Baclofen systemic toxicity: Experimental histopathological and biochemical study.

OBJECTIVE: The present study was designed to highlight the toxic impact of baclofen on both biochemical and histopathological aspects in rats' liver, gastric, lung, kidney, and brain tissues. METHODS: The study was performed on 30 healthy adult male albino rats divided into four groups with 5 rats in each control group, and 10 rats in either experimental groups (two experimental and two control groups). Five rats (negative control) were kept in a quite non-stressful environment, provided with food ad libitum and free access to water. Normal saline (1 ml) was given orally as placebo in the positive control group ( n = 5). Experimental group III, baclofen acute toxicity group (10 rats): Each animal received a single dose of lethal dose (LD50) of baclofen orally by gavage. It equals 145 mg/kg body weight. The rats were observed for acute toxicity manifestations as well as for LD50 deaths. Group IV, (baclofen-dependent group, 10 rats): Each animal received baclofen (1/10th LD50) in gradually increasing doses for 1 month. RESULTS: The levels of blood urea nitrogen, creatinine kinase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, cardiac troponin I, and prothrombin time in both baclofen-treated groups showed significant elevation when compared to controls. There were brain, lung, gastric, hepatic, and renal histopathological changes in baclofen-treated rats whose severity varied between the two experimental groups. CONCLUSION AND RECOMMENDATION: Baclofen toxicity is an under diagnosed emergency. Physicians should consider baclofen toxicity in users having hepatorenal dysfunction, presenting with altered mental status, bradycardia, and hypotension.

Potential effect of Olea europea leaves, Sonchus oleraceus leaves and Mangifera indica peel extracts on aromatase activity in human placental microsomes and CYP19A1 expression in MCF-7 cell line: Comparative study.

Aromatase inhibitors (AIs) provide novel approaches to the adjuvant therapy for postmenopausal women with estrogen-receptor-positive (ER+) breast cancers. In this study, different plant extracts from Olea europaea leaves (OLE), Sonchus oleraceus L. (SOE) and Mangifera indica peels (MPE) were prepared to identify phytoconstituents and measure antioxidant capacities. The effects of these three extracts on aromatase activity in human placental microsomes were evaluated. Additionally, the effects of these extracts on tissue-specific promoter expression of CYP19A1 gene in cell culture model (MCF-7) were assessed using qRT-PCR. Results showed a concentration-dependent decrease in aromatase activity after treatment with OLE and MPE, whereas, SOE showed a biphasic effect. The differential effects of OLE, SOE and MPE on aromatase expression showed that OLE seems to be the most potent suppressor followed by SOE and then MPE. These findings indicate that OLE has effective inhibitory action on aromatase at both the enzymatic and expression levels, in addition to its cytotoxic effect against MCF-7 cells. Also, MPE may be has the potential to be used as a tissue-specific aromatase inhibitor (selective aromatase inhibitor) and it may be promising to develop a new therapeutic agent against ER+ breast cancer.

Single dose, CYP2D6 genotype-stratified pharmacokinetic study of atomoxetine in children with ADHD.

The effect of CYP2D6 genotype on the dose-exposure relationship for atomoxetine has not been well characterized in children. Children 6-17 years of age diagnosed with attention-deficit hyperactivity disorder (ADHD) were stratified by CYP2D6 genotype into groups with 0 (poor metabolizers [PMs], n = 4), 0.5 (intermediate metabolizers [IMs], n = 3), one (extensive metabolizer [EM]1, n = 8) or two (EM2, n = 8) functional alleles and administered a single 0.5 mg/kg oral dose of atomoxetine (ATX). Plasma and urine samples were collected for 24 (IM, EM1, and EM2) or 72 hours (PMs). Dose-corrected ATX systemic exposure (area under the curve [AUC]0-∞ ) varied 29.6-fold across the study cohort, ranging from 4.4 ± 2.7 µM*h in EM2s to 5.8 ± 1.7 µM*h, 16.3 ± 2.9 µM*h, and 50.2 ± 7.3 µM*h in EM1s, IMs, and PMs, respectively (P < 0.0001). Simulated steady state profiles at the maximum US Food and Drug Administration (FDA)-recommended dose suggest that most patients are unlikely to attain adequate ATX exposures. These data support the need for individualized dosing strategies for more effective use of the medication.

Plasma ghrelin and liquid gastric emptying in children with functional dyspepsia consistent with post-prandial distress syndrome.

BACKGROUND: Adult studies indicate a role for ghrelin in functional dyspepsia (FD) mediated through ghrelin's effect on gastric emptying (GE). This study examines the relationship between ghrelin, liquid GE, and pain in children with FD. METHODS: Thirteen FD patients reporting symptoms consistent with post-prandial distress syndrome (PDS) and 17 healthy controls were enrolled. All participants received a liquid meal containing (13) C-sodium acetate. Pain severity, liquid GE utilizing exhaled (13) CO2 from the sodium acetate breath tests (ABT), plasma acyl ghrelin (AG), and des-acyl ghrelin concentrations were measured at specific intervals over 240 min following ingestion. KEY RESULTS: FD-PDS patients demonstrated lower mean baseline AG (14.8 ± 9.7 vs 27.2 ± 14.0 fmol/mL; p = 0.013), AG Cmax (24.6 ± 8.2 vs 40.5 ± 16.8 fmol/mL; p = 0.007), and AG flux (18.2 ± 7.8 vs 32.7 ± 17.3 fmol/mL; p = 0.015) than controls. The time to reach maximum exhaled (13) CO2 concentration (T max ) was longer in FD patients than controls (47.5 ± 18.5 vs 35.8 ± 11.8 min; p = 0.046). Significant relationships between ghrelin analyte ratios and ABT parameters were largely confined to control participants. CONCLUSIONS & INFERENCES: FD-PDS in children is associated with lower fasting and maximum AG concentrations, and dampened AG flux. These data suggest a possible role for altered ghrelin physiology in the pathogenesis of PDS.

Characterization of delayed liquid gastric emptying in children by the (13)C-acetate breath test.

The (13)C-acetate breath test represents a potential alternative to conventional scintigraphy to measure liquid gastric emptying (GE). The purpose of this study was to compare the (13)C-acetate breath test to gastric scintigraphy in children with functional dyspepsia. Simultaneous assessment of GE was performed in 28 children (9-17 years of age) using a liquid test meal that was double labeled with (13)C-acetate and (99 m)Technetium. (13)CO(2) versus time profiles were fit using traditional pharmacokinetic analyses. For each subject, GE half-life [Formula: see text] determined by scintigraphy was plotted against parameters determined from the (13)C-acetate breath test. Linear regression was used to explore the associations between the tests. Complete (13)CO(2) versus time profiles were available for 25 subjects. There was no association between the scintigraphy GE T½ and the(13)CO(2) half-exhalation time. However, significant associations were observed between the gastric half-emptying time as determined by scintigraphy and two of the breath test parameters: the enrichment of (13)CO(2) present in breath samples at 60 min (DOB(60)) (r = -0.52, p = 0.01) and the area under the curve from 0 to 60 min (AUC(0-60 min)) (r = -0.54; p < 0.01). The (13)C-acetate breath test has the potential to serve as a rapid, technically simple and inexpensive means to assess liquid GE in children with functional dyspepsia and possibly serve as a pharmacodynamic surrogate in studies of prokinetic drugs in children.

Three new cases of human infection with Dirofilaria repens, one pulmonary and two subcutaneous, in the Egyptian governorate of Assiut.

Human dirofilariasis caused by Dirofilaria repens is a parasitic infection, currently considered to be an emerging zoonosis, that has been observed in many areas of the Old World. Dogs are the main 'reservoir' host. In humans, D. repens can cause inflammatory nodules, most commonly in the subcutaneous tissues or in the subconjunctival space. Lung involvement, which is the most common of the non-cutaneous and non-ocular manifestations, is frequently mis-diagnosed as a primary or metastatic lung tumour. Two new subcutaneous cases and one new pulmonary case, all observed in the Egyptian governorate of Assiut, are described here. This represents the first report of human pulmonary dirofilariasis caused by D. repens on the African continent. All the worms collected from the cases, including a living worm from the left lung of the pulmonary case, were identified morphologically, and the identity of the lung parasite was confirmed by PCR.

Considerations in the rational design and conduct of phase I/II pediatric clinical trials: avoiding the problems and pitfalls.

Over the past decade, there has been a heightened awareness of the need to include children in the drug development process. With this awareness has come an expansion of the infrastructure for conducting studies in children and an increase in the sponsorship of pediatric clinical trials. However, the growth in pediatric research has, in many cases, not been accompanied by an increase in the involvement of trained pediatric investigators when it comes to trial design and/or interpretation. Pediatric phase I/II protocols continue to span a spectrum from those that are carefully constructed to those that are poorly designed. This paper highlights the basic elements of phase I/II protocols that merit unique consideration when the clinical trial involves children. Illustrations are provided from our experience, which highlight problems that may arise when trials are not designed with the pediatric patient in mind.

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans.

Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6(*)1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6(*)41B, (*)45A and B and (*)46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A -692(TGTG) deletion (CYP2D6(*)45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6(*)45 and (*)46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype.

Trichophyton tonsurans exocellular protease expression: correlation with clinical presentation in tinea capitis.

Tinea capitis remains an overwhelmingly prevalent disease in children. Despite the fact that it was described over a century ago, disease pathogenesis remains incompletely characterized. This investigation was designed to evaluate whether inter-strain variability in fungal protease expression for clinical Trichophyton tonsurans isolates correlates with disease severity. Children with tinea capitis were enrolled and a clinical severity score (CSS) determined for all subjects by grading eight symptoms on a 4-point scale. Fungal specimens were collected by brush culture, placed in aqueous medium and incubated at 32 degrees C for 5 days. The culture supernatant was lyophilized and aliquots used to characterize protease activity. Enzyme activity, normalized to total soluble protein, varied 550-fold, 150-fold and 6-fold for collagenase, elastase and keratinase, respectively. A significant decrease in elastase and collagenase activity was observed with increasing duration of infection. In one-half of the children, CSS increased in direct response to collagenase and elastase production, while CSS was independent of enzyme activity in the remaining children. The relationship between enzyme activity and time course of disease are consistent with theories on enzyme regulation in dermatophytoses; however, the finding that two potential subsets of children exist with varied response to fungal antigens has yet to be described.

Pharmacokinetics and metabolism of oral midazolam in preterm infants.

AIMS: To characterize the pharmacokinetics and metabolism of oral midazolam in 15 preterm infants. METHODS: After an oral dose (0.1 mg kg(-1)), blood was drawn up to 24 h after administration. Midazolam and 1-OH-midazolam concentrations were determined with GC-MS. In 8 out of these 15 patients the pharmacokinetics of intravenous midazolam was also studied. RESULTS: Apparent oral clearance, apparent volume of distribution, plasma half-life and 1-OH-Midazolam/Midazolam AUC ratio were [median (range)]: 2.7 [0.67-15.5] ml kg(-1) min(-1), 1.4 [0.3-12.1] l kg(-1), 7.6 [1.2-15.1], h and 0.03 [0.01-0.96], respectively. Absolute bioavailability was 0.49 [0.12-1.0]. CONCLUSIONS: Midazolam oral clearance is markedly decreased in preterm infants as compared with older children, probably because of immature CYP3A4 activity.

Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation.

Cytochrome P4502D6 (CYP2D6) activity has been shown to be a determinant of both the pharmacokinetics and pharmacodynamics of tramadol in adults. This study evaluated the association between CYP2D6 activity, as determined by dextromethorphan (DM) urinary metabolite ratio, and tramadol biotransformation in 13 children (7-16 years). CYP2D6 genotype was determined by XL-PCR and PCR/RFLP. Phenotype was assessed by HPLC quantitation of DM and its metabolites from a 12- to 24-hour urine collection following a single oral dose of DM. There was only a modest correlation between tramadol/M1 (metabolite 1) plasma concentration or AUC and the DM/dextrorphan (DX) urinary molar ratio in the study cohort; however, when subjects were segregated based on the number of functional CYP2D6 alleles, a much stronger relationship was observed for subjects with two functional alleles, with essentially no relationship evident in those individuals with one functional allele. Further evaluation of these data suggested that the CYP2D6-mediated metabolite (M1) is formed to a lesser extent, and the formation of the non-CYP2D6 product (M2) is more pronounced in subjects with one versus two functional alleles. Thus, the number of functional CYP2D6 alleles and the availability of alternative cytochromes P450 capable of metabolizing tramadol may explain the poor association between DM, a well-characterized CYP2D6 probe, and tramadol in a population of CYP2D6 extensive metabolizers.

Pharmacokinetics and metabolism of intravenous midazolam in preterm infants.

BACKGROUND: Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants. METHODS: The pharmacokinetics of midazolam and its hydroxylated metabolite (1-OH-midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1-OH-midazolam concentrations were determined by use of gas chromatography-mass spectrometry. RESULTS: Total body clearance, apparent volume of distribution, and plasma half-life of midazolam were (median [range]): 1.8 (0.7-6.7) ml/kg per min, 1.1 (0.4-4.2) L/kg, and 6.3 (2.6-17.7) h, respectively. In 19 of 24 preterm infants, 1-OH-midazolam concentrations could be detected: 1-OH-midazolam (1-OH-M) maximal concentration of drug in plasma (C(max)), time to reach C(max) (T(max)), and 1-OH-M/M area under the concentration-time curve from time zero to the last sampling time point (AUC(0-t)) ratio were [median (range)]: 8.2 (<0.5-68.2) ng/ml, 6 (1-12) h, and 0.09 (<0.001-1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure. DISCUSSION: Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1-OH-midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.

Sucrose analgesia for minor procedures in newborn infants.

OBJECTIVE: To evaluate the role of intraoral sucrose and other sweet-tasting solutions for the management of pain associated with minor procedures in newborns. DATA SOURCES: A search of MEDLINE articles from 1966 to August 1999 and an extensive review of journals was conducted. MeSH headings included analgesia, sucrose, and neonate. DATA SYNTHESIS: Newborn infants regularly undergo minor invasive procedures for which analgesics are not routinely used. Intraoral sucrose and other sweet-tasting solutions appear to diminish surrogate biomarkers of pain response as evidenced by a reduction in crying time, smaller increases in heart rate, and lower pain scale ratings. CONCLUSIONS: These studies appear to suggest that sucrose solution 0.5 g provides effective analgesia with no reported adverse effects.

Polymorphic exocellular protease expression in clinical isolates of Trichophyton tonsurans.

Tinea capitis continues to be an overwhelmingly prevalent disease in children. Despite the fact that it was recognized over a century ago, the factors that dictate the divergent clinical presentations seen with tinea capitis (e.g., carrier state, chronic non-inflammatory infection, acute severely-inflammatory infection) remain unknown. Given the pathogenic role of exocellular proteases in dermatophyte infections and their potential immunogenic role, this investigation was designed to characterize strain-specific variability in fungal protease expression and activity in Trichophyton tonsurans isolates identified from children with tinea capitis.

Histopathological studies on neoplasms in the genital tract of female donkeys in Egypt.

The genital tracts of 165 female donkeys were collected and examined with special concern to neoplasms. Ovarian Neoplasms were found in 12 cases (7.72%). A granulosa cell tumor was found in one case (0.61%). A cavernous haemangioma was found in 11 cases (6.67%). Uterine neoplasms were found in 14 cases (8.84%). Endometrial polyps and fibroleiomyoma were found in one case (0.61%) each. Leiomyoma was found in 2 cases (1.21%). Cavernous haemangioma was found in 10 cases (6.06%), and cervical polyps in 5 cases (3.03%).

Voriconazole: a new triazole antifungal.

OBJECTIVE: To review the currently available information on the pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of voriconazole. Comparative data for voriconazole and other azole antifungal agents are described where available. DATA SOURCES: A MEDLINE search restricted to English-language articles (1966 to September 1999) was conducted, and an extensive review of journals and meeting abstracts was performed. MeSH headings included itraconazole, fluconazole, voriconazole, UK-109,496, and amphotericin B. DATA EXTRACTION: The data on pharmacokinetics, adverse effects, and drug interactions were obtained from open-label and controlled studies and case reports. Controlled studies and case reports were evaluated to demonstrate the efficacy of voriconazole in treatment of various fungal infections. DATA SYNTHESIS: Voriconazole is a derivative of fluconazole that demonstrates enhanced in vitro activity against existent and emerging fungal pathogens. Limited data have revealed a favorable pharmacokinetic and safety profile for the agent. Moreover, select clinical trials and case studies of voriconazole suggest good in vivo efficacy against several fungal pathogens including Candida, Aspergillus, and Scedosporium. CONCLUSIONS: Voriconazole has shown promise in the treatment of superficial and systemic mycoses. While several unresolved issues remain, voriconazole may be a viable therapeutic alternative for fluconazole-resistant mucocutaneous candidiasis and in cases of mild to moderate systemic mycoses requiring chronic treatment or that are refractory to currently available agents.

Single dose pharmacokinetics of pleconaril in neonates. Pediatric Pharmacology Research Unit Network.

BACKGROUND: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection. METHODS: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). RESULTS: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different. CONCLUSIONS: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.

An investigation of the intradermal route as an effective means of immunization for microparticulate vaccine delivery systems.

Among the common routes of parenteral immunization, the skin is the only site that can function as an immune organ. Skin-associated lymphoid tissue contains specialized cells that enhance the immune response. The intercellular space in the skin interstitium provides a connection to the lymphatic capillaries and vessels that terminate in peripheral immune organs like the lymph nodes and spleen. The potential of intradermal immunization with microparticulate vaccine delivery systems was investigated in this study. The microparticulates used were muramyl dipeptide (MDP) loaded ovalbumin microspheres (OVA-MSs) and fluorescent latex microspheres of fixed sizes of 2.3 and 2.1 microm diameter, respectively. Similar doses of OVA-MSs were injected subcutaneously (s.c.) and intradermally (i.d.) in mice. The induced OVA-specific IgG antibody immune response was found to be significantly higher in i.d. immunized mice as compared to those injected s.c. The sc and i.d. administration of fluorescent latex microspheres in mice demonstrated that the uptake and translocation of microspheres from the site of injection depends primarily upon the surface area of the microspheres. The enhancement in antibody production upon i.d. administration was explained on the basis of (i) an increased surface area of microspheres and a lower number of microspheres per injection site, and (ii) an increased probability of interaction with the immune cells of the skin. Efficient lymph node targeting observed from the id administered microspheres may be the result of both of these factors. The results of this study demonstrated that the intradermal route is an effective means of immunization for microparticulate vaccine delivery systems, requiring lower doses and resulting in a higher immune response as compared to the traditionally used sc route.