Sensory neuronopathy is a specific and disabling neurological manifestation of autoimmune hepatitis.

BACKGROUND AND PURPOSE: Neurological manifestations have been identified in the context of autoimmune hepatitis (AIH). Previous case reports highlighted the association between AIH and sensory neuronopathy (SN). Despite that, little is known about the frequency of AIH-related SN and its clinical/neurophysiological profile. Moreover, it is not clear whether SN is an AIH-specific manifestation or related to chronic liver damage. METHODS: Seventy consecutive AIH patients were enrolled and their characteristics were compared with 52 consecutive patients with chronic active hepatitis B. All subjects underwent clinical and neurophysiological evaluation. Further comparisons were performed between AIH SN and AIH non-SN patients. RESULTS: Mean ages and male:female proportions in the AIH and chronic active hepatitis B groups were 42.2 ± 16.3/51.7 ± 13.6 years and 14:56/29:23, respectively. The frequencies of carpal tunnel syndrome, radiculopathy and polyneuropathy were similar between groups. In contrast, SN was identified only in AIH patients (5/70 vs. 0/52, P = 0.04); the overall prevalence of AIH-related SN was 7% with an average profile of a woman in her 40s with asymmetric onset of sensory deficits that chronically evolved to disabling proprioceptive ataxia associated with marked dysautonomia. Neurological disability and hepatocellular damage did not follow in parallel. Anti-fibroblast growth factor receptor type 3 antibodies were found in 3/5 (60%) of the patients with AIH-related SN. Clinical or demographic predictors of SN in the context of AIH could not be identified. CONCLUSION: Sensory neuronopathy, but not other peripheral nervous system diseases, is a specific AIH neurological manifestation. It is often disabling and, in contrast to hepatocellular injury, does not respond to immunosuppression.

Developmental and neurodegenerative damage in Friedreich's ataxia.

BACKGROUND AND PURPOSE: Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities and slowly progressive ataxia. All magnetic resonance imaging (MRI)-based studies have focused on the evaluation of adult patients. Therefore, we designed a cross-sectional multimodal MRI-based study to investigate the anatomical substrates involved in the early stages of FRDA. METHODS: We enrolled 37 patients (12 children) and 38 controls. All subjects underwent MRI in a 3T device to assess gray and white matter. We used measures from FreeSurfer and CERES to evaluate the cerebral and cerebellar cortices. The T1 multiatlas assessed deep gray matter. The diffusion tensor imaging multiatlas was used to investigate microstructural abnormalities in brain white matter and SpineSeg was used to assess the cervical spinal cord. All analyses were corrected for multiple comparisons. RESULTS: Comparison with age-matched controls showed that pediatric patients have spinal cord, inferior cerebellar peduncle and red nucleus damage. In contrast, adult patients showed more widespread white matter damage than pediatric patients. With regard to gray matter, we found cortical thinning at the left central sulcus and volumetric reduction in the thalami and hippocampi only in adult patients. Finally, values of fractional anisotropy in adult patients and radial diffusivity in pediatric patients from the inferior cerebellar peduncle correlated with disease duration and ataxia severity, respectively. CONCLUSIONS: Structural damage in FRDA begins in the spinal cord and inferior cerebellar peduncle as well as the red nucleus, and progresses to cerebral areas in adulthood. These results shed some light on the early stages of FRDA and highlight potential neuroimaging markers for therapeutic trials.

Autonomic dysfunction in hereditary spastic paraplegia type 4.

BACKGROUND AND PURPOSE: SPAST mutations are the most common cause of hereditary spastic paraplegia (SPG4-HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non-motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4-HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations. METHODS: Thirty-four molecularly confirmed SPG4 patients were recruited in a multicenter cross-sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease - Autonomic Questionnaire (SCOPA-AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age- and gender-matched healthy controls using non-parametric tests. P values <0.05 were considered significant. RESULTS: In the SPG4-HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA-AUT scores were similar between patients and controls (P = 0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, P = 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%, P < 0.001, and 64% vs. 0%, P = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4-HSP group. CONCLUSION: Our results indicate that SPG4-HSP patients have sudomotor dysfunction caused by damaged small post-ganglionic cholinergic fibers. Damage in SPG4-HSP extends to the peripheral nervous system.

Cross-cultural adaptation and psychometric evaluation of the Spanish version of the Knowledge and Attitudes of Pain questionnaire (KNAP) in physiotherapists.

BACKGROUND: Healthcare providers' attitudes and beliefs can influence how patients with persistent musculoskeletal pain are treated. A biopsychosocial approach is more effective than a purely biomedical approach. Ensuring healthcare professionals have appropriate pain science education (PSE) is essential for successful treatment outcomes. OBJECTIVE: To validate the Spanish version of the Knowledge and Attitudes of Pain (KNAP-SP) questionnaire among Spanish physiotherapists and students and analyze its psychometric properties. METHODS: From May to October 2022, two independent teams adapted the KNAP questionnaire from English to both European and Hispanic-Spanish. A cross-sectional validation study was conducted with 517 physiotherapists examining internal consistency (Cronbach's alpha), structural validity (exploratory factor analysis), and construct validity (hypothesis testing). Longitudinal analyses assessed test-retest reliability (intraclass correlation coefficient [ICC2,1; n = 63]) and responsiveness following a PSE intervention using Receiver Operating Characteristic (ROC) curve analysis and hypothesis testing (n = 70). RESULTS: The KNAP-SP showed strong internal consistency [overall α coefficient = 0.86; domain 1 (α = 0.82); domain 2 (α = 0.70)], explaining 32.3% of the variance. Construct validity was supported by 75% of the hypotheses. Test-retest reliability was high (ICC2,1 = 0.84). KNAP-SP's responsiveness was confirmed by ROC analysis (area under the curve [AUC] = 0.87 [95% CI: 0.79-0.96, p-value <.01]) and accepting 75% of prior hypotheses. The minimal clinically important change was 6.96 points. No floor or ceiling effects were detected. CONCLUSIONS: The KNAP-SP, with robust psychometric properties and successful adaptation and validation, is a valuable tool for assessing pain knowledge and attitudes among Spanish-speaking physiotherapists.

First Report of Homothallic Isolates of Phytophthora infestans in Commercial Potato Crops (Solanum tuberosum) in the Toluca Valley, Mexico.

Phytophthora infestans causes severe symptoms of wilt disease on potato crops (Solanum tuberosum) in the Toluca Valley (Mexico) despite the use of fungicides. P. infestans oospores produced by sexual reproduction can survive in the soil for many years, resisting harsh environments. In many agroecosystems, oospores germinate in the beginning of a season, which represents the initial inoculum for epidemics. The sexual cycle of the pathogen allows the generation of recombinant genotypes that can be more pathogenic or even resistant to chemicals. This paper presents a study of 20 isolates of P. infestans collected from potato crops in the Toluca Valley within the municipality of Zinacantepec (Mexico State). Isolates were obtained from potato foliar infected tissues. The pathogen was confirmed as P. infestans on the basis of morphological characters (1). Sporangia were caducous, ovoid, limoniform, semipapillate, and were 28.4 ± 1.3 × 17.6 ± 1.2 µm (height × width). Mycelium was coenocytic with hyphal diameter of 5 to 8 µm. Five isolates were collected in 2011, and 15 in 2012. Isolates were transferred by hyphal tip to culture medium plates with V8 juice agar and incubated at 19°C. All the isolates were mated to determine the mating type with the reference isolates J104 (A1) and J204 (A2), which were provided by the Michoacana University of San Nicolás de Hidalgo (Mx). Isolates that produced oospores with both A1 and A2 testers (J104 and J204) and in a single culture were designated homothallic. Results show that two out of the five isolates collected in 2011 were homothallic and the other three were type A1. Regarding the 15 isolates collected in 2012, six were typed as A1, five as A2, and four were homothallic. The heterothallic isolates only produce oospores when mated with the opposite mating type. The homothallic isolates possessed the ability to act as A1 and A2 during heterothallic mating and were found capable of producing sexual structures (oogonia and amphigynous antheridia) in a single culture, a phenomenon not observed in isolates that are strictly A1 or A2. Oospores formed were aplerotic and measured 32.2 ± 3.3 µm in diameter. Single-sporangium progeny were produced from the six homothallic isolates to be analyzed to confirm the occurrence of the self-fertility. Assessment of 48 single-sporangium progeny from the homothallic isolates resulted in 22 homothallic, 12 A1, 10 A2, and four sterile. These results differ from those found by Grünwald et al. (3), who conducted a study with isolates collected from the Toluca Valley region in 1997 and 1998, finding a 1:1 frequency between compatibility types A1 and A2. Fernandez et al. (2) studied a broad population of 27 isolates from potato crops in the state of Michoacán (Mx), and found two homothallic isolates among heterothallic isolates; the ratio was 1:1. Also, homothallic isolates have been found in Spain and China (4). To our knowledge, this is the first report of the occurrence of homothallic P. infestans isolates in commercial potato crops (S. tuberosum) in the Toluca Valley, Mexico. References: (1) D. C. Erwin and O. K. Ribeiro, Page 346 in: Phytophthora Diseases Worldwide. The American Phytopathological Society. St. Paul, MN, 1996. (2) S. P. Fernández et al. Rev. Mexicana Fitopatol. 23:191, 2005. (3) N. J. Grünwald et al. Phytopathology 91:883, 2001. (4) M. Han et al. J. Eukaryotic Microbiol. 60:79, 2013.

Chronic Inhibition of FAAH Reduces Depressive-Like Behavior and Improves Dentate Gyrus Proliferation after Chronic Unpredictable Stress Exposure.

Symptoms of depressive disorders such as anhedonia and despair can be a product of an aberrant adaptation to stress conditions. Chronic unpredictable stress model (CUS) can generate an increase in the activity of the hypothalamic-pituitary-adrenal axis (HPA) and induce a reduction of neurotrophin signaling and the proliferation of neural progenitors in the adult dentate gyrus, together with increased oxidative stress. Levels of the endocannabinoid anandamide (AEA) seem to affect these depression-by-stress-related features and could be modulated by fatty acid amide hydrolase (FAAH). We aimed to evaluate the effects of FAAH inhibitor, URB597, on depressive-like behavior and neural proliferation of mice subjected to a model of CUS. URB597 was administered intraperitoneally at a dose of 0.2 mg/kg for 14 days after CUS. Depressive-like behaviors, anhedonia, and despair were evaluated in the splash and forced swimming tests, respectively. Alterations at the HPA axis level were analyzed using the relative weight of adrenal glands and serum corticosterone levels. Oxidative stress and brain-derived neurotrophic factor (BDNF) were also evaluated. Fluorescence immunohistochemistry tests were performed for the immunoreactivity of BrdU and Sox2 colabeling for comparison of neural precursors. The administration of URB597 was able to reverse the depressive-like behavior generated in mice after the model. Likewise, other physiological responses associated with CUS were reduced in the treated group, among them, increase in the relative weight of the adrenal glands, increased oxidative stress, and decreased BDNF and number of neural precursors. Most of these auspicious responses to enzyme inhibitor administration were blocked by employing a cannabinoid receptor antagonist. In conclusion, the chronic inhibition of FAAH generated an antidepressant effect, promoting neural progenitor proliferation and BDNF expression, while reducing adrenal gland weight and oxidative stress in mice under the CUS model.

ß-Caryophyllene exerts protective antioxidant effects through the activation of NQO1 in the MPTP model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder, caused by the selective death of dopaminergic neurons in the substantia nigra pars compacta. ß-caryophyllene (BCP) is a phytocannabinoid with several pharmacological properties, producing anti-inflammatory and antihypertensive effects. In addition, BCP protects dopaminergic neurons from neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), yet it remains unclear if this effect is due to its antioxidant activity. To assess whether this is the case, the effect of BCP on the expression and activity of NAD(P)H quinone oxidoreductase (NQO1) was evaluated in mice after the administration of MPTP. Male C57BL/6 J mice were divided into four groups, the first of which received saline solution i.p. in equivalent volume and served as a control group. The second group received MPTP. The second group received MPTP hydrochloride (5 mg/kg, i.p.) daily for seven consecutive days. The third group received BCP (10 mg/kg) for seven days, administered orally and finally, the fourth group received MPTP as described above and BCP for 7 days from the fourth day of MPTP administration. The results showed that BCP inhibits oxidative stress-induced cell death of dopaminergic neurons exposed to MPTP at the same time as it enhances the expression and enzymatic activity of NQO1. Also, the BCP treatment ameliorated motor dysfunction and protected the dopaminergic cells of the SNpc from damage induced by MPTP. Hence, BCP appears to achieve at least some of its antioxidant effects by augmenting NQO1 activity, which protects cells from MPTP toxicity. Accordingly, this phytocannabinoid may represent a promising pharmacological option to safeguard dopaminergic neurons and prevent the progression of PD.

Effect of inhibition of fatty acid amide hydrolase on MPTP-induced dopaminergic neuronal damage. / Efecto del inhibidor de amida hidrolasa de ácidos grasos en el daño neuronal dopaminérgico inducido por MPTP.

INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative disorder characterised by balance problems, muscle rigidity, and slow movement due to low dopamine levels and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The endocannabinoid system is known to modulate the nigrostriatal pathway through endogenous ligands such as anandamide (AEA), which is hydrolysed by fatty acid amide hydrolase (FAAH). The purpose of this study was to increase AEA levels using FAAH inhibitor URB597 to evaluate the modulatory effect of AEA on dopaminergic neuronal death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). METHODS: Our study included 4 experimental groups (n = 6 mice per group): a control group receiving no treatment, a group receiving URB597 (0.2mg/kg) every 3 days for 30 days, a group treated with MPTP (30mg/kg) for 5 days, and a group receiving URB597 and subsequently MPTP injections. Three days after the last dose, we conducted a series of behavioural tests (beam test, pole test, and stride length test) to compare motor coordination between groups. We subsequently analysed immunoreactivity of dopaminergic cells and microglia in the SNpc and striatum. RESULTS: Mice treated with URB597 plus MPTP were found to perform better on behavioural tests than mice receiving MPTP only. According to the immunohistochemistry study, mice receiving MPTP showed fewer dopaminergic cells and fibres in the SNpc and striatum. Animals treated with URB597 plus MPTP displayed increased tyrosine hydroxylase immunoreactivity compared to those treated with MPTP only. Regarding microglial immunoreactivity, the group receiving MPTP showed higher Iba1 immunoreactivity in the striatum and SNpc than did the group treated with URB597 plus MPTP. CONCLUSION: Our results show that URB597 exerts a protective effect since it inhibits dopaminergic neuronal death, decreases microglial immunoreactivity, and improves MPTP-induced motor alterations.

Effects of extraction solvents on photoluminescent properties of eysenhardtia polystachia and their potential usage as biomarker.

Currently, nanomaterials had been used for several applications; one of them is as bio-markers. These nanomaterials contain fluorescent compounds as effective indicators for imaging and other applications in Biotechnology. In previous studies, we proposed a functionalized nanomaterial-based biomarker from silica and Eysenhardtia Polystachia, a medicinal tree known in Mexico as "palo azul" (Kidneywood). Our previous results showed the feasibility of the nanomaterial obtained as bio-marker. In this article, our purpose is to evaluate the effects of extraction solvents on fluorescence of that biomarker. The photoluminescence (PL) effect was evaluated at different pH (4, 7.4 and 8); four extraction solvents, ethanol, methanol, methanol-ethanol and methanol-ethanol-water were evaluated. A molecular dynamics simulation was performed to recognize molecular interaction between the compounds of the extracts with solvent molecules and to investigate the solvent molecules effect on photoluminescence spectra. The results were also compared with rhodamine 6G and we found that, at physiological pH (7.4), the fluorescent-coated silica nanoparticles obtained were also stable. We found that extraction solvents could be used for obtaining different nanomaterials for specific applications, and also found the best extraction solvent for obtaining EP nanomaterials for health care applications, specifically for imaging techniques.

Development of meniscus substitutes using a mixture of biocompatible polymers and extra cellular matrix components by electrospinning.

Despite the significant advances in the meniscus tissue engineering field, it is difficult to recreate the complex structure and organization of the collagenous matrix of the meniscus. In this work, we developed a meniscus prototype to be used as substitute or scaffold for the regeneration of the meniscal matrix, recreating the differential morphology of the meniscus by electrospinning. Synthetic biocompatible polymers were combined with the extracellular matrix component, collagen and used to replicate the meniscus. We studied the correlation between mechanical and structural properties of the polymer blend as a function of collagen concentration. Fibers were collected on a surface of a rapidly rotating precast mold, to accurately replicate each sectional morphology of the meniscus; different electro-tissues were produced. Detailed XRD analyses exhibited structural changes developed by electrospinning. We achieved to integrate all these electro-tissues to form a complete synthetic meniscus. Vascularization tests were performed to assess the potential use of our novel polymeric blend for promising meniscus regeneration.

Evaluation of different techniques in the diagnosis of Toxoplasma encephalitis.

This study evaluated the detection of antibodies, circulating antigens and parasite DNA by polymerase chain reaction (PCR) in the diagnosis of toxoplasma encephalitis. The detection of antibody classes and IgG avidity were not useful diagnostically. The detection of circulating antigens by the ELISA system described was not sufficiently sensitive. The detection of DNA by PCR was the most useful test especially in untreated patients, with a sensitivity of 62% overall, 81% in untreated patients and only 20% in treated patients. The use of non-isotopic probes makes the use of this technique feasible in routine diagnostic parasitology laboratories.

CA-125 levels in cervical mucus during the menstrual cycle.

OBJECTIVE: To determine CA-125 levels in cervical mucus (CM) during the menstrual cycle and their relationship to gonadal steroids and ovulation. DESIGN: Prospective study. SETTING: Two academic tertiary referral centers. PARTICIPANTS: Thirteen women with a normal fertility work-up. INTERVENTIONS: CA-125 and protein concentrations were measured in CM aspirated from the endocervical canal on alternate days in the early follicular and luteal phases and on a daily basis during the periovulatory period. Results were correlated with hormonal determinations, serum CA-125 levels, and ultrasound examination. RESULTS: Twenty ovulatory nonconceptional cycles were analyzed. Although the mean (+/- SD) concentration of CA-125 in CM (173,900 +/- 128,900 arbitrary U/mL) appeared relatively constant along the cycle, a large variation among the different samples was observed, ranging from 9,000 to 830,000 arbitrary U/mL. No clear trend could be detected as related to hormonal changes and ovulation. However, when the mucus CA-125 concentration was multiplied by the total volume of the correspondent sample, a clear periovulatory increase of total CA-125 levels was found. This was further supported by a similar trend showed by the calculated CA-125:protein concentration ratio. CONCLUSIONS: CA-125 is present in CM in high concentrations that vary widely along the cycle. Although no cyclical variation in CA-125 concentration could be determined, there was an apparent increase of total CA-125 levels parallel to the augmented mucus production during the periovulatory period. This further suggests a possible involvement of this glycoprotein in the secretory process of endocervical glands.

Pregnancy rates after timed intercourse or intrauterine insemination after human menopausal gonadotropin stimulation of normal ovulatory cycles: a controlled study.

Forty-eight patients with male (n = 16) or idiopathic (n = 32) infertility were stimulated with human menopausal gonadotropin. Intrauterine insemination (IUI) or natural intercourse were performed after either human chorionic gonadotropin (hCG)-induced or spontaneous, urinary luteinizing hormone (LH) surge-monitored ovulation. A total of 148 cycles were analyzed. In 40 cycles treated with hCG-induced ovulation and IUI, 3 (7.5%) patients conceived, whereas 37 women accomplished natural intercourse after hCG-induced ovulation and 2 (5.5%) became pregnant. When inseminated after a spontaneous LH surge, 3 (8.8%) of 34 patients achieved a pregnancy; no conception occurred in 37 spontaneously ovulatory cycles combined with timed intercourse. Pregnancy rates did not substantially differ between the treatment modalities or between mono-ovulatory and polyovulatory cycles. The cycle characteristics between spontaneous ovulatory and hCG-induced cycles significantly did differ.

Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic factors: a prospective, randomized, controlled study.

In the present prospective study we compared, in terms of pregnancy rates, the differences between intrauterine insemination (IUI) of in vitro capacitated husband's semen and timed natural intercourse in spontaneous or clomiphene citrate (CC) stimulated cycles. A rapid urinary luteinizing hormone peak detection test was used for timing of ovulation. Forty patients suffering from longstanding infertility of male (n = 17), cervical (n = 2), and idiopathic (n = 21) origin were randomly assigned into four distinct treatment modalities during 4 consecutive cycles. A total of 132 cycles were analyzed. In 35 cycles treated with CC plus IUI, five conceptions were achieved, whereas three pregnancies occurred in 32 inseminated spontaneous cycles. Only 1 patient conceived after timed intercourse in 31 CC stimulated cycles, and no pregnancy resulted from 34 spontaneous cycles combined with timed intercourse. There was a statistically significant higher conception rate in cycles in which IUI was performed, whereas the use of CC does not seem to improve the pregnancy rate. Analysis of results for other modifying factors did not substantially affect the relative risk (odds ratio) of pregnancy.

Kininogen, esterase and kininase activities in human peripheral venous plasma and in plasma from the intervillous space of human placenta, before and during labor.

Kininogen, esterase and kininase activity were measured in the peripheral venous and intervillous placental plasma of women submitted to cesarean section and of women who delivered normally. Kininogen consumption occurred in the intervillous placental plasma during labor. Kininase activity increased in the intervillous placental plasma during labor and was considerably higher than in peripheral venous plasma. Esterase activity was high during labor and decreased after delivery.

Reliability of urinary LH testing for planning of endometrial biopsies.

A rapid urinary luteinizing hormone (LH) test was used to plan a late luteal phase endometrial biopsy from 20 women undergoing an infertility evaluation. Histologic dating was correlated with the day of urinary LH surge detection, the day of the basal body temperature (BBT) nadir, and the onset of the next menstrual period (NMP). From 17 interpretable specimens, histologic dating correlated well with the day of the biopsy as determined following a positive LH test detection (P = 0.079). No correlation was found following the BBT shift (P = 0.65), and it was significantly correlated with the NMP (P = 0.016). Moreover, the urinary LH test showed to be the best method to predict the onset of the NMP. These findings confirm urinary LH testing as a valuable adjunct in the investigation of luteal phase disorders.

The reliability, acceptability and applications of basal body temperature (BBT) records in the diagnosis and treatment of infertility.

The possibilities and limitations of basal body temperature (BBT) records as an adjunct in the management of infertility were re-evaluated. To assess its accuracy as an index of ovulation, 172 charts were analyzed by three different physicians. While the average true positive rate was 90%, the false negative rate was only 2%. The remaining graphs (8%) were classified as non-interpretable, probably reflecting measurement problems. Retrospective assessment of 210 biphasic records showed the thermal nadir to occur within 1 day of the urinary luteinizing hormone (LH) surge in 75% of the cases, and in 90% when 2 days where considered. This confirms BBT as a relatively accurate guide for retrospective identification of the periovulatory period. Moreover, results of a study conducted to investigate how patients experienced daily recording of BBT graphs suggest that the method is well accepted by a high proportion of women. From all these it appears that there are many indications where BBT graphs can still be applied. Development of new electronic devices may further improve the reliability, acceptability and applications of the BBT records in the fertility investigation.

Methimazole-mediated enhancement of albendazole oral bioavailability and anthelmintic effects against parenteral stages of Trichinella spiralis in mice: the influence of the dose-regime.

The influence of methimazole (MTZ) inhibitor of the microsomal oxidases on the systemic availability of the albendazole sulpho-metabolites (ABZS-MT) albendazole-sulphoxide (ABZSO) and albendazole-sulphone (ABZSO2) and on its anthelmintic effects was investigated in a mouse model for helminthic infections. Plasma concentrations of the ABZS-MT were measured by high performance liquid chromatography (HPLC) following treatment of Swiss CD-1 mice with albendazole (ABZ) alone or ABZ plus MTZ, at both single and repeated doses. The anthelmintic effects were assessed in age-matched mice similarly treated following infection with Trichinella spiralis. MTZ significantly (p < 0.01) increased the ABZS-MT plasma concentrations although the pharmacokinetic profile varied greatly according to the dose of ABZ administered. When ABZ was given at a single dose of 50 mg/kg followed by MTZ at 3 mg/kg, a cumulative effect was observed in the ABZS-MT plasma levels with pharmacokinetic parameters (Tmax = 24 h, Cmax= 30.88 microg/ml and AUC = 1120.80 microg h/ml) significantly ( p < 0.01) higher than those following administration of ABZ alone (Tmax = 3 h, Cmax = 11.00 microg/ml and AUC = 268.03 microg h/ml). This cumulative effect was absent following administration of ABZ at 100 mg/kg where, after reaching a maximum (Cmax = 27.23 microg/ml) at 3 h post-administration (Tmax), the ABZS-MTplasma levels felt down quickly to values under those obtained after administration of ABZ at the same dose, but alone (AUC = 362.15 microg h/ml vs. 340.15 microg h/ml, respectively). When ABZ was given at 50 mg/kg together with MTZ three times every 24 h, a rapid decrease was observed in the ABZS-MT plasma levels following administration of both the second and third doses, respectively. The pharmacokinetic profile of ABZS-MT following administration of each of the three doses of ABZ at 100 mg/kg plus MTZ was the same as that obtained after the single treatment. The rapid decrease of the ABZS-MT plasma levels observed after the sustained treatment or after the single treatment at 100 mg/kg could be due to a microsomal oxidase inductive effect (probably the cytochrome P-450) caused by ABZSO. The co-administration of MTZ significantly (p < 0.01) increased the anthelmintic effects of ABZ against both migrating and encysted larvae of T. spiralis. Repeated treatment did not improve the anthelmintic effects of the single treatment as the efficacies against both stages of the parasite were always lower or identical to those of the single treatment at the corresponding doses.