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Formulation of sustained release tablets containing coated particles whose coating membrane is not damaged during compression was studied and several kinds of chitosan of different particle size were evaluated as protective agents for the membrane. Comparison was made with the dissolution rate of the coated particles. Ethylcellulose or ethylcellulose/hydroxypropylcellulose was chosen as a coating agent. When the coated particles were compressed with the small particle size chitosan (Marine Chito), the coating membrane was not ruptured, and the protective effect was not influenced by the compression pressure. Both the Eudragit RS-coated particles and the tablets manufactured by compressing the coated particles with Marine Chito were orally administered to dogs, and the plasma theophylline levels of the two dosage forms were compared to determine the drug release characteristics in the gastrointestinal tract. It was found that the plasma concentration-time curve of the tablets coincided with that of the coated particles, and the compressed tablet would disintegrate instantly and redisperse into many particles in the body after oral administration.
Using simple kinetic modelling, we estimated the effect of nucleophilic (renal) protecting agents (thiosulfate, mesna, diethyldithiocarbamate) on the half-life and the area under the concentration-time curve (AUC) of cis-diamminedichloroplatinum(II) (CDDP) in plasma and peritoneum. Our basic assumptions were that (a) under non-protecting conditions, the elimination of intact CDDP from plasma and peritoneum is a first-order process determined by the elimination-rate constant (k), and (b) under conditions of renal protection the elimination of CDDP is a first-order process determined by kCDDP,P = kCDDP+kN.[N], with kCDDP,P representing kCDDP under conditions of protection; kN, the second-order rate constant for direct interaction of the protecting nucleophile (N) and CDDP; and [N], the (steady-state) concentration of N. Half-lives under conditions of protection were 0.693/kCDDP,P. AUCs were obtained by integration of the first-order equations. The inactivation-indicating parameter was defined as being the ratio of the AUC under protecting conditions to the AUC under non-protecting conditions (Rinact). Rinact is approximately given by kCDDP/kCDDP,P. For renal protection with i.v. thiosulfate (TS, 2 g m-2h), the estimates of Rinact were 0.61 in plasma and 0.7 in the peritoneal cavity for i.p. injected CDDP and 0.87 in plasma for i.v. CDDP, indicating inactivation of CDDP under such conditions. Estimates of Rinact were 0.84 or 0.96 in plasma and 0.87 in the peritoneal cavity for supposed conditions of renal protection by systemic mesna (4.4 g m-2 h), suggesting only minor inactivation of i.p. or i.v. injected CDDP under such conditions. Under reported conditions of protection achieved with 4.4 g m-2 h systemic diethyldithiocarbamate (DDTC). Rinact was greater than 0.65 or 0.87 in plasma and greater than 0.75 in the peritoneal cavity for i.p. or i.v. injected CDDP, respectively. Thus, DDTC inactivates CDDP to a comparable or lesser extent than does TS.
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Agents which protect against the development of oxygen toxicity in vivo were tested in an in vitro system, the isolated urinary bladder of the toad Bufo marinus. None of the agents protected against the inhibition of sodium transport across the bladder by hyperbaric oxygen exposure. Two protective agents, disulfiram and diethyldithiocarbamic acid, significantly increased the rate and extent of sodium transport inhibition by 5 ATA of oxygen, either when added in vitro or given in vivo. It was concluded that oxygen toxicity protective agents may have a nonspecific action in vivo.
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HYPOTHESIS: The goals of this investigation were to compare the efficacy of three protective agents against cisplatin-induced elevation of auditory brainstem response (ABR) thresholds and to examine whether these protective agents prevent cisplatin-induced alterations of the antioxidant defense system in the cochlea of the rat. BACKGROUND: Cisplatin is an ototoxic antitumor agent. Previous animal studies have shown that cisplatin administration causes an elevation of ABR thresholds. These auditory changes are accompanied by alterations in the concentration of glutathione and the antioxidant enzymes in the cochlea. The authors' previous work has indicated that the protective agent diethyldithiocarbamate (DDTC) prevents decrease in glutathione (GSH), alteration of antioxidant enzyme activity, and disruption of cochlear function with cisplatin administration. METHODS: Wistar rats were sedated and underwent pretreatment ABR testing using clicks and tone burst stimuli at 8, 16, and 32 kHz. Control rats received saline by intraperitoneal (i.p.) injection. Positive control rats were administered cisplatin 16 mg/kg i.p. Three groups of rats received protective agents in combination with cisplatin. The DDTC-protected rats were given 600 mg/kg of DDTC subcutaneously 1 hour after cisplatin. Animals protected by 4-methylthiobenzoic acid (MTBA) were given 250 mg/kg of this agent i.p. 30 minutes before cisplatin. Animals protected with ebselen were given 16 mg/kg i.p. one hour before cisplatin. The ABR thresholds were recorded 72 hours after cisplatin administration in all groups. Cochleas were removed, and extracts of the tissues were analyzed for GSH, activities of antioxidant enzymes (superoxide dismutase [SOD], catalase, glutathione peroxidase, and glutathione reductase) and malondialdehyde (MDA) (as an index of lipid peroxidation). RESULTS: Cisplatin-treated rats had significant ABR threshold shifts, ranging from 27 to 40 dB. Rats administered each of the three protective agents in combination with cisplatin had ABR threshold shifts of <10 dB. The cochleae of rats administered cisplatin alone had nearly a 50% depletion of glutathione and about a 50% reduction in the activities of SOD, glutathione peroxidase, and glutathione reductase, while catalase activity was reduced to 70% of control values. These changes were accompanied by a reciprocal elevation of MDA of 165%. These changes, namely, the depletion of GSH and antioxidant enzyme activity and the elevation of MDA in the cochlea, were largely attenuated by the administration of the protective agents tested. CONCLUSION: These findings suggest that cisplatin ototoxicity is related to lipid peroxidation and that the use of protective agents prevents hearing loss and lipid peroxidation by sparing the antioxidant system in the cochlea. These results suggest the possibility that the clinical use of protective agents could effectively reduce or prevent damage to the inner ear of patients receiving cisplatin chemotherapy, provided that the antitumor effect is not altered.
It has been shown that unithiol diminishes toxic action of cysteamine, AET, and disulfide of WR-1065 on mice. This permits to enhance protection of animals against X-rays by increasing of protector doses. The effect of unithiol on cysteamine action in rats was the same. Antitoxic effect of unithiol on cysteamine was shown both at i.p. and p.o. protector administration. The effect was also revealed in Chinese hamster V-79 cell culture. Combined disulfide of cysteamine and unithiol was synthetized, which ensures effective prolonged protection against ionizing radiation.
The photo degradation of some agents of plant-protecting agents is illustrated by survey. The author proves that the photolytic degradation is a relevant process of the total degradation in many agents so that it has in an increasing manner to be taken into consideration with the ecologic-chemical assessment of plant-protecting agents. The photolysis of agents is discussed for the conditions in water, at surfaces of the ground, plants and glass at open grounds and models. The velocity of photolytic degradation of the agent mainly depends on the medium at or within which the agent exists. A correlation between stability of the photolysis and features of the structure of the chemical compound can be realized by means of the quantum efficiency.
UNLABELLED: IN THEORY: Combination use of a coxib with a gastro-protective agent does not appear justified since results of studies conducted on patients of all types demonstrated that the upper-digestive tract safety and tolerability profile of coxibs is good. IN SUMMARY: On the other hand, prescription-related descriptive data demonstrate that in real-life situations such a combination occurs in approximately 25% of cases. Two cases should be differentiated: in about half of cases, patients are receiving long-term therapy with a proton pump inhibitor (PPI) (for reflux oesophagitis, oesophagitis or dyspepsia) and when an NSAID is necessary, the prescribing physician logically turns to a coxib; in the other half of cases, it involves a true simultaneous co-prescription of a coxib and a gastro-protective agent (most often by far a PPI). Thus, it is only in 10-15% of patients that prescription of a coxib leads to prescription of a PPI. A SAFETY ATTITUDE: This approach can be justified by the physician's desire to be as cautious as possible in dealing a patient at high risk of GI disorders (elderly patients, previous history of digestive bleeding, co-prescription of aspirin and/or a steroid, co-morbidity) or in patients for whom the occurrence of GI bleeding would be very serious (i.e. a patient in poor condition due to multiple disorders, treatment with an oral anti-coagulant or heparin). In both cases, if the prescription of an NSAID cannot be avoided, it is therefore logical first to choose a coxib and second to prescribe simultaneously a gastro-protective agent.
The lectin wheat germ agglutinin (WGA) is an unusually effective agent in controlling both the forward and reverse reactions of the reversible morphology conversion discocyte in equilibrium with echinocyte for the human erythrocyte. Under conditions severe enough to drive the reactions to completion in either direction without the lectin, WGA is able to stabilize both these morphologies and to fully prevent conversion of either morphology. The lectin can quantitatively block both reactions. The ability of WGA to carry out these functions has no obvious rate limitation. Its effectiveness depends mainly on its binding stoichiometry, particularly toward the transmembrane glycoprotein, glycophorin. The critical binding stoichiometries for both the lectin and the echinocytic agent were determined in relation to the binding isotherms using 125I-labeled WGA and 35S-labeled dodecyl sulfate. There appear to be two principal stoichiometries for WGA binding that are important in its control of erythrocyte morphology. The first stoichiometry marks the threshold of obvious protection of the discocyte against strong echinocytic agents such as detergents and, likely, is simply a 1:1 stoichiometry of WGA: glycophorin, assuming currently recognized values of 3--5 x 10(5) copies of glycophorin per cell. The second important stoichiometry, whereby the cell's morphology is protected against extremely severe stress, involves binding of approximately 4--5 WGA molecules per glycophorin. The controls that WGA exerts can be instantly abolished by added N-acetylglucosamine. However, N-acetylglucosamine ligands on the erythrocyte are of less importance than membrane neuraminic acid residues in enabling WGA to control the cell's morphology, as is shown by comparing intact cells with completely desialated cells. WGA can also be used to produce elliptocytes in vitro, but it does this at levels approaching monolayer coverage of the cell with WGA.
1. An intervention to reduce ischaemia-reperfusion lung injury will be an important advance in transplant medicine. Although the mechanisms associated with producing ischaemia-reperfusion endothelial injury have not been completely elucidated, many of the injury mediators have been studied in detail. While no single pharmacological therapy is likely to be totally effective in eliminating this complex injury, we have developed a mixture of agents that are known to block pathways involved in producing ischaemia-reperfusion-associated lung vascular injury.2. The present study modified University of Wisconsin solution (UW) by adding one of the protective agents prostaglandin E1 (PGE1), dexamethasone (Dex) or dibutyryl cAMP (Bt2-cAMP), or a combination of these, to the perfusate of rat lungs exposed to 4 h of cold ischaemia followed by 1 h of reperfusion. Nine modified UW solutions were studied: (1) UW+Dex, (2) UW+PGE1, (3) UW+Bt2-cAMP, (4) UW+Dexx3, (5) UW+PGE1x3, (6) UW+Bt2-cAMPx3, (7) UW+Dex+PGE1, (8) UW+Dex+Bt2-cAMP, (9) UW+PGE1+Bt2-cAMP. These solutions were utilized in individual experiments to assess haemodynamic changes, lung weight gain, the capillary filtration coefficient (Kfc) and pathology in all lungs.3. The results indicate that lung weight gain and Kfc values were significantly lower than with UW alone in groups 1, 2 and 3, which contained only one additional protective agent. In groups 4, 5 and 6, which contain three times the concentration of each protective agent, both Kfc and lung weight gain were similar to those measured in groups 1, 2 and 3, i.e. lungs were protected but the protection was not dose dependent. In groups 7, 8 and 9, which contained two protective agents, lung weight gain and Kfc were greatly reduced compared with UW alone. Histopathological studies showed similar decreases in the injury profiles of lungs.4. Although UW contains several antioxidant protective agents such as allopurinol and glutathione, it did not provide effective protection in our ischaemia-reperfusion lung injury model. UW modified with an additive of PGE1, Dex or Bt2-cAMP attenuated ischaemia-reperfusion injury. Furthermore, UW containing two of these protective agents augmented the protection. Among the modified solutions, it appears that UW+PGE1+Bt2-cAMP protects the lungs to a greater extent than all other solutions used in our study. We suggest that preservation solutions containing PGE1-Bt2-cAMP will provide additional protective effects to organs stored for transplantation.
This study evaluated physiological heat strain from two developmental toxic agent protective systems compared with the standard Toxicological Agent Protective (TAP) suit during exercise-heat stress. Eight subjects (six men, two women) completed three experimental trials, at 38 degrees C, 30% rh, wearing: 1) Self Contained Toxic Environment Protective Outfit (STEPO) with rebreather (STEPO-R); 2) STEPO with tether (STEPO-T) or 3) the standard TAP. The STEPO systems provided effective body cooling of: STEPO-R, 200 +/- 36 W; and STEPO-T, 186 +/- 59 W. TAP had no cooling. All experimental trials used treadmill walking at 0.89 m x s(-1), 0% grade at exercise/rest cycles of 20/10 min for 240 min. Metabolic rates for the treatments were: STEPO-R, 298 +/- 26 W; STEPO-T, 299 +/- 34 W; and TAP, 222 +/- 40 W. Rate of heat storage was less (p < 0.05) in STEPO-R (37 +/- 8 W x m(-2)) and STEPO-T (38 +/- 12 W x m(-2)) than in TAP (77 +/- 15 W x m(-2)). Sweating rate was less (p < 0.05) in STEPO-T (10.0 +/- 4.8 g x min(-1)) than in TAP (23.8 x 11.4 g x min(-1)). There was no difference between STEPO-R (12.3 +/- 5.6 g min(-1)) and the other two uniform systems. Subjects did not complete targeted exposure times of 240 min. Exposure time was longer (p < 0.05) in STEPO-R (83 +/- 22 min) and STEPO-T (106 +/- 39 min) than in TAP (46 +/- 10 min). Predicted time to 39.0 degrees C was less (p < 0.05) in TAP (69 +/- 20 min) than in either STEPO-R (226 +/- 124 min) or STEPO-T (244 +/- 170 min). The results of this study show that cooling in STEPO significantly reduced heat storage relative to TAP. The new generation toxic cleanup uniform systems effectively reduced heat stress and increased work capabilities compared with the standard TAP suit.