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1.
BJUI Compass ; 2(2): 126-133, 2021 Mar.
Article in English | MEDLINE | ID: mdl-35474889

ABSTRACT

Objectives: To study high-frequency 29 MHz transrectal side-fire micro-ultrasound (micro-US) for the detection of clinically significant prostate cancer (csPCa) on prostate biopsy, and validate an image interpretation protocol for micro-US imaging of the prostate. Materials and methods: A prospective randomized clinical trial was performed where 1676 men with indications for prostate biopsy and without known prostate cancer were randomized 1:1 to micro-US vs conventional end-fire ultrasound (conv-US) transrectal-guided prostate biopsy across five sites in North America. The trial was split into two phases, before and after training on a micro-US image interpretation protocol that was developed during the trial using data from the pre-training micro-US arm. Investigators received a standardized training program mid-trial, and the post-training micro-US data were used to examine the training effect. Results: Detection of csPCa (the primary outcome) was no better with the first-generation micro-US system than with conv-US in the overall population (34.6% vs 36.6%, respectively, P = .21). Data from the first portion of the trial were, however, used to develop an image interpretation protocol termed PRI-MUS in order to address the lack of understanding of the appearance of cancer under micro-US. Micro-US sensitivity in the post-training group improved to 60.8% from 24.6% (P < .01), while specificity decreased (from 84.2% to 63.2%). Detection of csPCa in the micro-US arm increased by 7% after training (32% to 39%, P < .03), but training instituted mid-trial did not affect the overall results of the comparison between arms. Conclusion: Micro-US provided no clear benefit over conv-US for the detection of csPCa at biopsy. However, it became evident during the trial that training and increasing experience with this novel technology improved the performance of this first-generation system.

2.
Regul Toxicol Pharmacol ; 70(3): 673-80, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25455223

ABSTRACT

Fluopyram, a broad spectrum fungicide, caused an increased incidence of thyroid follicular cell (TFC) adenomas in males at the highest dose evaluated (750ppm equating to 105mg/kg/day) in the mouse oncogenicity study. A series of short-term mechanistic studies were conducted in the male mouse to characterize the mode of action (MOA) for the thyroid tumor formation and to determine if No Observed Effect Levels (NOELs) exist for each key event identified. The proposed MOA consists of an initial effect on the liver by activating the constitutive androstane (Car) and pregnane X (Pxr) nuclear receptors causing increased elimination of thyroid hormones followed by an increased secretion of thyroid stimulating hormone (TSH). This change in TSH secretion results in an increase of TFC proliferation which leads to hyperplasia and eventually adenomas after chronic exposure. Car/Pxr nuclear receptors were shown to be activated as indicated by increased activity of specific Phase I enzymes (PROD and BROD, respectively). Furthermore, evidence of increased T4 metabolism was provided by the induction of phase II enzymes known to preferentially use T4 as a substrate. Additional support for the proposed MOA was provided by demonstrating increased Tsh ß transcripts in the pituitary gland. Finally, increased TFC proliferation was observed after 28days of treatment. In these dose-response studies, clear NOELs were established for phase 2 liver enzyme activities, TSH changes and TFC proliferation. Furthermore, compelling evidence for Car/Pxr activation being the molecular initiating event for these thyroid tumors was provided by the absence of the sequential key events responsible for the TCF tumors in Car/Pxr KO mice when exposed to fluopyram. In conclusion, fluopyram thyroid toxicity is mediated by activation of hepatic Car/Pxr receptors and shows a threshold dependent MOA.


Subject(s)
Benzamides/toxicity , Fungicides, Industrial/toxicity , Pyridines/toxicity , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Thyroid Neoplasms/metabolism , Animals , Cell Proliferation/drug effects , Constitutive Androstane Receptor , Cytochrome P-450 Enzyme System/metabolism , Liver/drug effects , Liver/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , No-Observed-Adverse-Effect Level , Pituitary Gland/drug effects , Pituitary Gland/metabolism , Pregnane X Receptor , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Steroid/genetics , Thyroid Gland/cytology , Thyroid Gland/drug effects , Thyrotropin/blood , Thyrotropin/genetics , Thyrotropin/metabolism , Thyroxine/blood
3.
Regul Toxicol Pharmacol ; 70(3): 648-58, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25305127

ABSTRACT

Fluopyram is a broad spectrum fungicide targeting plant pathogenic fungi (eg. white dot, black mold, botrytis). During the general toxicity evaluation of fluopyram in rodents, the liver was identified as a target organ (hepatomegaly and liver hypertrophy were observed in all studies). At the end of the guideline carcinogenicity study, an increased incidence of hepatocellular adenomas and carcinomas was observed in female Wistar rats following exposure to the highest fluopyram dose evaluated (1500ppm). Short-term mechanistic studies (3, 7 or 28days of exposure) were conducted in the female rat to identify the initial key events responsible for the tumor formation and to establish thresholds for each of the early hepatic changes. Increased expression of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) inducible genes was recorded after each exposure period. Further confirmation of CAR/PXR activation was provided by increased activity of specific Phase I enzymes (PROD/BROD respectively). Increased hepatocellular proliferation (measured by Ki67) was observed after each exposure period with the greatest proliferative response occurring after 3days of treatment. In these studies, dose responses and clear thresholds were established for gene expression, enzyme activity and cell proliferation. Furthermore, these early hepatic changes were shown to be reversible following compound withdrawal. Other modes of action for liver tumor formation such as DNA damage, cytotoxicity and peroxisome proliferation were excluded during the investigations. In conclusion, fluopyram is a threshold carcinogen and the resultant hepatocellular carcinomas in the female rat are due to hepatocellular proliferation mediated by CAR/PXR activation.


Subject(s)
Adenoma, Liver Cell/metabolism , Benzamides/toxicity , Carcinoma, Hepatocellular/metabolism , Fungicides, Industrial/toxicity , Liver Neoplasms/metabolism , Pyridines/toxicity , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Steroid/metabolism , Adenoma, Liver Cell/chemically induced , Animals , Carcinoma, Hepatocellular/chemically induced , Constitutive Androstane Receptor , Cytochrome P-450 Enzyme System/metabolism , Female , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Neoplasms/chemically induced , Microsomes, Liver/metabolism , No-Observed-Adverse-Effect Level , Organ Size/drug effects , Pregnane X Receptor , Rats , Rats, Wistar
4.
Int J Immunopathol Pharmacol ; 25(4): 1121-30, 2012.
Article in English | MEDLINE | ID: mdl-23298502

ABSTRACT

This study sought to determine the appropriate starting dose of colchicine in children aged 2 to 4 years with familial Mediterranean fever (FMF) based on steady-state pharmacokinetics in pediatric patients with FMF from 2 to less than 16 years and adult patients with FMF from 16 to 65 years. Outpatients received colchicine for 90 days starting with a fixed dose for 14 days (blood sampling days 14 and 15). After starting doses of colchicine (0.6 mg/day [2 to less than 4 years], 0.9 mg/day [from 4 to less than 6 years], 0.9 mg/day [from 6 to less than 12 years], 1.2 mg/day [from 12 to less than 16 years], and 1.2 mg/day [from 16 to less than 65 years]), the observed steady-state pharmacokinetic parameters were comparable across age groups, despite the higher doses of colchicine on a mg/kg/day basis in the younger age groups. An exception occurred with once-daily colchicine, whereby mean Cmax for colchicine was higher in patients 4 to less than 6 years (9.4 ng/mL) compared with the younger and older age groups (6.1-6.7 ng/mL). Mean AUC0?24h values in children 2 to less than 4, 6 to less than 12, and 12 to less than 16 years were similar to those in adults. However, mean AUC0?24h values in children 4 to less than 6 years were 25 percent higher than those observed in adults. The results show that the recommended starting dose for children 2-4 years and 4-6 years should be 0.6 mg/day (half the US adult dose). Children aged 6 to less than 12 years should receive 0.9 mg/day (i.e. three-quarters of the US adult dose). The safety of colchicine in children 2 to less than 4 years was comparable to that in older children and adults.


Subject(s)
Colchicine/pharmacokinetics , Familial Mediterranean Fever/drug therapy , Adolescent , Adult , Aged , Child , Child, Preschool , Colchicine/administration & dosage , Colchicine/adverse effects , Female , Humans , Male , Middle Aged
5.
Int J Fertil Womens Med ; 45(4): 264-72, 2000.
Article in English | MEDLINE | ID: mdl-10997482

ABSTRACT

OBJECTIVE: To compare the clinical effects of a new oral synthetic conjugated estrogens, A (SCE), versus placebo in a clinically relevant population on the reduction in the mean number of moderate to severe vasomotor symptoms. DESIGN: A total of 120 healthy pre- and postmenopausal women (72 active, 48 placebo) were enrolled into a randomized, placebo-controlled, double-blind, multi-center clinical trial. Women of all races were enrolled, using minimal inclusion and exclusion criteria. Each subject received either orally administered SCE, in doses of 0.3 mg, 0.625 mg or 1.25 mg per day, or placebo. Analysis of variance was performed on the primary efficacy variable (change from baseline to weeks 4, 8, and 12 in the mean number of moderate to severe vasomotor symptoms). RESULTS: Changes in moderate to severe vasomotor symptoms in the intent to treat population showed statistically significant differences between the active and placebo treatments at week 4 (P < .022), week 8 (P < .010), and week 12 (P < .010). By week 12, the mean percentage reduction in moderate to severe vasomotor symptoms was 81%, from an average baseline of 96.8, to 16.5 hot flashes per week for the active treatment group. The overall incidence of expected estrogen-related adverse effects was modest. Laboratory tests and vital sign measurements did not reveal clinically significant changes or abnormalities from screening to the final visit in either treatment group. CONCLUSIONS: The results of this study confirm the efficacy and safety of SCE in the treatment of moderate to severe vasomotor symptoms in menopausal women. In addition, the study also demonstrated that the use of more liberal entry criteria did not materially affect the efficacy outcome.


Subject(s)
Estradiol Congeners/pharmacology , Hot Flashes/drug therapy , Menopause , Vasomotor System/drug effects , Administration, Oral , Adult , Aged , Double-Blind Method , Estradiol Congeners/administration & dosage , Estradiol Congeners/therapeutic use , Female , Humans , Middle Aged , Safety , Time Factors , Treatment Outcome
6.
Regul Toxicol Pharmacol ; 31(1): 59-67, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10715225

ABSTRACT

The aim of this study was to determine the effects of olestra and sorbitol consumption on three accepted objective measures of diarrhea (stool output >250 g/day, liquid/watery stools, bowel movement frequency >3/day), and how stool composition influences reports of common gastrointestinal symptoms. A double-blind, placebo-controlled study compared the effects of sorbitol (40 g/day in candy), a poorly absorbed sugar-alcohol with known osmotic effects, with those of olestra (20 or 40 g/day in potato chips), a nonabsorbed fat, on objective measures of stool composition and GI symptoms. Sixty-six subjects resided on a metabolic ward for 12 days: 2 days lead-in, 4 days baseline, 6 days treatment. Sorbitol 40 g/day resulted in loose/liquid stools within 1-3 h of consumption. In contrast, olestra resulted in a dose-responsive stool softening effect after 2-4 days of consumption. Subjects reported "diarrhea" when mean stool apparent viscosity (peak force (PF), g) decreased from a perceived "normal" (mean +/- SE, 1355 +/- 224 g PF; firm stool) to loose (260 +/- 68 g PF) stool. Mean apparent viscosity of stool during treatment: placebo, 1363 +/- 280 g (firm); olestra 20 g/day 743 +/- 65 g (soft); olestra 40 g/day, 563 +/- 105 g (soft); and sorbitol 40 g/day, 249 +/- 53 g (loose). Of the 1098 stool samples collected, 38% (419/1098) were rated by subjects as "diarrhea," yet only 2% of treatment days (all in the sorbitol treatment group) met commonly accepted criteria for a clinical diarrhea. Sorbitol, but not olestra, increased the severity of abdominal cramping, urgency and nausea compared to placebo. Olestra consumption, at levels far in excess of normal snacking conditions, resulted in a gradual stool softening effect after several days of consumption, did not meet any of the three objective measures of diarrhea, and did not increase GI symptoms. Sorbitol consumption, at only 80% of the dose requiring a "laxative effect" information label, resulted in rapid onset loose/liquid stools and a significant increase in abdominal cramping, urgency and nausea. Overall, subjects categorized stool as "diarrhea" when stool decreased from their perceived "normal," but the vast majority of these reports were not associated with clinically significant diarrhea.


Subject(s)
Diarrhea/chemically induced , Fat Substitutes/adverse effects , Fatty Acids/adverse effects , Gastrointestinal Diseases/chemically induced , Sorbitol/adverse effects , Sucrose/analogs & derivatives , Adolescent , Adult , Aged , Defecation/drug effects , Double-Blind Method , Electrolytes/metabolism , Feces , Female , Humans , Male , Middle Aged , Muscle Cramp/chemically induced , Sucrose/adverse effects , Viscosity , Water/analysis
7.
Ann Emerg Med ; 26(5): 652-5, 1995 Nov.
Article in English | MEDLINE | ID: mdl-7486378

ABSTRACT

Heart transplantation has become a highly successful, life-saving treatment for a number of otherwise fatal heart diseases. A major limiting factor in the growth of transplantation surgery has been the relative lack of suitable donor organs, and the appropriate criteria for selection of donor organs have been a topic of significant interest. Despite relatively favorable survival rates in the few patients who have received organs from victims of many types of poisonings and drug overdoses, patients dying of toxicologic causes are not usually considered suitable organ donors. Some centers routinely reject such individuals. Criteria for donor selection continue to be vague, unclear, or nonexistent in regard to organ transplantation from victims of all types of poisoning and toxic exposures. Carbon monoxide (CO) is a ubiquitous poison, and although victims of CO poisoning have occasionally served as suitable organ donors, heart transplantation in this scenario is still a very rare event. We describe the successful transplantation of the heart from a CO poisoning victim--to our knowledge, only the third such transplantation. Because the emergency department is a critical site for organ procurement, emergency physicians must be aware that patients dying of CO exposure may be acceptable organ donors.


Subject(s)
Carbon Monoxide Poisoning/complications , Heart Transplantation , Tissue and Organ Procurement/methods , Adult , Brain Death/diagnosis , Emergency Service, Hospital , Fatal Outcome , Follow-Up Studies , Humans , Male , Middle Aged , Patient Selection , Tissue Donors
8.
Pediatr Emerg Care ; 11(2): 109-11, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7596870

ABSTRACT

We present a case of a six-week-old infant who developed life-threatening complications after unintentional sodium bicarbonate intoxication. Baking soda was being used by the mother as a home remedy to "help the baby burp." A review of the literature regarding the use (or misuse) of baking soda follows. Our patient, along with the other noted case reports, emphasizes the need for warnings on baking soda products whose labels recommend its use as an antacid. Poisonings must be high in the differential diagnosis of any patient, regardless of age, who presents with altered mental status or status epilepticus.


Subject(s)
Medicine, Traditional , Sodium Bicarbonate/poisoning , Drug Labeling , Female , Humans , Hypernatremia/chemically induced , Infant , Infant Care , Poisoning/therapy
9.
Pediatr Emerg Care ; 10(6): 344-6, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7899121

ABSTRACT

Physicians who prescribe viscous lidocaine preparations should be aware of the adverse effects and the high risk for overdose in pediatric patients. Owing to altered pharmacokinetics (increased absorption, decreased clearance, and prolonged half-life), doses that are innocuous for adults may present a significant potential toxic hazard in children. Lidocaine should not be used to treat painful mouth lesions in children until further safety data are available. Benzocaine may be considered as a safe alternative to lidocaine. Its low incidence of side effects makes it a safer choice for infants and children. If no other choices are appropriate, then very specific instructions should be given to parents. The amount, frequency, maximum daily dose, and mode of administration should be clearly communicated (eg, cotton pledget to individual lesions, one-half dropper to each cheek every four hours, or 20 minutes before meals). They should never be prescribed on a "PRN" basis.


Subject(s)
Lidocaine/poisoning , Acute Disease , Administration, Topical , Drug Overdose , Humans , Infant , Infant, Newborn , Lidocaine/pharmacokinetics , Lidocaine/therapeutic use , Male , Pain/drug therapy , Stomatitis, Herpetic/physiopathology
11.
Pediatr Emerg Care ; 8(2): 82-3, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1603706

ABSTRACT

An 11-week-old infant experienced toxicity following the intranasal instillation of a four percent cocaine solution in preparation for an examination to rule out choanal stenosis. The child recovered fully but required the use of anticonvulsants and admission to the hospital. To our knowledge, this is the first case report where cocaine toxicity was experienced following this routine practice. We present our case and a review of the literature involving other instances where there have been complications with the use of topical cocaine. This report should alert the medical community to the potential complications of using topical cocaine for its anesthetic properties.


Subject(s)
Anesthesia, Local , Cocaine/adverse effects , Administration, Intranasal , Choanal Atresia/diagnosis , Female , Heart Rate/drug effects , Humans , Infant , Seizures/chemically induced , Solutions
12.
J Toxicol Clin Toxicol ; 30(1): 39-48, 1992.
Article in English | MEDLINE | ID: mdl-1542148

ABSTRACT

We studied five children with carbamazepine overdose. Two patients had acute overdose without previous exposure to carbamazepine while three presented with acute-on-chronic overdose. Multiple doses of activated charcoal were administered to four patients. One acute-on-chronic patient did not receive any activated charcoal. The mean half-life of carbamazepine was as follows: a) Acute vs. Acute-On-Chronic overdose: 8.63 h vs. 12.01 h (p less than 0.05); b) No Activated Charcoal vs. 30-50 g Activated Charcoal vs. 60-90 g Activated Charcoal: 23.3 h vs. 10.17 h vs. 7.21 h (p less than 0.05); c) No Activated Charcoal vs. 2-3 doses vs. 7-12 doses: 23.3 h vs. 8.96 h vs 7.55 h (ns). Although the half-life of carbamazepine decreased in a linear relationship with the total amount of activated charcoal administered (r = -0.86), there was no relationship between the time to complete recovery and administration of multiple doses of activated charcoal. Although multiple doses of activated charcoal increased the clearance of carbamazepine in our patients with overdose, it was not associated with clinical benefits.


Subject(s)
Carbamazepine/poisoning , Charcoal/therapeutic use , Acute Disease , Adolescent , Carbamazepine/pharmacokinetics , Charcoal/administration & dosage , Child, Preschool , Chronic Disease , Dose-Response Relationship, Drug , Drug Overdose/therapy , Female , Half-Life , Humans , Infant , Male
17.
J Emerg Med ; 7(6): 627-31, 1989.
Article in English | MEDLINE | ID: mdl-2696752

ABSTRACT

Superwarfarins consist of two classes of compounds, the 4-hydroxycoumarins and the indandiones. These compounds have replaced warfarin as an anticoagulant rodenticide. This article is a summary of the clinical effects produced by accidental and deliberate ingestions of superwarfarins. Most accidental ingestions occur in childhood and result in a benign outcome. Deliberate overdoses usually involve repeated ingestions of large quantities of superwarfarins that have resulted in prolonged laboratory evidence of interference with clotting; serious bleeding has been rare. This article suggests an approach to the management of patients with accidental and deliberate anticoagulant rodenticide ingestions.


Subject(s)
Rodenticides/poisoning , 4-Hydroxycoumarins/poisoning , Adolescent , Adult , Female , Humans , Male
18.
19.
Ann Emerg Med ; 18(6): 696-700, 1989 Jun.
Article in English | MEDLINE | ID: mdl-2729698

ABSTRACT

We report the case of a 5-month-old girl who was given an adult Fleet enema by her mother because of her concern that the baby was constipated. Within minutes the child became extremely ill. She developed shock, hyperphosphatemia, hypocalcemia, and acidosis. This case is presented to demonstrate that life-threatening events may result after the injudicious use of enemas in children.


Subject(s)
Acidosis/etiology , Enema/adverse effects , Hypocalcemia/etiology , Phosphates/adverse effects , Phosphates/blood , Shock/etiology , Acidosis/blood , Acidosis/therapy , Emergencies , Female , Fluid Therapy , Humans , Hypocalcemia/blood , Hypocalcemia/therapy , Infant , Shock/blood , Shock/therapy , Time Factors
20.
Prosthet Orthot Int ; 12(2): 101-2, 1988 Aug.
Article in English | MEDLINE | ID: mdl-3174406

ABSTRACT

In view of the importance of squatting and cross-legged sitting in the activities of daily living in Asian and African countries, a multiaxial orthotic hip joint has been developed which when fitted to a Hip-Knee-Ankle-Foot-Orthosis (HKAFO) can permit the user to squat and sit cross-legged. The design consists of a modified ball and socket joint.


Subject(s)
Ankle , Foot , Hip Prosthesis , Knee , Orthotic Devices , Prosthesis Design , Equipment Design , Humans , Posture
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