), DHS (microg/kg(-1) b.w.), prednisolone acetate (microg/kg(-1) b.w.) and procaine hydrochloride (mg/kg(-1) b.w.) in horses, cattle, pigs is 6000-15000, 10-11, 0.24-0.6 and 1.2-3.0; s.i.d., in sheep, foals, calves, piglets is 20000-40000, 10, 0.8-1.6 and 4-8; s.i.d., in dogs and cats is 30000-200000, 10, 0.8-1.6 and 4-8; s.i.d.. Intramammary injection dose (Vetramycin antimastitis ointment in syringe) in cows is 1000000 I.U. of procaine benzylpenicillin + 1000000 I.U. of dihydrostreptycin sulphate per quarter of udder, s.i.d., during 3 successive days.

The effect of external magnetic field (direct and alternating) on the targeted delivery and distribution in body tissues of experimental animals of anesthetics (novocain, lidocaine, and trimecaine) immobilized on highly dispersed ferromagnetics with biocompatible coating was studied by the method of emission spectral analysis. The results are compared with the results obtained earlier on highly dispersed iron powders with dextran coating. The parameters for the powders with dextran coating are considerably lower than those for the magnetic carriers with the polyacrylamide coating.

Background and Objectives: Prior to this investigation, there was no approach to compare both the potency of local anesthetics and their time course of action in a reproducible nociceptive system in humans. We tested whether the vascularly isolated vein segment is appropriate for such an approach., Methods: In six healthy men, a hand vein segment was vascularly isolated and intraluminally stimulated with electropulses of constant current intensity. The subjects rated pain between threshold and maximally tolerable pain on a visual analogue scale. For determining minimal blocking concentrations (a measure of potency), the vein segment was continuously perfused with Tyrode's solution with increasing concentrations of bupivacaine or procaine for at least 10 minutes each until pain was completely blocked. Subsequently, the respective local anesthetic was rinsed off with Tyrode's solution to determine the time course of recovery., Results: Both bupivacaine and procaine blocked pain in a concentration-related fashion, the minimal blocking concentrations being 1.6 (0.6-1.9; median and range) mmol/L for bupivacaine and 15.0 (7.5-22.5) mmol/L for procaine. Whereas the onset of block (time of 50% block) did not differ significantly between bupivacaine and procaine [43 s (range, 3-80) vs 53 s (range, 30-115)], local anesthesia lasted significantly longer after application of bupivacaine [278 s (range, 215-325)] than after procaine [183 s (range, 125-225)]., Conclusions: The vascularly isolated vein segment is well suited to compare in vivo the properties of local anesthetics with a minimally invasive approach at a reproducible nociceptive system in humans.

A rapid and sensitive method for the extraction and quantification of penicillin-G and procaine in horse urine and plasma samples has been successfully developed. The method involves the use of solid-phase extraction (SPE) for penicillin-G, liquid-liquid extraction (LLE) for procaine, and high-performance liquid chromatography (HPLC) for the quantification of penicillin-G and procaine. The new method described here has been successfully applied in the pharmacokinetic studies of procaine, penicillin-G and procaine-penicillin-G administrations in the horse.

Background: The potentiating effect of sodium bicarbonate on local anesthetic action is attributed to two mechanisms: (1) an increase in the un-ionized local anesthetic due to extracellular alkalinization, and (2) an accelerated conversion of local anesthetic from un-ionized to ionized form with intracellular acidification caused by bicarbonate. To evaluate these hypotheses, the intracellular pH, intracellular ionized procaine concentration, and evoked action potentials were measured in crayfish giant axons., Methods: In all measurements, axon preparations from crayfish were perfused extracellularly for 15 min with either bicarbonate-containing solution at pH 7.6 (bicarb/7.6) or bicarbonate-free solution at pH 7.6 (nonbicarb/7.6) or pH 8.0 (nonbicarb/8.0). Intracellular pH was measured using a pH-sensitive microelectrode. Intracellular anesthetic concentration was measured using a specially designed procaine-sensitive microelectrode with each of three solutions containing 1 mM procaine hydrochloride. Membrane potential was measured and, as an index of anesthetic action, the dV/dt of evoked action potential was calculated during perfusion with procaine., Results: Mean intracellular pH was significantly lower in the bicarb/7.6 (7.16+/-0.07) group than in the nonbicarb/7.6 (7.33+/-0.09) and nonbicarb/8.0 (7.33+/-0.12) groups (P < 0.01). The mean intracellular ionized procaine concentration was significantly higher in the bicarb/7.6 (0.53+/-0.08 mM; P < 0.05) and nonbicarb/8.0 (0.58+/-0.13 mM; P < 0.01) than in nonbicarb/7.6 (0.32+/-0.14 mM) group but did not differ between the bicarb/7.6 and nonbicarb/8.0 groups. The mean percentage decrease in dV/dtmax was approximately coincident with the mean intracellular procaine concentration in each solution., Conclusion: The presence of bicarbonate or extracellular alkalinization increased the intracellular concentration of ionized procaine and the anesthetic effect.

A drug with cationic characteristics such as procaine can be conveyed in a Carbomer hydrogel in two different ways: (i) in the form of salt in solution in the aqueous phase, and (ii) in the base form salified with the same polymer. Introduction of the drug into the hydrogel with different concentrations of polymer produced, in both cases, a reduction in viscosity in relation to drug concentration. The gels with procaine salified with the polymer showed greater viscosity. The drug release rate, in general, diminished with the increase in polymer concentration. Nevertheless, when this concentration was maintained, there was no variation in release rate when the viscosity produced as a consequence of drug concentration was changed. Gels with procaine salified with the carboxyvinylic polymer had a faster release rate than those with procaine in the hydrochloride form dissolved in the aqueous phase. These results have also been confirmed by a simulated absorption test.

Directed delivery and distribution of anaesthetics (novocaine, lidocaine, trimecaine) immobilized on finely dispersed iron powders under the influence of an external magnetic field in body tissues of test animals have been studied. The data of emission spectral analysis relating to concentration of iron in soft and bone tissues of animals influenced by constant and alternating magnetic field on front and reverse sides over a period from 0 to 180 min are given.

Rabbit experiments showed that distribution of drugs in the body in intratissue electrophoresis is related to current type. The drugs reach the target organ and are deposited best under the influence of sinusoidal modulated and galvanic currents. The experiments' evidence may serve the basis for differential use of electric currents for intratissue electrophoresis.

This in vitro study was designed to determine if in fact silicone expanders are readily permeable to metronidazole and procaine. The expanders were filled with 0.2% metronidazole or 2% procaine through the filler valves and then immersed wholly in normal saline. At several intervals over 120 hours, a certain amount of the surrounding saline was sampled and the drug levels subsequently determined. In this study, the silicone expanders were indeed readily permeable to the drugs, as measured with an ultraviolet spectrophotometer. A consistent diffusion curve was demonstrated. The rate of diffusion of a drug is inversely proportional to its molecular weight; i.e., the smaller the given drug's molecular weight, the greater is its ability to permeate an expander. In view of this, in the course of expansion, 0.2% metronidazole could be used in clinical expansion instead of normal saline, and a certain amount of antibiotic would diffuse out of the expander to prevent and control the infection.

With the aid of permanent cultured MDCK (Madin Darby Canine Kidney) epithelial cell a model for investigations dealing with phonophoresis effects was developed. The permeation of procaine hydrochloride through cell monolayers was examined while applying therapeutical ultrasound simultaneously. It could be shown that this permeation follows Higuchi kinetics. A comparison of the velocity factors, using a continuous irradiation of 1.0 W/cm2, shows about a 4.8 fold increase. Single Ultrasound pulses, however, result in a short-time enhancement of the permeation. The conclusion can be drawn that extent and velocity of the permeation of the permeation of procaine hydrochloride through MDCK monolayer can be controlled by phonophoresis.

The penetration of 14C-labelled alcohols (methanol, ethanol, n-butanol), 14C-labelled carbonic acids (formic, acidic, propionic, valerianic, octanoic, malonic, succinic and lactic acid), 14C-drugs (procain, barbital), and 14C-sugars (saccharose, xylose) into about 800 human deciduous or permanent teeth, both healthy and carious, was investigated. Dental enamel up to the cemento-enamel junction was incubated at a pH-value of 5.0 or 6.8 for 1 or 24 hours. For measurement of radioactivity, the dentine of the root was obtained by trepanation. Between intact and carious permanent teeth only slight differences were observed in case of the diffusion of methanol and ethanol (2% of the incubation medium), while n-butanol penetrated the dentine to an extent of 4.2% at a pH of 5.0. The monocarbonic acids penetrated the enamel of healthy teeth within 24 hours to an extent of 6.6-19.2% of the content of the incubation medium, while the dicarbonic (succinic and malonic) acids reached amounts of 3.6 and 9.2%, and the percentage of lactid acid which penetrated the enamel reached 2.9%, respectively. Under all conditions tested, saccharose penetration was higher in carious than in healthy teeth (3.8 vs 6.5%). The highest uptake was found in experiments with barbital; it was more pronounced in deciduous than permanent teeth (16.2 vs 12.4%). The data could be of interest in the therapy of inflammatory and other processes of the pulp.

1. Intrapericardial procaine, used to produce cardiac nerve blockade in both conscious and anaesthetized animals, has been reported to also produce changes in respiration. This study systematically investigated the effects of two doses of intrapericardial procaine on respiration in the conscious rabbit. 2. Rabbits were pre-instrumented with a chronic diaphragm electromyogram (dEMG) recording electrode and intrapericardial catheter. Arterial pressure, heart rate, dEMG and respiratory excursions (recorded with a pneumograph) were monitored in the conscious rabbit before and after intrapericardial and intravenous infusion of 2 and 5% procaine. Efficacy of cardiac nerve blockade was tested by intravenous infusion of phenyl biguanide. Arterial blood gases were determined at rest and during changes in respiration. 3. Following a low dose of intrapericardial procaine (12 mg), dEMG and respiratory excursions increased (65 +/- 13 and 76 +/- 32%, respectively) with no change in breathing frequency or arterial blood gases. Following a high dose of intrapericardial procaine (30 mg), four of six animals exhibited a similar response. However, four of the six rabbits also exhibited a second type of response pattern characterized by a further increase in respiratory efforts (430 +/- 336%), abolition of dEMG, and a mild hypoxaemia. 4. Intravenous infusion of a low dose of procaine was without effect, whereas intravenous infusion of a high dose of procaine produced minor behavioural responses. 5. In four additional anaesthetized rabbits, it was demonstrated that high doses of intrapericardial procaine anaesthetized the phrenic nerve to produce the observed alterations in respiration. 6. We conclude that if intrapericardial procaine is used to block cardiac nerves in conscious rabbits, it should be used in a low concentration and at the lowest possible total dose to avoid complications due to changes in respiration.

The blood esterase that mediates the metabolism of flestolol, an ultra short-acting beta blocker, was characterized. Esterase activity occurred in plasma of human, dog, rat, and guinea pig and not in erythrocytes of the same species. The esterase activity was greatest in humans and guinea pigs followed by dogs and rats. Purified human serum cholinesterase was very active against flestolol while human serum albumin was slightly active. Human and bovine erythrocyte membrane acetylcholinesterases, electric eel acetylcholinesterase, human hemoglobin, dog, rat, chicken, and bovine serum albumin were all inactive. Esterase activity with flestolol was inhibited in human, dog, and rat blood by echothiophate, eserine, and sodium fluoride. Guinea pig blood esterase activity was inhibited by echothiophate and sodium fluoride, but not by eserine. Metabolic interaction studies indicated that succinylcholine, procaine, and chloroprocaine interfere with the metabolism of flestolol in human blood. Succinylcholine prolonged the in vitro half-life of flestolol in dog blood, but acetylcholine, procaine, and chloroprocaine had no effect. Flestolol did not affect the metabolism of procaine or chloroprocaine in human and dog blood. The metabolism rate of flestolol decreased in individuals with atypical, fluoride-resistant and silent forms of serum cholinesterase.

The distribution and elimination kinetics of cis-diamminedichloroplatinum (II) (DDP) in female BDF1 mice bearing 6-day P388 leukemia were investigated in the presence and absence of procaine hydrochloride (P.HCl) exposure. DDP was administered as a single i.p. dose of 8 mg/kg in a 0.9% NaCl solution 6 days after tumor inoculum. P.HCl was administered as a single i.v. dose of 40 mg/kg immediately after DDP. The combined treatment with P.HCl produced marked changes in the plasma concentration-time profile of Pt. The unbound fraction of Pt was significantly increased both in the ascites fluid and plasma following DDP + P.HCl administration. P.HCl treatment induced a significant reduction (P < 0.01) in the rate constant of the protein-bound of Pt in plasma of tumored mice. Urinary excretion of Pt was unaffected by P.HCl, and there was no significant P.HCl-induced modification in the concentrations of Pt in the P388 leukemic cells. A statistically significant reduction of kidney and spleen Pt content was observed in female mice exposed to a dose of 8 mg/kg DDP + P.HCl. A similar reduction was observed in kidneys and testes of tumored mice receiving 16 mg/kg DDP along with 40 mg/kg P.HCl, which also showed lower renal and testicular cisplatin-DNA adducts after DDP + P.HCl than after DDP treatment. Potential explanations for the ability of P.HCl to interfere with the pharmacokinetics and biodistribution of DDP are discussed.

1. Procaine, 2-chloroprocaine, ethyl aminobenzoate and methyl salicylate were added at various concentrations to liver esterase, supernatant of skin homogenate, or single-pass perfused ears of rabbits. 2. Vmax of product formation by purified liver esterase correlated with the rank order of the distribution coefficients (n-octanol/buffer) of the substrates and ranged between 11 and 1100 pmol/min per micrograms protein. Km values were between 20 and 50 microM. 3. No correlation was observed when the apparent enzyme kinetics, calculated by non-linear adaptation, were compared with each other after substrate administration to skin, arterial influx, or incubation with skin homogenate. 4. An acid labile conjugate of ethyl 4-aminobenzoate was found, mainly during arterial perfusion and in supernatant of skin homogenate, after administration of ethyl 4-aminobenzoate. 5. Acetamidobenzoic acid was observed in quantities of about 10% of the free 4-aminobenzoic acid during dermal or arterial application of procaine. This metabolite was not found with ethyl 4-aminobenzoate. 6. The results from isolated rabbit ear perfusion differ quantitatively and qualitatively with those obtained from supernatant of skin homogenate or purified liver esterase.

The release from a matrix compressed from a physical mixture of procaine hydrochloride, chlorinated poly(propylene), lactose, and a surfactant was investigated. With nonionic and cationic surfactants incorporated in the matrix, the release of procaine hydrochloride was linearly related to the square root of time, and as the concentration of the surfactants increased, the release was faster. When an anionic surfactant (sodium lauryl sulfate) was incorporated in the matrix, the release of procaine hydrochloride was linearly related to the square root of time; however, the release pattern depended on the concentration of the anionic surfactant. As the concentration of sodium lauryl sulfate increased to 4%, the release progressively slowed to a minimum because of the formation of a poorly soluble complex between the cationic procaine and the anionic surfactant. As the concentration of anionic surfactant increased further, the release increased as the complex was micellarly solubilized.

Plasma and urinary concentrations of procaine were examined in Standardbred mares after subcutaneous administration of various doses (80 mg to 1600 mg) of procaine hydrochloride. Regardless of dose, peak plasma procaine values occurred within 1 h, but remained detectable in a dose-dependent manner, with procaine present at 1 h with the 80 mg dose and 6 h at the 1600 mg dose. Similarly, peak urinary procaine concentrations were attained within 1.5 to 3 h, irrespective of dose, while detection time was dose-dependent, being 23 h for 80-200 mg doses but as long as 30-54 h with the 1600 mg dose. When mares were given a single intramuscular injection of a penicillin G-procaine preparation (Ethacillin, Cillimycin, Penamycin, Derapen A, Azimycin or Diathal), peak plasma procaine concentrations varied and were reached from 10 min to 3 h in all cases, with detection from 3 to 20 h after drug administration. Although the peak urinary levels of procaine occurred between 30 mins and 6 h, detection in urine in most cases was as long as 78-120 h except for Diathal for which detection was limited to 54 h. Daily administration of a penicillin G-procaine preparation (Pen-Di-Strep) for 5 days produced a biphasic peak in plasma procaine at 3 and at 6-9 h with detection from 16 to 23 h after drug treatment. Although peak urinary procaine values were reached at similar times after single or multiple injections, the duration of detection was markedly longer (425 h) after the multiple-dose regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

A simple, rapid and sensitive method for procaine determination is described. Isotope dilution mass spectrometry with (15N)procaine as internal standard was used. The analysis was performed at 4000 resolution by selected ion monitoring with temperature programming. The sample was measured in underivatized form in the direct inlet system. The method shows good analytical parameters: linearity between 0 and 40 micrograms ml-1, good precision and accuracy. The method was applied to the in vitro pharmacokinetic study of the metabolism of procaine in liver homogenates of Wistar rats. The method is rapid, permitting about six samples to be run per hour. Sensitivity of the method permits analysis at a signal-to-noise ratio of 5:1.

The aim of this study was to obtain information about the absorption of procaine in the rat small intestine (Fisher-Parsons preparation). In the range from 0.25-10 mmol.l-1 procaine in the luminal perfusate, much more of the unchanged drug was absorbed in segments of the ileum than of the duodenum and jejunum. Besides procaine, two metabolites, p-aminobenzoic acid (PABA) and acetylated p-aminobenzoic acid (AABA), formed in the intestinal mucosa, appeared in the absorbate. With increasing substrate concentration in the perfusate the PABA in the absorbate increased considerably in all three segments; from 0.75 mmol.l-1 procaine upwards the PABA produced was highest in the jejunum. AABA formed in the mucosa and measured in the absorbate did not increase in the same manner with increasing substrate concentration; in the absorbate of jejunal segments the amount of AABA was significantly higher than in duodenal and ileal segments. Taking into account that in rats the microclimate of the ileum differs considerably from that of the upper part of the small intestine, the marked difference observed in the absorption of procaine between ileal segments on the one side, and duodenal and jejunal segments on the other, can be explained on the basis of the "non-ionic diffusion" theory.

Gerovital was compared with placebo and another procaine preparation in a double blind study of 88 rehabilitation patients suffering from back or hip disease. In an open part of the study procaine from intramuscularly injected Gerovital disappeared from the plasma within 15-30 minutes. In patients treated with Gerovital or another procaine no clinical, physiological or psychological benefits were found in addition to the improvements following rehabilitation compared with placebo treatment. Clinical examination showed that the benefits of rehabilitation were similar in patients receiving Gerovital, another procaine and placebo.

Lidocaine was recently found to rapidly cross the placenta and result in considerable fetal exposure after local infiltration of the perineum for episiotomy. For this reason, a more appropriate agent for local perineal infiltration might be a drug with rapid metabolism and inactive metabolites. 2-Chloroprocaine, an ester-linked local anesthetic agent, is available but is not commonly used for this procedure. The purpose of this study was to evaluate the placental transfer of 2-chloroprocaine after local perineal infiltration. The drug was administered to 17 normal term pregnant women for episiotomy. After local perineal infiltration, the levels of 2-chloroprocaine and/or its metabolite, chloroaminobenzoic acid, were quantitated in maternal and neonatal plasma or urine. The pharmacologic data indicated that 2-chloroprocaine was nondetectable at delivery in maternal and umbilical cord vein; one patient had trace levels in the cord. Chloroprocaine was not detectable in neonatal plasma, but chloroaminobenzoic acid was detectable in both maternal and cord vein plasma. Mean levels of chloroaminobenzoic acid in maternal plasma at delivery were 1.04 +/- 0.32 micrograms/ml, and mean levels in cord vein were 0.35 +/- 0.54 micrograms/ml. Clinically, 2-chloroprocaine provided good analgesia. These results indicate that very little, if any pharmacologically active drug, reaches the fetus after local perineal infiltration with 2-chloroprocaine. Therefore 2-chloroprocaine appears to be preferable to lidocaine when used for local perineal infiltration.

The anaesthetic action of procaine on the crayfish claw nerve was studied electrophysiologically. The onset time of conduction block (block time) was shortened and the minimum dose of procaine required for the blockade was significantly reduced in the presence of monocarboxylate anions. To investigate the mechanism of this anaesthetic enhancement, the action of procaine was considered on the basis of a simple Langmuir-type adsorption model. Rate constants in the model were estimated by observing the time course of procaine desorption from the nerve using the UV light absorption technique. The dependence of block time on procaine concentration which was simulated from the model corresponded quite well to the electrophysiological data. The model suggested the following two points. 1. The anaesthetic enhancement by some organic anions could be explained by the acceleration of procaine adsorption and lowering of the critical adsorption ratio. 2. The maximum adsorption of procaine observed was about 40 mumol per 1 g wet weight of the nerve, the value of which corresponded to 1:1 adsorption of procaine to phospholipids in the membrane.

A formulation for tablets with diethylaminoethanol p-acetylaminobenzoate was set. The obtained tablets are adequate from the point of view of organoleptic qualities, mean weight weight variations, mechanical strength and disaggregation, both after processing and one year storage. The kinetics of water and artificial gastric juice, determined with the help of a Nogami device, by tablets capillarity reveals a homogeneous porosity, fact that determines the complete disintegration of the tablets in due time, and thus a good availability.

Contribution of Ca2+-influx via the slow channel to generation of the transient inward current in guinea-pig ventricular muscles was studied using a single sucrose gap voltage clamp technique. The transient inward current (TI) was induced from superfusion of the preparations with the low-K+ (0 mM), high-Ca2+ (3.6 mM) solution. Application of 2 mM-CO2+ quickly and reversibly suppressed the TI amplitude to 25% of the control and delayed its peak timing to 153% during 10-20 min. Inhibition developed as quickly as Co2+ suppressed the slow inward current (Is), and its recovery took place without apparent time lag behind its effect on Is. The block of both TI and Is by Co2+ was antagonized by raising external Ca2+ to 7.2 mM. Removal of external Ca2+ caused a prompt suppression of both Is and TI. Application of 2 or 5 mM-procaine HCl produced a complete abolition of TI with a mild depression of Is. While 1 mM-caffeic caused a suppression of TI after a transient augmentation, 10 mM-caffeine completely eliminated it without abolishing Is. These results indicate that the Ca2+-influx through the slow channel acts not only to load the cell with those ions, but also to influence somehow the Ca2+-release from the stores under the Ca2+-overloaded conditions.

The influence of orally administrated procaine hydrochloride and of its metabolites diethylaminoethanol, monoethylaminoethanol and ethanolamine on specific intermediary processes in rats was tested. While the animals got procaine hydrochloride in a single dose or via food the incorporation rate of amino acids in protein was measured in homogenisates of liver tissue by the incorporation of a mixture of 14C-amino acids. Procaine hydrochloride, the commercial product K. H. 3, as well as diethylaminoethanol, monoethylaminoethanol and ethanolamine increased the amino acid incorporation rate in a dose and time dependent mode, while p-aminobenzoic acid remained without any effect. The dose of procaine hydrochloride inducing a maximal reaction was in the range of 50 to 100 mg/kg b. w. (250 to 500 mg/kg food). The minimal active dose was nearly at 10 mg/kg b. w. Paying regard to a metabolic factor of 10 the effective dose-range is nearly the dose used in experience with human beings to influence geriatric complaints. In the study described here haematoporphyrine (a component of the commercial product K. H. 3, not absorbed) shows no specific intermediary effect. May be it promotes the intestinal absorption of procaine hydrochloride by protection against intestinal hydrolysis. The intermediary effect of procaine hydrochloride is to measure on cellular or subcellular level without compatibility to the activity as a local anaesthetic. With regard to other intermediary effects mentioned in the literature like growth promotion or inhibition of monoamine oxidase activity, it is discussed whether the increase of the hepatic amino acid incorporation rate is corresponding to geriatric experiences made with procaine hydrochloride.