Long-term Low-dose Administration Research Articles

Development of a droplet digital PCR assay to detect illicit glucocorticoid administration in bovine.

Glucocorticoids are often used illegally in food-producing animals for the growth promotion of livestock animals. In accordance to official chemical methods for glucocorticoid detection, an animal is declared as non-compliant when a residue is identified in the sample. Neverthless, growth promoting molecules can often escape identification due to their rapid elimination or due to the use of non-detectable new generation drugs. Therefore, an indirect screening method able to detect the biological effect of long-term administration of low doses of dexamethasone and prednisolone on livestock has been developed to support official methods. As already described, FKBP5 (FKBP prolyl isomerase 5) expression in bovine thymus is regulated by glucocorticoids, and this specific regulation can be exploited in an indirect screening assay. In the present study, male veal calves and young bulls were considered in three different trials in which estradiol, dexamethasone, and prednisolone were administered alone or in combination with Revalor-200 subcutaneous pellets. Thoracic thymus was sampled from all animals and molecular analysis was performed. A duplex droplet digital PCR assay with EvaGreen® was employed to detect the target gene expression using absolute quantification. The developed droplet digital PCR assay was precise, showing intra- and inter-assay mean coefficient of variation values of about 6.16% and 3.17%, respectively. It was also highly specific (100%) with Youden’s index of 76.92% and 53.57% applied to veal calves and young bulls, respectively. The lowest detection limit in which the target gene expression level was kept constant, was 0.05 ng/μl of cDNA with 1 copies/μL and 0.5 copies/μL for target and reference gene, respectively. This study establishes the basis for using a digital PCR-based assay as an efficient test to identify animals illegally treated with glucocorticoids.

The partial \xb5-opioid agonist buprenorphine in autism spectrum disorder: a case report

BackgroundThere are currently no approved medications for impaired social cognition and function, core symptoms of autism spectrum disorder. We describe marked improvement of these symptoms with long-term low-dose administration of the partial µ-opioid agonist buprenorphine. We discuss these observations in the context of a role for endogenous opioid systems in social attachment, and theories integrating those findings mechanistically with autism spectrum disorder.Case presentationM, a 43-year-old Caucasian male, is medically healthy. Despite social difficulties since childhood, he completed high school with better-than-average grades, but failed university education. A psychiatric evaluation in his twenties diagnosed attention deficit hyperactivity disorder but also noted symptoms of coexisting autism spectrum disorder. M accidentally came across buprenorphine in his late twenties and experienced progressively improved social functioning on a low daily dosage (0.5–1.0 mg/day), an effect maintained for 15 years. He lived independently and maintained a part-time occupation. After abrupt discontinuation of treatment, his autistic symptoms returned, and function deteriorated. Following evaluation by our team, buprenorphine was resumed, with gradual return to prior level of functioning. An attempt to formally evaluate M both on and off medication was agreed with him and approved by the Swedish Ethics Authority, but medication had to be resumed when the patient worsened following discontinuation.ConclusionsAccording to the µ-opioid receptor balance model, both excessive and deficient μ-receptor activity may negatively influence social behavior, and accordingly both opioid agonist and opioid antagonist treatment may be able to improve social functioning, depending on an individual’s opioid tone before treatment. Our case report is consistent with these hypotheses, and given the extensive unmet medical needs in individuals with autism spectrum disorders, randomized controlled trial appears warranted.

Metronomická terapie v léčbě nádorových onemocnění

Metronomic therapy is a therapeutic method in selected oncological diseases, using long-term administration of low doses of drugs with direct or indirect antitumor effect. In addition, to direct cytotoxic eradication of tumor cells, metronomic therapy can very strongly affect the tumor microenvironment; it also has an immunomodulatory and antiangiogenic effect. Its minimal toxic profile allows for use in patients with severe organ dysfunctions and directly impacts the quality of life and social inclusion of oncological patients.

The Effect of Acute Oral Galactose Administration on the Redox System of the Rat Small Intestine.

Galactose is a ubiquitous monosaccharide with important yet incompletely understood nutritive and physiological roles. Chronic parenteral d-galactose administration is used for modeling aging-related pathophysiological processes in rodents due to its ability to induce oxidative stress (OS). Conversely, chronic oral d-galactose administration prevents and alleviates cognitive decline in a rat model of sporadic Alzheimer’s disease, indicating that galactose may exert beneficial health effects by acting in the gut. The present aim was to explore the acute time-response of intestinal redox homeostasis following oral administration of d-galactose. Male Wistar rats were euthanized at baseline (n = 6), 30 (n = 6), 60 (n = 6), and 120 (n = 6) minutes following orogastric administration of d-galactose (200 mg/kg). The overall reductive capacity, lipid peroxidation, the concentration of low-molecular-weight thiols (LMWT) and protein sulfhydryls (SH), the activity of Mn and Cu/Zn superoxide dismutases (SOD), reduced and oxidized fractions of nicotinamide adenine dinucleotide phosphates (NADPH/NADP), and the hydrogen peroxide dissociation rate were analyzed in duodenum and ileum. Acute oral administration of d-galactose increased the activity of SODs and decreased intestinal lipid peroxidation and nucleophilic substrates (LMWT, SH, NADPH), indicating activation of peroxidative damage defense pathways. The redox system of the small intestine can acutely tolerate even high luminal concentrations of galactose (0.55 M), and oral galactose treatment is associated with a reduction rather than the increment of the intestinal OS. The ability of oral d-galactose to modulate intestinal OS should be further explored in the context of intestinal barrier maintenance, and beneficial cognitive effects associated with long-term administration of low doses of d-galactose.

GATA4-targeted compound exhibits cardioprotective actions against doxorubicin-induced toxicity in vitro and in vivo: establishment of a chronic cardiotoxicity model using human iPSC-derived cardiomyocytes

Doxorubicin is a widely used anticancer drug that causes dose-related cardiotoxicity. The exact mechanisms of doxorubicin toxicity are still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose doxorubicin treatments. Here, we developed an in vitro model of long-term low-dose administration of doxorubicin utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Moreover, given that current strategies for prevention and management of doxorubicin-induced cardiotoxicity fail to prevent cancer patients developing heart failure, we also investigated whether the GATA4-targeted compound 3i-1000 has cardioprotective potential against doxorubicin toxicity both in vitro and in vivo. The final doxorubicin concentration used in the chronic toxicity model in vitro was chosen based on cell viability data evaluation. Exposure to doxorubicin at the concentrations of 1–3 µM markedly reduced (60%) hiPSC-CM viability already within 48 h, while a 14-day treatment with 100 nM doxorubicin concentration induced only a modest 26% reduction in hiPCS-CM viability. Doxorubicin treatment also decreased DNA content in hiPSC-CMs. Interestingly, the compound 3i-1000 attenuated doxorubicin-induced increase in pro-B-type natriuretic peptide (proBNP) expression and caspase-3/7 activation in hiPSC-CMs. Moreover, treatment with 3i-1000 for 2 weeks (30 mg/kg/day, i.p.) inhibited doxorubicin cardiotoxicity by restoring left ventricular ejection fraction and fractional shortening in chronic in vivo rat model. In conclusion, the results demonstrate that long-term exposure of hiPSC-CMs can be utilized as an in vitro model of delayed doxorubicin-induced toxicity and provide in vitro and in vivo evidence that targeting GATA4 may be an effective strategy to counteract doxorubicin-induced cardiotoxicity.

A mixture of routinely encountered xenobiotics induces both redox adaptations and perturbations in blood and tissues of rats after a long-term low-dose exposure regimen: The time and dose issue

Exposure of humans to xenobiotic mixtures is a continuous state during their everyday routine. However, the majority of toxicological studies assess the in vivo effects of individual substances rather than mixtures. Therefore, our main objective was to evaluate the impact of the 12- and 18-month exposure of rats to a mixture containing 13 pesticides, food, and life-style additives in three dosage levels (i.e. 0.0025 × NOAEL, 0.01 × NOAEL, and 0.05 × NOAEL), on redox biomarkers in blood and tissues. Our results indicate that the exposure to the mixture induces physiological adaptations by enhancing the blood antioxidant mechanism (i.e., increased glutathione, catalase and total antioxidant capacity and decreased protein carbonyls and TBARS) at 12 months of exposure. On the contrary, exposure to the 0.05 × NOAEL dose for 18 months induces significant perturbations in blood and tissue redox profile (i.e., increased carbonyls and TBARS). This study simulates a scenario of real-life risk exposure to mixtures of xenobiotics through a long-term low-dose administration regimen in rats. The results obtained could support, at least in part, the necessity of introducing testing of combined stimuli at reference doses and long term for the evaluation of the risk from exposure to chemicals.

Abstract 781: Doxorubicin-Induced Cardiotoxicity and Novel GATA4-Targeted Compounds

Doxorubicin (DOX) is a widely used anticancer drug which, unfortunately, induces dose-related cardiotoxicity. A deep understanding of DOX’s toxicity is still unclear, partly because most in vitro studies have evaluated the effects of short-term high-dose DOX treatments. Thus, a more precise model of DOX cardiotoxicity is needed to more accurately simulate clinical scenario. The first aim of this study was to establish an in vitro model of long-term low-dose administration of DOX utilizing human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The second aim was to investigate if novel GATA4-targeted compounds can protect CMs from DOX toxicity. Acute toxicity was studied in both primary neonatal rat ventricular cardiomyocytes (NRVCs) and hiPSC-CMs. The cells were exposed to 0.1-3 μM DOX for 48 h, after which the lactate dehydrogenase and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were carried out. To study long-term toxicity, hiPSC-CMs were exposed to 100 nM DOX for up to 14 days. MTT assay and high-content analysis were carried out after 4, 7 and 14-day exposures. The effect of the test compound was studied by exposing the cells simultaneously to DOX and the compound. A 48-hour exposure to DOX at 1 and 3 μM concentrations induced more than 62% reductions in both NRVC and hiPSC-CM viability, whereas a 14-day exposure to 100 nM DOX induced a 26% reduction in hiPSC-CM viability. A 4-day exposure to 100 nM DOX induced a 3.1-fold increase in the percentage of cells positive for pro-B-type natriuretic peptide (proBNP) compared to control. When the cells were exposed simultaneously to 100 nM DOX and the test compound (10 μM), the percentage of proBNP+ cells increased only 1.4-fold compared to control. However, over 14-day exposure the compound at 10 μM concentration reduced hiPSC-CM viability 50% compared to control. A long-term exposure of hiPSC-CMs can be utilized as an in vitro model to investigate the mechanisms of delayed DOX-induced cardiotoxicity. The GATA4-targeted test compound exhibited cardioprotective potential against subacute DOX toxicity. Over chronic exposure the compound was, however, toxic to CMs, indicating that further structural optimization is required to develop non-toxic derivatives.

HPLC-ESI-MS/MS assessment of the tetrahydro-metabolites of cortisol and cortisone in bovine urine: promising markers of dexamethasone and prednisolone treatment

ABSTRACTThe effects of long-term administration of low doses of dexamethasone (DX) and prednisolone (PL) on the metabolism of endogenous corticosteroids were investigated in veal calves. In addition to cortisol (F) and cortisone (E), whose interconversion is regulated by 11β-hydroxysteroid dehydrogenases (11βHSDs), special attention was paid to tetrahydrocortisol (THF), allo-tetrahydrocortisol (aTHF), tetrahydrocortisone (THE) and allo-tetrahydrocortisone (aTHE), which are produced from F and E by catalytic activity of 5α and 5β-reductases. A specifically developed HPLC-ESI-MS/MS method achieved the complete chromatographic separation of two pairs of diastereoisomers (THF/aTHF and THE/aTHE), which, with appropriate mass fragmentation patterns, provided an unambiguous conformation. The method was linear (r2 > 0.9905; 0.5–25 ng ml−1), with LOQQ of 0.5 ng ml−1. Recoveries were in range 75–114%, while matrix effects were minimal. The experimental study was carried out on three groups of male Friesian veal calves: group PL (n = 6, PL acetate 15 mg day–1 p.o. for 31 days); group DX (n = 5, 5 mg of estradiol (E2) i.m., weekly, and 0.4 mg day–1 of DX p.o. for 31 days) and a control group (n = 8). Urine was collected before, during (twice) and at the end of treatment. During PL administration, the tetrahydro-metabolite levels decreased gradually and remained low after the suspension of treatment. DX reduced urinary THF that persisted after the treatment, while THE levels decreased during the experiment, but rebounded substantially after the DX was withdrawn. Both DX and PL significantly interfered with the production of F and E, leading to their complete depletion. Taken together, the results demonstrate the influence of DX and PL administration on 11βHSD activity and their impact on dysfunction of the 5-reductase pathway. In conclusion, profiling tetrahydro-metabolites of F and E might serve as an alternative, indirect but reliable, non-invasive procedure for assessing the impact of synthetic glucocorticosteroids administration.

Changes in the subcellular and tissue location of estrogen and progesterone receptors in rat uterus after long-term treatment with analogs of gonadoliberin.

Certain therapies with the use of analogs of gonadotropin-releasing hormone (GnRH, gonadoliberin) aim at achieving the effect of desensitization of the pituitary gland that causes inhibition of the hypothalamic-pituitary-gonadal axis. The resulting hormonal changes may influence the location and expression of estrogen and progesterone receptors, as well as their endogenous functions. The aim of the study was to investigate whether long-term administration of low doses of dalarelin (GnRH agonist) and cetrorelix (GnRH antagonist) affected subcellular and tissue-specific location of ERalpha and ERbeta estrogen receptors and progesterone receptor (PR) in rat uterus, as well as explore the extent to which the changes were reversible. Analogs were administered to SPD adult females in the course of 3 months, at a dose of 6 microg/kg b.w. Afterwards, the ovaries and the uterus were resected--in the course of 4 weeks after treatment completion. Tissue paraffin-embedded samples were stained with hematoxyline-eosin for morphological studies or incubated with specific antibodies for the immunohistochemical studies (ABC method). GnRH analogs induced desensitization, resulting in specific and relatively persistent histological changes in the ovaries and the uterus. Strong nuclear reaction for ERalpha in the lining and the glandular epithelial cells in dalarelin-treated rats, and lack of expression changes in cetrorelix-treated rats, were observed in the uterus. Epithelial ERalpha expressions were accompanied by diminished ERbeta and elevated PR expression, as well as diminished ERalpha and ERbeta expression, and unchanged PR expression in the stromal and muscle cells, in both dalarelin- and cetrorelix-treated rats. The majority of the changes were reversible after treatment discontinuation. Long-term exposure to low doses of GnRH analogs causes morphological changes in the uterine tissues, accompanied by reversible changes of the ERalpha, ERbeta and PR expression, possibly influencing tissue sensitivity. These changes indicate that agonist and antagonist regulate ERalpha expression by means of different mechanisms. A functional interaction between the receptors, depending on ERbeta expression, direct influence of analogs on the local hormonal axes, and dose-dependent effects, cannot be excluded. After discontinuation of the analog treatment, the time needed for stabilization of ER and PR expression is shorter than the period of time required to restore histological structure of the uterus.

Long-term low-dose antibiotics in recalcitrant chronic rhinosinusitis: a retrospective analysis

In recalcitrant Chronic RhinoSinusitis (CRS) treatment with intranasal corticosteroids, short-term antibiotics and even sinus surgery is frequently insufficient. Long-term low-dose administration of antibiotics has been suggested as a treatment option in these patients. We analysed the outpatient clinic population treated with different long-term low-dose antibiotics at the AMC Amsterdam. Eligible patients, who were treated with trimethoprim-sulfamethoxazole or macrolides, were retrospectively identified from our outpatient clinic in 2009. The two main outcome measures were sinonasal complaints and nasal endoscopic findings. A 5-point grading scale was used to score the results compared with the pre-treatment situation. This was measured at several time-points during, and after the antibiotic course, and at the end of the follow-up term. Seventy-six patients were included, 53 per cent had asthma and all of them had undergone sinus surgery. Seventy-eight per cent showed improvement of the symptoms, and 84 per cent demonstrated improvement of the sinonasal mucosa at the end of the course. No significant difference was found between the trimethoprim-sulfamethoxazole and macrolide group. Long-term low-dose treatment with antibiotics seems to improve CRS symptoms and the appearance of the sinonasal mucosa on nasal endoscopy. However, at this stage, strong conclusions are immature because no placebo-group has been included. Despite increasing use of long-term low-dose treatment of recalcitrant CRS in referral centres, hard clinical evidence is lacking. More research is urgently required.

The effect of mercury on thyroid function in sheep

The purpose of this experiment was to determine the effect of long-term low-dose administration of mercury (Hg) on thyroid function in sheep. In this experiment, 10 clinically healthy, adult, male Iranian sheep, aged approximately 1 year, were randomly allocated into the control (n=5) and mercury (Hg-)-treated (n=5) groups. Both groups were kept under identical conditions in terms of food and environment. The treatment group received mercuric chloride (5 mg/kg/day) orally for eight weeks. Blood samples were drawn between the hours of 0800 and 0900 from both groups on days 0, 14, 28, 42, 56 and 70. Thyroid function was evaluated by measuring the levels of the serum thyroid hormones, including triiodothyronine (T3), thyroxine (T4), free T3 (FT3), free T4 (FT4) and thyroid-stimulating hormone (TSH). Hepatic function was evaluated in both groups by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), ?-glutamyltransferase (GGT) and total bilirubin (TBIL). Renal function was assessed using serum creatinine (Cr) and blood urea nitrogen (BUN) levels. Serum T3 (from day 28 onwards) and serum T4, FT3, FT4 and TSH (from day 14 onwards) decreased in the Hg-treated group (p

Long-term administration of aspirin inhibits tumour formation and triggers anti-neoplastic molecular changes in a pre-clinical model of colon carcinogenesis

Despite numerous studies aimed at verifying the anti-tumour activity of aspirin on colon carcinogenesis little is known on the molecular targets involved in the anti-carcinogenic properties of this drug. We investigated the long-term administration of low dose of aspirin in a model of experimental colon carcinogenesis in rats. Adult Wistar rats received an intraperitoneal injection of azoxymethane (AOM) once a week for two weeks in order to initiate colon carcinogenesis. One week after AOM injection, rats received daily 0.01% aspirin (6 mg/kg body weight) in drinking water for 10 months. Compared to AOM control rats, aspirin treatment for 10 months caused a 50% reduction of the number of aberrant crypt foci associated with a 50% reduction of prostaglandin E2 (PGE2) concentration and suppressed by 80% tumour formation in the colon. RT-PCR quantitative analysis showed that aspirin treatment reduced significantly (P<0.01) the AOM-triggered increase in mRNA levels of soluble inflammatory mediators (TNFalpha and IL-1beta) and metalloproteinases (MMP3 and MMP7). Conversely, we detected an increased expression level of alpha-defensin-5 (Rd-5, 2 fold) and lipocalin-2 (LCN2, 4 fold), two markers of the innate immunity system. The expression of apoptosis-related genes such as death receptors and their ligands were reduced by aspirin and the Bcl-2/Bax transcript ratio droped, Bcl-2 expression being reduced to the level found in saline control rats. The present study identifies new molecular targets triggered by aspirin in the colonic mucosa and may support the use of non-toxic low dose of aspirin in long-term treatments as a prophylactic approach against colon carcinogenesis.

Regression of chronic posterior leukoencephalopathy after stop of methotrexate treatment

Posterior reversible leukoencephalopathy (PRLE) is a neurological disorder caused by a variety of pathological conditions such as high doses or long-term low-doses of immunosuppressive therapy. PRLE associated with methotrexate (MTX) is well known but it was rarely observed in adult patients submitted to long-term low-dose administration via the oral route. Here we report the case of a patient affected by psoriasis, treated by chronic oral low-dose of MTX, who presented with limb ideomotor apraxia. Magnetic resonance (MRI) of the brain showed, on T2-weighted images, a diffuse hyperintensity involving bilaterally the white matter of the occipital, parietal and frontal lobes. MTX treatment was stopped and, at the 6-month follow-up, the neuropsychological performances was improved. Two years later, the neuropsychological profile was normal and MRI showed a regression of the white matter abnormalities.

Early long-term exposure with caffeine induces cross-sensitization to methylphenidate with involvement of DARPP-32 in adulthood of rats

Chronic ingestion of caffeine causes dependence and sleep disturbance in children and adolescents. In rodents, the administration of caffeine may produce behavioral cross-sensitization to some psychostimulants, such as dopaminergic psychoactive drugs. Methylphenidate (MPH; Ritalin®) is a psychostimulant used in pediatric- and adult human populations to manage the symptoms associated with attention-deficit hyperactivity disorder (ADHD). Previous studies have suggested that dopamine- and cAMP-regulated phosphoproteins of 32kDa (DARPP-32) participate in the manifestation of behavioral activity following ingestion of caffeine or MPH. The aim of the present study was to evaluate whether long-term administration of low doses of caffeine in rodents during their adolescence induces cross-sensitization to MPH challenge in their adulthood and investigate the involvement of DARPP-32 in this model. Young rats (P25) consumed water or caffeine (0.3g/L; mean consumption was 7.5mg/day/kg) for 28 days. The caffeine consumption was then suspended for 14 days (washout period) when the animals received saline solution or MPH (1, 2, or 10mg/kg) (P67) intraperitoneally. The locomotor activity of these rats was assessed using the open-field test, following which the immunocontent of DARPP-32 was evaluated in samples of their prefrontal cortex, striatum, or hippocampus. Rats chronically exposed to caffeine in their adolescent period and to inactive doses of MPH (1mg/kg) in adulthood showed augmented locomotor activity. The behavioral effect observed was accompanied by increased levels of DARPP-32 in the striatum and prefrontal cortex compared to control groups (saline or caffeine). However, no alteration caused by these treatments was noted in the hippocampus. In conclusion, chronic caffeine exposure induces likely long-term cross-sensitization to MPH in a DARPP-32-dependent pathway.

Vascular Pathology in Male Lewis Rats following Short-Term, Low-Dose Rotenone Administration

The long-term administration of low doses of rotenone has been used to produce a model of Parkinson disease (PD) in rats. However, only about 50% of similarly treated rats develop the PD-like syndrome, with many dying during the first few days of treatment. The lesions in male Lewis rats that became moribund or died after short-term, low-dose rotenone administration are described. Dosed rats had fibrinoid change and acute hemorrhage involving small arteries and arterioles of the brain and lungs. The thalamus, hypothalamus, and medulla oblongata were most frequently and severely affected. Blood vessels in the brain of some male Lewis rats appeared acutely susceptible to the effects of rotenone. Understanding the selective nature of the fibrinoid change and hemorrhage might explain how rotenone produces PD-like signs and lesions in rats, and it might also provide the basis for a model of intraparenchymal hemorrhagic cerebrovascular disease (i.e., hemorrhagic strokes) in humans.

Effect of cadmium on thyroid function in sheep

The objective of this experiment was to determine the effect of long-term low-dose administration of cadmium on thyroid function in sheep. In this experiment, ten healthy Iranian male sheep, aged about 1 year old, were randomly allocated into two equal groups of control (n = 5) and experiment (n = 5). Both groups were kept under the same conditions of food and environment. Treatment group received cadmium chloride (1 mg/kg/day) orally for 8 weeks. Blood sampling of two groups was done on days 0, 14, 28, 42, 56, and 70 every morning (8 to 9 a.m.). The function of the thyroid was evaluated by measuring the levels of serum thyroid hormones T3, T4, FT3, FT4, and TSH. The hepatic function in both groups was evaluated by measuring hepatic enzyme activities including alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ glutamyl transferase (GGT), and total bilirubin (TBIL). Serum levels of T3, T4, FT3, FT4, and TSH significantly decreased in cadmium-treated sheep when compared to control group (p < 0.05). Serum enzyme activities of ALT, AST, GGT, and TBIL in Cd-treated sheep were significantly increased in comparison with control group (p < 0.05). Our findings suggest that Cd-exposed sheep can be at a risk of low thyroid function.

Effect of macrolides on the expression of human leukocyte antigen-DR and costimulatory molecules on cultured human mononuclear cells

Although the clinical effectiveness of long-term low-dose administration of macrolides for diffuse pan- bronchiolitis, sinobronchial syndrome, chronic sinusitis and otitis media with effusion has been well documented, the mechanism of action remains to be determined. To clarify the effect of macrolides on the initiation of immune responses, we investigated changes in the expression levels of human leukocyte antigen (HLA)-DR, a major histocompatibility complex class II antigen, and of costimulatory molecules, such as CD54, CD80 and CD86, on monocytes following administration of macrolides. The expression of HLA-DR, CD54, CD80 and CD86 on cultured human peripheral mononuclear cells following stimulation by interferon (IFN)-γ and lipopolysaccharides (LPS) was analyzed using flow cytometry in the presence and absence of macrolides. The macrolides tested inhibited the expression of CD54, CD80 and CD86 on cultured monocytes following stimulation by IFN-γ and LPS, while the expression of HLA-DR on monocytes was not affected. Suppression of CD80 expression was the most significant among the costimulatory molecules tested and occurred in a dose-dependent manner. These results suggest that macrolides may downregulate the expression levels of costimulatory molecules, such as CD80, and may normalize the hyperimmune responses that may be responsible for the chronic intractable inflammation.

Extended high-frequency ototoxicity induced by the first administration of cisplatin

The ototoxicity induced by cisplatin results in high-frequency hearing loss. The sound-pressure thresholds at extended high frequencies of 8 to 20 kHz were measured in 12 patients with head and neck cancer before and after the first administration of cisplatin. Ototoxicity was defined statistically by the newly introduced regression-line analysis. This analysis revealed that the threshold of 1 of the 12 patients increased evenly from 8 to 10 kHz, and the damage to the hearing system of this patient was permanent. The reasons for such a low rate of ototoxicity might be the long-term administration of low doses of cisplatin and the addition of fosfomycin. (Otolaryngol Head Neck Surg 2000;122:828-33.)

Extended high-frequency ototoxicity induced by the first administration of cisplatin.

The ototoxicity induced by cisplatin results in high-frequency hearing loss. The sound-pressure thresholds at extended high frequencies of 8 to 20 kHz were measured in 12 patients with head and neck cancer before and after the first administration of cisplatin. Ototoxicity was defined statistically by the newly introduced regression-line analysis. This analysis revealed that the threshold of 1 of the 12 patients increased evenly from 8 to 10 kHz, and the damage to the hearing system of this patient was permanent. The reasons for such a low rate of ototoxicity might be the long-term administration of low doses of cisplatin and the addition of fosfomycin.

Learning and Memory of Rats after Long-Term Administration of Low Doses of Parathion

A set of four learning and memory tests (Morris Maze I for reference memory, Morris Maze II for working memory, one-way active avoidance, and passive avoidance) were employed to address the questions whether parathion impaired cognitive functions after low, long-term exposure and could cause persistent changes in cognition. Motor activity and general behavior were investigated in a functional observational battery. Parathion was administered in rat food in low doses which caused no clinical symptoms and no or borderline brain acetylcholinesterase inhibition. Parathion doses of 0.5, 2, or 8 ppm in rat food produced the averaged uptake of 24, 100, or 400 microg/kg body weight per group per day in male rats and 36, 152, or 550 microg/kg per day in female rats in week 13. Learning tests were performed in weeks 1 to 4 and 10 to 14, as well as 30 to 34 weeks after the end of treatment, when the male and female rats were about 13 months old. Low doses of parathion given daily for 13 weeks had no cumulative or adverse effects on learning and memory, either during treatment or after the extended treatment-free period, in any of the tests. A significant improvement of learning compared to control observed in the Morris Water Maze I during the first week of treatment (males dose group 0.5 ppm) shows that parathion can improved cognitive functions in rats. Results of the study indicate that adverse effects changing learning and memory in animals may occur only at higher doses of organophosphates, at which the peripheral and brain acetylcholinesterases are inhibited to a greater extent than those in the present study.