Plasma, bone, hip capsule, and drain fluid concentrations of cephazolin during total hip replacement

1 A rapid intravenous bolus injection of cephazolin (4.0 g) was administered immediately before induction of anaesthesia to seven patients having total hip replacement.

2 The plasma, bone, hip capsule and drain fluid concentrations of cephazolin following rapid intravenous injection of cephazolin were all well above the minimum bactericidal concentration of this antibiotic against a wide range of organisms, in particular, the penicillin resistant Staph. aureus, most Gram negative rods and Bacteroides species that cause postoperative infections in these patients.

3 These results suggest that an intravenous bolus injection of cephazolin (4·0 g) given during induction of general anaesthesia should provide safe, effective prophylactic cover against all the organisms that cause postoperative wound infections in patients who undergo total hip replacement. This pharmacokinetic finding needs to be confirmed in a larger clinical trial of cephazolin.

4 The optimum empirical prophylactic mode of administration of cephazolin that provides high plasma and tissue concentrations during this procedure appears to be a rapid intravenous bolus injection before induction of anaesthesia.

5 The intravenous injections of cephazolin were well tolerated in every patient. No cases of thrombophlebitis occurred and no other side or toxic effects were reported.

     

Assessment of the morbidity and value of prophylactic cephazolin sodium in urinary tract instrumentation in out-patients

Summary

A pilot study showed that following urinary tract endoscopy in out-patients there is a significant incidence of subsequent rigor and general practitioner call-out. A double-blind study was carried out in 690 consecutive patients to assess the effectiveness of prophylactic doses (1 g) of cephazolin, given intravenously or intramuscularly at the time of the procedure, compared with no treatment or placebo. The results, assessed from replies to a questionnaire, showed that whereas cephazolin given intravenously did not affect the incidence of subsequent rigor there was a significant reduction compared with controls when the antibiotic was given in the same dose intramuscularly.     

Therapeutic use of cephazolin to prevent complications of spine surgery

Discitis, caused by pyogenic organisms, is a potential complication of any procedure which involves entering the intervertebral disc during open or percutaneous procedures. While there are wide variations in the severity of symptoms, the characteristic feature of discitis is the development of increasingly severe back pain, which is not relieved by rest, or narcotic analgesics. While there is a tendency to spontaneous resolution over time, a self-limiting course does not always eventuate. Serious complications resulting from spread of the infective process can lead to vertebral osteomyelitis or to the formation of an epidural abscess with further risk of neural compression. Clinical and experimental evidence now supports the prophylactic use of a suitable antibiotic, but some uncertainties exist about the benefits of antibiotic therapy in treating established discitis. While cephazolin is a widely favoured choice of antibiotic, the timing of its administration to prevent or treat discitis has been complicated by the lack of suitable methods for detecting and measuring the concentration of cephazolin in the plasma and disc in experimental and clinical conditions. This paper describes a high-performance liquid chromatography technique for detecting the antibiotic cephazolin. The results conclude cephazolin can be detected in the plasma and disc after administering an intravenous bolus dose. However, concentration of cephazolin in the outer disc was 12 times greater than that of the inner disc. Received 28 July 2005; revised 2 February 2006; accepted 9 February 2006     

Ion-selective electrodes for determining cephazolin in biological media

An ion-selective electrode with plasticized polyvinylchloride membrane that is based on a cephazolin—tetradecylammonium ionic associate has been developed. The ratio of components and the solubility product of the ionic associates [(2.2 ± 0.1) × 10^{− 8}] were determined. The compound is thermally stable up to 70°C. The EMF is linearly dependent on the cephazolin concentration in the range from 1 × 10 − 5 to 1 × 10^{− 1} M. The slope of the electrode function is 56 ± 2 mV/pC. The selectivity to inorganic ions allows the proposed system to be used for cephazolin determination in biological media. In particular, a method for rapid determination of cephazolin in complex saliva is developed. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 8, pp. 41–44, August, 2008.     

天麻素经鼻给药吸收特性的研究

目的 考察天麻素的离体、在体经鼻吸收特性,为天麻素经鼻给药制剂的研究提供依据。方法 采用改良Franz扩散池法,选用新鲜的家猪鼻黏膜作为渗透屏障,以黏膜渗透系数为指标,评价天麻素离体鼻黏膜吸收特性;采用鼻腔循环灌流法,以含天麻素的生理盐水为鼻腔循环液,HPLC测定天麻素含量,考察天麻素在体大鼠鼻黏膜吸收特性。结果 天麻素低、中、高剂量组的离体猪鼻黏膜渗透系数分别为1.9×10^-3,1.3×10^-3,4.3×10^-3 cm^-2·min^-1;大鼠在体吸收速度常数分别为2.9×10^-3,6.0×10^-3,2.4×10^-3 min^-1。天麻素的黏膜吸收量随其浓度的增加而增加,但其吸收速度常数较小,且在体实验所选择的中浓度天麻素的鼻黏膜吸收速度常数要大于低浓度和高浓度。结论 天麻素可经鼻吸收,但其在体吸收速度与黏膜渗透系数都较小,在制备其鼻腔给药制剂时,需要通过增加促渗剂或改变剂型等方法以增加鼻黏膜吸收。     

Effect of tetracycline on chondrocyte mitochondria—an explanation of tetracycline-induced defects of mineralized tissues

To investigate the mechanism of tetracycline (TC)-induced defects of mineralization, the effect of the antibiotic on Ca²⁺ transport by chick chondrocyte mitochondria was studied. Multiple injections of TC resulted in a profound drop in the intramitochondrial Ca²⁺ concentration and an increase in the serum Ca²⁺ level. The antibiotic caused a reduction in Ca²⁺ uptake and an increase in Ca²⁺ efflux from the mitochondria in vitro; in the presence of 1 mM TC, the effect on efflux was greater than uptake. The addition of ATP to TC-treated mitochondria did not prevent Ca²⁺ release. Using rat liver mitochondria, it was found that. while the antibiotic had an oligomycin-like effect on respiration, this inhibitory action could be prevented by preincubating the organelles with 10 mM Mg²⁺ The results of the studies both in vitro and in vivo suggest that TC interferes with mitochondrial Ca²⁺ translocation. It is concluded that critical levels of intramitochondrial Ca²⁺ are prerequisite for the normal mineralization process and that interference with Ca²⁺ accumulation leads to defective mineralization.     

Effect of Chlordecone (Kepone®) on Calcium Transport Mechanisms in Rat Heart Sarcoplasmic Reticulum*

Previous studies from our laboratory have indicated that chlordecone (Kepone®, CD), an organochlorine insecticide, inhibited cardiac sodium pump activity and catecholamine uptake suggesting that CD may interfere with cardiac function. Sarcoplasmic reticulum (SR) calcium pump has an important role in myocardial contraction and relaxation, besides Na⁺ transport. Since CD interferes with cardiac Na⁺ ion translocases, we have studied CD effects on cardiac SR calcium pump activity. Experiments were carried out both in vitro and in vivo. SR was isolated from heart ventricles of male Sprague-Dawley rats. Cardiac SR Ca²⁺-ATPase, ⁴⁵Ca-uptake and cAMP as well as calmodulin (CaM) dependent protein phosphorylation were measured. Ca²⁺-ATPase was differentiated into low affinity and high affinity forms by measuring the activity using 50 and 0.7 μM free Ca²⁺ respectively. CD in vitro inhibited ⁴⁵Ca-uptake by SR in a concentration dependent manner with an IC50 value of 7 μM and SR ⁴⁵Ca-uptake was totally inhibited at 20–30 μM CD. In agreement with this, both high affinity and low affinity Ca²⁺-ATPases, which are involved in Ca²⁺ transport across membranes, were also inhibited by CD in a concentration dependent manner with IC50 values of 0.7 and 3.2 μM respectively. Both Ca²⁺-ATPase and ⁴⁵Ca-uptake by cardiac SR were significantly lower in rats treated with CD (25, 50 or 75 mg/kg) when compared to control rats. cAMP as well as CaM significantly elevated the ³²P-binding to SR proteins in vitro to about 70–80%. In the presence of CD, this ³²P-binding was reduced, however, not concentration dependent. In agreement with in vitro studies, ³²P-bound to proteins was significantly lowered in rats treated with CD. SDS-polyacrylamide gel electrophoresis of the cardiac SR revealed the presence of at least 30 comassie blue-stainable bands with mobilities corresponding to molecular weights ranging from 9 to 120 kDa using 15% acrylamide gels. Autoradiographs from samples incubated in the presence of cAMP or CaM indicated ³²P-incorporation in 7 bands. Of these, bands corresponding to about 24 kDa and adjacent lower molecular weights decreased in their intensity by CD in vitro as well as in vivo. These results indicate that CD treatment may be reducing SR calcium transport mechanisms by altering phosphorylation of a number of proteins including phospholamban in rat cardiac SR.     

Optimizing Iontophoretic Drug Delivery: Identification and Distribution of the Charge-Carrying Species

Purpose. To identify and quantify, in vitro and in vivo (in humans), the charge-carrying species during transdermal iontophoresis of lidocaine hydrochloride as a function of the concentration of drug relative to that of sodium chloride in the anodal solution. Methods. In vitro experiments in standard diffusion cells quantified lidocaine delivery and the outward migration of chloride across the skin. Electrotransport of Na⁺ was inferred by difference, allowing transport numbers of the three main charge-carrying species to be deduced. In vivo, outward electrotransport of Cl^– was measured and compared to the corresponding in vitro results. Results. The transport number of lidocaine increased linearly with increasing mole fraction and reached 0.15-0.20 at X_L = 1.0. In the absence of Na⁺, most of the charge was carried by Cl^– (>80%) despite the skin retaining its net negative charge and cation permselectivity. In vivo data correlated very well with in vitro results. Conclusions. The mole faction of drug (relative to competing ions of like polarity) is the crucial determinant of the extent to which it can carry charge across the skin during iontophoresis. The outward electromigration of Cl^–, in the sense opposite to drug delivery, may offer a useful means by which to optimize iontophoretic efficiency in the absence of competing cations in the anode formulation.     

In vitro effect of nickel on bovine spermatozoa motility and annexin V‐labeled membrane changes

In this study the effect of in vitro culture of bovine spermatozoa with nickel (NiCl₂) on spermatozoa motility and membrane changes was analyzed. The spermatozoa motility significantly decreased after 120 min of culture at the concentration of 1000 μm Ni ml^?1 (P < 0.05) and after 240 min of culture at the concentration of 500 and 1000 μm Ni ml^?1 (P < 0.001) as compared with control. The progressive motility was the highest in the control group and in the groups with the lowest nickel concentrations (7.8 and 125 μm Ni ml^?1). The progressive spermatozoa motility was significantly altered even after 30 min of culture in the group with the highest nickel concentration (1000 μm Ni ml^?1). A significant decrease in progressive motility from the concentration of 250 μm Ni ml^?1 was detected after 240 min of culture. Concentrations from 125 μm Ni ml^?1 in various time periods of culture stimulated spermatozoa motility after 30 min (P < 0.001), but later an inhibitory effect was noted. After 240 min of in vitro spermatozoa culture with 125 μm Ni ml^?1 a typical Annexin V fluorescence reaction was detected. Fluorescence was detected in mitochondrial segment of bovine spermatozoa. In spermatozoa exposed to higher nickel concentrations the Annexin V‐positive reaction was detected also on the spermatozoa head membrane. In the group with the highest concentration and the longest time of exposure (1000 μm Ni ml^?1; 240 min) the apoptotic Annexin‐positive regions were detected not only in the mitochondrial part, but also in the spermatozoa head (acrosomal and postacrosomal part), showing significant alteration of spermatozoa membrane integrity. Copyright © 2010 John Wiley & Sons, Ltd.     

Use of in Vitro Critical Inhibitory Concentration, a Novel Approach to Predict in Vivo Synergistic Bactericidal Effect of Combined Amikacin and Piperacillin Against Pseudomonas aeruginosa in a Systemic Rat Infection Model

Purpose This study was undertaken to explore the use of in vitro critical inhibitory concentration (CIC) as a surrogate marker relating the pharmacokinetic (PK) parameters to in vivo bactericidal synergistic effect [pharmacodynamic (PD)] of amikacin + piperacillin combination against Pseudomonas aeruginosa in a systemic rat infection model. Methods The in vitro antibacterial activities of amikacin and piperacillin, alone and in combinations at various ratios of the concentrations, were tested against a standard [5 × 10⁵ colony-forming units (CFU)/ml] and a large (1.5 × 10⁸ CFU/ml) inoculum of P. aeruginosa ATCC 9027 using a modified survival-time method. The CIC of each individual antibiotic for the different combinations was determined using a cup-plate method. In vivo studies were performed on Sprague-Dawley rats using a systemic model of infection with P. aeruginosa ATCC 9027. PK profiles and in vivo killing effects of the combination at different dosing ratios were studied. Results An inoculum effect was observed with the antibiotics studied. Synergy was seen against both the inocula at the following concentration ratios: 70% C_ami + 30% C_pip and 75% C_ami + 25% C_pip, where C_ami and C_pip are the concentrations of amikacin and piperacillin to produce a 1000-fold decrease in bacterial population over 5 h, respectively. The CIC values determined corroborated with the order of in vitro bacterial killing observed for the antibiotic combinations. The dosing ratio of 12.6 mg/kg amikacin + 36 mg/kg piperacillin (a 70:30 ratio of the individual doses) exhibited the greatest killing in vivo when compared to the other ratios. The PK–PD relationships were described by simple, linear regression equations using the area under the in vivo killing curve as a PD marker and the AUCIC_ami/CIC_ami + AUCIC_pip/CIC_pip, AUC_ami/CIC_ami + AUC_pip/CIC_pip, C_max,ami/CIC_ami + C_max,pip/CIC_pip, and AUCIC_ami/MIC_ami + AUCIC_pip/MIC_pip as PK markers for the amikacin + piperacillin combination. Conclusion The combination of amikacin and piperacillin exhibited synergistic killing effect on P. aeruginosa that could be modeled using CIC as a surrogate marker relating the PK parameters to in vivo bactericidal effect.     

Potentiation of pro-inflammatory cytokine suppression and survival by microencapsulated dexamethasone in the treatment of experimental sepsis

Cytokine inhibiting drugs are much more effective when delivered intracellularly to phagocytic cells in the microencapsulated form. Dexamethasone is a powerful inhibitor of TNF-α cytokine through inhibition of NF-κB which is a gene regulator of multiple pro-inflammatory cytokines. We have determined the effect of microencapsulated dexamethasone in pro-inflammatory cytokine release both in in vitro using whole blood model, and in vivo using peritonitis model of septic shock. Microspheres of 1–4 μm mean size were prepared by using albumin polymer matrix in a one-step spray drying method. Microencapsulated form of dexamethasone with concentration of 10^?1, 10^?2 and 10^?3 M was compared to an equivalent concentration of solution form of dexamethasone in the in vitro whole blood model. The results show microencapsulated dexamethasone inhibited tumor necrosis factor-alpha (TNF-α) and interleukin-beta (IL-1β) significantly in comparison with the solution form of dexamethasone. The in vivo peritonitis model also demonstrated significant inhibition of TNF-α and IL-1β cytokines in microencapsulated form in comparison with solution form of dexamethasone. In the in vivo study, the animal survival rate after 5 days was 90%, dexamethasone in solution with gentamicin was 40% and gentamicin alone was 30%. This study demonstrates significantly improved inhibition of TNF-α and IL-1β both in vivo and in vitro when dexamethasone was used in microencapsulated form.     

款冬花多糖抗氧化能力测定

目的用流动注射化学发光法探讨中药款冬花多糖的体外抗氧化作用。方法将款冬花多糖提取液加入3种化学发光体系,测量其发光强度,根据系统化学发光被抑制的程度评价款冬花对活性氧自由基的清除能力,并以抗坏血酸（Vc）为阳性对照。结果款冬花多糖对.OH有很好的清除作用,对O2.、H2O2也有一定的清除作用,且在0.25～4.4 mg.L 1内清除作用随浓度的增加而增强;对自由基的清除能力大小：.OH〉H2O2〉O2.。结论在一定浓度范围内,款冬花多糖具有一定的抗氧化活性。     

Interaction of Hydroflumethiazide and 2,4-Disulfamyl-5-trifluoromethylaniline with Cyclic AMP Phosphodiesterase and Carbonic Anhydrase

Abstract: The inhibitory effect of hydroflumethiazide (HFT) and its metabolite, 2,4-disulfamyl-5-trifluoro-methylaniline (DTA) on cyclic AMP phosphodiesterase and the binding of HFT and DTA to carbonic anhydrase was studied in vitro. Significant inhibition of rat kidney low-K_m cyclic AMP phosphodiesterase was observed with DTA concentration above 2.5 × 10^?4 mol/1 and with HFT concentration above 1 × 10^?4 mol/1. 50% inhibition was observed at a DTA concentration of 1 × 10^?3 mol/1. Binding of DTA and HFT to commercially obtained bovine erythrocyte carbonic anhydrase was demonstrated by equilibrium dialysis. Data were consistent with one class of binding sites. The product of n (number of binding sites) and K_ass (association constant) was 5 × 10⁵ M for DTA and 3.3 × 10⁴ M for HFT at 2°. In human blood in vitro at 37°, the equilibrium erythrocyte/plasma concentration ratio was 18 for DTA and 1.6 for HFT. It is concluded that HFT and DTA have approximately the same potency as cyclic AMP phosphodiesterase inhibitors, whereas DTA is more extensively bound by erythrocyte carbonic anhydrase.     

Rapid detection of ciprofloxacin effects on Fusarium graminearum and F. avenaceum cells in modulating environmental pH using a reactive, non-toxic food-dye indicator

The objective of the study was to assess the effect of ciprofloxacin antibiotic on the physiological or phenotypic characteristics of food-borne toxigenic Fusarium graminearum and F. avenaceum molds under in vitro conditions.In the presence of ciprofloxacin, Fusarium mycelia growth and morphology were altered based on the antibiotic concentration range used. Results showed that ciprofloxacin in concentrations ≥40 μg/mL induced chlamydospore formation in Fusaria and as such, this antibiotic should be considered as an important abiotic stress factor and growth inhibitor.A novel method was investigated to correlate chlamydospore formation with the colour changes observed in FD&C Green Number 3, a common water soluble food dye. The antibiotic-treated F. graminearum and F. avenaceum isolates produced chamydospores, which in turn altered environmental pH with concomitant changes in the colour and intensity of the dye. The colour changes observed as a function of environmental pH were supported by instrumental methods (pH meter and spectroscopy), and a commercial pH indicator (thymol blue) results.In conclusion, we propose that FD&C Green Number 3 can be used as an accurate indicator for the rapid assessment of Fusarium molds when grown on ciprofloxacin antibiotic-containing substrate. Special emphasis should be given to an indirect risk assessment of antibiotic effects on toxic molds.     

Optimization and evaluation of pluronic lecithin organogels as a transdermal delivery vehicle for sinomenine

The purpose of the present study was to prepare and optimize sinomenine (SIN) pluronic lecithin organogels system (PLO), and to evaluate the permeability of the optimized PLO in vitro and in vivo. Box–Behnken design was used to optimize the PLO and the optimized formulation was pluronic F127 of 19.61%, lecithin of 3.60% and SIN of 1.27%. The formulation was evaluated its skin permeation and drug deposition both in vitro and in vivo compared with gel. Permeation and deposition studies of PLO were carried out with Franz diffusion cells in vitro and with microdialysis in vivo. In vitro studies, permeation rate (J_ss) of SIN from PLO was 146.55?±?2.93?μg/cm²/h, significantly higher than that of gel (120.39?μg/cm²/h) and the amount of SIN deposited in skin from the PLO was 10.08?±?0.86?μg/cm², significantly larger than that from gel (6.01?±?0.04?μg/cm²). In vivo skin microdialysis studies showed that the maximum concentration (C_max) of SIN from PLO in “permeation study” and “drug-deposition study” were 150.27?±?20.85?μg/ml and 67.95?μg/ml, respectively, both significantly higher than that of SIN from gel (29.66 and 6.73?μg/ml). The results recommend that PLO can be used as an advantageous transdermal delivery vehicle to enhance the permeation and skin deposition of SIN.     

A comparative study of ofloxacin and ciprofloxacin erythrocyte distribution

The present work deals with the in vitro and in vivo distribution of ofloxacin and ciprofloxacin in erythrocytes. In vitro studies were carried out in standard solutions prepared using fresh blood for a concentration range between 100 and 0.25 μg mL⁻¹. A 5 mg kg⁻¹ bolus dose was administered to rabbits and erythrocyte and plasma kinetics were determined over 8 h. A linear model was used to establish the relationship between plasma and erythrocyte concentrations of both quinolones in vitro. The mean partition coefficient values obtained were 1.04±0.02 and 1.32±0.03 for ofloxacin and ciprofloxacin, respectively. A decrease in the ciprofloxacin partition coefficient was observed at higher concentrations. Values ranged between 2.54±0.40 and 1.38±0.15 as the concentrations increased. The partition coefficients obtained from the linear relationship between plasma and erythrocyte concentrations established from the in vivo data were 0.80±0.58 for ofloxacin and 0.61±0.30 for ciprofloxacin. In vivo plasma and erythrocyte data analysis was performed by a deconvolution method and the theoretical transfer curves in erythrocytes were estimated. The distribution of both quinolones to erythrocytes is very rapid, probably due to a high permeability of erythrocyte membranes to these drugs. This was also confirmed by the parallelism between plasma and erythrocyte kinetics. © 1998 John Wiley & Sons, Ltd.     

Influence of antibiotic therapy on the level of selected angiogenic factors in patients with benign gynecologic tumors--preliminary report

An increased fibrin level enhances the activity of proangiogenic factors and may contribute to tumor formation. Formation of new blood vessels during angiogenesis leads to neoplasm development through interaction with factors such as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukins. The aim of this study was to investigate the influence of perioperative antibiotic therapy in women with benign gynecological tumors with regard to basic fibroblast growth factor level, fibrinogen concentration and fibrin viscosity. The influence of clindamycin plus metronidazole therapy (group I) and cephazolin therapy (group II) on fibrinogen concentration, level of bFGF and fibrin viscosity was studied in women diagnosed with nonmalignant myomas and cysts. In patients with benign gynecologic tumors, higher bFGF levels (51.40 +/- 13.72 pg/ml), fibrinogen concentration (348.26 +/- 164.74 mg/dl) and fibrin viscosity (2.63 +/- 0.36 mPa) were observed, as compared with healthy women. There were strong indications that antiangiogenic activity occurred with both clindamycin plus metronidazole and cephazolin, although the response to these particular antibiotic therapies was different. The use of various drug therapies in groups I and II resulted in faster and delayed antiangiogenic effects, respectively. Further research is essential to provide more detailed information about the mechanisms of the induction of antiangiogenic activity by perioperative adjuvant antibiotic treatment.     

Radiosynthesis,biodistribution and scintigraphy of the 99mTc‐Teicoplanin complex in artificially infected animal models

Radiocomplexation of Teicoplanin (TIN), a new glycopeptide antibiotic with technetium‐99m, was investigated. The ^99mTc‐TIN complex was assessed for its radiochemical permanence, in vitro stability in serum, binding with methicillin‐resistant Staphylococcus aureus (MRSA), biodistribution in Model Rats (MRT) and for scintigraphic precision in Model Rabbit (MRB). Radiochemically, a stable ^99mTc‐TIN was observed with 98.90±0.50% yield and remained staunch more than 90% up to 120 min, by mixing TIN, 1.5 mg in 0.5 ml of saline with 2.5 mCi sodium pertechnetate and 150 µl of stannous chloride dihydrate at pH 5.4. The ^99mTc‐TIN was found stable in serum with an insignificant undesirable yield of free and unhydrolyzed technetium (5.25±0.10 and 13.5±0.14%, n = 10) up to 120 min of incubation. The ^99mTc‐TIN showed in vitro binding with MRSA in the range of 55–65%. The ^99mTc‐TIN showed almost six‐fold elevated uptake in the infected (IFT) muscle of the MRT as compared with the inflamed (IFM) and normal (NL) muscles. This higher uptake of the ^99mTc‐TIN in the IFT was scintigraphically confirmed after the whole body scanning of the MRB. The radiochemical eternalness with high yield, in vitro stability in serum, binding with MRSA, significant biodistribution performance, and scintigraphic precision posed the ^99mTc‐TIN, a new glycopeptide radiotracer for the infection imaging. Copyright © 2010 John Wiley & Sons, Ltd.     

Influence of Citalopram and Chlorimipramine on Uptake of 5-HT by Isolated Perfused Guinea Pig Lungs

Abstract A method is described for the preparation and perfusion in vitro of isolated guinea pig lungs. 5-HT is rapidly taken up from a perfusing solution by this organ (about 70% uptake). In the concentration range 10^-7 to 5 × 10^-6 M citalopram concentration dependently inhibited the uptake of 5-HT by the lung preparation. Chlorimipramine inhibited the uptake of 5-HT only by 40–50%, and the inhibition was not concentration dependent. The method used seems to be a reliable model for studying the uptake of 5-HT.     

In Vitro-In Vivo Myotoxicity of Intramuscular Liposomal Formulations

Purpose. The first objective was to study the in vitro myotoxicity of empty liposomes and to examine whether liposome size, charge and fluidity affect liposome myotoxicity. The second objective was to investigate the effect of liposomal encapsulation on the in vitro and in vivo myotoxicity of loxapine compared to the loxapine commercial preparation (Loxitane^®). Methods. The in vitro myotoxicity of empty liposomes and loxapine liposomes was evaluated by the cumulative efflux of the cytosolic enzyme creatine kinase (CK) from the isolated rat extensor digitorum longus (EDL) muscle over a 2 hour period. In the in vivo studies, the area under plasma CK curve over 12 hours was used to evaluate muscle damage. Results. The in vitro myotoxicity for all empty liposomal formulations was not statistically different from negative controls (untreated control muscles and normal saline injected muscles). However, these empty liposomal formulations were significantly less myotoxic than the positive controls (muscles injected with phenytoin and muscle sliced in half). In vitro-in vivo studies showed that the liposomal encapsulation of loxapine resulted in significant (P < 0.05) reduction in myotoxicity (80% in vitro and 60% in vivo) compared to the commercially available formulation which contains propylene glycol (70% V/V) and polysor-bate 80 (5% W/V) prepared at equal concentration. Conclusions. Results indicate that empty liposomes do not induce myotoxicity. Furthermore, liposomal size, charge and fluidity do not affect myotoxicity. In addition, in vitro and in vivo studies have demonstrated that liposomal encapsulation of loxapine can reduce myotoxicity compared to a formulation containing organic cosolvents.