Comparative study of the circulation of semisynthetic cephalosporins in the blood of rabbits]

Circulation of 4 semisynthetic cephalosporins, such as cephaloridin, cephalotin, cephradin and cephacetryl in the blood of rabbits after their intramuscular administration in single doses of 5 or 20 mg/kg was studied. The above antibiotics were satisfactorily absorbed into the blood reaching the maximum level within 15 to 30 minutes. The blood levels of cephalotin were the lowest and the rate of its elimination from the blood was higher than that of the other drugs. A four-fold increase in the doses of cephalosporins was not accompanied by a proportional increase in their levels in the rabbit blood, the time of the antibiotic circulation in the blood being not significantly changed.     

Comparative study of the distribution of semisynthetic cephalosporins in the body of rats]

Distribution of 6 cephalosporin antibiotics, i. e. cephaloridin, cephalotin, cephradin cephacetryl, cephazolin and cephapyrin for parenteral use was studied comparatively on rats. The studies showed that all the above cephalosporins were well absorbed into the blood after intramuscular administration. The highest serum levels were achieved with the use of cephozolin. Still, its levels in the animal organs were mainly not higher and sometimes even lower than those provided by the other antibiotics. The highest levels of cephalosporins were detected in the kidneys. Cephalotin, cephapyrin and cephacetryl differed by the character of their distribution in the rats from the other 3 antibiotics: the levels of cephalotin and cephapyrin in the heart, spleen and muscles were lower than those of the other cephalosporins; sometimes they were even not detected in these organs; cephacetryl was not found in these organs. The levels of these 3 antibiotics in the kidneys were lower than those of the other cephalosporins. Cephalotin, cephacetryl and sometimes cephapyrin were not detected in the rat liver. None of the cephalosporins was found in the brain tissue.     

Comparative study of the interaction of cephalosporins with blood serum proteins and organ homogenates

Interaction of 7 semisynthetic antibiotics (cephaloridine, cephalexin, cephradine, cephazolin, cephalotin, cephacetrile and cephapirin) with proteins of human, bovine and rabbit blood serum, as well as organ and tissue homogenates of rats was studied comparatively. The study showed that binding of the cephalosporins by the blood serum depended on both the chemical structure of the antibiotic and the species affiliation of the protein substrate. The binding lvels of cephazolin and cephalotin by the blood serum proteins (except bovine serum) were the highest, while the binding level of cephaloridine was the lowest. A significant decrease in the values of binding by the serum proteins of the drugs with high percentage of binding was observed when the drug concentrations in solution were increased. Binding of the cephalosporins by the blood serum proteins was in most cases completely reversible. The activity of the cephalosporins decreased in the presence of the rat organ and tissue homogenates. The levels of the activity decrease as compared to the theoretical ones were the highest with the use of cephalotin, cephacetrile and cephapirin. The lowest values of detection of these antibiotics were noted on their incubation with the liver, kidneys and lungs.     

Comparative study of cephalexin and cephradine distribution in the body of rats]

Distribution regularities of cephalexin and cephradine, 2 semisynthetic cephalospor in antibiotics for oral use were studied on rats. It was found that the cephalosporins had a capacity for satisfactory penetration through the histochematological barriers. The drugs were rather rapidly absorbed from the gastrointestinal tract of the rats into the blood. Their maximum blood levels were determined 1 hour after the administration. The highest cephalosporin concentrations were detected in the kidneys and liver. Still, the level of cephradine in the kidneys was lower and that in the liver was higher than the levels of cephalexin. The lowest concentrations were found in the skeletal muscles. The character of cephradine distribution in the lungs, heart and spleen differed from that of cephalexin; the maximum concentrations of cephradine in these organs were achieved 1 hour after its administration, while those of cephalexin were achieved in 30 minutes. The antibiotics were not detected in the brain tissue. No increase in the concentration gradient with time was observed.     

Suppressed expression of calcium-binding protein regucalcin mRNA in the renal cortex of rats with chemically induced kidney damage

The alteration of Ca²⁺-binding protein regucalcin mRNA expression in the kidney cortex of rats administered cisplatin and cephaloridine, which can induce kidney damage, was investigated. Cisplatin (0.25, 0.5 and 1.0 mg/100 g body weight) or cephaloridine (25, 50 and 100 mg/100 g) was intraperitoneally administered in rats, and 1, 2 and 3 days later they were sacrificed. The alteration in serum findings after the administration of cisplatin (1.0 mg/100 g) or cephaloridine (50 and 100 mg/100 g) demonstrated chemically induced kidney damage; blood urea nitrogen (BUN) concentration increased markedly and serum inorganic phosphorus or calcium concentration decreased significantly. Moreover, the administration of cisplatin (1.0 mg/100 g) or cephaloridine (100 mg/100 g) caused a remarkable increase of calcium content in the kidney cortex of rats, indicating kidney damage. The expression of regucalcin mRNA in the kidney cortex was markedly reduced by the administration of cisplatin or cephaloridine in rats, when the mRNA levels were analyzed by Northern blotting using rat liver regucalcin cDNA (0.9 kb). The mRNA decreases were seen with the used lowest dose of cisplatin or cephaloridine. The present study clearly demonstrates that the mRNA expression of Ca²⁺-binding protein regucalcin in the kidney cortex of rats is decreased by chemically induced kidney damage.     

Cephazolin and cephapirin circulation in the blood of rabbits

Circulation of 2 semi-synthetic cephalosporins, i. e. cephazoline and cephapyrine in the blood of rabbits after their intramuscular administration in single doses of 5 and 20 mg/kg was studied. It was found that the antibiotics were well adsorbed into the blood. Their maximum blood levels were achieved 15--30 minutes after administration. Cephazoline provided a higher blood level persisting for longer periods of time as compared to cephapyrine. The value of the time of the two-fold decrease in the cephazoline blood level was higher. A four-fold increase in the dose of the cephalosporines resulted in an increase in their blood levels but did not induce any significant increase in the time of their circulation.     

Decreased first-pass metabolism of labetalol in chronic liver disease.

The effect of chronic liver disease on the rate of elimination and extent of "first-pass" metabolism of labetalol was studied. Pharmacokinetic measurements were made after both oral and intravenous administration to seven healthy subjects and to 10 patients with chronic liver disease. Plasma half life was similar in the two groups. Plasma concentrations were considerably higher in the patients than in the healthy subjects after oral administration but similar after intravenous injection. Thus the bioavailability of labetalol was increased in liver disease due to reduced first-pass metabolism. Bioavailability in the group of patients correlated negatively with serum albumin concentration. There were falls in supine heart rate and blood pressure which tended to be greater after oral administration in the patients with liver disease, suggesting an exaggerated response related to the increased bioavailability. Oral dosage requirements of labetalol and possibly other drugs susceptible to first-pass metabolism are reduced in the presence of liver disease.     

Elimination of Homologous And Heterologous (Bovine) Serum Albumin from the Blood Circulation in the Dog)

The elimination of intravenously administered I131-labelled bovine serum albumin has been compared to the elimination rate of relabelled homologous serum albumin in normal and bled dogs, which had lost considerable blood volumes. The investigation shows that during the first four to five days after the administration the elimination is similar of heterologous and homologous serum albumin. This proves that bovine serum albumin can be regarded to be an equivalent plasma expander to homologous serum albumin in the dog. Elimination of homologous as well as heterologous serum albumin follows a simple exponential curve during four to five days after administration. The intravascular half-lives for homologous serum albumin were 6.4 ±1.5 days and 6.4 ± 0.6 days respectively in control and bled dogs. Corresponding values for heterologous (bovine) serum albumin were 5.0 ± 0.3 and 4.8 ± 0.4 days respectively. The quote for cencentrations of homologous and heterologous serum albumin in different tissues was found to be relatively constant approximately 1.4. An exception was the stomach wall in bled dogs which had a quote of 1.1 only.     

Evaluation of the antibacterial activity in vitro of various cephalosporins on different gram-negative bacterial species of recent clinical isolation

The Authors have compared the antibacterial activity "in vitro" of new cephalosporines (cephuroxim, cephoxitin and cephaclor) with other cephalosporines having an action which is already known (cephaloridine, cephazoline and cephalexine) on the Gram-negative bacterial strains of recent clinical isolation. The results show that the cephalosporines of last generation, having in their molecular nucleus a methoximinic group, realize a greater antibacterial protection than those cephalosporines of antecedent preparation.     

Azelastine and suplatast shorten the distribution half-life of IgE in rats

We aim to clarify whether suplatast and azelastine (anti-allergic drugs) can shorten the half-life of imnunoglobulin E (IgE) in the circulating blood. Thirty Wistar rats were divided into six groups. Distilled water or anti-allergic drugs were given orally for 6 days after the first sensitization. Two milligrams of monoclonal dinitrophenyl (DNP)-specific rat IgE was administered to the rats, which had been given suplatast or azelastine orally. The level of DNP-specific rat IgE in the serum was estimated by IgE-capture enzyme-linked immunosorbent assay, and the turnover of IgE was analyzed from its pharmacokinetic parameters. The elimination half-life of rat IgE was about 12 h irrespective of the sensitized state. The intercompartmental rate constants (Kct and Ktc) in the suplatast-administered or azelastine-administered group were larger than those of the distilled water-administered group under non-sensitized conditions. These findings suggested that the anti-allergic drugs used in the present study facilitated the excretion of IgE from the circulation in rats.     

Des-enkephalin-gamma-endorphin: bioavailability in rats following the subcutaneous and intramuscular route of administration

A pharmacokinetic study with [3H]des-enkephalin-gamma-endorphin (3H-DE gamma E) was performed in rats after the intravenous, subcutaneous and intramuscular route of administration. Disappearance of non-metabolized 3H-DE gamma E from blood upon intravenous dosing followed a biphasic decay with half-lives of 0.7 +/- 0.3 (+/- S.D.) min for the initial distribution phase and 6.3 +/- 2.7 min for the terminal elimination phase. The central and peripheral volumes of distribution were strikingly high (0.38 and 0.55 1 X kg-1, respectively). Extensive metabolism occurred already within the first minutes after injection. The blood clearance rate was found to be 0.29 +/- 0.12 1 X min-1 X kg-1, which value points to remarkable extrahepatic elimination of the neuropeptide. As compared to the intravenous route of administration, subcutaneous or intramuscular injection of 3H-DE gamma E resulted in low but longer-lasting peptide levels in blood. These levels reached already peak values at 2 min after both routes of administration and then declined to below the limit of detection at 2-3 h. The absolute bioavailability of DE gamma E after subcutaneous injection amounted to 30.9 +/- 16.3% (range 16.0-46.9%), whereas the bioavailability after intramuscular injection was observed to be 3.5 times lower (8.5 +/- 3.0%; range 4.6-12.0%). These data suggest that subcutaneous dosing of DE gamma E might be more effective in displaying CNS activity than the intramuscular route.     

Circadian variation in methotrexate toxicity in streptozotocin-induced diabetes mellitus rats

The effects of diabetes mellitus and circadian rhythm on pharmacokinetics or pharmacodynamics of drugs have been previously separately reviewed. In our previous study, a circadian rhythm has been described in the pharmacokinetics of MTX in streptozotocin-induced diabetes mellitus (SIDM) rats. The aim of the present study was to investigate the effects of circadian rhythm on the toxicity of MTX in SIDM rats. The hematologic parameters and serum folic acid levels were measured in control and SIDM groups before and after MTX administration to evaluate its toxicity. We observed that circadian rhythm in basal peripheral WBC counts disappeared after MTX administration in the first hour and were phase shifted on the fifth day. Circadian variations were not observed in the other blood cells. One hour after MTX administration, folic acid levels were high in both groups. However, a circadian rhythm was present only in the diabetic group. The alteration in the rhythm of WBC counts in diabetic rats may originate not only from the effect of MTX but also physiological alterations due to diabetes and/or the varying cell cycle entry rates in the hematopoetic stem cells.     

A three years follow-up of total serum IgE levels in three patients treated for strongyloidiasis.

A three years follow-up of the level of serum total IgE was made for the first time in three patients with strongyloidiasis after efficient treatment. The decrease of IgE was slow and progressive, showing a logarithmic curve. This regular decrease of total serum IgE could be used as an additional criterion for the evaluation of the efficiency of drug therapy in patients with strongyloidiasis. The persistence of high levels of total IgE two or three years after the elimination of the intestinal parasites, after the return of blood eosinophils to a normal level (within six months), and after the disappearance of specific antibodies, shows that the regulation of the IgE elimination seems to be a complex mechanism.     

Drugs elevating extracellular adenosine administered in vivo induce serum colony-stimulating activity and interleukin-6 in mice

Our previous studies have shown that the combined administration of drugs elevating extracellular adenosine, i.e. dipyridamole (DP) and adenosine monophosphate (AMP), enhances murine hematopoiesis and potentiates the action of granulocyte colony-stimulating factor (G-CSF). In this study, colony-stimulating activity (CSA) of blood serum of mice treated with DP+AMP, G-CSF or all these drugs in combination, i.e. the ability of the sera to stimulate the growth of GM-CFC colonies, was assayed in vitro. Furthermore, the concentration of GM-CSF and IL-6 in the sera was determined. Administration of DP+AMP was found to enhance significantly serum CSA at all time intervals of serum sampling including 24 h after the last injection of the tested drugs. Additive effects of DP+AMP and G-CSF on serum CSA were noted at early intervals after administration of the drugs. Furthermore, IL-6 levels were significantly elevated in the sera of mice which were administered DP+AMP either alone or in combination with G-CSF. Our results show that the effects of DP+AMP are indirect, mediated through the induction of some cytokine(s) and/or growth factor(s) and that extracellular adenosine can act in cooperation with G-CSF. These findings contribute to the further elucidation of the role of adenosine in hematopoiesis.     

Variations of prolactin content in human cerebrospinal fluid after metoclopramide and morphine

Serum and cerebrospinal fluid (CSF) prolactin (PRL) concentrations were determined in fourteen patients of both sexes suffering from hydrocephalus, in basal conditions and after i.m. administration of 10 mg metoclopramide or 10 mg morphine. A significant increase in both serum and CSF hormone values was found after administration of both drugs. Serum and CSF PRL values after metoclopramide administration increased earlier and to a greater extent than after morphine. Furthermore, the metoclopramide induced CSF PRL increase immediately followed the serum peak, whereas after morphine administration an evident delay in the CSF hormone peak with respect to the serum increase was found. These data suggest that PRL entry in the CSF compartment is subject to a controlling mechanism which acts at the blood/brain barrier.     

Effects of Capsaicin and Isoflavone on Blood Pressure and Serum Levels of Insulin-Like Growth Factor-I in Normotensive and Hypertensive Volunteers with Alopecia

Insulin-like growth factor-I (IGF-I) reduces arterial blood pressure. Since administration of capsaicin and isoflavone increases serum levels of IGF-I by sensory neuron stimulation in subjects with alopecia, it is possible that administration of capsaicin and isoflavone reduces arterial blood pressure in patients with hypertension. Systolic and diastolic blood pressure (BP) and serum levels of IGF-I were determined before and at 1, 3, and 5 months after administration of capsaicin and isoflavone in 42 volunteers with alopecia, 29 normotensive and 13 hypertensive volunteers. Neither systolic nor diastolic BP changed in the normotensive volunteers after combined administration of capsaicin and isoflavone. In contrast, systolic and diastolic BP was significantly reduced in hypertensive volunteers after administration of capsaicin and isoflavone. Serum levels of IGF-I significantly increased in both normotensive and hypertensive volunteers after administration of capsaicin and isoflavone. These observations suggest that administration of capsaicin and isoflavone might reduce BP in hypertensive, but not in normotensive subjects, probably by increasing serum levels of IGF-I.     

Elimination of I131-labelled heterologous antigen from the blood of chickens after total body X-irradiation

A study was made on the effect of ionizing radiation upon the rate of elimination of I¹³¹. labelled human serum albumin (HSA I¹³¹) from the blood and upon antibody formation in chickens irradited with 1,2 00R(i.e.with LD₅₀) and injected with antigen 30 min, 6 days or 14 days after irradiation. The elimination curve from unirradiated control birds followed the typical three-phase pattern. The effect of irradiation was most marked with chickens injected with antigen 6 days after irradiation, resulting in an extension of the second phase with practically no third phase at all. Exposure to irradiation 30 min prior to antigen administration resulted in an extension of the second phase by 2 days as compared to the controls, with the onset of the third phase occurring on day 7. Irradiation 14 days prior to antigen administration resulted in an extension of the second phase by 1 day as compared to the controls, with the onset of the third phase occurring on day 6. Elimination of HSA I¹³¹ in the second phase was more rapid than that of I¹³¹-labelled chicken serum albumin (CSA I¹³¹) no matter whether the chickens were irradiated or not. This suggests that the capacity of specific antigen uptake is not affected by irradiation. Antigen elimination curves from control irradiated groups given CSA I¹³¹ followed the same pattern as that found in control unirradiated birds injected with homologous antigen.     

Effect of propranolol on lidocaine pharmacokinetics

The study aimed at investigating an effect of propranolol on lidocaine pharmacokinetic parameters, especially elimination rate and total clearance rate. The study was carried out in 8 rabbits with cross-over technique. The animals were examined twice. Sequence of therapy was established randomly. Some group of the animals were given propranolol and lidocaine first while the remaining animals were given lidocaine alone. Sequence of drugs administration was changed after one week. Propranolol was given in a single dose of 0.05 mg/kg b.w. intravenously. Lidocaine was injected in a single dose of 3 mg/kg b.w. during 5 minutes i.v. after a 30-minute interval. All drugs were injected into ear vein. Blood for assays was collected 8 times within 6 hours after lidocaine administration. TDx system manufactured by Abbott was used for drug concentration assay with immunofluorescence polarization method. One-compartment open model was used for calculations. The results were analysed with Student t-test for pairs. Significant decrease in AUC, marked decrease in distribution volume and total body clearance following lidocaine and propranolol were noted. The study has shown that there is interaction between propranolol and lidocaine leading to a decrease in total body lidocaine clearance.     

Effect of a modified terrilytin on ampicillin pharmacokinetics in experimental peritonitis

The effect of modified terrilytin, a new enzyme of the microbial origin on the pharmacokinetics of ampicillin in experimental peritonitis was studied on 16 pubertal rabbits. Peritonitis was caused by laparotomy and administration of a 15 per cent fecal suspension into the abdominal cavity. The drugs were injected intramuscularly: the enzyme in a dose of 5 PU/kg and the antibiotic in a dose of 10 mg/kg. The ampicillin levels in the blood and peritoneal exudate were determined with the agar-diffusion method. The specimens were collected 30 minutes, 1, 1.5 and 2 hours after administration of the drugs. The animals were divided into 2 groups: control (not treated with the enzyme) and experimental. An increase in the antibiotic levels in the blood and peritoneal exudate by 50--54 per cent was observed. The maximum increase was recorded 30 minutes after simultaneous administration of the drugs.     

Decreased Serum Choline Concentrations in Humans after Surgery,Childbirth, and Traumatic Head Injury

The serum levels of choline decreased by approximately 50% in patients having a surgery under general as well as epidural anesthesia. The decrease is lasts for two days after surgery. Intravenous administration of succinylcholine, either by a single bolus injection or by a slow continuous infusion, increased the serum choline levels several folds during surgery. In these patients, a significant decrease in the serum choline levels was observed one and two days after surgery. In 16 pregnant women at the term, serum choline levels were higher than the value observed in 19 non-pregnant women. The serum choline levels decreased by about 40% or 60% after having a child-birth either by vaginal delivery or caesarean section, respectively. Serum choline levels in blood obtained from 9 patients with traumatic head injury were significantly lower than the observed levels in blood samples obtained from healthy volunteers. These observations show that serum choline levels increase during pregnancy and decrease during stressful situations in humans.