Drugs In Guinea Pigs Research Articles

Pharmacokinetics and absolute oral bioavailability of meloxicam in guinea pigs (Cavia porcellus)

ObjectiveTo investigate the pharmacokinetics and absolute oral bioavailability of meloxicam in guinea pigs. Study designProspective crossover study. AnimalsA group of six healthy male Dunkin Hartley guinea pigs. MethodsA single dose of meloxicam (1.5 mg kg−1) was administered orally and intravenously (IV) to six healthy male guinea pigs. A wash-out period of 48 hours was taken into account between administrations (oral and IV) in the same animal. Blood was sampled through a central venous catheter before administration (t = 0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 and 28 hours post administration. After centrifugation, plasma concentrations of meloxicam were measured by high-performance liquid chromatography with UV detection, and pharmacokinetic parameters were calculated using noncompartmental analysis. ResultsMeloxicam in guinea pigs exhibited a moderate absorption rate after oral dosing (time to maximal plasma concentration 3.7 ± 1.7 hours) and maximal plasma concentration was 0.92 ± 0.30 μg mL−1. After IV administration, total body clearance and volume of distribution were 0.13 ± 0.04 and 0.72 ± 0.36 L kg−1, respectively. Terminal half-life was 3.7 ± 0.7 hours and 3.5 ± 1.1 hours after IV and oral administration, respectively. Body extraction ratio was 0.0087 and mean absorption time was 3.8 ± 1.7 hours. The absolute oral bioavailability was 0.54 ± 0.14 in unfasted guinea pigs. Conclusions and clinical relevanceThis study reported the pharmacokinetics of meloxicam in guinea pigs. Studies concerning efficacy and safety are the next step towards a rational use of this drug in guinea pigs.

Comparison of ototoxicity among four kinds of anticancer platinum drugs in guinea pigs

Comparison of ototoxicity among four kinds of anticancer platinum drugs in guinea pigs

Effects of KATP openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs

Abstract Objectives This work evaluated the potential usefulness of pharmacological activation of cardiac ATP-sensitive potassium channels (KATP) in the prevention of drug-induced QT prolongation in anaesthetised guinea-pigs. Prolongation of cardiac repolarisation and QT interval is an adverse effect of many drugs blocking HERG potassium channels. This alteration can be dangerously arrhythmogenic and has been associated with the development of a particular form of ventricular tachyarrhythmia known as torsade de pointes. Methods The well-known KATP openers aprikalim, cromakalim and pinacidil were used. Moreover, three benzothiazine derivatives, which have been reported as potent activators of KATP channels, were also used. Key findings Pharmacological activation of KATP channels caused a reduction of the QT prolongation, induced by astemizole, cisapride, quinidine and thioridazine. In contrast, the QT prolongation induced by haloperidol, sotalol and terfenadine, which are known to block HERG channels but also KATP channels, was not influenced by KATP activation. Glibenclamide and tolbutamide (non-selective blockers of KATP channels expressed both in sarcolemmal and in mitochondrial membranes) antagonised the effects of KATP openers, whereas 5-hydroxydecanoic acid (selective blocker of the mitochondrial KATP channels) failed to antagonise the effects of KATP openers, indicating that only the sarcolemmal KATP is involved in the cardioprotective activity. Conclusions The data suggest that pharmacological KATP activation might represent an option for treatment of patients exposed to QT-prolonging drugs.

Treatment of External Wounds by Using Indigenous Medicinal Plants and Patent Drugs in Guinea Pigs

Treatment of External Wounds by Using Indigenous Medicinal Plants and Patent Drugs in Guinea Pigs

Corticosteroid dermal delivery with skin-lipid liposomes

Skin-lipid liposomes were prepared to improve corticosteroid dermal delivery and hence, their therapeutic effectiveness. Skin-lipid liposome formulations, and for comparison also phospholipid based liposomes, were prepared by hydrating a thin lipid film followed by extrusion through polycarbonate filters. The liposomes obtained were unilamellar vesicles with a mean size of 100 nm and a narrow size distribution. The steroidal anti-inflammatory drugs selected were situated in the bilayer structures of the vesicles. Skin-lipid liposomes provided the highest drug disposition within the deeper skin layers, i.e. in the epidermis and dermis. The therapeutic effectiveness was evaluated by measurement of the blanching effect following UV-induced erythema. Skin-lipid liposomes showed a 6 and 1.3 times higher blanching effect than that obtained with a control formulation ointment and the phospholipid-based liposome formulation, respectively. Skin-lipid liposomes also produced a reduction in drug levels in the blood and urine. These findings were supported by the body distribution of the drugs in guinea pigs after topical treatment. In particular, skin-lipid liposomes provided a corticosteroid uptake in the thalamic region (site of corticosteroid collateral effects) 5.1 times lower than the control formulation. Skin-lipid liposomes appeared to be a suitable corticosteroid delivery system, increasing the pharmacological effectiveness and reducing possible side effects.

Enhancement of the opiate withdrawal response by antipsychotic drugs in guinea-pigs is not mediated by sigma binding sites

Haloperidol, a ‘typical’ neuroleptic, with affinity for both dopamine (DA) receptors and σ binding sites, exacerbates morphine withdrawal in guinea-pigs. In this study, the effects of σ ligands (+)- and (−)-SKF 10,047 (1 and 10 mg/kg s.c.), pentazocine (20 mg/kg s.c.) and DTG (1 and 10 mg/kg s.c.), non-competitive NMDA antagonists ketamine hydrochloride (20 mg/kg s.c.) and MK-801 (0.025, 0.1 and 1 mg/kg s.c.), ‘atypical’ neuroleptic drugs with (remoxipride 25 mg/kg s.c.) and without (raclopride 10 mg/kg s.c.; clozapine 25 mg/kg s.c.) affinity for σ sites, and atropine sulphate (20 mg/kg s.c.), were investigated on the opiate withdrawal response induced by naloxone hydrochloride (15 mg/kg s.c.) in guinea-pigs treated 2 h before with a single dose of morphine sulphate (15 mg/kg s.c.). (+)- and (−)-SKF 10,047, pentazocine, ketamine and MK-801, given 0.5 h before naloxone, significantly attenuated the increased locomotor activity and other behaviours associated with morphine withdrawal in guinea-pigs. The selective σ ligand DTG, and remoxipride had no effect on the withdrawal response but raclopride, clozapine, and atropine exacerbated the response. It is concluded that exacerbation of the morphine withdrawal response by neuroleptics is not related to σ activity but to other mechanisms. Furthermore NMDA but not σ mechanisms might play a role in the morphine withdrawal response.

Effects of aminoglycoside antibiotics on the auditory brainstem response and post rotatory nystagmus in rats

Effects of three aminoglycoside antibiotics, amikacin (AMK), tobramycin (TOB), and gentamicin (GM), on the auditory and vestibular functions were assessed in rats, the most frequently used species in toxicity studies. Chronic electrodes for auditory brainstem response (ABR) recording were implanted on the epidural surface, and those for post rotatory nystagmus (PRN) were implanted at the nictitating membrane and the outer canthus. AMK, TOB, and GM were given intramuscularly twice daily for 3–4 weeks at a daily dose of 350, 150, and 100 mg/kg, respectively. The amplitude of each wave of the ABR was decreased or disappeared in the groups treated with AMK, TOB, and GM. In the PRN, the duration of the nystagmus was decreased in the TOB group and completely lost in the GM group. No abnormality was observed in the PRN in the AMK group. These results were similar to those reported in the ototoxicity studies of these drugs in guinea pigs and indicate that ototoxicity can be evaluated in rats as successfully as in guinea pigs by this procedure.

Drug-specific immune responses induced by procainamide, hydralazine and isoniazid in guinea-pigs

The drug-induced graft vs host reaction (GVHR) hypothesis requires, as the first step, specific T-cell immune responses to the drug-modified self. Procainamide, isoniazid and hydralazine are known to provoke various allergic reactions including GVHR-like adverse effects in man. We now report that drug-specific immune responses can easily be included by these drugs in guinea-pigs. Twenty-five milligrams of each of these drugs and penicillin G, which is known to make covalent bonds with proteins and to also induce drug-specific immune responses, were mixed complete Freund's (CFA) and subcutaneously (s.c.) injected twice at an interval of 2 weeks into female Hartley guinea-pigs. The antibodies to these drugs were assessed by means of an enzyme-linked immunosorbent assay (ELISA). Two weeks after the last injection, all animals treated with isoniazid, hydralazine and penicillin G produced high titers of antibodies to these drugs. Antibodies to procainamide were also detected, although their antibody titers were low. The specificity of the antibodies produced were tested by the inhibition of ELISA and concentration-dependent inhibition was observed. Delayed type hypersensitivity (DTH) reactions were also observed in the animals treated with procainamide, isoniazed and hydralazine 2 weeks after the last injection. The results suggest that the allergic reactions observed in clinical use ate related to the inducing potential of drug-specific immune responses in an animal system. therefore, immunization of guinea-pigs with test drugs and CFA may give useful information for predicting the occurence of allergic reactions in man.

Effects of Aminoglycoside Antibiotics on the Auditory Brainstem Response and Post Rotatory Nystagmus in Rats

Effects of three aminoglycoside antibiotics, amikacin (AMIK), tobramycin (TOB), and gentamicin (GM), on the auditory and vestibular functions were assessed in rats, the most frequently used species in toxicity studies. Chronic electrodes for auditory brainstem response (ABR) recording were implanted on the epidural surface, and those for post rotatory nystagmus (PRN) were implanted at the nictitating membrane and the outer canthus. AMK, TOB, and GM were given intramuscularly twice daily for 3–4 weeks at a daily dose of 350, 150, and 100 mg/kg, respectively. The amplitude of each wave of the ABR was decreased or disappeared in the groups treated with AMK, TOB, and GM. In the PRN, the duration of the nystagmus was decreased in the TOB group and completely lost in the GM group. No abnormality was observed in the PRN in the AMK group. These results were similar to those reported in the ototoxicity studies of these drugs in guinea pigs and indicate that ototoxicity can be evaluated in rats as successfully as in guinea pigs by this procedure.

Drug-specific immune responses induced by immunization with drugs in guinea pigs and mice.

In order to develop a system for evaluating the allergenicity of drugs in clinical use, we tested drugs for the ability to induce drug-specific immune responses in guinea pigs and mice. Test drugs were benzylpenicillin, procainamide, hydralazine, isoniazid, alpha-methyldopa, D-penicillamine, captopril, sulfamethoxazole and 2,4-dinitrochlorobenzene (DNCB), which are known to induce allergic responses in man including hypersensitivity reactions and drug-induced auto-immune responses. Guinea pigs were immunized with an emulsion of complete Freund's adjuvant (CFA) and 25 mg of each drug. Mice were immunized with an emulsion of CFA and 2 mg of each drug or a mixture of aluminum hydroxide gel and 2 mg of each drug. In order to examine drug-specific immune responses, we employed detection of antibodies by enzyme-linked immunosorbent assay (ELISA) and passive cutaneous anaphylaxis tests, active systemic anaphylaxis (ASA) tests and delayed type hypersensitivity (DTH) tests. In guinea pigs, drug-specific antibodies were detected following immunization with benzylpenicillin, procainamide, hydralazine, isoniazid, captopril, sulfamethoxazole or DNCB. Some of these drugs were also positive in DTH tests and/or ASA tests. In mice, however, only DNCB gave positive results. Therefore, our system involving immunization of guinea pigs with CFA emulsion of a drug and detection of drug-specific immune responses is considered to be an effective test method for evaluating drug allergenicity.

Generalized Rash Induced by Sulfhydryl Drug in Guinea Pigs

Adverse reactions produced by sulfhydryl compounds with active thiol groups have generally formed a distinctive pattern in man when they are viewed as a class. It has been reported that cutaneous SH-induced drug eruptions have a wide variety of clinical presentations; histologically, they show a pattern of eosinophilic necrosis and/or satellite necrosis similar to that seen in cutaneous graft vs host reactions. In the present experiments, guinea pigs were sensitized with cephalothin (CET) and thiol compounds such as tiopronin (TP), D-penicillamine, gold sodium thiomalate or thiomalate, using a method similar to that described previously. In lymphocyte stimulation tests, lymph node cells from the sensitized animals responded positively to spleen cells pulsed with each thiol compound. Intracutaneous tests revealed some positive reactions to each thiol compound; there was a tendency to produce a tuberculin type reaction with indurated erythema rather than the Jones-Mote type seen in CET-induced reactions. The dose-requirements for positive intracutaneous tests and generalized rash (GR) due to thiol compounds were lower than for CET, which required relatively large doses. Histologically, infiltration of basophilic cells was prominent in the skin lesions induced by intracutaneous tests with CET and in those of CET-induced GR. On the other hand, intracutaneous tests with TP following the induction of TP-induced GR revealed eosinophilic degeneration of epidermal cells, which was similar to the eosinophilic necrosis seen in cutaneous GVHR. Intracutaneous tests after the induction of CET-GR did not show any eosinophilic changes in the epidermal cells. These findings are reminiscent of the characteristics of eruptions induced by thiol compounds in man, which differ from the eruptions induced by CET.

Metabolism of an antiallergic Agent, 1-(2-Ethoxyethyl)-2-(hexahydro-4-methyl-1<I>H</I>-1, 4-diazepin-1-yl)-1<I>H</I>-benzimidazole Difumarate (KG-2413), in Rats and Guinea Pigs

The metabolism of an antiallergic agent, 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1, 4-diazepin-1-yl)-1H-benzimidazole difumarate (KG-2413), was studied in rats and guinea pigs after oral administration of the 14C labelled compound.KG-2413 and its metabolites in the urine, bile, plasma and liver of rats were quantified. The major metabolites of KG-2413 in rats were 5-hydroxylated compound (M 5 b), 6-hydroxylated compound (M 5 a) and their conjugated metabolites. Tracer concentration of the unchanged drug was found, so it was assumed that KG-2413 was rapidly metabolized in rats.The urinary metabolites in guinea pigs were also quantified. The major metabolite was N-oxide compound (M9), and M 5 a and M 5 b were present mostly as conjugated metabolites, but the amounts of them were about one sixth of M9. The urinary excretion of the unchanged drug in guinea pigs was higher than that in rats.There were remarkable interspecies differences in the urinary excretion of the metabolites after oral administration of KG-2413.

Specific Suppression of Delayed Hypersensitivity: The Possible Presence of a Suppressor B Cell in the Regulation of Delayed Hypersensitivity

Abstract Delayed hypersensitivity to purified protein antigens in incomplete Freund's adjuvant is of a transient nature in guinea pigs. This decrease in delayed reactivity can be transferred adoptively to a sensitized recipient with lymphoid cells from the spleens and peritoneal exudate of donors 8 days after sensitization with ovalbumin. When such mixtures of donor lymphoid cells are adoptively transferred at subsequent times after sensitization, the delayed hypersensitivity of the recipient is not suppressed. When a hapten-protein conjugate, such as para-aminobenzoic acid-azo-hen egg albumin is used as a sensitizing antigen in the donor, and when the donor cells are removed at various time intervals after the decline in delayed skin tests to the carrier protein as antigen, such as 10 to 23 days after sensitization, adoptive transfer of lymphoid cells into sensitized recipients suppresses the elicitation of delayed skin hypersensitivity to the carrier. When spleen cells are compared with peritoneal exudate (PE) cells in their suppressive capacities, only the spleen cells show suppressive action. The duration of delayed responses varied inversely with the dose of the immunosuppressive drug in guinea pigs treated with varying doses of cyclophosphamide 72 hr before sensitization. In view of the observations that PE cells are an enriched source of T cells and that the particular schedule of treatment with cyclophosphamide affects rapidly dividing cells, the suggestion is made that a suppressor B cell may regulate the activity of a T cell in the expression of delayed skin hypersensitivity.

On the action and kinetics of propylthiouracil

Goitres were produced in guinea pigs by administering propylthiouracil (PTU) dissolved in drinking water. It was found that a diurnal pattern of blockade of hormone synthesis and relief from such blockade developed. Evidence presented for thyroid blockade are gland weights of 500 mg or more; for relief from block, high uptake in vitro of 125I −1, formation in vitro of thyroid hormones, and great sensitivity to thyrotropic hormone (TSH). Methods for estimating PTU are described which permit studies of the kinetics of this drug in guinea pigs and mice. Guinea pigs do not develop tolerance to PTU. The t 1 2 for a single oral dose was 7.5 ± 1.5 hr; after 3 months of daily intake of PTU, another t 1 2 estimate gave 6.2 ± 1.3 hr. In mice, at least two phases (0.5 and 2.7 hr) in the disappearance of i.v. PTU were found. Several unidentified metabolites could be shown in guinea-pig tissues. The ratio of the radioactivities of bile and serum after a single oral dose of 35S-PTU was greater than 10 : 1. As bile did not contain any unchanged PTU, guinea-pig liver appears to metabolize PTU rapidly.

Depression of Parasitemia in Trypanosoma lewisi Infection of Rats Injected with 6-Mercaptopurine

Daily intramuscular doses of 6-mercaptopurine (6-MP) were administered to rats at levels of 0.15, 0.30, 0.60, 0.90, 1.20, and 1.50 mg/100 g rat body weight. The animals were inoculated with Trypanosoma lewisi on the day after the first drug injection, the same day as the first drug injection but 4 hr afterward, or the day of the eighth injection. Depression of both the density and duration of the parasitemia resulted. With a dosage of only 0.10 mg of the drug no effect was observed. It appeared that the reduction in trypanosome population of the blood was effected without interfering significantly with reproduction of the trypanosomes. Depression of the parasitemia was achieved instead of the enhancement that had been considered possible. After heavy challenging injections of the parasite in the reproductive phase, reinfection succeeded with 11 of 38 surviving rats previously subjected to dosages of 0.30 to 1.50 mg of 6-MP. Reinfection did not occur in the case of other recovered rats, either those receiving smaller dosages of the drug or the untreated controls. Prevention of the formation of antibodies by rabbits repeatedly injected with crystalline bovine albumin and simultaneously with the purine analog, 6-mercaptopurine (6-MP),1 was demonstrated by Schwartz, Stack, and Dameschek (1958). (See also Schwartz, Eisner, and Dameschek, 1959, and Goh, Miller, and Diamond, 1961). Genghof and Battisto (1961), however, reported no suppressive action with the same drug in guinea pigs. Lack of agreement among reports of attempts to achieve with viable pathogenic microorganisms induced Festenstein and Bokkenheuser (1961) to study further the possibility of bringing about immunological tolerance to this type of antigen; however, they did not succeed in producing to Treponema pallidum in experimental infections in rabbits born of syphilitic does, nor in others infected with T. pallidum at birth. Parasitemia of infection with Trypanosoma lewisi in rats has been altered by administrations of salicylic acid (Becker and Gallagher, 1947). Since prolongment of the reproductive phase of the trypanosome and suppression of the antibody ablastin occurred in this process Received for publication 17 March 1962. * Supported in part by Research Grant E-4170, National Institutes of Health, to Maricopa County Health Department, Phoenix 34, Arizona. California Corp. for Biochemical Research, Los Angeles, Calif., and Burroughs Wellcome & Co., Tuckahoe, N. Y. (see Lysenko, 1951), comparison of possible effects of 6-MP in the same infection was indicated. Sc wartz et al. (1958, 1959) and Goh et al. (1961) commenced administration of the drug on the 1st day of antigen injection (Day 0) and continued it for 13 additional days. Our regimens, described below, were also deigned to test for increasing or decreasing susceptibility during treatment, and for residual susceptibility to reinfection after termination of parasitemia. MATERIALS AND METHODS Daily intramuscular inoculations of 6-MP in the dosages described below were administered over 14-day periods, and were through the ventral surfaces of the thighs, alternating right and left. Normal sodium hydroxide was added to preweighed samples of 6-MP each day and dilutions made with normal saline to obtain the required concentrations (see Schwartz et al., 1958). Control groups of rats were given injections of sodium hydroxide diluted with normal saline to the same concentration (0.006 N) as that used for the test groups receiving the 6-MP. During the study, daily doses of 0.10, 0.15, 0.30, 0.60, 0.90, 1.20, and 1.50 mg/100 g body weight were given to groups of rats receiving the drug. The final dilution of sodium hydroxide was 0.013 N in the last experiment. The strain of T. lewisi was the one previously employed (see Becker, 1961a). The rats were young and mostly of the Sprague-Dawley strain. Approximate mean weights appear in table III. Our observations suggest that the infections studied were Bartonella-free, since these parasites were not observed in the rat erythrocytes. Inoculations were made intraperitoneally with diluted blood

Toxicologic and clinical appraisal of buclizine, a new antihistaminic compound

1. 1. Buclizine, 1-p-chlorbenzhydryl-4-p-tertiary butylbenzylpiperazine dihydrochloride, a new antihistaminic drug, was administered in seventy patients with allergic and related states, with the majority of these patients under observation for many months. 2. 2. Buclizine, taken orally in doses of 25 to 75 mg. daily for an average of four months, produced no significant abnormalities in the formed blood elements or in hepatic and renal function. 3. 3. In contrast to the prolonged activity of the drug in guinea pigs, the duration of action of comparable dosage in man in relatively short—a point deserving further study. 4. 4. The drug appeared to be effective is relieving the symptoms in the majority of patients with perennial allergic rhinitis, vasomotor rhinitis, and urticaria.

The Use of Sulfanilamide in Experimental Brucellosis

During the past few years the literature on the therapeutic effect of sulfanilamide and its derivatives has grown to large proportions and both clinical and experimental results have demonstrated the value of sulfanilamide in certain infectious diseases particularly those due to some members of the Coccaceae. Long and Bliss1 carried out extensive studies in this field and, in a recent series of publications, adequately reviewed the literature. Among the diseases investigated for possible treatment with sulfanilamide, Brucella infections have received comparatively little attention. Until the recent introduction of sulfanilamide in the treatment of human Brucellosis no successful therapeutic methods had been available. Reports2 from Europe and America have indicated that sulfanilamide treatment has given successful results in human infections due to Br. melitensis and Br. abortus. Twenty-one cases have been reported in the literature all of which responded rapidly to treatment and recovered with no relapses. Only a few reports have been made on the sulfanilamide treatment of Brucella infections in experimental animals. The author3 reported the prophylactic effect of sulfanilamide following experimental infections of guinea pigs with Br. abortus and Br. suis. Welch, Wentworth and Mickle4 have demonstrated that sulfanilamide produces a marked increase in opsonocytophagic activity in Brucella infected guinea pigs. The present report deals with the effect of sulfanilamide on Br. melitensis, Br. abortus and Br. suis in vitro and the prophylactic and therapeutic effect of this drug in guinea pigs experimentally infected with Brucella. In these experiments old stock strains and also recently isolated strains of Brucella were used. The latter were kindly supplied by Dr. I. F. Huddleson of the Michigan State College of Agriculture. All the strains were pathogenic for guinea pigs.