Depletion study

The biochemical theory of depression is in a state of crisis. The data just do not fit the theory. The neurotransmitter depletion studies that I described earlier in this chapter show that lowering serotonin or norepinephrine levels does not make most people depressed. When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree. And the effect of anti-depressants, which was the basis for proposing the chemical-imbalance theory in the first place, turns out to be largely a placebo effect. 

Equation 8 was also applied by Sperry (12), although the underlying assumptions are different in his model. There is also a close analogy between Equation 8 and the pair potential used by De Hek and Vrij. Indeed, Equation 4 of Ref. 6 reduces to our Equation 8 for H = 0, provided that 2A is interpreted as the hard sphere diameter of the polymer molecule. Hence, in dilute solutions (where A a rg) the two approaches are very similar. However, in our model A is a function of the polymer concentration. Because most experimental depletion studies are carried out at values for that are comparable in magnitude to <)>, our model... 

Mathieson, P. W. et al., Immunoregulation of mercuric chloride-induced autoimmunity in Brown Norway rats A role for CD8+ T cells revealed by in vivo depletion studies. Eur. J. Immunol., 21, 2105, 1991. 

Because of its widespread therapeutic use and because the question of residues in food producing animals, SDM was selected for a study between species to compare its metabolism, the pharmacokinetics of the parent drug as well as its metabolites. Residue depletion studies were performed in edible tissues of calves, pigs and in the eggs of laying-hens. 

Pharmacology Atomoxetine is a selective norepinephrine reuptake inhibitor. The precise mechanism by which it produces its therapeutic effects in ADHD is unknown, but it is thought to be related to selective inhibition of the presynaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. Pharmacokinetics ... 

As illustrated by the [PS / ] phenomenon the relative abundance of the eRFl/eRF3 complexes is an important determinant for the efficiency of translation termination. Similar effects have been obtained in depletion studies and with eRF3 and eRFl mutants that decrease their cellular concentration (Stansfield et al. 1996 Moskalenko et al. 2003 Chabelskaya et al. 2004 Salas-Marco and Bedwell 2004). Wild type yeast contains approximately 10- to 20-fold fewer termination factors compared to ribosomes (Didichenko et al. 1991 Stansfield et al. 1992). The threshold level of eRFl/eRF3 required to maintain viability is even lower. A 10-fold decrease reduces viability by only about 10% (Valouev et al. 2002) and a decrease in eRF3 of 99% does not affect viability of the cells significantly (Chabelskaya et al. 2004). As eRF3 is associated with polysomes or ribosomes, the mechanism of translation termination depends on efficient recycling (Didichenko et al. 1991 and compare below). 

These data and findings from serotonin depletion studies show that, in patients treated successfully, NA and serotonin systems are involved in maintenance of drug-induced remission. However, the absence of an increased severity in depressive symptoms in drug-free patients with depression suggests that alterations in serotonin and catecholamine release may not be causally involved in the pathophysiology of mood disorders. 

Bell, C, Forshall, S, Adrover, M., et aI Does 5-HT restrain panic A tryptophan depletion study in panic disorder patients recovered on paroxetine. J. Psychopharmacol. 16(1), 5-14, 2002. 

Residue depletion studies with piglets orally dosed with 30 mg spectinomycin/kg bw/day for 5 consecutive days showed that the average concentrations of the parent drug in liver, kidney, muscle, and skin/fat were 1030, 7700, less than 300, and less than 394 ppb, respectively, at 3 days, and less than 198, 500, 300, and 26 ppb, respectively, at 14 days postdosing. Broilers given water dosed at 50 mg spectinomycin/kg bw/day for 5 consecutive days were not found to contain detectable spectinomycin concentrations (limit of detection 500 ppb for liver and kidney and 250 ppb for muscle and skin/fat) in any edible tissue even only 1 day after the last dose. 

Residue depletion studies in orally treated beef cattle showed that liver, kidney, and muscle contained 65-77 ppb, 50-115 ppb, and less than 20 ppb thiamphenicol, respectively, at 4 days after dosing, but less than 20 ppb at 10 days after dosing. Milk from dairy cows intramuscularly dosed with thiamphenicol contained residues 800 ppb 1 day after the cessation of treatment, but less than 20 ppb 48 h later. 

Residue depletion studies in sea bream administered once daily for 5 consecutive days feed medicated with 4 ppm thiamphenicol showed that residue... 

The pharmacokinetic characteristics of florfenicol have been described in goats (40), calves (41), and chickens (42). The efficacy of florfenicol in aquaculture has been also demonstrated against bacteria involved in some major fish pathologies, especially in salmon and trout (43, 44). Pharmacokinetic studies in Atlantic salmon indicated that the compound was well absorbed and distributed following oral administration (45). Tissue residue depletion studies after an oral daily administration of 10 mg/kg bw florfenicol in rainbow ftout at 10 C for 10 days showed that muscle/skin tissue contained 150 ppb drug at 15 days after the last dose (46). 

The presence of detectable levels in plasma and urine of treated cows indicates that nafcillin is absorbed systematically following intramammary administration. The major part of nafcillin is excreted in the milk, but a higher proportion of nafcillin is absorbed from the udder when nafcillin is administered at drying off. Residue depletion studies (70) with lactating cows showed that residues in all edible tissues were below 300 ppb at 72 h after cessation of treatment, while residues in milk were below 30 ppb from the fourth milking onwards, after cessation of the treatment. 

Residue depletion studies in dairy cows following intramuscular administration of 8.5 mg benzathine cephapirin/kg bw showed that residue levels in kidney, muscle, and liver were 1-5 ppm, less than 0.008-0.024 ppm, and less than 0.045 ppm, respectively, at 4.5 h postdosing (73). After intramuscular administration of 10 mg/kg bw sodium cephapirin to lactating cows, residue levels of 0.03-0.11 ppm were present in milk at 1-4 h, whereas 0.01 ppm were found from 4-8 h postdosing. In piglets, after intramuscular treatment witlr 20 mg/kg bw sodium cephapirin, residues could not be detected in liver, kidney, spleen, lung, and muscle at 24-120 h after treatment. 

Residue depletion studies in pigs after intramuscular administration of ceftiofur showed total residue concentrations of 590, 1190, 250, 400, and 1320 ppb in liver, kidney, muscle, skin/fat, and injection site, respectively, at 12 h after dosing. In cattle, intramuscular administration of radiolabeled ceftiofur resulted in total residue concentrations of 1294, 250, 60, and 60 ppb equivalents in liver 3508, 853, 159, and 159 ppb equivalents in kidney 208, 20, 10, and 10 ppb... 

Residue depletion studies (87) after intramammary administration of cefquinome to lactating cows showed that residues in edible tissues could be detected only in kidney at 24 h posttreatment and at concentrations below 200 ppb. High concentrations of cefquinome were found in milk at the first milking posttreatment, while at the 10th milking the residue concentrations in all milk samples were below 20 ppb. 

Residue depletion studies in pigs given intramuscularly the recommended treatment regimen showed that injection sites contained up to 208 ppb cefquinome 24 h after the last injection, declining to no measurable amounts at 144 h. Kidney contained 88-293 ppb at 24 h, but no measurable residues at 48, 72, and 120 h after the treatment. Liver, fat, skin, and muscle excluding the injection site were not found to contain detectable cefquinome up to 72 h after treatment. 

The main excretion pathway is through the urine in both calves and swine. Residue depletion studies did not showed detectable ( 0.01 ppm) residues in calves treated orally with 8 mg clavulanic acid-ampicillin formulation/kg bw for 3 days and slaughtered after 3 days or in calves, pigs, and sheep treated intramuscularly with 1.75 mg/kg bw for 5 days and slaughtered after 10, 7, and 14 days, respectively. 

Residue depletion studies in pigs fed 330 mg kitasamycin/kg feed for 14 days showed that at zero withdrawal only liver (100 ppb) and kidney (60 ppb) contained detectable residues. One day after withdrawal of the treatment, residual antibiotic activity was detectable only in the liver. Residue depletion studies in chickens fed 500 mg kitasamycin/kg feed for 14 days showed that at zero withdrawal only liver (70 ppb) contained detectable residues. One day after withdrawal, residual antibiotic activity could not be detected in any tissue. 

Residue depletion studies in chickens showed that 1 day after the end of treatment tire concentrations of the microbiologically active residues in liver, kidney, and fat/skin were490,240, and 330-41,810 ppb, respectively. Eggs from laying hens similarly treated contained residues ranged from less than 100 ppb to 450 ppb during treatment and at 3 days after treatment. 

Residue depletion studies in pigs showed that 2 days after the end of treatment the concentrations of microbiologically active residues in muscle, fat, skin, and kidney were from less than 100 ppb to 190 ppb, 4100 ppb, 780 ppb, and from less than 100 ppb to 1660 ppb, respectively. 

Residue depletion studies with radiolabeled furazolidone have shown that the almost complete degradation of the drug in the body resulted in formation of a variety of protein-bound metabolites that were not solvent-extractable. Thus, when pigs were given radiolabeled furazolidone orally at 16.5 mg/kg bw/day for 14 days (123), total residual radioactivity in liver, kidney, muscle, and fat accounted for 41.1 ppm, 34.4 ppm, 13.2 ppm, and 6.2 ppm furazolidone equivalents, respectively, at zero withdrawal (132). Total residues were substantially lower by 21 days withdrawal, but were still in the ppm range at 45 days withdrawal. Extraction of the incurred muscle tissue at 0 and 45 days withdrawal with organic solvents led to removal of 21.8 and 13.7% of the total radioactivity, respectively. In contrast, 44 and 8.3% of the total radioactivity was extracted from liver on days 0 and 45, respectively. 

This nonextractable radioactivity was probably the result of covalent binding of the furazolidone intermediates to endogenous macromolecules. The bioavailability of these bound tissue residues from the above pig residue depletion study was determined by feeding rats lyophilized samples of liver and muscle tissues from animals sacrificed at 0 and 45 days after the last treatment (132). Results showed that the fraction of the bound residues bioavailable to rats was in the range 16-41%. The toxicological impact of these bioavailable bound residues has not been yet determined. 

Residue depletion studies in chickens showed that residues of danofloxacin in muscle declined from 36-90 ppb at 6 h to less than 25 ppb at 18 h after withdrawal of treatment. Residues of the A-desmethyl metabolite were less than 25 ppb at all time points. Residues of danofloxacin in liver declined from 157-319 ppb at 6 h to 18-66 ppb at 36 h after withdrawal of treatment. Residues of the A-desmethyl metabolite were 35-193 ppb and less than 10 ppb over the same time points. 

In a residue depletion study in cattle given the normal therapeutic treatment, residues of danofloxacin in liver declined from 372 ppb at 12 h after the last dose to 13 ppb at 5 days after the last dose. Over the same time period, residues at the injection site, kidney, and muscle declined from 669 ppb to less than 10 ppb, from 426 ppb to 5 ppb, and from 112 ppb to less than 10 ppb, respectively. Residues in most fat samples were below 10 ppb. 

Residue depletion studies in pigs given three daily intramuscular injections of 1.25 mg danofloxacin/kg bw showed that residues of the parent drug in liver were 27 ppb at 2 days after the last dose and below 10 ppb at later time points. Mean danofloxacin concentrations in kidney declined from 36 ppb at 2 days after the last dose to 5.5 ppb at 6 days after the last dose and to below 5 ppb at later time points. Two days after the last dose, mean danofloxacin concentrations in muscle, fat, and at the injection site were 15 ppb, below 5 ppb, and 17 ppb, respectively at later time points residues could not be detected. Residues of A-... 

Residue depletion studies in chickens and turkeys orally dosed with 10 mg enrofloxacin/kg bw for 7 days showed that the sum of enrofloxacin and ciprofloxacin, which has been designated as the market residue for regulatory purposes, in the chicken liver declined from 42 ppb at 3 day withdrawal to 11 ppb at 15 day withdrawal in turkeys, the level of the marker residue in liver... 

When pigs and calves were subcutaneously given marbofloxacin, residues persisted in liver and kidney for up to 4 days posttreatment. Almost all of the residues detected in muscle and fat were due to the parent drug, whereas residues in liver and kidney were also due to drug-related metabolites as well. Residue depletion studies in dairy cows similarly treated showed that a proportion of 73-89% of the total residues in the milk was due to the parent marbofloxacin. 

Baquiloprim residue depletion studies in cattle treated by oral and parenteral route and in swine treated by parenteral route showed that 14-42 days after administration, the parent compound amounted to a very small proportion of the total residues in liver, kidney, and at the injection site. This was also the case with all identified metabolites. The concentrations of the residues in fat and normal muscle were too low to permit examination of their presence. However, pig skin contained a relatively high proportion of the parent compound. Pigs generally showed a faster degradation and elimination profile than cattle at comparable times after administration, resulting in lower total and parent drug residue levels. 

Residue depletion studies in cattle, swine, sheep, chickens, and turkeys given oral forms of oxytetracycline including feed premixes, soluble powders, and tablets showed that residues in all edible tissues, with the exception of kidney, were cleared of detectable amounts of oxytetracycline within 5 days postdose. Injectable forms of oxytetracycline yielded higher residue levels that persisted longer than the oral forms, while long-acting formulations of oxytetracycline required extended withdrawal periods (234). 

From residue data with pigs, poultry, and cattle after oral administration, and with cattle after intravenous administration, it appears that the distribution profde of doxycycline in these animals is roughly comparable to that of oxytetracycline. Highest residue concentrations are found in kidney, followed by liver, skin, fat, and muscle. Tissue depletion studies in pigs treated intramuscularly with doxycycline at a 10 mg/kg bw dose for 4 days showed that the parent compound was absorbed and efficiently distributed in tissues (252). The concentrations of doxycycline detected in lung, muscle, liver, and kidney tissues at day 6 after treatment were 0.067, 0.047, 0.18, and 0.47 ppb, respectively detectable doxycycline residues were not present in fat at that withdrawal time. 

Residue depletion studies of rifaximin in lactating cows or in cows at drying off showed that the drug could not be detected (detection limit, 0.01 ppm) in plasma or milk following intramammary treatment. Oral or topical administration of rifaximin also led to a negligible systemic absorption of the active ingredient. 

Following therapeutic treatment, thiophanate residues are higher in liver, with significant levels also being present in kidney relatively lower concentrations are detected in the other edible tissues (9). Residue depletion studies in sheep given a single oral dose of 100 mg thiophanate/kg bw showed that the mean thiophanate residue concentrations in liver, kidney, muscle, and fat were 930, 1,060, 670, and 2930 ppb, respectively, after 1 day, and below 100 ppb on days 3 and 7 after dosing. 

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