Local Procaine Research Articles

Spectrophotometric determination of procaine hydrochloride using oxidative coupling and cloud point extraction

A method with rapid, sensitive, accurate, and selective for estimation of local anesthetic procaine hydrochloride (PRO.HCl) is crucial, due to its bad damage to health if administrated excessively. In this work two spectrophotometric methods oxidative coupling and cloud point extraction (CPE) were utilized for determination of PRO.HCl in its standard state and pharmaceutical preparations. Method A, based on the oxidative coupling reaction using sodium hypochlorite as an oxidant and 2,5-dimethylphenol as coupling agent. The blue colored product has high absorption at 600 nm. Method B based on the CPE relying on the previous reaction, with addition of Triton X-114, after extracting the colored product, it was measured at 630 nm. Beer’s law of both methods are linear in the concentration ranges 2.50-50 µg/mL (method A) and 1.25-3.75 µg/mL (method B). The molar absorptivity coefficients of methods (A) and (B) are 4.01 x 103 and 1.34 x 104 L/mol.cm, respectively. For (method A) limit of detection and limit of quantification were calculated and found that 0.26 µg/mL and 0.87 µg/mL, respectively, while for (method B) were found to be 0.16 and 0.54 µg/mL, respectively. Both methods (A and B) are applied to evaluate PRO.HCl in pharmaceutical preparations (injection). KEY WORDS: Cloud point extraction, 2,5-Dimethylphenol reagent, Odxiative-coupling, Procaine-hydrochloride, Spectrophotometry, Triton X-114. Bull. Chem. Soc. Ethiop. 2025, 39(1), 1-13. DOI: https://dx.doi.org/10.4314/bcse.v39i1.1

ProcCluster® and procaine hydrochloride inhibit the growth of Aspergillus species and exert antimicrobial properties during coinfection with influenza A viruses and A. fumigatus in vitro.

Influenza-associated pulmonary aspergillosis is associated with high mortality rates and limited treatment options. The current standard practice involves treating each pathogen separately. However, the use of antifungal drugs can lead to serious side effects, and the presence of triazole-resistant Aspergillus strains can complicate antifungal therapy. In addition, drug-resistant influenza viruses are becoming an increasing concern in clinics. A drug that affects fungal and viral propagation could overcome these disadvantages. Thus, we conducted a study to examine the antifungal and antiviral properties of ProcCluster® and procaine hydrochloride (HCl), which are prodrugs derived from the local anesthetic procaine. Conidia of different A. fumigatus strains, A. flavus and A. terreus were treated with the test substances in a human cell-free system and antifungal properties were analyzed either by fluorescence microscopy or absorption measurements. Changes in metabolic activity and intracellular Ca2+ distribution during treatment of A. fumigatus with ProcCluster® were observed using fluorescence microscopy. In addition, antifungal and antiviral properties of ProcCluster® and procaine HCl were investigated during in vitro coinfection of lung epithelial cells with A. fumigatus and influenza A viruses (IAV). Analysis was performed by fluorescence microscopy, standard plaque assay and Western blot assay. Both substances inhibited the growth of the fungus, even when applied after germination or in the presence of purified IAV particles. ProcCluster® remained effective against triazole-resistant A. fumigatus strains. However, the addition of CaCl2 reversed the antifungal effect, indicating that ProcCluster® inhibited fungal growth by disrupting fungal Ca2+ homeostasis. Furthermore, in vitro studies showed that ProcCluster® and procaine HCl reduced the pathogen load of IAV and A. fumigatus during coinfection. Finally, the combination of ProcCluster® with the antiviral drug favipiravir exhibited increased antipathogenic activity, particularly against IAV replication. This research highlights ProcCluster® and procaine HCl as substances with anti-infective properties against various pathogens.

ProcCluster® and procaine hydrochloride inhibit the replication of influenza A virus in vitro.

Treatment of influenza A virus infections is currently limited to few direct acting antiviral substances. Repurposing other established pharmaceuticals as antivirals could aid in improving treatment options. This study investigates the antiviral properties of ProcCluster® and procaine hydrochloride, two derivatives of the local anesthetic procaine, in influenza A virus infection of A549, Calu-3 and MDCK cells. Both substances inhibit replication in all three of these cell lines in multi-cycle experiments. However, cell line-dependent differences in the effects of the substances on viral RNA replication and subsequent protein synthesis, as well as release of progeny viruses in single-cycle experiments can be observed. Both ProcCluster® and procaine hydrochloride delay endosome fusion of the virus early in the replication cycle, possibly due to the alkaline nature of the active component procaine. In A549 and Calu-3 cells an additional effect of the substances can be observed at late stages in the first replication cycle. Interestingly, this effect is absent in MDCK cells. We demonstrate that ProcCluster® and procaine hydrochloride inhibit phospholipase A2 (PLA2) enzymes from A549 but not MDCK cells and confirm that specific inhibition of calcium independent PLA2 but not cytosolic PLA2 has antiviral effects. We show that ProcCluster® and procaine hydrochloride inhibit influenza A virus infection at several stages of the replication cycle and have potential as antiviral substances.

The Local Anaesthetic Procaine Prodrugs ProcCluster® and Procaine Hydrochloride Impair SARS-CoV-2 Replication and Egress In Vitro.

As vaccination efforts against SARS-CoV-2 progress in many countries, there is still an urgent need for efficient antiviral treatment strategies for those with severer disease courses, and lately, considerable efforts have been undertaken to repurpose existing drugs as antivirals. The local anaesthetic procaine has been investigated for antiviral properties against several viruses over the past decades. Here, we present data on the inhibitory effect of the procaine prodrugs ProcCluster® and procaine hydrochloride on SARS-CoV-2 infection in vitro. Both procaine prodrugs limit SARS-CoV-2 progeny virus titres as well as reduce interferon and cytokine responses in a proportional manner to the virus load. The addition of procaine during the early stages of the SARS-CoV-2 replication cycle in a cell culture first limits the production of subgenomic RNA transcripts, and later affects the replication of the viral genomic RNA. Interestingly, procaine additionally exerts a prominent effect on SARS-CoV-2 progeny virus release when added late during the replication cycle, when viral RNA production and protein production are already largely completed.

Local anaesthetic procaine derivatives protect rat against diabetic nephropathy via inhibition of DPP-4, inflammation and oxidative stress.

Diabetic nephropathy (DN) is a serious devastating disease. However, the current clinical options to treat DN are not adequate. Thus, in the present study, we intend to develop novel series of procaine-embedded thiazole-pyrazoles as protective agent against DN. The compounds were tested for inhibition of dipeptidyl peptidase (DPP)-4, -8, and - 9 enzyme subtypes, where they selectively and potently inhibit DPP-4 as compared to other subtypes. The top three ranked DPP-4 inhibitors (8i, 8e and 8k) were further screened for inhibitory activity against NF-ĸB transcription. Among these three, compound 8i was identified as the most potent NF-ĸB inhibitor. The pharmacological benefit of compound 8i was further established in streptozotocin-induced diabetic nephropathy in rats. Compound 8i showed marked improvements in blood glucose, ALP, ALT, total protein, serum lipid profile such as total cholesterol, triglyceride, HDL levels and renal functions such as urine volume, urinary protein excretion, serum creatinine, blood urea nitrogen and creatinine clearance as compared to nontreated diabetic control group. It also reduces oxidative stress (MDA, SOD and GPx) and inflammation (TNF-α, IL-1β and IL-6) in the rats as compared to disease control group rats. This study demonstrated the discovery of procaine-embedded thiazole-pyrazole compounds as a novel class of agent against diabetic nephropathy.

SERS and EC-SERS detection of local anesthetic procaine using Pd loaded highly reduced graphene oxide nanocomposite substrate

The localized surface plasmon resonance (LSPR) excitations are critical towards achieving sizable spectral enhancements of the Raman scattered light. Herein, the synthesis of palladium-based highly reduced graphene oxide (Pd-HRG) with LSPR properties as an effective surface-enhanced Raman scattering (SERS) substrate and its utility in the highly sensitive detection of procaine are reported. The concentration detection of procaine samples was optimized by applying a set of pre-concentration parameters. The Pd-HRG nanocomposite showed a remarkable LSPR response with a Raman enhancement factor of 8.7 × 102. The Pd-HRG is employed to modify fluorine doped tin oxide electrode (Pd-HRG/FTO), resulted with an enhancement factor of 7.5 × 104 corresponding to the EC-SERS technique. The electronic and surface properties of synthesized Pd-HRG and functionalized FTO electrode were evaluated using Raman, infrared, EIS, XRD, FESEM and EDX techniques. Quantum chemical calculations were carried out to elaborate on the nature of interaction of procaine molecules with a nanostructured surface model. Pd-HRG, with an efficient and cost-effective fabrication, can be considered as a promising EC-SERS substrate for the detection of organic therapeutic drugs.

Review of Genetic Variants of Butyrylcholinesterase and Their Potential Impact on Human Health

Butyrylcholinesterase (BChE) is an enzyme found in plasma and many other parts of the body. It is enzyme that hydrolyses drugs containing ester bonds such as drugs acting at the neuromuscular junction (succinylcholine) and local anaesthetics (procaine). Examination of the gene for mutations or polymorphisms causing the observed biochemical phenotypes has isolated those responsible for all the most widely known variants. The molecular bases of several genetic variants of BChE have been reported, such as the Atypical variant, fluoride-resistant variant, silent variant, K variant, J variant and C5 variant. In general, BChE polymorphisms have been shown to produce enzymes with varying levels of catalytic activity. Genetic variants of human butyrylcholinesterase were one of the first examples in the new field of pharmacogenetics when it was recognized that abnormal response to the succinylcholine was due to a mutated enzyme with low binding affinity. Beside that, variant of BChE has potential impact for Alzheimer disease patology.

Review of Genetic Variants of Butyrylcholinesterase and Their Potential Impact on Human Health

Butyrylcholinesterase (BChE) is an enzyme found in plasma and many other parts of the body. It is enzyme that hydrolyses drugs containing ester bonds such as drugs acting at the neuromuscular junction (succinylcholine) and local anaesthetics (procaine). Examination of the gene for mutations or polymorphisms causing the observed biochemical phenotypes has isolated those responsible for all the most widely known variants. The molecular bases of several genetic variants of BChE have been reported, such as the Atypical variant, fluoride-resistant variant, silent variant, K variant, J variant and C5 variant. In general, BChE polymorphisms have been shown to produce enzymes with varying levels of catalytic activity. Genetic variants of human butyrylcholinesterase were one of the first examples in the new field of pharmacogenetics when it was recognized that abnormal response to the succinylcholine was due to a mutated enzyme with low binding affinity. Beside that, variant of BChE has potential impact for Alzheimer disease patology.

Vertical Lobes of the Mushroom Bodies Are Essential for View-Based Navigation in Australian Myrmecia Ants

Prior to leaving home, insects acquire visual landmark information through a series of well-choreographed walks or flights of learning [1-4]. This information allows them to pinpoint goals both when in their vicinity [5-7] and from locations they have not previously visited [8-10]. It is presumed that animals returning home match memorized views to their current view for successful view-based navigation [11]. While view-based navigation strategies have been incorporated into several navigation models [8, 12, 13], we still know little about how this behavior is performed by the insect brain. Mushroom bodies are essential for visual learning and memory [14-16], and therefore we investigated their role in view-based navigation in a visually oriented ant, Myrmecia midas. We injected the local anesthetic procaine [15, 17, 18] into the mushroom body vertical lobes (VLs) to selectively inhibit neural activity in this region. We compared the behavior of VL-procaine-treated ants with three groups: untreated control, VL-saline, and off-target (antennal lobe) procaine. Experienced foragers were collected, treated, and released in their familiar environment where we documented their behavior. Animals with procaine-inactivated VLs had tortuous paths and were unable to find their nest, whereas ants from the untreated and off-target procaine groups were well directed and were the most successful at returning home. Untreated animals walked faster when their gaze was directed toward home, and this behavior was eliminated by anesthetizing the VL region. Our data provide neurobiological evidence that the mushroom body vertical lobes are necessary for retrieving visual memories for successful view-based navigation.

Uterine contractility changes in a perfused swine uterus model induced by local anesthetics procaine, lidocaine, and ropivacaine.

BackgroundLocal anesthetics (LAs) are increasingly used as therapeutics due to their multiple molecular effects. They may be potential agents also in gynecology and reproductive medicine. The objective of this study was to investigate the contractility response of the perfused swine uterus to different concentrations of the LAs procaine, lidocaine, and ropivacaine.Methods and findingsIn an extracorporeal perfusion model with fresh swine uteri, effects of administered boli of these three LAs in concentrations of 0.1 mg/mL, 0.5 mg/mL and 1.0 mg/mL on uterine contractility and peristalsis were assessed using an intrauterine double-chip micro-catheter. A dose-dependent increase in intrauterine pressure (IUP) in the isthmus and corpus uteri was observed after the administration of the ester-LA procaine 0.1, 0.5, and 1.0%, which was not seen with lower concentrations, or buffer solution. An increase-decrease curve was found after increasing concentrations of the amide-LA lidocaine and ropivacaine, with an IUP plateau with 0.1 and 0.5%, and a decrease with 1% (p<0.01). All reactions were seen in both the isthmus and corpus uteri. The difference of the contractility pattern between ester- and amide-LA at 1% concentration was significant.ConclusionLAs dose-dependently modulate contractility in non-pregnant swine uteri. The amid-LAs lidocaine and ropivacaine reduce contractility in higher concentrations and may be used as therapeutics in disorders with increased uterine contractility, as dysmenorrhoea, endometriosis, and infertility. The multiple molecular effects of LAs may explain these effects. This in-vitro pilot study in vitro provides initial data for designing further studies to transfer the results onto humans.

Büchi's model based analysis of local anesthetic action in procaine hydrochloride: Vibrational spectroscopic approach

The drug action of ester type local anesthetic (LA) procaine hydrochloride (PRC HCl) is activated by blocking Na+ ion flow when it binds to the ion channel in the ligand gated sodium ion channel protein. Büchi's model, explains binding action of ester type LA drug with receptor in terms of charge transfer, dipole-dipole, hydrogen bonding and van der Waals interactions through lipophilic, ester and hydrophilic moieties. The present work investigates molecular structural and vibrational spectral features of para amino benzoate group, ester part and tertiary amino group respectively belonging to lipophilic, ester and hydrophilic moieties, accountable for the binding of drug to sodium channel. The electron transport mechanism through the ring responsible for structural deviation from benzenoid to quinonoid form and consequent dipolar nature of carbonyl group have been investigated, based on the analysis of XRD, DFT computed molecular structure, 8a ring mode and NBO charges. The characteristic UV absorption peaks and vibrational marker bands of LA drugs have been identified and the charge transfer interaction responsible for lipophilic binding has been investigated. The blocking of Na+ in the ion channel has been probed using attractive and repulsive energy profile. The molecular polarizability has been computed to substantiate the correlation between the structure activity relationship of LA drug molecule and molecular polarizability. The low toxicity of PRC HCl was evaluated using in vitro cytotoxicity study, confirming it as a potential short acting local anesthetic.

Inhibition of Ion Transport through Gramicidin A Channels by the Addition of Local Anesthetic Procaine

AbstractThe blocking effects of the cationic procaine, a typical local anesthetic (LA), on ion transport through gramicidin A (gA) channels between two aqueous phases (W1 and W2) were electrochemically elucidated. Although the gA channels promoted the permeation of monovalent cations, especially Cs+, the addition of procaine to W1 decreased the permeation of Cs+ through these channels from W1 to W2. This can be explained based on the following mechanism. Hydrophobic cationic procaine tends to approach the pore of a gA channel. Since it is too large to enter the pore, it cannot pass through the channel. Thus, cationic procaine inhibits the permeation of Cs+ from W1 to W2 by competing with Cs+ for access to the entrances of the gA channels. It is postulated that the decrease in the apparent activity of Cs+ caused by this competition prevents ion transport through the gA channels.

Efficacy of Local Anesthetics in Detachment of Normal 3T3 Mouse Fibroblasts and Prostate Cancer AT-2 Cells from Substrata, in Maintenance of Viable Cells in a Non-Adherent State, and in Preservation of Cell Surface Markers Detected with FlowSight Image Cytometry.

The local anesthetics procaine, lidocaine and tetracaine permit the reversible detachment of viable cells and their passaging or preservation in a non-adherent state in the absence of proteolytic enzymes. The effects of these anesthetics, dissolved in various media, on cell viability, cell detachment from substrata and preservation of cells in a non-adherent state, were compared using the AT-2 line of rat prostate carcinoma cells of moderate malignancy and the 3T3 mouse fibroblast cell line. It was found that all three local anesthetics can induce cell rounding followed by detachment of over 95% of viable cells in both lines in Ca2+/Mg(2+)-free PBS. Tetracaine in 1 mM concentration was the most effective in induction of fast cell detachment. However, procaine and lidocaine in 16 mM concentrations were found to be optimal for preservation of cells in a non-adherent state and for the maintenance of cell viability for at least 2 h. The tested anesthetics also cause cell rounding and detachment when present in various cell culture media but these processes occurred much more slowly and less efficiently than in Ca2+/Mg(2+)-free PBS. Normal 3T3 mouse fibroblasts after detachment and passaging undertake growth reaching the same saturation density in cultures after detachment with procaine or lidocaine as after passaging using trypsin solution. The results suggest that the application of local anesthetics can be a very simple and effective technique for cell passaging in tissue cultures. This technique might decrease side-effects and cell injury caused by trypsinization or cell scraping. The preservation of cells in suspension in a non-adherent state may facilitate analysis of cell surface properties and fractionation of cell mixtures. Avoiding the use of trypsin allows for the preservation of cell surface proteins ICAM, CXCR4, and HCAM analyzed with FlowSight image flow cytometry.

Hippocampal theta rhythm after local administration of procaine or amphetamine into the ventral tegmental area in fear conditioned rats

The ventral tegmental area (VTA) is thought to be an important component in the mesocorticolimbic system involved in the regulation of theta rhythm in the hippocampus. In this study we investigate the effect of pharmacological inactivation (local procaine infusion) or activation (local amphetamine infusion) of the VTA on theta rhythm parameters during task specific behavior in fear conditioned, freely moving rats. Animals were implanted with bilateral recording electrodes into the dorsal hippocampus (CA1) and bilateral injection cannulas into the VTA. Behavioral activities and hippocampal local field potentials (LFP) were recorded throughout the experiment, in pre- and post-injection conditions. We found that intra-VTA injection of procaine temporarily suppressed fear conditioned avoidance response (escape from the foot-shock arena) and also influenced hippocampal theta rhythm parameters during immobility linked with arousal and/or attention. Procaine infusion decreased the signal power (Pmax) of theta rhythm during immobility behavior, in comparison to the control group (water infusion), whereas administration of amphetamine had no effect on the behavior and hippocampal LFP. Our results indicate that temporal inactivation of neuronal activity in the VTA affects hippocampal theta rhythm linked with attentional immobility and suppresses avoidance response in fear conditioned animals.

Neuralgia of the glossopharyngeal nerve in a patient with posttonsillectomy scarring: recovery after local infiltration of procaine-case report and pathophysiologic discussion.

We describe a patient with a three-year history of severe progressive left-sided glossopharyngeal neuralgia (GPN) that failed to adequately respond to various drug therapies. The application of lidocaine spray to the posterior pharyngeal wall provided no more than short-term relief. Apart from a large hypertrophic tonsillectomy scar on the left side all clinical and radiologic findings were normal. In terms of therapeutic local anaesthesia, the hypertrophic tonsillectomy scar tissue was completely infiltrated with the local anaesthetic (LA) procaine 1%. The patient has been almost completely pain-free ever since, and the lidocaine spray is no longer needed. Six weeks after the first treatment a repeat infiltration of the tonsillectomy scar led to the complete resolution of all symptoms. The patient has become totally symptom-free without the need to take any medication now for two and a half years. This is the first report of a successful therapeutic infiltration of a tonsillectomy scar using an LA in a patient with GPN that has been refractory to medical treatment for several years. A possible explanation may be that the positive feedback loop maintaining neurogenic inflammation is disrupted and “sympathetically maintained pain” resolved by LA infiltration.

Differential mechanism of the effects of ester-type local anesthetics on sarcoplasmic reticulum Ca-ATPase

The effect of the local anesthetics procaine and tetracaine on sarcoplasmic reticulum membranes isolated from two masticatory muscles, masseter and medial pterygoid, was tested and compared to fast-twitch muscles. The effects of the anesthetics on Ca-ATPase activity, calcium binding, uptake, and phosphorylation of the enzyme by inorganic phosphate (Pi) were tested with radioisotopic methods. Calcium binding to the Ca-ATPase was non-competitively inhibited, and the enzymatic activity decreased in a concentration-dependent manner. The inhibition of the activity depended on pH, calcium concentration, the presence of the calcium ionophore calcimycin, and the membrane protein concentration. Unlike fast-twitch membranes, the pre-exposure of the masseter and medial pterygoid membranes to the anesthetics enhanced the enzymatic activity in the absence of calcimycin, supporting their permeabilizing effect. Procaine and tetracaine also interfered with the calcium transport capability, decreasing the maximal uptake without modification of the calcium affinity for the ATPase. Besides, the anesthetics inhibited the phosphorylation of the enzyme by Pi in a competitive manner. Tetracaine revealed a higher inhibitory potency on Ca-ATPase compared to procaine, and the inhibitory concentrations were lower than usual clinical doses. It is concluded that procaine and tetracaine not only affect key steps of the Ca-ATPase enzymatic cycle but also exert an indirect effect on membrane permeability to calcium and suggest that the consequent myoplasmic calcium increase induced by the anesthetics might account for myotoxic effects, such as sustained contraction and eventual rigidity of both fast-twitch and masticatory muscles.

Characterization of β-cyclodextrin inclusion complex with procaine hydrochloride by 1H NMR and ITC

The inclusion of local anesthetic drug procaine hydrochloride by β-cyclodextrin was investigated by 1D and 2D proton NMR spectroscopy and isothermal titration calorimetry (ITC) at 298 K. The stoichiometry of the complex was determinate by the method of continuous variation, using the chemical induced shift of both host and guest protons. The association constant K, of the obtained complex was calculated and found to be 293.17 M−1. Rotating frame NOE spectroscopy, was used to ascertain the solution geometry of the host–guest complex. The result reveals that the procaine molecule penetrates into the β-cyclodextrin cavity with the aromatic ring. The energetics of complexation process is investigated by ITC technique. The analysis indicates that the complexation of procaine by β-CD is an exothermic process and show that both enthalpy and entropy contribute to the binding process. The obtained value for the association constant is in good agreement with that obtained from NMR.

Inhibition by capsaicin and its related vanilloids of compound action potentials in frog sciatic nerves

AimsAlthough capsaicin not only activates transient receptor potential vanilloid-1 (TRPV1) channels but also inhibits nerve conduction, the latter action has not yet been fully examined. The purpose of the present study was to know whether various vanilloids have an inhibitory action similar to that of capsaicin and further to compare their actions with that of local anesthetic procaine. Main methodsFast-conducting compound action potentials (CAPs) were recorded from frog sciatic nerve fibers by using the air-gap method. Key findingsCapsaicin reversibly and concentration-dependently reduced the peak amplitude of the CAP. TRPV1 antagonist capsazepine did not affect the capsaicin activity, and powerful TRPV1 agonist resiniferatoxin had no effect on CAPs, indicating no involvement of TRPV1 channels. Capsaicin analogs and other various vanilloids also inhibited CAPs in a concentration-dependent manner. An efficacy sequence of these inhibitions was capsaicin=dihydrocapsaicin>capsiate>eugenol>guaiacol≥zingerone≥vanillin>vanillylamine. Vanillic acid had almost no effect on CAPs; olvanil and curcumin appeared to be effective less than capsaicin. Capsaicin and eugenol were, respectively, ten- and two-fold effective more than procaine in CAP inhibition, while each of guaiacol, zingerone and vanillin was five-fold effective less than procaine. SignificanceVarious vanilloids exhibit CAP inhibition, the extent of which is determined by the property of the side chain bound to the vanillyl group, and some of them are more effective than procaine. These results may serve to unveil molecular mechanisms for capsaicin-induced conduction block and to develop antinociceptive drugs related to capsaicin.

Electroacupuncture Reduces Cocaine-Induced Seizures and Mortality in Mice

The aims of this study were to characterize the protective profile of electroacupuncture (EA) on cocaine-induced seizures and mortality in mice. Mice were treated with EA (2 Hz, 50 Hz, and 100 Hz), or they underwent needle insertion without anesthesia at the Dazhui (GV14) and Baihui (GV20) acupoints before cocaine administration. EA at 50 Hz applied to GV14 and GV20 significantly reduced the seizure severity induced by a single dose of cocaine (75 mg/kg; i.p.). Furthermore, needle insertion into GV14 and GV20 and EA at 2 Hz and 50 Hz at both acupoints significantly reduced the mortality rate induced by a single lethal dose of cocaine (125 mg/kg; i.p.). In the sham control group, EA at 50 Hz applied to bilateral Tianzong (SI11) acupoints had no protective effects against cocaine. In addition, EA at 50 Hz applied to GV14 and GV20 failed to reduce the incidence of seizures and mortality induced by the local anesthetic procaine. In an immunohistochemistry study, EA (50 Hz) pretreatment at GV14 and GV20 decreased cocaine (75 mg/kg; i.p.)-induced c-Fos expression in the paraventricular thalamus. While the dopamine D3 receptor antagonist, SB-277011-A (30 mg/kg; s.c), did not by itself affect cocaine-induced seizure severity, it prevented the effects of EA on cocaine-induced seizures. These results suggest that EA alleviates cocaine-induced seizures and mortality and that the dopamine D3 receptor is involved, at least in part, in the anticonvulsant effects of EA in mice.

Therapeutic Properties and Tolerance of Procaine and Phenazone Containing Ear Drops in Infants and Very Young Children

Since ear pain is often intolerable in very young children with acute otitis media (AOM), a safe pain reduction is indispensable both from the medical as well as from the ethical point of view. To confirm the safety and therapeutic properties of ear drops (Otalgan) consisting of the short acting local anesthetic procaine hydrochloride (CAS 51-05-8) and the anti-inflammatory component phenazone (CAS 60-80-0), a multi-center, non-interventional post marketing surveillance (PMS) study was performed in 428 children (f/m: 45.6%/ 54.4%) aged between 0 and 6 years (mean 3.44 ys). Otalgia as the overall diagnostic criterion present in all children was allotted to otitis media in 398 (93%) and to otitis externa in 28 patients (6.5%), while in two patients, both diagnoses were documented. No adverse drug reactions (ADR) to the target medication have been detected during the entire study. The evaluation of tolerance by the physicians (mean score 1.38) and by the children/ parents (mean score 1.48) was in compliance with the absence of ADR. The drug tolerance was rated by the physicians in 99.8% of the cases as very good (62.2%; n = 266) or good (37.6%; n = 161). In one child (0.2%), the tolerance was evaluated by the physician as moderate. The judgement of parents revealed for all children either a very good (51.9%; n = 222) or good (48.1%; n = 206) evaluation of tolerance. The target medication was tolerated well, independent of the duration of treatment (2 to 10 days with a median of 5 days), of the daily dose and of the accumulated dose per treatment cycle, i.e. longer treatments and higher doses were not associated with a worsening of tolerance evaluations. Even in the highest dose class of over 100 drops per treatment cycle, no changes of tolerance could be revealed. As far as can be derived from non-controlled observational data, the results also confirm the known efficacy profile of the target medication in children. Under the treatment, the initial mean pain score of 2.33 was reduced by nearly 93% down to 0.17, accompanied by a corresponding normalization of the otoscopic findings of the ear canal and the tympanic membrane, and by the Improvement of the general condition. In 95.3% of the children, the physicians rated the efficacy of the target medication as very good (n = 156; 36.4%) or good (n = 252; 58.9%) while in 14 patients (3.3%) the efficacy was scored as moderate, in 4 patients (0.9%) as minimal and in two patients as inadequate (0.5%). The results also demonstrate that with the use of the target medication for local symptomatic treatment of pain in the outer ear canal and in AOM in children, the use of antibiotics in most of the cases can be avoided. The findings are in full accordance with the results of former clinical studies, with positive evaluations of ototoxicity and with accumulated pharmacovigilance data showing that since introduction of the drug in 1911, no ADR have ever been reported in children. The study confirms that the target medication provides a safe and rapid pain reduction and improvement of inflammation in very young children suffering from painful acute inflammatory ear conditions.