Disposition of amiodarone in rats after single and multiple intraperitoneal doses.

The pharmacokinetics of amiodarone was studied after single and multiple dosing in two groups of male Wistar and Albino rats. The first group (40 rats) received a single intraperitoneal (i.p.) dose of amiodarone (100 mg/kg) and 4 rats sacrificed 1, 2, 4, 6, 12, 18, 24, 36, 48 and 72 hours post dosing. The second group (42 rats) received amiodarone (50 mg/kg, i.p. daily) for 5 days a week for 5 weeks and 6 rats were sacrificed at 1, 2, 3, 4, 5, 6 and 8 weeks. Rats of both groups were sampled for blood, heart, lung and fat and the concentrations of amiodarone in these samples were determined using High Performance Liquid Chromatography (HPLC). The elimination of amiodarone from plasma after single dose followed a biphasic pattern with a terminal half-life of 54.7+/-8.2 hours. The concentrations of amiodarone in the tissues were halved within 26.8, 34.9 and 37.45 hours in the heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat after single dose were 1.24 microg/ml, 1.73 microg/mg and 29.01 microg/mg, respectivelly. The concentrations of amiodarone after multiple dosing were halved within 8.4, 5.5, 6.4 and 9.8 days, for the plasma, heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat during multiple doses were 0.97 microg/ml, 1.41 microg/mg, 7.63 microg/mg and 65.01 microg/mg respectively. In conclusion, after multiple dosing, the elimination half-life of amiodarone and its fat contents were 3.7 and 2.8 times greater than that after single dosing. The excessive amount of amiodarone observed in fat tissues after multiple dosing is probably the reason for the prolonged elimination half-life. Based on the elimination half-lives data, the time to steady state is about two weeks and the drug should be withheld for less than a month if a patient required discontinuation because of serious adverse effects.

The preventive role of deferoxamine against acute doxorubicin-induced cardiac, renal and hepatic toxicity in rats.

The iron chelating activity of deferoxamine (DFO) has been exploited to obtain protection against the peroxidative damage in rat heart which was induced by the administration of an acute dose of doxorubicin (DXR, 25 mg x kg(-1), i.v.). The peroxidative lesions were evaluated both biochemically and histopathologically, 48 h after DXR administration. Abnormal biochemical changes including a marked increase in the levels of serum creatine kinase isoenzyme (CK-MB), and lactate dehydrogenase (LDH), as well as elevated serum creatinine, blood urea nitrogen and transaminases (ALT and AST) levels were observed. Myocardial tissue from DXR treated rats showed a marked increase in malondialdehyde (MDA) production and depletion of reduced glutathione (GSH) contents. Similar results were also observed in both kidney and liver tissues. Pretreatment of rats with DFO, given i.p. 30 min prior to DXR injection, substantially reduced the peroxidative damage in the myocardium, hepatic and renal tissues and markedly lowered the serum CK-MB, LDH and the other biochemical variables. The protective effects obtained by DFO administration, however, were not complete and did not reach those of the control group. The significant protection against DXR-induced cardiomyopathy by DFO was evident from the histopathological findings observed by light microscopy. DFO at a dosing level equivalent to 10-fold of that of DXR was useful to obtain protective effects. Higher DFO dosing levels did not, however, show more improvement in the DXR-induced cardiotoxicity and at the same time exhibited hepatoxicity which was confirmed by microscopical examination. These results strongly suggest that DFO protects against acute DXR-induced cardiotoxicity in a dose-dependent manner with recognizing the presence of mild DFO-related biochemical and cytological hepatic toxicity.

Effects of gemcitabine on cisplatin-induced nephrotoxicity in rats: schedule-dependent study.

The effects of gemcitabine (dFdC) on the lipid peroxidation and kidney histopathology in the nephrotoxicity of an antitumour drug cisplatin (CDDP) were studied in rats. dFdC was administered intraperitoneally (i.p.) at single doses of 90 mgkg(-1) while CDDP was administered i.p. at single doses of 6 mgkg(-1). Both drugs were injected either alone or sequentially in combination. In one case, CDDP preceded dFdC by 4 h and 24 h and in the other case, dFdC preceded CDDP by 4 h and 24 h. Seven days after CDDP administration, the nephrotoxicity was manifested biochemically by elevation of serum creatinine, blood urea nitrogen and an increase in the kidney weight as a percentage of total body weight. In addition, marked decreases in serum albumin and calcium levels were observed. Lipid peroxidation in the kidney was monitored by measuring the malondialdehyde (MDA) production level and kidney glutathione (GSH) content, which were increased and depleted, respectively. Administration of dFdC 4 h and 24 h after CDDP administration did not significantly change the indices of CDDP-induced nephrotoxicity or the kidney platinum concentration levels in comparison with those animals treated with CDDP alone. On the contrary, administration of dFdC 4 h and 24 h prior to CDDP administration significantly aggravated CDDP-induced nephrotoxicity which was manifested by severe increases in the serum creatinine and blood urea nitrogen levels as well as kidney weight as a percentage of total body weight. In addition, kidney tissue showed severe GSH depletion and increases in the MDA production and platinum concentration levels. Moreover, treatment of rats with dFdC 24 h prior to CDDP resulted in much more aggravation of CDDP-induced nephrotoxicity in comparison with those animals treated with dFdC 4 h prior to CDDP. Histopathological examination demonstrated tubular atrophy, tubular necrosis and drug-induced nuclear changes in the CDDP-treated group. However, pretreatment of rats with dFdC 4 h and 24 h prior to CDDP revealed extensive interstitial nephritis, renal tubular atrophy and tubular necrosis with 'sloughing off' of the lining cells, especially with those rats treated with dFdC 24 h prior to CDDP. These results might suggest that administration of dFdC prior to CDDP enhanced the lipid peroxidation in kidney tissue and aggravated CDDP-induced nephrotoxicity.

Cisplatin pharmacokinetics and its nephrotoxicity in diabetic rabbits.

BACKGROUND: This study was designed to investigate the relationship between the attenuation of cisplatin (CDDP)-induced nephrotoxicity in experimental diabetic rabbits and the plasma pharmacokinetics of the free ultrafilterable and total plasma platinum (Pt) levels. METHODS: Two groups of age-matched male New Zealand white rabbits were used; the first group consisted of rabbits with streptozotocin-induced diabetes (single i.v. bolus dose of streptozotocin of 65 mg/kg in citrate buffer, pH 4.6), and the second group of nondiabetic rabbits treated with the same volume of citrate buffer. Both groups were treated with CDDP (5 mg/kg, single i.v. bolus dose) 3 days after induction of the diabetic state in the first group. The plasma Pt levels were followed for 4 h after CDDP administration, in which the free ultrafilterable and total plasma Pt concentrations were determined by atomic absorption spectrometry. The pharmacokinetic parameters of free ultrafilterable plasma Pt were determined using a noncompartment pharmacokinetic model of analysis. RESULTS: The total plasma Pt levels declined in a biphasic manner and were adequately described by a two-compartment model. No significant change was observed in the pharmacokinetics of either the free ultrafilterable or total plasma Pt levels in the diabetic group in comparison with the control nondiabetic group (p > 0.05). However, 4 h after CDDP administration, the total plasma Pt level of the nondiabetic group was significantly higher than that of the diabetic rabbits (p < 0.001). Indices of nephrotoxicity were determined 7 days after CDDP administration. The results revealed that the diabetic state protected against CDDP-induced nephrotoxicity. The nondiabetic rabbits exhibited highly significant elevations in the serum creatinine and urea levels and a decrease in the serum albumin level (p < 0.001) in comparison with the diabetic group. CONCLUSIONS: These findings might suggest that the reduction in CDDP-induced nephrotoxicity in diabetic rabbits is not due to a change in the plasma pharmacokinetic profile within the drug follow-up period. It could be anticipated that the rapid decline in the total plasma Pt level after CDDP administration to diabetic rabbits, as well as the reduction in the terminal elimination half-life of the total plasma Pt level might be responsible for the reduction in CDDP-induced nephrotoxicity. Also, alterations in the how kidneys of diabetics deal with the renal excretion of Pt and reduction of its accumulation in kidney tissue are not excluded.

The effect of rebamipide on cisplatin-induced nephrotoxicity in rats.

This study aimed to evaluate the protective effect of rebamipide (free radical scavenger) against the nephrotoxic effect induced by cisplatin in normal rats. Twenty-four male Wister albino rats were divided equally into four groups: control, rebamipide, cisplatin and cisplatin plus rebamipide-treated groups. Nephrotoxicity was induced with single intravenous (i.v.) cisplatin dose of 6 mg kg(-1)and measured through the estimation of kidney weight, serum albumin (Alb), serum creatinine (Cr), blood urea nitrogen (BUN), kidney glutathione (GSH) and malondialdehyde (MDA) production. In the cisplatin-treated group the kidney weight as a percent of the total body weight, serum Alb, serum Cr, BUN, GSH content and MDA amount were: 0.61+/-0.054%, 2.84+/-0.24 g dl(-1), 2.99+/-0.10 mg dl(-1), 147.08+/-7.46 mg dl(-1), 3.11+/-0.238 micromol g(-1)and 1449. 09+/-127.36 nmol g(-1), respectively. All the previous changes were significantly (P<0.01) different from the corresponding values in the control group. In addition, histopathological examination of the kidney tissue revealed degenerative cellular material and apoptotic tubular cells were seen in the renal tubules. Rebamipide treatment (140 mg kg(-1), i.p.) for 1 week ameliorated all the previous changes and the results recorded for the cisplatin plus rebamipide-treated group were: 0.45+/-0.035%, 4.17+/-0.091 g dl(-1), 1.37+/-0.209 mg dl(-1), 72.25+/-5.14 mg dl(-1), 5.063+/-0.269 micromol g(-1)and 560.23+/-21.98 nmol g(-1)for the previous tests, respectively. Furthermore, significant improvement in the kidney histopathology was observed. The results of this study clearly revealed that rebamipide protected the kidney against the nephrotoxic effect of cisplatin. These results suggest that lipid peroxidation is not the only mechanism by which cisplatin induced nephrotoxicity. More investigations are needed to confirm the effect of rebamipide and at the same time to elucidate the exact mechanism by which cisplatin induces nephrotoxicity.

Liquid chromatographic assay of nifedipine in human plasma and its application to pharmacokinetic studies.

A highly sensitive, selective and reproducible reversed-phase high-performance liquid chromatographic method has been developed for the determination of nifedipine in human plasma with minimum sample preparation. The method is sensitive to 3 ng/ml in plasma, with acceptable within- and between-day reproducibilities and linearity (r2 > 0.99) over a concentration range from 10-200 ng/ml. Acidified plasma samples were extracted using diethyether containing diazepam as internal standard and chromatographic separation was accomplished on C18 column using a mobile phase consisting of acetonitrile, methanol and water (35:17:48, v/v). The within-day precision ranged from 2.22 to 4.64% and accuracy ranged from 102.4-106.4%. The day-to-day precision ranged from 2.34-7.07% and accuracy from 95.1-100.1%. The relative recoveries of nifedipine from plasma ranged from 91.0-107.3% whereas extraction recoveries were 88.6-93.3%. Following eight 6-week freeze-thaw cycles, nifedipine in plasma samples proved to be stable with accuracy ranging from 0.64 to 3.0% and precision ranging from 3.6 to 4.15%. Nifedipine was also found to be photostable for at least 120 min in plasma, 30 min in blood and for 60 min in aqueous solutions after exposure to light. The method is sensitive and reliable for pharmacokinetic studies and therapeutic drug monitoring of nifedipine in humans after the oral administration of immediate-release capsules and sustained-release tablets to five healthy subjects.

Bioequivalence evaluation of two brands of cefuroxime 500 mg tablets (Cefuzime and Zinnat) in healthy human volunteers.

A bioequivalence study of two oral formulations of 500 mg cefuroxime axetil was carried out in 24 healthy volunteers following a single dose, standard two-treatment cross-over design at the College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, working jointly with King Khalid University Hospital. The two formulations used were Cefuzime (Julphar, United Arab Emirates) as the test and Zinnat (Glaxo Wellcome, England) as the reference product. Both test and reference tablets were administered to each subject after an overnight fasting on two treatment days separated by a 1-week washout period. After dosing, serial blood samples were collected for a period of 8 h. Plasma harvested from blood was analysed for cefuroxime by a sensitive, reproducible and accurate high pressure liquid chromatography (HPLC) method. Various pharmacokinetic parameters including AUC(0-t), AUC(0-infinity), C(max), T(max), T(1/2) and K(el) were determined from plasma concentrations of both formulations and found to be in good agreement with reported values. AUC(0-t), AUC(0-infinity) and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on an analysis of variance (ANOVA); 90% confidence interval for test/reference ratio of these parameters were found within bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Cefuzime is bioequivalent to Zinnat.

Disposition of amiodarone in rats after single and multiple intra-peritoneal doses.

The pharmacokinetics of amiodarone was studied after single and multiple dosing in two groups of male Wistar and Albino rats. The first group (40 rats) received a single intraperitoneal (i.p.) dose of amiodarone (100 mg/kg) and 4 rats sacrificed 1, 2, 4, 6, 12, 18, 24, 36, 48 and 72 hours post dosing. The second group (42 rats) received amiodarone (50 mg/kg, i.p., daily) for 5 days a week for 5 weeks and 6 rats were sacrificed at 1, 2, 3, 4, 5, 6 and 8 weeks. Rats of both group were sampled for blood, heart, lung and fat and the concentrations of amiodarone in these samples were determined using. The elimination of amiodarone from plasma after single dose followed a biphasic pattern with a terminal half-life of 54.7 +/- 8.2 hours. The concentrations of amiodarone in the tissues were halved within 26.8, 34.9 and 37.45 hours in the heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat after single dose were 1.24 micrograms/ml, 1.73 micrograms/mg, 7.61 micrograms/mg and 29.01 micrograms/mg, respectively. The concentration of amiodarone after multiple dosing were halved within 8.4, 5.5, 6.4 and 9.8 days, for the plasma, heart, lung and fat, respectively. The average concentrations of amiodarone in plasma, heart, lung and fat during multiple doses were 0.97 microgram/mg, 7.63 micrograms/mg and 65.01 micrograms/mg respectively. In conclusion, after multiple dosing, the elimination half-life of amiodarone and its fat contents were 3.7 and 2.8 times greater than that after single dosing. The excessive amount of amiodarone observed in fat tissues after multiple dosing is probably the reason for the prolonged elimination half-life. Based on the elimination half-lives data, the time to steady state is about two weeks and the drug should be withheld for less than a mont if a patient required discontinuation because of serious adverse effects.

Influence of piperacillin on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate.

The influence of concomitant administration of piperacillin (PIP) on the pharmacokinetic parameters of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) was studied in rabbits. Six rabbits received an initial i.v. bolus (0.21 mg kg(-1)) followed by a constant-rate i.v. infusion of the drug (5 microg min(-1) kg(-1)) for 240 min. The PIP dose (30 mg kg(-1)) was repeated every 30 min until the end of the infusion period. The control group consisted of four rabbits treated the same way except for the addition of PIP. There were significant increases in the mean residence times found for MTX (MRTinf) and 7-OH-MTX (MRTm,inf) following PIP administration. Concomitant administration of PIP with MTX also produced significant 1.5- and 2.8-fold increases in the area under the curve of MTX and 7-OH-MTX, respectively. The total body clearance of MTX and the operative total body clearance of 7-OH-MTX significantly decreased, but in a less than proportional manner. The study demonstrates that the interaction between MTX and PIP is mainly due to the reduced clearance of both MTX and 7-OH-MTX combined with a slight increase in the formation clearance of the metabolite.

Bioequivalence and pharmacokinetics of chlorpheneramine in healthy human volunteers.

This study was carried out to evaluate the bioavailability of a new regular release tablet formulation of chlorphenamine (CPA) (Histop) relative to a reference formula (Piriton) using 13 human healthy volunteers. Each one received the two formulations as two 4 mg tablets in a two-way double-blind, crossover study. The concentration of CPA was measured with a sensitive high performance liquid chromatography (HPLC). The geometric mean for the area under the curve up to the last concentration (AUC0-t), to infinity (AUC0-oo) and the maximum concentration (Cp max) were 316.5, 315 + 439.8, 431.2 (ngh/ml) and 22, 20.5 (ug/ml) for the test (T) and reference (R) formulations, respectively. The parametric 90% confidence intervals of T/R ratio of the above parameters were within the bioequivalence acceptable range of 80-125%. The mean time to the maximum concentration Tmax (h) were 2.5 and 2.08 for the two formulations respectively and the parametric 90% confidence intervals of the Tmax difference (T-R) were in the range of -0.26-1.14 h, with point estimate of 0.44 h. The two formulations were found to be bioequivalent by the Schuirmann two one-sided t-test. Based on the pharmacokinetic results obtained frequent (ie, Q 4-6 h) CPA daily dosing may not be required particularly for the adults because of its long elimination half-life.

Comparison of high-performance liquid chromatography with fluorescence polarization immunoassay for the analysis of vancomycin in patients with chronic renal failure.

Eighty-two plasma samples from patients with chronic renal failure undergoing vancomycin treatment and hemodialysis (HD) were analyzed with fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). Vancomycin was infused once and the samples were collected during three subsequent HD sessions at 2 h, 3 days and 5 days post-infusion. The HPLC method, modified from an earlier assay, was simple. There was a wide variation in the estimated concentration between the two assay methods. The results obtained by HPLC were 69% lower than those obtained by FPIA. This difference in vancomycin concentration was independent of the sampling time after vancomycin infusion. HPLC analysis commenced approximately 1.5 year after that of FPIA. To study the effect of in vitro degradation, the vancomycin concentration in ten of the samples was redetermined with FPIA during HPLC analysis. The concentrations of those samples decreased to 78-98% (average 92%) of the original concentration. Because FPIA appears to lack specificity, there is a need of other methods such as HPLC for vancomycin measurements, particularly in samples from patients with end-stage renal failure.

Comparison of the effects of three haemodialysis membranes on vancomycin disposition.

Polysulfone (PSF) and polyacrylonitrile (PAN) were recently introduced haemodialysis (HD) membranes. The effect of each on vancomycin disposition was compared with cuprophan (SCE) in 12 chronic HD patients who received 14 infusions. Vancomycin (1 g) was infused over 1 hour, followed by three 4-hour HD sessions over 5 days, beginning 1 hour after the end of infusion. The intradialytic clearances of vancomycin were 73, 54 and 15 ml/min for PSF, PAN and SCE, respectively. At the end of the third HD session, vancomycin concentration dropped to subtherapeutic level (< 7.5 micrograms/ml) only in patients dialysed with PSF and PAN. The corresponding elimination half-lives (t1/2 beta) were 61, 60 and 86 hours for the three membranes, respectively. According to these findings, vancomycin should be given every three HD sessions for PSF and PAN. The dosage interval should be extended up to every 5 HD sessions for patients on SCE. The peak (mean +/- S.D.) obtained one hour after the end of infusion was 34.2 +/- 11.4 micrograms/ml, which is within the therapeutic range.

Cervical and mediastinal emphysema secondary to mandible fracture: case report and review of the literature.

Cervical and mediastinal emphysema is a rare but serious, life-threatening complication associated with mandibular fractures secondary to high-impact trauma. A case is reported in which a 24-year-old white man involved in a motor vehicle accident presented with an isolated mandibular fracture, cervical emphysema, and pneumomediastinum. A review of the literature is presented, and relevant anatomy and management are discussed.

Sensitivity of human colon tumor metastases to anticancer drugs in athymic (nude) mice.

We have studied the metastatic behavior of five human colon tumor cell lines (LS174T, WiDr, Caco-2, SW 620 and SW 480) using intrasplenic-nude mouse (ISMS) and intravenous-nude mouse (IVMS) model systems. LS174T was highly metastatic in both systems. In the IVMS system, LS174T cells produced lung metastasis and also grew in the skin as if the cells had been injected subcutaneously. We have also studied the anti-metastatic activity of three anticancer drugs (5-fluorouracil (5-FU), doxorubicin (DX) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) using LS174T cells and both ISMS and IVMS systems. The drugs were given intravenously on day 19 and 26 of tumor cell injection. Mice were sacrificed and organs observed for metastatic growth 4-6 weeks after cell injection. The results show that in the ISMS system, BCNU and 5-FU are inactive against both the liver metastasis and primary growth in the spleen. DX inhibits metastatic growth but not the primary growth. In the IVMS system, BCNU is inactive, whereas 5-FU and DX are active against the metastatic growth. Thus, DX may have activity against blood-borne human colon tumor metastasis.

Pharmacokinetics of methotrexate in children with acute lymphocytic leukemia.

Plasma methotrexate (MTX) levels were measured in 10 children (age 3-12 years) who received a total of 43 infusions of MTX. The total dose (1,000 mg/m2) was administered as a bolus of 200 mg/m2 with 24-hour infusions of 800 mg/m2. The clearance was fast at 158 +/- 81 ml/min/m2 and the elimination half-life (t1/2 beta) 3.0 +/- 0.7 h (mean +/- SD). The inter- and intrapatient variations in the steady state were wide, up to 6 times, suggesting the need for dose adjustment during infusion. The patients were at low risk for toxicity with a predicted MTX concentration at 39 h (5 half-lives) postinfusion of 0.28 +/- 0.10 mumol/l (mean +/- SD). None of them required leucovorin rescue 72 h postinfusion. An additional assessment of the MTX level may be useful as a guide to the duration of leucovorin rescue, which may be more or less than the routine 72 h postinfusion. The time suggested for this assessment was 48 h postinfusion. The mean +/- SD concentration at this time was 0.23 +/- 0.12 mumol/l and it correlated (r = 0.841) with the level measured 36 h postinfusion (n = 10). The value of this level needs to be investigated on a larger number of infusions.

Effect of indomethacin on the pharmacokinetics of methotrexate in rabbits.

The interaction between indomethacin (IND) and methotrexate (MTX) was investigated in rabbits. The study was designed so as to evaluate the effect of IND (1 mg h-1) during a continuous MTX infusion (1 x 2 mg kg-1) over 240 min. IND was injected i.v. at hourly intervals after a steady state MTX concentration had been established. Plasma MTX concentration before and after IND did not differ significantly (p greater than 0.05). The elimination half-life (t1/2 beta) calculated during the washout interval (mean +/- SD) was 47 x 4 +/- 21 x 5 min which is close to that calculated in a reference group of rabbits. This excludes the possibility of delayed elimination as responsible for this toxicity. The toxicity of this combination was confirmed despite the absence of significant pharmacokinetic changes. It is possible that the toxic interaction was caused by enhanced cytotoxic effect of MTX.

Comparison of a new high-performance liquid chromatography method with fluorescence polarization immunoassay for analysis of methotrexate.

A simple high-performance liquid chromatography (HPLC) method for the determination of methotrexate (MTX) in biological fluids is described. The assay is rapid, the time required for analysis is less than 30 min, and it is sensitive, up to 0.01 microgram/ml, which is three times below the toxic MTX concentration. Fifty plasma samples drawn from acute lymphocytic leukemia (ALL) patients were used to compare this method with that of fluorescence polarization immunoassay (FPIA). A good correlation (r = 0.979) was obtained between the results of the two analyses. FPIA constantly overestimates the concentration in samples collected during elimination and underestimates those collected during infusion. The difference between the means of the two methods was 29% and 13% for the elimination and infusion samples, respectively. The means of the peak height ratio of the metabolite to MTX in the HPLC chromatograms were 3.39 and 0.33 during elimination and infusion, respectively. The results therefore indicate that HPLC is more specific when tracing the washout of MTX concentration. Because of this specificity and simplicity, the method is recommended for therapeutic drug monitoring. The stability of MTX in human saliva was investigated in this study. MTX was found to be stable at room temperature and at -20 degrees C for a minimum of 3 h and 3 weeks, respectively.

Peritoneal absorption of cefoperazone in rats.

The peritoneal absorption of cefoperazone, administered by intraperitoneal (ip) perfusion in a large volume (100 mg/40 ml), was investigated in rats. Its pharmacokinetics was also studied after ip or intravenous (iv) injection of 100 mg/kg in two groups of rats. The peritoneal uptake after the two modes of ip administration was rapid, peaking in less than 20 minutes and the means of peak concentrations were similar. The peak remained high in the group perfused with a large volume for at least 4 hours, which was the end of sample collection. In addition, the absorption half-life and the fraction (F) reaching systemic circulation were calculated and found to be 10.0 +/- 2.5 min and 0.93, respectively. A brief distribution phase (t1/2 alpha 8.0 +/- 0.67 minutes) appeared only after the iv bolus. Otherwise the decline in serum concentration was monoexponential with half-lives of 39.0 +/- 4.0 and 63.6 +/- 7.5 min for the iv and ip injected groups, respectively. The stability of cefoperazone in plasma was also investigated in this study. It was found to be unstable at physiological pH even at -30 degrees C and the samples collected should be buffered in acidic media to optimize stability. The degradation process is likely to contribute to its elimination kinetics during in vivo administration.

Enhanced osseointegration of hydroxylapatite implant material.

This study was undertaken to determine whether the addition of calcium sulfate to hydroxylapatite (HA) implant material would improve its working properties without adversely affecting its osseointegration. The clinical and histologic examinations of bone response of three implant materials, hard tissue replacement (HTR), HA, and HA composite (HA plus calcium sulfate), were performed after 2-, 4-, and 6-week implantation in tibia and mandible of rabbits. No sign of extensive chronic inflammatory response was detected. The highest rate of bone ingrowth occurred with the HA composite, followed by HA, with HTR showing the least ingrowth. Bone was deposited directly on the surface of HA and HA composite implant materials. In contrast, HTR particles had a thin layer of fibrous tissue encapsulation with the normal bony investment.

Effect of the venom of the snake Cerastes cerastes (African desert horned viper) on the response of the rat vas deferens to field stimulation.

Cerastes cerastes venom in low concentrations (0.8-2.5 micrograms/ml) inhibited the response of the rat vas deferens to field stimulation, while higher concentrations (4-8 micrograms/ml) causes a contracture that was reversed by washing and transiently blocked by phentolamine. The effect of the venom and guanethidine (10(-7) M) was reversed by tyramine (4.6 x 10(-8) M) but unaffected by hexamethonium (1.4 x 10(-7) M). When the response to field stimulation was inhibited by the venom the response to norepinephrine was either potentiated or unchanged.