Clinical nephrotoxicity of tobramycin and gentamicin. A prospective study.

Nearly 3.2 million people in this country receive aminoglycoside antibiotics annually. Gentamicin sulfate and tobramycin sulfate continue to demonstrate ototoxicity and nephrotoxicity in both animal and clinical studies. In this study, 62 patients with confirmed initial normal renal function and treated with 2 to 5 mg/kg/day of gentamicin sulfate or tobramycin sulfate for a minimum of seven days were followed up prospectively for the development of aminoglycoside-related renal failure, defined as at least a one-third reduction in renal function. In these 62 patients, no other causes for renal failure could be identified. Five of 33 (15%) of the tobramycin-treated patients and 16 of 29 (55.2%) of the gentamicin-treated patients had renal failure. Thus, gentamicin was associated with renal failure more than three times as often as was tobramycin.

nephrotoxicity

tobramycin

gentamicin

aminoglycoside

Gentamicin sulfate

tobramycin sulfate

ototoxicity

nephrotoxicity

gentamicin sulfate

tobramycin sulfate

aminoglycoside

renal failure

renal failure

tobramycin

gentamicin

renal failure

gentamicin

renal failure

tobramycin


Neuroprotective action of MPEP, a selective mGluR5 antagonist, in methamphetamine-induced dopaminergic neurotoxicity is associated with a decrease in dopamine outflow and inhibition of hyperthermia in rats.

The aim of this study was to examine the role of metabotropic glutamate receptor 5 (mGluR5) in the toxic action of methamphetamine on dopaminergic neurones in rats. Methamphetamine (10 mg/kg sc), administered five times, reduced the levels of dopamine and its metabolites in striatal tissue when measured 72 h after the last injection. A selective antagonist of mGluR5, 2-methyl-6-(phenylethynyl)pyridine (MPEP; 5 mg/kg ip), when administered five times immediately before each methamphetamine injection reversed the above-mentioned methamphetamine effects. A single MPEP (5 mg/kg ip) injection reduced the basal extracellular dopamine level in the striatum, as well as dopamine release stimulated either by methamphetamine (10 mg/kg sc) or by intrastriatally administered veratridine (100 microM). Moreover, it transiently diminished the methamphetamine (10 mg/kg sc)-induced hyperthermia and reduced basal body temperature. MPEP administered into the striatum at high concentrations (500 microM) increased extracellular dopamine levels, while lower concentrations (50-100 microM) were devoid of any effect. The results of this study suggest that the blockade of mGluR5 by MPEP may protect dopaminergic neurones against methamphetamine-induced toxicity. Neuroprotection rendered by MPEP may be associated with the reduction of the methamphetamine-induced dopamine efflux in the striatum due to the blockade of extrastriatal mGluR5, and with a decrease in hyperthermia.

MPEP

methamphetamine

neurotoxicity

dopamine

hyperthermia

glutamate

methamphetamine

Methamphetamine

dopamine

MPEP

methamphetamine

methamphetamine

MPEP

dopamine

dopamine

methamphetamine

veratridine

methamphetamine

hyperthermia

MPEP

dopamine

MPEP

methamphetamine

toxicity

MPEP

methamphetamine

dopamine

hyperthermia


Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl.

OBJECTIVE: In vitro work has demonstrated that cinacalcet is a strong inhibitor of cytochrome P450 isoenzyme (CYP) 2D6. The purpose of this study was to evaluate the effect of cinacalcet on CYP2D6 activity, using desipramine as a probe substrate, in healthy subjects. METHODS: Seventeen subjects who were genotyped as CYP2D6 extensive metabolizers were enrolled in this randomized, open-label, crossover study to receive a single oral dose of desipramine (50 mg) on two separate occasions, once alone and once after multiple doses of cinacalcet (90 mg for 7 days). Blood samples were obtained predose and up to 72 h postdose. RESULTS: Fourteen subjects completed both treatment arms. Relative to desipramine alone, mean AUC and C(max) of desipramine increased 3.6- and 1.8-fold when coadministered with cinacalcet. The t (1/2,z) of desipramine was longer when desipramine was coadministered with cinacalcet (21.0 versus 43.3 hs). The t (max) was similar between the regimens. Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33 versus 86%), the most frequent of which (nausea and headache) have been reported for patients treated with either desipramine or cinacalcet. CONCLUSION: This study demonstrates that cinacalcet is a strong inhibitor of CYP2D6. These data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for drugs that demonstrate a narrow therapeutic index and are metabolized by CYP2D6.

desipramine HCl

cinacalcet HCl

cinacalcet

cinacalcet

desipramine

desipramine

cinacalcet

desipramine

desipramine

cinacalcet

desipramine

desipramine

cinacalcet

desipramine

desipramine

cinacalcet

nausea

headache

desipramine

cinacalcet

cinacalcet

cinacalcet


Proteomic analysis of striatal proteins in the rat model of L-DOPA-induced dyskinesia.

L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson's disease (PD) patients after a prolonged treatment with L-DOPA. To this day, transcriptome analysis has been performed in a rat model of LID [Neurobiol. Dis., 17 (2004), 219] but information regarding the proteome is still lacking. In the present study, we investigated the changes occurring at the protein level in striatal samples obtained from the unilaterally 6-hydroxydopamine-lesion rat model of PD treated with saline, L-DOPA or bromocriptine using two-dimensional difference gel electrophoresis and mass spectrometry (MS). Rats treated with L-DOPA were allocated to two groups based on the presence or absence of LID. Among the 2000 spots compared for statistical difference, 67 spots were significantly changed in abundance and identified using matrix-assisted laser desorption/ionization time-of-flight MS, atmospheric pressure matrix-assisted laser desorption/ionization and HPLC coupled tandem MS (LC/MS/MS). Out of these 67 proteins, LID significantly changed the expression level of five proteins: alphabeta-crystalin, gamma-enolase, guanidoacetate methyltransferase, vinculin, and proteasome alpha-2 subunit. Complementary techniques such as western immunoblotting and immunohistochemistry were performed to investigate the validity of the data obtained using the proteomic approach. In conclusion, this study provides new insights into the protein changes occurring in LID.

L-DOPA

dyskinesia

L-DOPA

dyskinesia

LID

Parkinson's disease

PD

L-DOPA

LID

PD

L-DOPA

bromocriptine

L-DOPA

LID

LID

LID


Pseudo-allergic reactions to corticosteroids: diagnosis and alternatives.

Two patients treated with parenteral paramethasone (Triniol) and dexamethasone (Sedionbel) are described. A few minutes after administration of the drugs, they presented urticaria (patients 1 and 2) and conjunctivitis (patient 1). The purpose of our study was to determine the cause of the patients' reactions, the immunological mechanisms involved and whether these patients would be able to tolerate any kind of corticoid. Clinical examinations and skin, oral and parenteral challenges with different corticosteroids and ELISA tests were performed. In the two patients, skin and ELISA tests with paramethasone were negative, as was the prick test with each of its excipients. A single-blind parenteral challenge with Triniol was positive in both patients after the administration of 1 ml of the drug, and negative with its excipients. We also carried out oral and parenteral challenges with other corticosteroids and found intolerance to some of them. These results suggest that paramethasone caused pseudoallergic reactions in our patients. Corticosteroids different from paramethasone also produced hypersensitivity reactions in these patients; however, a few of them were tolerated. The basic mechanisms of those reactions are not yet fully understood. To our knowledge, this is the first report of a pseudo-allergy caused by paramethasone.

allergic reactions

corticosteroids

paramethasone

dexamethasone

urticaria

conjunctivitis

corticosteroids

paramethasone

corticosteroids

paramethasone

paramethasone

hypersensitivity

allergy

paramethasone


Valproic acid induced encephalopathy--19 new cases in Germany from 1994 to 2003--a side effect associated to VPA-therapy not only in young children.

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well-tolerated. Rare serious complications may occur in some patients, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity and VPA-induced encephalopathy. The typical signs of VPA-induced encephalopathy are impaired consciousness, sometimes marked EEG background slowing, increased seizure frequency, with or without hyperammonemia. There is still no proof of causative effect of VPA in patients with encephalopathy, but only of an association with an assumed causal relation. We report 19 patients with VPA-associated encephalopathy in Germany from the years 1994 to 2003, none of whom had been published previously.

Valproic acid

encephalopathy

VPA

Valproic acid

VPA

pancreatitis

bone marrow suppression

VPA

hepatotoxicity

VPA

encephalopathy

VPA

encephalopathy

impaired consciousness

seizure

hyperammonemia

VPA

encephalopathy

VPA

encephalopathy


Haemolytic-uraemic syndrome after treatment with metronidazole.

This paper describes the clinical features of six children who developed the haemolytic-uraemic syndrome after treatment with metronidazole. These children were older and were more likely to have undergone recent bowel surgery than are other children with this condition. While the involvement of metronidazole in the aetiology of the haemolytic-uraemic syndrome is not established firmly, the action of this drug in sensitizing tissues to oxidation injury and the reported evidence of oxidation changes in the haemolytic-uraemic syndrome suggest a possible link between metronidazole treatment and some cases of the haemolytic-uraemic syndrome.

Haemolytic-uraemic syndrome

metronidazole

haemolytic-uraemic syndrome

metronidazole

metronidazole

haemolytic-uraemic syndrome

haemolytic-uraemic syndrome

metronidazole

haemolytic-uraemic syndrome


Risk factors of sensorineural hearing loss in preterm infants.

Among 547 preterm infants of < or = 34 weeks gestation born between 1987 and 1991, 8 children (1.46%) developed severe progressive and bilateral sensorineural hearing loss. Perinatal risk factors of infants with hearing loss were compared with those of two control groups matched for gestation and birth weight and for perinatal complications. Our observations demonstrated an association of hearing loss with a higher incidence of perinatal complications. Ototoxicity appeared closely related to a prolonged administration and higher total dose of ototoxic drugs, particularly aminoglycosides and furosemide. Finally, we strongly recommend to prospectively and regularly perform audiologic assessment in sick preterm children as hearing loss is of delayed onset and in most cases bilateral and severe.

sensorineural hearing loss

sensorineural hearing loss

hearing loss

hearing loss

Ototoxicity

ototoxic

aminoglycosides

furosemide

hearing loss


Pharmacokinetic and clinical studies in patients with cimetidine-associated mental confusion.

15 cases of cimetidine-associated mental confusion have been reported. In order that this syndrome might be investigated changes in mental status (M.S.) were correlated with serum concentrations and renal and hepatic function in 36 patients, 30 patients had no M.S. change on cimetidine and 6 had moderate to severe changes. These 6 patients had both renal and liver dysfunction (P less than 0.05), as well as cimetidine trough-concentrations of more than 1.25 microgram/ml (P less than 0.05). The severity of M.S. changes increased as trough-concentrations rose, 5 patients had lumbar puncture. The cerebrospinal fluid: serum ratio of cimetidine concentrations was 0.24:1 and indicates that cimetidine passes the blood-brain barrier; it also raises the possibility that M.S. changes are due to blockade of histamine H2-receptors in the central nervous system. Patients likely to have both raised trough-concentrations and mental confusion are those with both severe renal and hepatic dysfunction. They should be closely observed and should be given reduced doses of cimetidine.

cimetidine

confusion

cimetidine

confusion

cimetidine

renal and liver dysfunction

renal dysfunction

liver dysfunction

cimetidine

cimetidine

cimetidine

histamine

confusion

renal and hepatic dysfunction

renal dysfunction

hepatic dysfunction

cimetidine


Different lobular distributions of altered hepatocyte tight junctions in rat models of intrahepatic and extrahepatic cholestasis.

Hepatocyte tight junctions (TJs), the only intercellular barrier between the sinusoidal and the canalicular spaces, play a key role in bile formation. Although hepatocyte TJs are impaired in cholestasis, attempts to localize the precise site of hepatocyte TJ damage by freeze-fracture electron microscopy have produced limited information. Recently, several TJ-associated proteins like ZO-1 and 7H6 have been identified and characterized. Immunolocalization of 7H6 appears to closely correlate with paracellular permeability. We used rat models of intrahepatic cholestasis by ethinyl estradiol (EE) treatment and extrahepatic cholestasis by bile duct ligation (BDL) to precisely determine the site of TJ damage. Alterations in hepatocyte TJs were assessed by double-immunolabeling for 7H6 and ZO-1 using a confocal laser scanning microscope. In control rats, immunostaining for 7H6 and ZO-1 colocalized to outline bile canaliculi in a continuous fashion. In contrast, 7H6 and ZO-1 immunostaining was more discontinuous, outlining the bile canaliculi after BDL. Immunostaining for 7H6, not ZO-1, decreased and predominantly appeared as discrete signals in the submembranous cytoplasm of periportal hepatocytes after BDL. After EE treatment, changes in immunostaining for 7H6 and ZO-1 were similar to those seen in periportal hepatocytes after BDL, but distributed more diffusely throughout the lobule. This study is the first to demonstrate that impairment of hepatocyte TJs occurs heterogenously in the liver lobule after BDL and suggests that BDL and EE treatments produce different lobular distributions of increased paracellular permeability.

intrahepatic cholestasis

extrahepatic cholestasis

cholestasis

intrahepatic cholestasis

ethinyl estradiol

EE

extrahepatic cholestasis

EE

EE


Long term audiological evaluation of beta-thalassemic patients.

OBJECTIVE: The objective of this study was to identify the incidence and to monitor the progression of hearing loss in children and young adults with beta-thalassemia major. METHODS: One hundred and four (104) patients aged 6-35 years (mean 17,2 years) participated in the study. All patients were on a regular transfusion-chelation program maintaining a mean hemoglobin level of 9.5 gr/dl. Subjects were receiving desferrioxamine (DFO) chelation treatment with a mean daily dose of 50-60 mg/kg, 5-6 days a week during the first six years of the study, which was then reduced to 40-50 mg/kg for the following eight years. Patients were followed for 8-14 years. RESULTS: Overall, 21 out of 104 patients (20.2%) presented with high frequency sensorineural hearing loss (SNHL), either unilateral or bilateral. No ototoxic factor, other than DFO, was present in any of the patients. Patients with SNHL presented with relatively lower serum ferritin levels than those with normal hearing, however, no statistically significant difference was observed. Subjects with SNHL were submitted to DFO reduction or temporary withdrawal. Following intervention, 7 out of 21 affected patients recovered, 10 remained stable and 4 demonstrated aggravation. CONCLUSION: The findings are indicative of DFO's contributing role in the development of hearing impairment. Regular audiologic evaluation is imperative in all thalassemic patients so that early changes may be recognized and treatment may be judiciously adjusted in order to prevent or reverse hearing impairment.

beta-thalassemic

hearing loss

beta-thalassemia

desferrioxamine

DFO

sensorineural hearing loss

SNHL

ototoxic

DFO

SNHL

SNHL

DFO

DFO

hearing impairment

thalassemic

hearing impairment


Design and analysis of the HYPREN-trial: safety of enalapril and prazosin in the initial treatment phase of patients with congestive heart failure.

Since the introduction of angiotensin converting enzyme (ACE) inhibitors into the adjunctive treatment of patients with congestive heart failure, cases of severe hypotension, especially on the first day of treatment, have occasionally been reported. To assess the safety of the ACE inhibitor enalapril a multicenter, randomized, prazosin-controlled trial was designed that compared the incidence and severity of symptomatic hypotension on the first day of treatment. Trial medication was 2.5 mg enalapril or 0.5 prazosin. Subjects were 1210 inpatients with New York Heart Association (NYHA) functional class II and III. Patients who received enalapril experienced clinically and statistically significantly less symptomatic hypotension (5.2%) than the patients who received prazosin (12.9%). All patients recovered. It was concluded that treatment with enalapril was well tolerated and it is, therefore, unreasonable to restrict the initiation of treatment with enalapril to inpatients.

enalapril

prazosin

congestive heart failure

congestive heart failure

hypotension

ACE inhibitor

enalapril

prazosin

hypotension

enalapril

prazosin

enalapril

hypotension

prazosin

enalapril

enalapril


Antagonism between interleukin 3 and erythropoietin in mice with azidothymidine-induced anemia and in bone marrow endothelial cells.

Azidothymidine (AZT)-induced anemia in mice can be reversed by the administration of IGF-IL-3 (fusion protein of insulin-like growth factor II (IGF II) and interleukin 3). Although interleukin 3 (IL-3) and erythropoietin (EPO) are known to act synergistically on hematopoietic cell proliferation in vitro, injection of IGF-IL-3 and EPO in AZT-treated mice resulted in a reduction of red cells and an increase of plasma EPO levels as compared to animals treated with IGF-IL-3 or EPO alone. We tested the hypothesis that the antagonistic effect of IL-3 and EPO on erythroid cells may be mediated by endothelial cells. Bovine liver erythroid cells were cultured on monolayers of human bone marrow endothelial cells previously treated with EPO and IGF-IL-3. There was a significant reduction of thymidine incorporation into both erythroid and endothelial cells in cultures pre-treated with IGF-IL-3 and EPO. Endothelial cell culture supernatants separated by ultrafiltration and ultracentrifugation from cells treated with EPO and IL-3 significantly reduced thymidine incorporation into erythroid cells as compared to identical fractions obtained from the media of cells cultured with EPO alone. These results suggest that endothelial cells treated simultaneously with EPO and IL-3 have a negative effect on erythroid cell production.

azidothymidine

anemia

Azidothymidine

AZT

anemia

AZT

thymidine

thymidine


Interactive effects of variations in [Na]o and [Ca]o on rat atrial spontaneous frequency.

The effects of varying the extracellular concentrations of Na and Ca ([Na]o and [Ca]o) on both, the spontaneous beating and the negative chronotropic action of verapamil, were studied in the isolated rat atria. Basal frequency (BF) evaluated by surface electrogram was 223 +/- 4 beats/min. in control Krebs-Ringer containing 137 mM Na and 1.35 mM Ca (N). It decreased by 16 +/- 3% by lowering [Na]o to 78 mM (LNa), 23 +/- 2% by lowering simultaneously [Na]o to 78 mM and [Ca]o to 0.675 mM (LNa+LCa) and 31 +/- 5% by lowering [Na]o to 78 mM plus increasing [Ca]o to 3.6 mM (LNa+HCa). At normal [Na]o, decrease (0.675 mM) or increase (3.6 mM) of [Ca]o did not modify BF; a reduction of ten times (0.135 mM of normal [Ca]o was effective to reduce BF by 40 +/- 13%. All negative chronotropic effects were BF-dependent. Dose-dependent bradycardia induced by verapamil was potentiated by LNa, LCa, and HCa. Independent but not additive effects of Na and Ca are shown by decreases in the values of [verapamil]o needed to reduce BF by 30% (IC30) with the following order of inhibitory potency: LNa > LCa > HCa > N, resulting LNa+HCa similar to LNa. The [verapamil]o that arrested atrial beating (AC) was also potentiated with the order LNa = LNa+LCa = LNa+HCa = LCa > HCa = N. The results indicate that rat atrial spontaneous beating is more dependent on [Na]o than on [Ca]o in a range of +/- 50% of their normal concentration. Also the enhancement of verapamil effects on atrial beating was more pronounced at LNa than at LCa.(ABSTRACT TRUNCATED AT 250 WORDS)

Ca

Ca

Ca

verapamil

Ca

Ca

Ca

Ca

Ca

bradycardia

verapamil

Ca

verapamil

verapamil

Ca

verapamil


Sodium status influences chronic amphotericin B nephrotoxicity in rats.

The nephrotoxic potential of amphotericin B (5 mg/kg per day intraperitoneally for 3 weeks) has been investigated in salt-depleted, normal-salt, and salt-loaded rats. In salt-depleted rats, amphotericin B decreased creatinine clearance linearly with time, with an 85% reduction by week 3. In contrast, in normal-salt rats creatinine clearance was decreased but to a lesser extent at week 2 and 3, and in salt-loaded rats creatinine clearance did not change for 2 weeks and was decreased by 43% at week 3. All rats in the sodium-depleted group had histopathological evidence of patchy tubular cytoplasmic degeneration in tubules that was not observed in any normal-salt or salt-loaded rat. Concentrations of amphotericin B in plasma were not significantly different among the three groups at any time during the study. However, at the end of 3 weeks, amphotericin B levels in the kidneys and liver were significantly higher in salt-depleted and normal-salt rats than those in salt-loaded rats, with plasma/kidney ratios of 21, 14, and 8 in salt-depleted, normal-salt, and salt-loaded rats, respectively. In conclusion, reductions in creatinine clearance and renal amphotericin B accumulation after chronic amphotericin B administration were enhanced by salt depletion and attenuated by sodium loading in rats.

Sodium

amphotericin B

nephrotoxicity

nephrotoxic

amphotericin B

amphotericin B

creatinine

creatinine

creatinine

sodium

amphotericin B

amphotericin B

creatinine

amphotericin B

amphotericin B

sodium


Reversible inferior colliculus lesion in metronidazole-induced encephalopathy: magnetic resonance findings on diffusion-weighted and fluid attenuated inversion recovery imaging.

OBJECTIVE: This is to present reversible inferior colliculus lesions in metronidazole-induced encephalopathy, to focus on the diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) imaging. MATERIALS AND METHODS: From November 2005 to September 2007, 8 patients (5 men and 3 women) were diagnosed as having metronidazole-induced encephalopathy (age range; 43-78 years). They had been taking metronidazole (total dosage, 45-120 g; duration, 30 days to 2 months) to treat the infection in various organs. Initial brain magnetic resonance imaging (MRI) were obtained after the hospitalization, including DWI (8/8), apparent diffusion coefficient (ADC) map (4/8), FLAIR (7/8), and T2-weighted image (8/8). Follow-up MRIs were performed on 5 patients from third to 14th days after discontinuation of metronidazole administration. Findings of initial and follow-up MRIs were retrospectively evaluated by 2 neuroradiologists by consensus, to analyze the presence of abnormal signal intensities, their locations, and signal changes on follow-up images. RESULTS: Initial MRIs showed abnormal high signal intensities on DWI and FLAIR (or T2-weighted image) at the dentate nucleus (8/8), inferior colliculus (6/8), corpus callosum (2/8), pons (2/8), medulla (1/8), and bilateral cerebral white matter (1/8). High-signal intensity lesions on DWI tended to show low signal intensity on ADC map (3/4), but in one patient, high signal intensity was shown at bilateral dentate nuclei on not only DWI but also ADC map. All the lesions in dentate, inferior colliculus, pons, and medullas had been resolved completely on follow-up MRIs in 5 patients, but in 1 patient of them, corpus callosal lesion persisted. CONCLUSIONS: Reversible inferior colliculus lesions could be considered as the characteristic for metronidazole-induced encephalopathy, next to the dentate nucleus involvement.

inferior colliculus lesion

metronidazole

encephalopathy

inferior colliculus lesions

metronidazole

encephalopathy

metronidazole

encephalopathy

metronidazole

infection

metronidazole

callosal lesion

inferior colliculus lesions

metronidazole

encephalopathy


Comparison of the respiratory effects of i.v. infusions of morphine and regional analgesia by extradural block.

The incidence of postoperative respiratory apnoea was compared between five patients receiving a continuous i.v. infusion of morphine (mean 73.6 mg) and five patients receiving a continuous extradural infusion of 0.25% bupivacaine (mean 192 mg) in the 24-h period following upper abdominal surgery. Monitoring consisted of airflow detection by a carbon dioxide analyser, chest wall movement detected by pneumatic capsules, and continuous electrocardiograph recorded with a Holter ambulatory monitor. Both obstructive (P less than 0.05) and central apnoea (P less than 0.05) occurred more frequently in patients who had a morphine infusion. There was also a higher incidence of tachyarrhythmias (P less than 0.05) and ventricular ectopic beats (P less than 0.05) in the morphine infusion group.

morphine

apnoea

morphine

bupivacaine

carbon dioxide

obstructive (P less than 0.05)
apnoea

central apnoea

morphine

tachyarrhythmias

ventricular ectopic beats

morphine


Magnetic resonance volumetry of the cerebellum in epileptic patients after phenytoin overdosages.

The aim of this study was to evaluate the relationship between phenytoin medication and cerebellar atrophy in patients who had experienced clinical intoxication. Five females and 6 males, 21-59 years of age, were examined with a 1.5-T whole-body system using a circular polarized head coil. Conventional spin echo images were acquired in the sagittal and transverse orientation. In addition, we performed a high-resolution 3D gradient echo, T1-weighted sequences at a 1-mm slice thickness. The images were subsequently processed to obtain volumetric data for the cerebellum. Cerebellar volume for the patient group ranged between 67.66 and 131.08 ml (mean 108.9 ml). In addition 3D gradient echo data sets from 10 healthy male and 10 healthy female age-matched volunteers were used to compare cerebellar volumes. Using linear regression we found that no correlation exists between seizure duration, elevation of phenytoin serum levels and cerebellar volume. However, multiple regression for the daily dosage, duration of phenytoin treatment and cerebellar volume revealed a correlation of these parameters. We conclude that phenytoin overdosage does not necessarily result in cerebellar atrophy and it is unlikely that phenytoin medication was the only cause of cerebellar atrophy in the remaining patients. Quantitative morphometric studies of the cerebellum provide valuable insights into the pathogenesis of cerebellar disorders.

epileptic

phenytoin

overdosages

phenytoin

cerebellar atrophy

seizure

phenytoin

phenytoin

phenytoin

overdosage

cerebellar atrophy

phenytoin

cerebellar atrophy

cerebellar disorders


Evaluation of cardiac troponin I and T levels as markers of myocardial damage in doxorubicin-induced cardiomyopathy rats, and their relationship with echocardiographic and histological findings.

BACKGROUND: Cardiac troponins I (cTnI) and T (cTnT) have been shown to be highly sensitive and specific markers of myocardial cell injury. We investigated the diagnostic value of cTnI and cTnT for the diagnosis of myocardial damage in a rat model of doxorubicin (DOX)-induced cardiomyopathy, and we examined the relationship between serial cTnI and cTnT with the development of cardiac disorders monitored by echocardiography and histological examinations in this model. METHODS: Thirty-five Wistar rats were given 1.5 mg/kg DOX, i.v., weekly for up to 8 weeks for a total cumulative dose of 12 mg/kg BW. Ten rats received saline as a control group. cTnI was measured with Access(R) (ng/ml) and a research immunoassay (pg/ml), and compared with cTnT, CK-MB mass and CK. By using transthoracic echocardiography, anterior and posterior wall thickness, LV diameters and LV fractional shortening (FS) were measured in all rats before DOX or saline, and at weeks 6 and 9 after treatment in all surviving rats. Histology was performed in DOX-rats at 6 and 9 weeks after the last DOX dose and in all controls. RESULTS: Eighteen of the DOX rats died prematurely of general toxicity during the 9-week period. End-diastolic (ED) and end-systolic (ES) LV diameters/BW significantly increased, whereas LV FS was decreased after 9 weeks in the DOX group (p<0.001). These parameters remained unchanged in controls. Histological evaluation of hearts from all rats given DOX revealed significant slight degrees of perivascular and interstitial fibrosis. In 7 of the 18 rats, degeneration and myocyte vacuolisation were found. Only five of the controls exhibited evidence of very slight perivascular fibrosis. A significant rise in cTnT was found in DOX rats after cumulative doses of 7.5 and 12 mg/kg in comparison with baseline (p<0.05). cTnT found in rats after 12 mg/kg were significantly greater than that found after 7.5 mg/kg DOX. Maximal cTnI (pg/ml) and cTnT levels were significantly increased in DOX rats compared with controls (p=0.006, 0.007). cTnI (ng/ml), CK-MB mass and CK remained unchanged in DOX rats compared with controls. All markers remained stable in controls. Analysis of data revealed a significant correlation between maximal cTnT and ED and ES LV diameters/BW (r=0.81 and 0.65; p<0.0001). A significant relationship was observed between maximal cTnT and the extent of myocardial morphological changes, and between LV diameters/BW and histological findings. CONCLUSIONS: Among markers of ischemic injury after DOX in rats, cTnT showed the greatest ability to detect myocardial damage assessed by echocardiographic detection and histological changes. Although there was a discrepancy between the amount of cTnI and cTnT after DOX, probably due to heterogeneity in cross-reactivities of mAbs to various cTnI and cTnT forms, it is likely that cTnT in rats after DOX indicates cell damage determined by the magnitude of injury induced and that cTnT should be a useful marker for the prediction of experimentally induced cardiotoxicity and possibly for cardioprotective experiments.

myocardial damage

doxorubicin

cardiomyopathy

myocardial cell injury

myocardial damage

doxorubicin

DOX

cardiomyopathy

cardiac disorders

DOX

DOX

DOX

DOX

DOX

toxicity

DOX

DOX

fibrosis

fibrosis

DOX

DOX

DOX

DOX

ischemic injury

DOX

myocardial damage

DOX

DOX

cardiotoxicity


Calcineurin-inhibitor induced pain syndrome (CIPS): a severe disabling complication after organ transplantation.

Bone pain after transplantation is a frequent complication that can be caused by several diseases. Treatment strategies depend on the correct diagnosis of the pain. Nine patients with severe pain in their feet, which was registered after transplantation, were investigated. Bone scans showed an increased tracer uptake of the foot bones. Magnetic resonance imaging demonstrated bone marrow oedema in the painful bones. Pain was not explained by other diseases causing foot pain, like reflex sympathetic dystrophy, polyneuropathy, Morton's neuralgia, gout, osteoporosis, avascular necrosis, intermittent claudication, orthopaedic foot deformities, stress fractures, and hyperparathyroidism. The reduction of cyclosporine- or tacrolimus trough levels and the administration of calcium channel blockers led to relief of pain. The Calcineurin-inhibitor Induced Pain Syndrome (CIPS) is a rare but severe side effect of cyclosporine or tacrolimus and is accurately diagnosed by its typical presentation, magnetic resonance imaging and bone scans. Incorrect diagnosis of the syndrome will lead to a significant reduction of life quality in patients suffering from CIPS.

pain

CIPS

pain

pain

pain

bone marrow oedema

bone marrow

oedema

Pain

pain

reflex sympathetic dystrophy

polyneuropathy

Morton's neuralgia

gout

osteoporosis

avascular necrosis

intermittent claudication

foot deformities

stress fractures

hyperparathyroidism

cyclosporine

tacrolimus

calcium

pain

Pain

CIPS

cyclosporine

tacrolimus

CIPS


The haemodynamic effects of propofol in combination with ephedrine in elderly patients (ASA groups 3 and 4).

The marked vasodilator and negative inotropic effects of propofol are disadvantages in frail elderly patients. We investigated the safety and efficacy of adding different doses of ephedrine to propofol in order to obtund the hypotensive response. The haemodynamic effects of adding 15, 20 or 25 mg of ephedrine to 200 mg of propofol were compared to control in 40 ASA 3/4 patients over 60 years presenting for genito-urinary surgery. The addition of ephedrine to propofol appears to be an effective method of obtunding the hypotensive response to propofol at all doses used in this study. However, marked tachycardia associated with the use of ephedrine in combination with propofol occurred in the majority of patients, occasionally reaching high levels in individual patients. Due to the risk of this tachycardia inducing myocardial ischemia, we would not recommend the use in elderly patients of any of the ephedrine/propofol/mixtures studied.

propofol

ephedrine

propofol

ephedrine

propofol

hypotensive

ephedrine

propofol

ephedrine

propofol

hypotensive

propofol

tachycardia

ephedrine

propofol

tachycardia

myocardial ischemia

ephedrine

propofol


Neurotoxicity of halogenated hydroxyquinolines: clinical analysis of cases reported outside Japan.

An analysis is presented of 220 cases of possible neurotoxic reactions to halogenated hydroxyquinolines reported from outside Japan. In 80 cases insufficient information was available for adequate comment and in 29 a relationship to the administration of clioquinol could be excluded. Of the remainder, a relationship to clioquinol was considered probable in 42 and possible in 69 cases. In six of the probable cases the neurological disturbance consisted of an acute reversible encephalopathy usually related to the ingestion of a high dose of clioquinol over a short period. The most common manifestation, observed in 15 further cases, was isolated optic atrophy. This was most frequently found in children, many of whom had received clioquinol as treatment for acrodermatitis enteropathica. In the remaining cases, a combination of myelopathy, visual disturbance, and peripheral neuropathy was the most common manifestation. Isolated myelopathy or peripheral neuropathy, or these manifestations occurring together, were infrequent. The onset of all manifestations (except toxic encephalopathy) was usually subacute, with subsequent partial recovery. Older subjects tended to display more side effects. The full syndrome of subacute myelo-optic neuropathy was more frequent in women, but they tended to have taken greater quantities of the drug.

Neurotoxicity

halogenated hydroxyquinolines

neurotoxic

halogenated hydroxyquinolines

clioquinol

clioquinol

neurological disturbance

encephalopathy

clioquinol

optic atrophy

clioquinol

acrodermatitis enteropathica

myelopathy

visual disturbance

peripheral neuropathy

myelopathy

peripheral neuropathy

encephalopathy

myelo-optic neuropathy

myelo neuropathy

optic neuropathy


Epileptic seizures following cortical application of fibrin sealants containing tranexamic acid in rats.

BACKGROUND: Fibrin sealants (FS) derived from human plasma are frequently used in neurosurgery. In order to increase clot stability, FS typically contain aprotinin, a natural fibrinolysis inhibitor. Recently, synthetic fibrinolysis inhibitors such as tranexamic acid (tAMCA) have been considered as substitutes for aprotinin. However, tAMCA has been shown to cause epileptic seizures. We wanted to study whether tAMCA retains its convulsive action if incorporated into a FS. METHOD: FS containing aprotinin or different concentrations of tAMCA (0.5-47.5 mg/ml) were applied to the pial surface of the cortex of anaesthetized rats. The response of the animals was evaluated using electroencephalography and by monitoring the clinical behaviour during and after recovery from anaesthesia. FINDINGS: FS containing tAMCA caused paroxysmal brain activity which was associated with distinct convulsive behaviours. The degree of these seizures increased with increasing concentration of tAMCA. Thus, FS containing 47.5 mg/ml tAMCA evoked generalized seizures in all tested rats (n=6) while the lowest concentration of tAMCA (0.5 mg/ml) only evoked brief episodes of jerk-correlated convulsive potentials in 1 of 6 rats. In contrast, FS containing aprotinin did not evoke any paroxysmal activity. INTERPRETATION: Tranexamic acid retains its convulsive action within FS. Thus, use of FS containing tAMCA for surgery within or close to the CNS may pose a substantial risk to the patient.

Epileptic seizures

tranexamic acid

tranexamic acid

tAMCA

tAMCA

epileptic seizures

tAMCA

convulsive

tAMCA

tAMCA

convulsive

seizures

tAMCA

tAMCA

generalized seizures

tAMCA

convulsive

Tranexamic acid

convulsive

tAMCA


A diet promoting sugar dependency causes behavioral cross-sensitization to a low dose of amphetamine.

Previous research in this laboratory has shown that a diet of intermittent excessive sugar consumption produces a state with neurochemical and behavioral similarities to drug dependency. The present study examined whether female rats on various regimens of sugar access would show behavioral cross-sensitization to a low dose of amphetamine. After a 30-min baseline measure of locomotor activity (day 0), animals were maintained on a cyclic diet of 12-h deprivation followed by 12-h access to 10% sucrose solution and chow pellets (12 h access starting 4 h after onset of the dark period) for 21 days. Locomotor activity was measured again for 30 min at the beginning of days 1 and 21 of sugar access. Beginning on day 22, all rats were maintained on ad libitum chow. Nine days later locomotor activity was measured in response to a single low dose of amphetamine (0.5 mg/kg). The animals that had experienced cyclic sucrose and chow were hyperactive in response to amphetamine compared with four control groups (ad libitum 10% sucrose and chow followed by amphetamine injection, cyclic chow followed by amphetamine injection, ad libitum chow with amphetamine, or cyclic 10% sucrose and chow with a saline injection). These results suggest that a diet comprised of alternating deprivation and access to a sugar solution and chow produces bingeing on sugar that leads to a long lasting state of increased sensitivity to amphetamine, possibly due to a lasting alteration in the dopamine system.

sugar dependency

behavioral cross-sensitization

amphetamine

drug dependency

behavioral cross-sensitization

amphetamine

sucrose

amphetamine

sucrose

hyperactive

amphetamine

sucrose

amphetamine

amphetamine

amphetamine

sucrose

amphetamine

dopamine


D-penicillamine-induced angiopathy in rats. The effect of high dose D-penicillamine treatment on aortic permeability to albumin and on the ultrastructure of the vessel.

Male Sprague-Dawley rats were treated with D-penicillamine (D-pen) 500 mg/kg/day for 10 or 42 days. Pair fed rats served as controls. Changes in aortic morphology were examined by light- and transmission-electron microscopy (TEM). In addition, the endothelial permeability and the penetration through the aortic wall of albumin were studied 10 minutes, 24 and 48 hours after i. v. injection of human serum 131I-albumin (131I-HSA). TEM revealed extensive elastolysis in the arterial wall of D-pen-treated rats, consistent with an inhibitory effect on crosslink formation. In experimental animals excess deposition of collagen and glycoaminoglycans was observed in the subendothelial and medial layer of the aortic wall, together with prominent basal membrane substance around aortic smooth muscle cells. The aorta/serum-ratio and the radioactive build-up 24 and 48 hours after injection of 131I-HSA was reduced in animals treated with D-pen for 42 days, indicating an impeded transmural transport of tracer which may be caused by a steric exclusion effect of abundant hyaluronate. The endothelial ultrastructure was unaffected by D-pen, and no differences in aortic 131I-HSA radioactivity or aorta/serum-ratio were recorded between experimental and control groups 10 minutes after tracer injection, indicating that the permeability of the endothelial barrier to albumin remained unaffected by D-pen treatment. These observations support the hypothesis that treatment with high doses of D-pen may induce a fibroproliferative response in rat aorta, possibly by an inhibitory effect on the cross-linking of collagen and elastin.

D-penicillamine

angiopathy

D-penicillamine

D-penicillamine

D-pen

D-pen

D-pen

hyaluronate

D-pen

D-pen

D-pen


Brain natriuretic peptide is a predictor of anthracycline-induced cardiotoxicity.

Anthracyclines are effective antineoplastic drugs, but they frequently cause dose-related cardiotoxicity. The cardiotoxicity of conventional anthracycline therapy highlights a need to search for methods that are highly sensitive and capable of predicting cardiac dysfunction. We measured the plasma level of brain natriuretic peptide (BNP) to determine whether BNP might serve as a simple diagnostic indicator of anthracycline-induced cardiotoxicity in patients with acute leukemia treated with a daunorubicin (DNR)-containing regimen. Thirteen patients with acute leukemia were treated with a DNR-containing regimen. Cardiac functions were evaluated with radionuclide angiography before chemotherapies. The plasma levels of atrial natriuretic peptide (ANP) and BNP were measured at the time of radionuclide angiography. Three patients developed congestive heart failure after the completion of chemotherapy. Five patients were diagnosed as having subclinical heart failure after the completion of chemotherapy. The plasma levels of BNP in all the patients with clinical and subclinical heart failure increased above the normal limit (40 pg/ml) before the detection of clinical or subclinical heart failure by radionuclide angiography. On the other hand, BNP did not increase in the patients without heart failure given DNR, even at more than 700 mg/m(2). The plasma level of ANP did not always increase in all the patients with clinical and subclinical heart failure. These preliminary results suggest that BNP may be useful as an early and sensitive indicator of anthracycline-induced cardiotoxicity.

anthracycline

cardiotoxicity

Anthracyclines

cardiotoxicity

cardiotoxicity

anthracycline

cardiac dysfunction

anthracycline

cardiotoxicity

acute leukemia

daunorubicin

DNR

acute leukemia

DNR

congestive heart failure

heart failure

heart failure

heart failure

heart failure

DNR

heart failure

anthracycline

cardiotoxicity


Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study.

OBJECTIVE: To estimate the association between antibacterial medications and selected birth defects. DESIGN, SETTING, AND PARTICIPANTS: Population-based, multisite, case-control study of women who had pregnancies affected by 1 of more than 30 eligible major birth defects identified via birth defect surveillance programs in 10 states (n = 13 155) and control women randomly selected from the same geographical regions (n = 4941). MAIN EXPOSURE: Reported maternal use of antibacterials (1 month before pregnancy through the end of the first trimester). MAIN OUTCOME MEASURE: Odds ratios (ORs) measuring the association between antibacterial use and selected birth defects adjusted for potential confounders. RESULTS: The reported use of antibacterials increased during pregnancy, peaking during the third month. Sulfonamides were associated with anencephaly (adjusted OR [AOR] = 3.4; 95% confidence interval [CI], 1.3-8.8), hypoplastic left heart syndrome (AOR = 3.2; 95% CI, 1.3-7.6), coarctation of the aorta (AOR = 2.7; 95% CI, 1.3-5.6), choanal atresia (AOR = 8.0; 95% CI, 2.7-23.5), transverse limb deficiency (AOR = 2.5; 95% CI, 1.0-5.9), and diaphragmatic hernia (AOR = 2.4; 95% CI, 1.1-5.4). Nitrofurantoins were associated with anophthalmia or microphthalmos (AOR = 3.7; 95% CI, 1.1-12.2), hypoplastic left heart syndrome (AOR = 4.2; 95% CI, 1.9-9.1), atrial septal defects (AOR = 1.9; 95% CI, 1.1-3.4), and cleft lip with cleft palate (AOR = 2.1; 95% CI, 1.2-3.9). Other antibacterial agents that showed associations included erythromycins (2 defects), penicillins (1 defect), cephalosporins (1 defect), and quinolones (1 defect). CONCLUSIONS: Reassuringly, penicillins, erythromycins, and cephalosporins, although used commonly by pregnant women, were not associated with many birth defects. Sulfonamides and nitrofurantoins were associated with several birth defects, indicating a need for additional scrutiny.

birth defects

Birth Defects

birth defects

birth defects

birth defect

birth defects

Sulfonamides

anencephaly

hypoplastic left heart syndrome

coarctation of the aorta

choanal atresia

transverse limb deficiency

diaphragmatic hernia

Nitrofurantoins

anophthalmia

microphthalmos

hypoplastic left heart syndrome

atrial septal defects

cleft lip

cleft palate

erythromycins

penicillins

cephalosporins

quinolones

penicillins

erythromycins

cephalosporins

birth defects

Sulfonamides

nitrofurantoins

birth defects


Incidence of neoplasms in patients with rheumatoid arthritis exposed to different treatment regimens.

Immunosuppressive drugs have been used during the last 30 years in treatment of patients with severe rheumatoid arthritis. The drugs commonly used are cyclophosphamide and chlorambucil (alkylating agents), azathioprine (purine analogue), and methotrexate (folic acid analogue). There is evidence that all four immunosuppressive drugs can reduce synovitis, but disease activity almost always recurs after therapy is stopped. Since adverse reactions are frequent, less than 50 percent of patients are able to continue a particular drug for more than one year. Since it takes three to 12 months to achieve maximal effects, those patients who are unable to continue the drug receive little benefit from it. Patients treated with alkylating agents have an increased risk of development of acute nonlymphocytic leukemia, and both alkylating agents and azathioprine are associated with the development of non-Hodgkin's lymphoma. Cyclophosphamide therapy increases the risk of carcinoma of the bladder. There have been several long-term studies of patients with rheumatoid arthritis treated with azathioprine and cyclophosphamide and the incidence of most of the common cancers is not increased. Data on the possible increased risk of malignancy in rheumatoid arthritis are still being collected, and until further information is available, the use of immunosuppressive drugs, particularly alkylating agents, in the treatment of rheumatoid arthritis should be reserved for patients with severe progressive disease or life-threatening complications.

neoplasms

rheumatoid arthritis

rheumatoid arthritis

cyclophosphamide

chlorambucil

alkylating agents

azathioprine

purine

methotrexate

folic acid

synovitis

alkylating agents

acute nonlymphocytic leukemia

alkylating agents

azathioprine

non-Hodgkin's lymphoma

Cyclophosphamide

carcinoma of the bladder

carcinoma of the bladder

carcinoma

rheumatoid arthritis

azathioprine

cyclophosphamide

cancers

malignancy

rheumatoid arthritis

alkylating agents

rheumatoid arthritis


Patterns of hepatic injury induced by methyldopa.

Twelve patients with liver disease related to methyldopa were seen between 1967 and 1977. Illness occurred within 1--9 weeks of commencement of therapy in 9 patients, the remaining 3 patients having received the drug for 13 months, 15 months and 7 years before experiencing symptoms. Jaundice with tender hepatomegaly, usually preceded by symptoms of malaise, anorexia, nausea and vomiting, and associated with upper abdominal pain, was an invariable finding in all patients. Biochemical liver function tests indicated hepatocellular necrosis and correlated with histopathological evidence of hepatic injury, the spectrum of which ranged from fatty change and focal hepatocellular necrosis to massive hepatic necrosis. Most patients showed moderate to severe acute hepatitis or chronic active hepatitis with associated cholestasis. The drug was withdrawn on presentation to hospital in 11 patients, with rapid clinical improvement in 9. One patient died, having presented in hepatic failure, and another, who had been taking methyldopa for 7 years, showed slower clinical and biochemical resolution over a period of several months. The remaining patient in the series developed fulminant hepatitis when the drug was accidentally recommenced 1 year after a prior episode of methyldopa-induced hepatitis. In this latter patient, and in 2 others, the causal relationship between methyldopa and hepatic dysfunction was proved with the recurrence of hepatitis within 2 weeks of re-exposure to the drug.

hepatic injury

methyldopa

liver disease

methyldopa

Jaundice

hepatomegaly

anorexia

nausea

vomiting

abdominal pain

necrosis

hepatic injury

fatty change

necrosis

massive hepatic necrosis

acute hepatitis

chronic active hepatitis

cholestasis

hepatic failure

methyldopa

fulminant hepatitis

methyldopa

hepatitis

methyldopa

hepatic dysfunction

hepatitis


A phase I/II study of paclitaxel plus cisplatin as first-line therapy for head and neck cancers: preliminary results.

Improved outcomes among patients with head and neck carcinomas require investigations of new drugs for induction therapy. Preliminary results of an Eastern Cooperative Oncology Group study of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) reported a 37% response rate in patients with head and neck cancer, and the paclitaxel/cisplatin combination has been used successfully and has significantly improved median response duration in ovarian cancer patients. We initiated a phase I/II trial to determine the response and toxicity of escalating paclitaxel doses combined with fixed-dose cisplatin with granulocyte colony-stimulating factor support in patients with untreated locally advanced inoperable head and neck carcinoma. To date, 23 men with a median age of 50 years and good performance status have entered the trial. Primary tumor sites were oropharynx, 10 patients; hypopharynx, four; larynx, two; oral cavity, three; unknown primary, two; and nasal cavity and parotid gland, one each. Of 20 patients evaluable for toxicity, four had stage III and 16 had stage IV disease. Treatment, given every 21 days for a maximum of three cycles, consisted of paclitaxel by 3-hour infusion followed the next day by a fixed dose of cisplatin (75 mg/m2). The dose levels incorporate escalating paclitaxel doses, and intrapatient escalations within a given dose level are permitted if toxicity permits. At the time of this writing, dose level 4 (260, 270, and 280 mg/m2) is being evaluated; three patients from this level are evaluable. With paclitaxel doses of 200 mg/m2 and higher, granulocyte colony-stimulating factor 5 micrograms/kg/d is given (days 4 through 12). Of 18 patients evaluable for response, seven (39%) achieved a complete response and six (33%) achieved a partial response. Three patients had no change and disease progressed in two. The overall response rate is 72%. Eleven responding patients had subsequent surgery/radiotherapy or radical radiotherapy. Two pathologic complete responses were observed in patients who had achieved clinical complete responses. Alopecia, paresthesias, and arthralgias/myalgias have occurred frequently, but with one exception (a grade 3 myalgia) they have been grade 1 or 2. No dose-limiting hematologic toxicity has been seen. Paclitaxel/cisplatin is an effective first-line regimen for locoregionally advanced head and neck cancer and continued study is warranted. Results thus far suggest no dose-response effect for paclitaxel doses above 200 mg/m2.

paclitaxel

cisplatin

head and neck cancers

head and neck carcinomas

paclitaxel

Taxol

head and neck cancer

paclitaxel

cisplatin

ovarian cancer

toxicity

paclitaxel

cisplatin

head and neck carcinoma

tumor

toxicity

paclitaxel

cisplatin

paclitaxel

toxicity

paclitaxel

Alopecia

paresthesias

arthralgias

myalgias

myalgia

toxicity

Paclitaxel

cisplatin

head and neck cancer

paclitaxel


A phase I study of 4'-0-tetrahydropyranyladriamycin. Clinical pharmacology and pharmacokinetics.

A Phase I study of intravenous (IV) bolus 4'-0-tetrahydropyranyladriamycin (Pirarubicin) was done in 55 patients in good performance status with refractory tumors. Twenty-six had minimal prior therapy (good risk), 23 had extensive prior therapy (poor risk), and six had renal and/or hepatic dysfunction. A total of 167 courses at doses of 15 to 70 mg/m2 were evaluable. Maximum tolerated dose in good-risk patients was 70 mg/m2, and in poor-risk patients, 60 mg/m2. The dose-limiting toxic effect was transient noncumulative granulocytopenia. Granulocyte nadir was on day 14 (range, 4-22). Less frequent toxic effects included thrombocytopenia, anemia, nausea, mild alopecia, phlebitis, and mucositis. Myelosuppression was more in patients with hepatic dysfunction. Pharmacokinetic analyses in 21 patients revealed Pirarubicin plasma T 1/2 alpha (+/- SE) of 2.5 +/- 0.85 minutes, T beta 1/2 of 25.6 +/- 6.5 minutes, and T 1/2 gamma of 23.6 +/- 7.6 hours. The area under the curve was 537 +/- 149 ng/ml x hours, volume of distribution (Vd) 3504 +/- 644 l/m2, and total clearance (ClT) was 204 + 39.3 l/hour/m2. Adriamycinol, doxorubicin, adriamycinone, and tetrahydropyranyladriamycinol were the metabolites detected in plasma and the amount of doxorubicin was less than or equal to 10% of the total metabolites. Urinary excretion of Pirarubicin in the first 24 hours was less than or equal to 10%. Activity was noted in mesothelioma, leiomyosarcoma, and basal cell carcinoma. The recommended starting dose for Phase II trials is 60 mg/m2 IV bolus every 3 weeks.

Pirarubicin

tumors

renal and/or hepatic dysfunction

renal dysfunction

hepatic dysfunction

granulocytopenia

thrombocytopenia

anemia

nausea

alopecia

phlebitis

mucositis

Myelosuppression

hepatic dysfunction

Pirarubicin

Adriamycinol

doxorubicin

adriamycinone

tetrahydropyranyladriamycinol

doxorubicin

Pirarubicin

mesothelioma

leiomyosarcoma

basal cell carcinoma


Differential effects of gamma-hexachlorocyclohexane (lindane) on pharmacologically-induced seizures.

Gamma-hexachlorocyclohexane (gamma-HCH), the active ingredient of the insecticide lindane, has been shown to decrease seizure threshold to pentylenetrazol (PTZ) 3 h after exposure to gamma-HCH and conversely increase threshold to PTZ-induced seizures 24 h after exposure to gamma-HCH (Vohland et al. 1981). In this study, the severity of response to other seizure-inducing agents was tested in mice 1 and 24 h after intraperitoneal administration of 80 mg/kg gamma-HCH. One hour after the administration of gamma-HCH, the activity of seizure-inducing agents was increased, regardless of their mechanism, while 24 h after gamma-HCH a differential response was observed. Seizure activity due to PTZ and picrotoxin (PTX) was significantly decreased; however, seizure activity due to 3-mercaptopropionic acid (MPA), bicuculline (BCC), methyl 6,7-dimethoxy-4-ethyl-B-carboline-3-carboxylate (DMCM), or strychnine (STR) was not different from control. In vitro, gamma-HCH, pentylenetetrazol and picrotoxin were shown to inhibit 3H-TBOB binding in mouse whole brain, with IC50 values of 4.6, 404 and 9.4 microM, respectively. MPA, BCC, DMCM, and STR showed no inhibition of 3H-TBOB (t-butyl bicyclo-orthobenzoate) binding at concentrations of 100 micron. The pharmacological challenge data suggest that tolerance may occur to seizure activity induced by PTZ and PTX 24 h after gamma-HCH, since the response to only these two seizure-inducing agents is decreased. The in vitro data suggest that the site responsible for the decrease in seizure activity 24 h after gamma-HCH may be the GABA-A receptor-linked chloride channel.

gamma-hexachlorocyclohexane

lindane

seizures

Gamma-hexachlorocyclohexane

gamma-HCH

lindane

seizure

PTZ

gamma-HCH

PTZ

seizures

gamma-HCH

seizure

gamma-HCH

gamma-HCH

seizure

gamma-HCH

Seizure

PTZ

picrotoxin

PTX

seizure

3-mercaptopropionic acid

MPA

bicuculline

BCC

DMCM

strychnine

STR

gamma-HCH

pentylenetetrazol

picrotoxin

MPA

BCC

DMCM

STR

t-butyl bicyclo-orthobenzoate

seizure

PTZ

PTX

gamma-HCH

seizure

seizure

gamma-HCH

GABA


Severe ocular and orbital toxicity after intracarotid injection of carboplatin for recurrent glioblastomas.

BACKGROUND: Glioblastoma is a malignant tumor that occurs in the cerebrum during adulthood. With current treatment regimens including combined surgery, radiation and chemotherapy, the average life expectancy of the patients is limited to approximately 1 year. Therefore, patients with glioblastoma sometimes have intracarotid injection of carcinostatics added to the treatment regimen. Generally, carboplatin is said to have milder side effects than cisplatin, whose ocular and orbital toxicity are well known. However, we experienced a case of severe ocular and orbital toxicity after intracarotid injection of carboplatin, which is infrequently reported. CASE: A 58-year-old man received an intracarotid injection of carboplatin for recurrent glioblastomas in his left temporal lobe. He complained of pain and visual disturbance in the ipsilateral eye 30 h after the injection. Various ocular symptoms and findings caused by carboplatin toxicity were seen. RESULTS: He was treated with intravenous administration of corticosteroids and glycerin for 6 days after the injection. Although the intraocular pressure elevation caused by secondary acute angle-closure glaucoma decreased and ocular pain diminished, inexorable papilledema and exudative retinal detachment continued for 3 weeks. Finally, 6 weeks later, diffuse chorioretinal atrophy with optic atrophy occurred and the vision in his left eye was lost. CONCLUSION: When performing intracarotid injection of carboplatin, we must be aware of its potentially blinding ocular toxicity. It is recommended that further studies and investigations are undertaken in the effort to minimize such severe side effects.

ocular and orbital toxicity

ocular toxicity

orbital toxicity

carboplatin

glioblastomas

Glioblastoma

malignant tumor

glioblastoma

carboplatin

cisplatin

ocular and orbital toxicity

ocular toxicity

orbital toxicity

ocular and orbital toxicity

ocular toxicity

orbital toxicity

carboplatin

carboplatin

glioblastomas

pain
in the ipsilateral eye

carboplatin

toxicity

glycerin

glaucoma

ocular pain

papilledema

retinal detachment

chorioretinal atrophy

optic atrophy

carboplatin

ocular toxicity


Phase II study of the amsacrine analogue CI-921 (NSC 343499) in non-small cell lung cancer.

CI-921 (NSC 343499; 9-[[2-methoxy-4-[(methylsulphonyl)amino]phenyl]amino] -N,5-dimethyl- 4-acridinecarboxamide) is a topoisomerase II poison with high experimental antitumour activity. It was administered by 15 min infusion to 16 evaluable patients with non-small cell lung cancer (NSCLC) (7 with no prior treatment, 9 patients in relapse following surgery/radiotherapy) at a dose (648 mg/m2 divided over 3 days, repeated every 3 weeks) determined by phase I trial. Patients had a median performance status of 1 (WHO), and median age of 61 years. The histology comprised squamous carcinoma (11), adenocarcinoma (1), mixed histology (2), bronchio-alveolar carcinoma (1) and large cell undifferentiated carcinoma (1). Neutropenia grade greater than or equal to 3 was seen in 15 patients, infections with recovery in 3, and grand mal seizures in 1 patient. Grade less than or equal to 2 nausea and vomiting occurred in 66% courses and phlebitis in the infusion arm in 37%. 1 patient with squamous cell carcinoma achieved a partial response lasting 5 months. Further testing in this and other tumour types using multiple daily schedules is warranted.

amsacrine

NSC 343499

non-small cell lung cancer

NSC 343499

non-small cell lung cancer

NSCLC

squamous carcinoma

adenocarcinoma

bronchio-alveolar carcinoma

undifferentiated carcinoma

Neutropenia

infections

seizures

nausea

vomiting

phlebitis

squamous cell carcinoma

tumour


Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy.

The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection. We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.

Alpha-lipoic acid

mitochondrial damage

neurotoxicity

neuropathy

alpha-lipoic acid

neurotoxicity

mitochondrial damage

toxic neurodegenerative cascade

alpha-lipoic acid

peripheral neuropathy

paclitaxel

cisplatin

alpha-lipoic acid

axonal damage

alpha-lipoic acid

cisplatin

paclitaxel

mitochondrial impairment

Alpha-lipoic acid

neurotoxicity

mitochondrial toxicity

mitochondrial toxicity

paclitaxel

cisplatin

neurotoxicity

Alpha-lipoic acid

alpha-lipoic acid

peripheral nerve toxicity


Optimising stroke prevention in non-valvular atrial fibrillation.

Atrial fibrillation is associated with substantial morbidity and mortality. Pooled data from trials comparing antithrombotic treatment with placebo have shown that warfarin reduces the risk of stroke by 62%, and that aspirin alone reduces the risk by 22%. Overall, in high-risk patients, warfarin is superior to aspirin in preventing strokes, with a relative risk reduction of 36%. Ximelagatran, an oral direct thrombin inhibitor, was found to be as efficient as vitamin K antagonist drugs in the prevention of embolic events, but has been recently withdrawn because of abnormal liver function tests. The ACTIVE-W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) study has demonstrated that warfarin is superior to platelet therapy (clopidogrel plus aspirin) in the prevention af embolic events. Idraparinux, a Factor Xa inhibitor, is being evaluated in patients with atrial fibrillation. Angiotensin-converting enzyme inhibitors and angiotensin II receptor-blocking drugs hold promise in atrial fibrillation through cardiac remodelling. Preliminary studies suggest that statins could interfere with the risk of recurrence after electrical cardioversion. Finally, percutaneous methods for the exclusion of left atrial appendage are under investigation in high-risk patients.

stroke

atrial fibrillation

Atrial fibrillation

warfarin

stroke

aspirin

warfarin

aspirin

strokes

Ximelagatran

vitamin K

embolic events

abnormal liver function

Atrial Fibrillation

Clopidogrel

Irbesartan

warfarin

clopidogrel

aspirin

embolic events

Idraparinux

atrial fibrillation

Angiotensin

angiotensin II

atrial fibrillation

cardiac remodelling

statins


Interaction of cyclosporin A with antineoplastic agents.

A synergistic effect of etoposide and cyclosporin A was observed in a patient with acute T-lymphocytic leukemia in relapse. The concomitant administration of etoposide and cyclosporin A resulted in eradication of hitherto refractory leukemic infiltration of bone marrow. Severe side effects in terms of mental confusion and progressive hyperbilirubinemia, however, point to an enhancement not only of antineoplastic effects but also of toxicity in normal tissues. This report demonstrates for the first time that the pharmacodynamic properties of cyclosporin A may not be confined strictly to suppression of normal T-cell functions.

cyclosporin A

etoposide

cyclosporin A

acute T-lymphocytic leukemia

etoposide

cyclosporin A

leukemic infiltration

confusion

hyperbilirubinemia

toxicity

cyclosporin A


The hematologic effects of cefonicid and cefazedone in the dog: a potential model of cephalosporin hematotoxicity in man.

Cephalosporin antibiotics cause a variety of hematologic disturbances in man, the pathogeneses and hematopathology of which remain poorly characterized. There is a need for a well-defined animal model in which these blood dyscrasias can be studied. In four subacute toxicity studies, the intravenous administration of cefonicid or cefazedone to beagle dogs caused a dose-dependent incidence of anemia, neutropenia, and thrombocytopenia after 1-3 months of treatment. A nonregenerative anemia was the most compromising of the cytopenias and occurred in approximately 50% of dogs receiving 400-500 mg/kg cefonicid or 540-840 mg/kg cefazedone. All three cytopenias were completely reversible following cessation of treatment; the time required for recovery of the erythron (approximately 1 month) was considerably longer than that of the granulocytes and platelets (hours to a few days). Upon rechallenge with either cephalosporin, the hematologic syndrome was reproduced in most dogs tested; cefonicid (but not cefazedone)-treated dogs showed a substantially reduced induction period (15 +/- 5 days) compared to that of the first exposure to the drug (61 +/- 24 days). This observation, along with the rapid rate of decline in red cell mass parameters of affected dogs, suggests that a hemolytic component complicated the red cell production problem and that multiple toxicologic mechanisms contributed to the cytopenia. We conclude that the administration of high doses of cefonicid or cefazedone to dogs can induce hematotoxicity similar to the cephalosporin-induced blood dyscrasias described in man and thus provides a useful model for studying the mechanisms of these disorders.

cefonicid

cefazedone

cephalosporin

hematotoxicity

Cephalosporin

hematologic disturbances

blood dyscrasias

toxicity

cefonicid

cefazedone

anemia

neutropenia

thrombocytopenia

anemia

cytopenias

cefonicid

cefazedone

cytopenias

cephalosporin

hematologic syndrome

cefonicid

cefazedone

hemolytic

cytopenia

cefonicid

cefazedone

hematotoxicity

cephalosporin

blood dyscrasias


A pyridoxine-dependent behavioral disorder unmasked by isoniazid.

A 3-year-old girl had behavioral deterioration, with hyperkinesis, irritability, and sleeping difficulties after the therapeutic administration of isoniazid. The administration of pharmacologic doses of pyridoxine hydrochloride led to a disappearance of symptoms. After discontinuing isoniazid therapy a similar pattern of behavior was noted that was controlled by pyridoxine. A placebo had no effect, but niacinamide was as effective as pyridoxine. Periodic withdrawal of pyridoxine was associated with return of the hyperkinesis. The level of pyridoxal in the blood was normal during the periods of relapse. Metabolic studies suggested a block in the kynurenine pathway of tryptophan metabolism. The patient has been followed for six years and has required pharmacologic doses of pyridoxine to control her behavior.

pyridoxine

behavioral disorder

isoniazid

behavioral deterioration

hyperkinesis

irritability

sleeping difficulties

isoniazid

pyridoxine hydrochloride

isoniazid

pyridoxine

niacinamide

pyridoxine

pyridoxine

hyperkinesis

pyridoxal

kynurenine

tryptophan

pyridoxine


A selective dopamine D4 receptor antagonist, NRA0160: a preclinical neuropharmacological profile.

NRA0160, 5 - [2- ( 4- ( 3 - fluorobenzylidene) piperidin-1-yl) ethyl] - 4 -(4-fluorophenyl) thiazole-2-carboxamide, has a high affinity for human cloned dopamine D4.2, D4.4 and D4.7 receptors, with Ki values of 0.5, 0.9 and 2.7 nM, respectively. NRA0160 is over 20,000fold more potent at the dopamine D4.2 receptor compared with the human cloned dopamine D2L receptor. NRA0160 has negligible affinity for the human cloned dopamine D3 receptor (Ki=39 nM), rat serotonin (5-HT)2A receptors (Ki=180 nM) and rat alpha1 adrenoceptor (Ki=237 nM). NRA0160 and clozapine antagonized locomotor hyperactivity induced by methamphetamine (MAP) in mice. NRA0160 and clozapine antagonized MAP-induced stereotyped behavior in mice, although their effects did not exceed 50% inhibition, even at the highest dose given. NRA0160 and clozapine significantly induced catalepsy in rats, although their effects did not exceed 50% induction even at the highest dose given. NRA0160 and clozapine significantly reversed the disruption of prepulse inhibition (PPI) in rats produced by apomorphine. NRA0160 and clozapine significantly shortened the phencyclidine (PCP)-induced prolonged swimming latency in rats in a water maze task. These findings suggest that NRA0160 may have unique antipsychotic activities without the liability of motor side effects typical of classical antipsychotics.

dopamine

dopamine

dopamine

dopamine

dopamine

serotonin

clozapine

hyperactivity

methamphetamine

MAP

clozapine

MAP

clozapine

catalepsy

clozapine

apomorphine

clozapine

phencyclidine

PCP


Prolonged cholestasis after troleandomycin-induced acute hepatitis.

We report the case of a patient in whom troleandomycin-induced hepatitis was followed by prolonged anicteric cholestasis. Jaundice occurred after administration of troleandomycin for 7 days and was associated with hypereosinophilia. Jaundice disappeared within 3 months but was followed by prolonged anicteric cholestasis marked by pruritus and high levels of alkaline phosphatase and gammaglutamyltransferase activities. Finally, pruritus disappeared within 19 months, and liver tests returned to normal 27 months after the onset of hepatitis. This observation demonstrates that prolonged cholestasis can follow troleandomycin-induced acute hepatitis.

cholestasis

troleandomycin

hepatitis

troleandomycin

hepatitis

cholestasis

Jaundice

troleandomycin

hypereosinophilia

Jaundice

cholestasis

pruritus

pruritus

hepatitis

cholestasis

troleandomycin

hepatitis


HMG CoA reductase inhibitors. Current clinical experience.

Lovastatin and simvastatin are the 2 best-known members of the class of hypolipidaemic agents known as HMG CoA reductase inhibitors. Clinical experience with lovastatin includes over 5000 patients, 700 of whom have been treated for 2 years or more, and experience with simvastatin includes over 3500 patients, of whom 350 have been treated for 18 months or more. Lovastatin has been marketed in the United States for over 6 months. Both agents show substantial clinical efficacy, with reductions in total cholesterol of over 30% and in LDL-cholesterol of 40% in clinical studies. Modest increases in HDL-cholesterol levels of about 10% are also reported. Clinical tolerability of both agents has been good, with fewer than 3% of patients withdrawn from treatment because of clinical adverse experiences. Ophthalmological examinations in over 1100 patients treated with one or the other agent have revealed no evidence of significant short term (up to 2 years) cataractogenic potential. One to 2% of patients have elevations of serum transaminases to greater than 3 times the upper limit of normal. These episodes are asymptomatic and reversible when therapy is discontinued. Minor elevations of creatine kinase levels are reported in about 5% of patients. Myopathy, associated in some cases with myoglobinuria, and in 2 cases with transient renal failure, has been rarely reported with lovastatin, especially in patients concomitantly treated with cyclosporin, gemfibrozil or niacin. Lovastatin and simvastatin are both effective and well-tolerated agents for lowering elevated levels of serum cholesterol. As wider use confirms their safety profile, they will gain increasing importance in the therapeutic approach to hypercholesterolaemia and its consequences.

Lovastatin

simvastatin

lovastatin

simvastatin

Lovastatin

cholesterol

cholesterol

cholesterol

creatine

Myopathy

myoglobinuria

renal failure

lovastatin

cyclosporin

gemfibrozil

niacin

Lovastatin

simvastatin

cholesterol

hypercholesterolaemia


Sulfasalazine-induced lupus erythematosus.

Pneumonitis, bilateral pleural effusions, echocardiographic evidence of cardiac tamponade, and positive autoantibodies developed in a 43-year-old man, who was receiving long-term sulfasalazine therapy for chronic ulcerative colitis. After cessation of the sulfasalazine and completion of a six-week course of corticosteroids, these problems resolved over a period of four to six months. It is suggested that the patient had sulfasalazine-induced lupus, which manifested with serositis and pulmonary parenchymal involvement in the absence of joint symptoms. Physicians who use sulfasalazine to treat patients with inflammatory bowel disease should be aware of the signs of sulfasalazine-induced lupus syndrome.

Sulfasalazine

lupus erythematosus

Pneumonitis

pleural effusions

cardiac tamponade

sulfasalazine

ulcerative colitis

sulfasalazine

sulfasalazine

lupus

serositis

sulfasalazine

inflammatory bowel disease

sulfasalazine

lupus syndrome


Optimization of levodopa therapy.

While there is no single correct starting dose for levodopa therapy, many individuals can be started on either the 25/100 or controlled-release formula, following the general rule not to attempt to titrate carbidopa-levodopa to the point of "normality," which can lead to toxicity. The physician should also determine the proper use of any adjunctive medications; such combined therapy has become the standard approach to treatment. Following the initial period of therapy, emerging difficulties require a reassessment of therapeutic approaches, such as dosage adjustment or introduction of a dopamine agonist. Other possible adverse effects--such as gastrointestinal disorders, orthostatic hypotension, levodopa-induced psychosis, sleep disturbances or parasomnias, or drug interactions--also require carefully monitored individual treatment. Nonpharmacologic concerns can help the Parkinson's disease patient achieve and maintain optimal functioning, including daily exercise, physical therapy, and involvement with support groups.

levodopa

levodopa

carbidopa

levodopa

toxicity

dopamine

gastrointestinal disorders

orthostatic hypotension

levodopa

psychosis

sleep disturbances

parasomnias

Parkinson's disease


Alpha and beta coma in drug intoxication uncomplicated by cerebral hypoxia.

Four patients who were rendered comatose or stuporous by drug intoxication, but who were not hypoxic, are described. Three patients received high doses of chlormethiazole for alcohol withdrawal symptoms, and one took a suicidal overdose of nitrazepam. The patient with nitrazepam overdose and two of those with chlormethiazole intoxication conformed to the criteria of 'alpha coma', showing non-reactive generalized or frontally predominant alpha activity in the EEG. The fourth patient who was unconscious after chlormethiazole administration exhibite generalized non-reactive activity in the slow beta range. All four recovered completely without neurological sequelae following the withdrawal of the offending agents. The similarities between the effects of structural lesions and pharmacological depression of the brain stem reticular formation are discussed. It is suggested that in both situations disturbed reticulo-thalamic interactions are important in the pathogenesis of alpha coma. It is concluded that when this electroencephalographic and behavioural picture is seen in drug intoxication, in the absence of significant hypoxaemia, a favourable outcome may be anticipated.

coma

cerebral hypoxia

comatose

stuporous

chlormethiazole

alcohol

withdrawal symptoms

overdose

nitrazepam

nitrazepam

overdose

chlormethiazole

coma

chlormethiazole

neurological sequelae

depression

coma

hypoxaemia


Omitting fentanyl reduces nausea and vomiting, without increasing pain, after sevoflurane for day surgery.

BACKGROUND AND OBJECTIVE: Despite advantages of induction and maintenance of anaesthesia with sevoflurane, postoperative nausea and vomiting occurs frequently. Fentanyl is a commonly used supplement that may contribute to this, although it may also improve analgesia. METHODS: This double-blind study examined the incidence and severity of postoperative nausea and vomiting and pain in the first 24 h after sevoflurane anaesthesia in 216 adult day surgery patients. Patients were randomly allocated to either receive or not receive 1 1 fentanyl, while a third group received dexamethasone in addition to fentanyl. RESULTS: Omission of fentanyl did not reduce the overall incidence of postoperative nausea and vomiting, but did reduce the incidence of vomiting and/or moderate to severe nausea prior to discharge from 20% and 17% with fentanyl and fentanyl-dexamethasone, respectively, to 5% (P = 0.013). Antiemetic requirements were reduced from 24% and 31% to 7% (P = 0.0012). Dexamethasone had no significant effect on the incidence or severity of postoperative nausea and vomiting. Combining the two fentanyl groups revealed further significant benefits from the avoidance of opioids, reducing postoperative nausea and vomiting and nausea prior to discharge from 35% and 33% to 22% and 19% (P = 0.049 and P = 0.035), respectively, while nausea in the first 24 h was decreased from 42% to 27% (P = 0.034). Pain severity and analgesic requirements were unaffected by the omission of fentanyl. Fentanyl did reduce minor intraoperative movement but had no sevoflurane-sparing effect and increased respiratory depression, hypotension and bradycardia. CONCLUSION: As fentanyl exacerbated postoperative nausea and vomiting without an improvement in postoperative pain and also had adverse cardiorespiratory effects, it appears to be an unnecessary and possibly detrimental supplement to sevoflurane in day surgery.

fentanyl

nausea

vomiting

pain

sevoflurane

sevoflurane

postoperative nausea and vomiting

Fentanyl

postoperative nausea and vomiting

pain

sevoflurane

fentanyl

dexamethasone

fentanyl

fentanyl

postoperative nausea and vomiting

vomiting

nausea

fentanyl

fentanyl

dexamethasone

Dexamethasone

postoperative nausea and vomiting

fentanyl

postoperative nausea and vomiting

nausea

nausea

Pain

fentanyl

Fentanyl

sevoflurane

respiratory depression

hypotension

bradycardia

fentanyl

postoperative nausea and vomiting

postoperative pain

sevoflurane


Renal Fanconi syndrome and myopathy after liver transplantation: drug-related mitochondrial cytopathy?

Advances in the field of transplantation provide a better quality of life and allow more favorable conditions for growth and development in children. However, combinations of different therapeutic regimens require consideration of potential adverse reactions. We describe a 15-yr-old girl who had orthotopic liver transplantation because of Wilson's disease. Tacrolimus, MMF, and steroids were given as immunosuppressant. Lamivudine was added because of de nova hepatitis B infection during her follow-up. Three yr after transplantation she developed renal Fanconi syndrome with severe metabolic acidosis, hypophosphatemia, glycosuria, and aminoaciduria. Although tacrolimus was suspected to be the cause of late post-transplant renal acidosis and was replaced by sirolimus, acidosis, and electrolyte imbalance got worse. Proximal muscle weakness has developed during her follow-up. Fanconi syndrome, as well as myopathy, is well recognized in patients with mitochondrial disorders and caused by depletion of mtDNA. We suggest that our patient's tubular dysfunction and myopathy may have resulted from mitochondrial dysfunction which is triggered by tacrolimus and augmented by lamivudine.

Renal Fanconi syndrome

myopathy

mitochondrial cytopathy

Wilson's disease

Tacrolimus

MMF

steroids

Lamivudine

hepatitis B infection

renal Fanconi syndrome

metabolic acidosis

hypophosphatemia

glycosuria

aminoaciduria

tacrolimus

acidosis

sirolimus

acidosis

muscle weakness

Fanconi syndrome

myopathy

mitochondrial disorders

tubular dysfunction

myopathy

mitochondrial dysfunction

tacrolimus

lamivudine


Antipsychotic-like profile of thioperamide, a selective H3-receptor antagonist in mice.

Experimental and clinical evidence points to a role of central histaminergic system in the pathogenesis of schizophrenia. The present study was designed to study the effect of histamine H(3)-receptor ligands on neuroleptic-induced catalepsy, apomorphine-induced climbing behavior and amphetamine-induced locomotor activities in mice. Catalepsy was induced by haloperidol (2 mg/kg p.o.), while apomorphine (1.5 mg/kg s.c.) and amphetamine (2 mg/kg s.c.) were used for studying climbing behavior and locomotor activities, respectively. (R)-alpha-methylhistamine (RAMH) (5 microg i.c.v.) and thioperamide (THP) (15 mg/kg i.p.), per se did not cause catalepsy. Administration of THP (3.75, 7.5 and 15 mg/kg i.p.) 1 h prior to haloperidol resulted in a dose-dependent increase in the catalepsy times (P < 0.05). However, pretreatment with RAMH significantly reversed such an effect of THP (15 mg/kg i.p.). RAMH per se showed significant reduction in locomotor time, distance traveled and average speed but THP (15 mg/kg i.p.) per se had no effect on these parameters. On amphetamine-induced hyperactivity, THP (3.75 and 7.5 mg/kg i.p.) reduced locomotor time, distance traveled and average speed (P < 0.05). Pretreatment with RAMH (5 microg i.c.v.) could partially reverse such effects of THP (3.75 mg/kg i.p.). Climbing behavior induced by apomorphine was reduced in animals treated with THP. Such an effect was, however, reversed in presence of RAMH. THP exhibited an antipsychotic-like profile by potentiating haloperidol-induced catalepsy, reducing amphetamine-induced hyperactivity and reducing apomorphine-induced climbing in mice. Such effects of THP were reversed by RAMH indicating the involvement of histamine H(3)-receptors. Findings suggest a potential for H(3)-receptor antagonists in improving the refractory cases of schizophrenia.

thioperamide

schizophrenia

histamine

catalepsy

apomorphine

amphetamine

Catalepsy

haloperidol

apomorphine

amphetamine

(R)-alpha-methylhistamine

RAMH

thioperamide

THP

catalepsy

THP

haloperidol

catalepsy

RAMH

THP

RAMH

THP

amphetamine

hyperactivity

THP

RAMH

THP

apomorphine

THP

RAMH

THP

haloperidol

catalepsy

amphetamine

hyperactivity

apomorphine

THP

RAMH

histamine

schizophrenia


Transient platypnea-orthodeoxia-like syndrome induced by propafenone overdose in a young woman with Ebstein's anomaly.

In this report we describe the case of a 37-year-old white woman with Ebstein's anomaly, who developed a rare syndrome called platypnea-orthodeoxia, characterized by massive right-to-left interatrial shunting with transient profound hypoxia and cyanosis. This shunt of blood via a patent foramen ovale occurred in the presence of a normal pulmonary artery pressure, and was probably precipitated by a propafenone overdose. This drug caused biventricular dysfunction, due to its negative inotropic effect, and hypotension, due to its peripheral vasodilatory effect. These effects gave rise to an increase in the right atrial pressure and a decrease in the left one with a consequent stretching of the foramen ovale and the creation of massive right-to-left shunting. In our case this interatrial shunt was very accurately detected at bubble contrast echocardiography.

platypnea-orthodeoxia-like syndrome

propafenone

overdose

Ebstein's anomaly

Ebstein's anomaly

platypnea-orthodeoxia

hypoxia

cyanosis

patent foramen ovale

propafenone

overdose

biventricular dysfunction

hypotension


A Phase II trial of cisplatin plus WR-2721 (amifostine) for metastatic breast carcinoma: an Eastern Cooperative Oncology Group Study (E8188).

BACKGROUND: Cisplatin has minimal antitumor activity when used as second- or third-line treatment of metastatic breast carcinoma. Older reports suggest an objective response rate of 8% when 60-120 mg/m2 of cisplatin is administered every 3-4 weeks. Although a dose-response effect has been observed with cisplatin, the dose-limiting toxicities associated with cisplatin (e.g., nephrotoxicity, ototoxicity, and neurotoxicity) have limited its use as a treatment for breast carcinoma. WR-2721 or amifostine initially was developed to protect military personnel in the event of nuclear war. Amifostine subsequently was shown to protect normal tissues from the toxic effects of alkylating agents and cisplatin without decreasing the antitumor effect of the chemotherapy. Early trials of cisplatin and amifostine also suggested that the incidence and severity of cisplatin-induced nephrotoxicity, ototoxicity, and neuropathy were reduced. METHODS: A Phase II study of the combination of cisplatin plus amifostine was conducted in patients with progressive metastatic breast carcinoma who had received one, but not more than one, chemotherapy regimen for metastatic disease. Patients received amifostine, 910 mg/m2 intravenously over 15 minutes. After completion of the amifostine infusion, cisplatin 120 mg/m2 was administered over 30 minutes. Intravenous hydration and mannitol was administered before and after cisplatin. Treatment was administered every 3 weeks until disease progression. RESULTS: Forty-four patients were enrolled in the study of which 7 (16%) were ineligible. A median of 2 cycles of therapy was administered to the 37 eligible patients. Six partial responses were observed for an overall response rate of 16%. Most patients (57%) stopped treatment because of disease progression. Neurologic toxicity was reported in 52% of patients. Seven different life-threatening toxicities were observed in patients while receiving treatment. CONCLUSIONS: The combination of cisplatin and amifostine in this study resulted in an overall response rate of 16%. Neither a tumor-protective effect nor reduced toxicity to normal tissues was observed with the addition of amifostine to cisplatin in this trial.

cisplatin

amifostine

breast carcinoma

Cisplatin

breast carcinoma

cisplatin

cisplatin

toxicities

cisplatin

nephrotoxicity

ototoxicity

neurotoxicity

breast carcinoma

amifostine

Amifostine

alkylating agents

cisplatin

cisplatin

amifostine

cisplatin

nephrotoxicity

ototoxicity

neuropathy

cisplatin

amifostine

breast carcinoma

amifostine

amifostine

cisplatin

mannitol

cisplatin

Neurologic toxicity

toxicities

cisplatin

amifostine

tumor

toxicity

amifostine

cisplatin


Warfarin-induced iliopsoas hemorrhage with subsequent femoral nerve palsy.

We present the case of a 28-year-old man on chronic warfarin therapy who sustained a minor muscle tear and developed increasing pain and a flexure contracture of the right hip. Surgical exploration revealed an iliopsoas hematoma and femoral nerve entrapment, resulting in a femoral nerve palsy and partial loss of quadriceps functions. Anticoagulant-induced femoral nerve palsy represents the most common form of warfarin-induced peripheral neuropathy; it is characterized by severe pain in the inguinal region, varying degrees of motor and sensory impairment, and flexure contracture of the involved extremity.

Warfarin

hemorrhage

femoral nerve palsy

warfarin

muscle tear

pain

contracture

hematoma

nerve entrapment

femoral nerve palsy

partial loss of quadriceps functions

femoral nerve palsy

warfarin

peripheral neuropathy

pain

motor and sensory impairment

contracture


Myasthenia gravis caused by penicillamine and chloroquine therapy for rheumatoid arthritis.

We have described a unique patient who had reversible and dose-related myasthenia gravis after penicillamine and chloroquine therapy for rheumatoid arthritis. Although acetylcholine receptor antibodies were not detectable, the time course was consistent with an autoimmune process.

Myasthenia gravis

penicillamine

chloroquine

rheumatoid arthritis

myasthenia gravis

penicillamine

chloroquine

rheumatoid arthritis

acetylcholine


Nephrotoxicity of combined cephalothin-gentamicin regimen.

Two patients developed acute tubular necrosis, characterized clinically by acute oliguric renal failure, while they were receiving a combination of cephalothin sodium and gentamicin sulfate therapy. Patients who are given this drug regimen should be observed very carefully for early signs of nephrotoxicity. High doses of this antibiotic combination should be avoided especially in elderly patients. Patients with renal insufficiency should not be given this regimen.

Nephrotoxicity

cephalothin

gentamicin

acute tubular necrosis

oliguric renal failure

oliguric

renal failure

cephalothin sodium

gentamicin sulfate

nephrotoxicity

renal insufficiency


Components of lemon essential oil attenuate dementia induced by scopolamine.

The anti-dementia effects of s-limonene and s-perillyl alcohol were observed using the passive avoidance test (PA) and the open field habituation test (OFH). These lemon essential oils showed strong ability to improve memory impaired by scopolamine; however, s-perillyl alcohol relieved the deficit of associative memory in PA only, and did not improve non-associative memory significantly in OFH. Analysis of neurotransmitter concentration in some brain regions on the test day showed that dopamine concentration of the vehicle/scopolamine group was significantly lower than that of the vehicle/vehicle group, but this phenomenon was reversed when s-limonene or s-perillyl alcohol were administered before the injection of scopolamine. Simultaneously, we found that these two lemon essential oil components could inhibit acetylcholinesterase activity in vitro using the Ellman method.

dementia

scopolamine

dementia

s-limonene

s-perillyl alcohol

memory impaired

scopolamine

s-perillyl alcohol

deficit of associative memory

dopamine

scopolamine

s-limonene

s-perillyl alcohol

scopolamine


The selective 5-HT6 receptor antagonist Ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat.

Antagonists at serotonin type 6 (5-HT(6)) receptors show activity in models of learning and memory. Although the underlying mechanism(s) are not well understood, these effects may involve an increase in acetylcholine (ACh) levels. The present study sought to characterize the cognitive-enhancing effects of the 5-HT(6) antagonist Ro4368554 (3-benzenesulfonyl-7-(4-methyl-piperazin-1-yl)1H-indole) in a rat object recognition task employing a cholinergic (scopolamine pretreatment) and a serotonergic- (tryptophan (TRP) depletion) deficient model, and compared its pattern of action with that of the acetylcholinesterase inhibitor metrifonate. Initial testing in a time-dependent forgetting task employing a 24-h delay between training and testing showed that metrifonate improved object recognition (at 10 and 30 mg/kg, p.o.), whereas Ro4368554 was inactive. Both, Ro4368554 (3 and 10 mg/kg, intraperitoneally (i.p.)) and metrifonate (10 mg/kg, p.o., respectively) reversed memory deficits induced by scopolamine and TRP depletion (10 mg/kg, i.p., and 3 mg/kg, p.o., respectively). In conclusion, although Ro4368554 did not improve a time-related retention deficit, it reversed a cholinergic and a serotonergic memory deficit, suggesting that both mechanisms may be involved in the facilitation of object memory by Ro4368554 and, possibly, other 5-HT(6) receptor antagonists.

memory deficiency

serotonin

acetylcholine

ACh

scopolamine

tryptophan

TRP

metrifonate

metrifonate

metrifonate

memory deficits

scopolamine

TRP

memory deficit


Lone atrial fibrillation associated with creatine monohydrate supplementation.

Atrial fibrillation in young patients without structural heart disease is rare. Therefore, when the arrhythmia is present in this population, reversible causes must be identified and resolved. Thyroid disorders, illicit drug or stimulant use, and acute alcohol intoxication are among these causes. We report the case of a 30-year-old Caucasian man who came to the emergency department in atrial fibrillation with rapid ventricular response. His medical history was unremarkable, except for minor fractures of the fingers and foot. Thyroid-stimulating hormone, magnesium, and potassium levels were within normal limits, urine drug screen was negative, and alcohol use was denied. However, when the patient was questioned about use of herbal products and supplements, the use of creatine monohydrate was revealed. The patient was admitted to the hospital, anticoagulated with unfractionated heparin, and given intravenous diltiazem for rate control and intravenous amiodarone for rate and rhythm control. When discharged less than 24 hours later, he was receiving metoprolol and aspirin, with follow-up plans for echocardiography and nuclear imaging to assess perfusion. Exogenous creatine is used by athletes to theoretically improve exercise performance. Vegetarians may also take creatine to replace what they are not consuming from meat, fish, and other animal products. Previous anecdotal reports have linked creatine to the development of arrhythmia. Clinicians must be diligent when interviewing patients about their drug therapy histories and include questions about their use of herbal products and dietary supplements. In addition, it is important to report adverse effects associated with frequently consumed supplements and herbal products to the Food and Drug Administration and in the literature.

atrial fibrillation

creatine

Atrial fibrillation

heart disease

arrhythmia

Thyroid disorders

acute alcohol intoxication

atrial fibrillation

fractures

magnesium

potassium

alcohol

creatine

heparin

diltiazem

amiodarone

metoprolol

aspirin

creatine

creatine

creatine

arrhythmia


Comparison of developmental toxicity of selective and non-selective cyclooxygenase-2 inhibitors in CRL:(WI)WUBR Wistar rats--DFU and piroxicam study.

BACKGROUND: Cyclooxygenase (COX) inhibitors are one of the most often ingested drugs during pregnancy. Unlike general toxicity data, their prenatal toxic effects were not extensively studied before. The aim of the experiment was to evaluate the developmental toxicity of the non-selective (piroxicam) and selective (DFU; 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanon) COX-2 inhibitors. METHODS: Drugs were separately, orally once daily dosed to pregnant rats from day 8 to 21 (GD1=plug day). Doses were set at 0.3, 3.0 and 30.0mg/kg for piroxicam and 0.2, 2.0 and 20.0mg/kg for DFU. Fetuses were delivered on GD 21 and routinely examined. Comprehensive clinical and developmental measurements were done. The pooled statistical analysis for ventricular septal (VSD) and midline (MD) defects was performed for rat fetuses exposed to piroxicam, selective and non-selective COX-2 inhibitor based on present and historic data. RESULTS: Maternal toxicity, intrauterine growth retardation, and increase of external and skeletal variations were found in rats treated with the highest dose of piroxicam. Decrease of fetal length was the only signs of the DFU developmental toxicity observed in pups exposed to the highest compound dose. Lack of teratogenicity was found in piroxicam and DFU-exposed groups. Prenatal exposure to non-selective COX inhibitors increases the risk of VSD and MD when compared to historic control but not with selective COX-2 inhibitors. CONCLUSION: Both selective and non-selective COX-2 inhibitors were toxic for rats fetuses when administered in the highest dose. Unlike DFU, piroxicam was also highly toxic to the dams. Prenatal exposure to selective COX-2 inhibitors does not increase the risk of ventricular septal and midline defects in rat when compared to non-selective drugs and historic control.

toxicity

DFU

piroxicam

toxicity

toxicity

piroxicam

DFU

piroxicam

DFU

ventricular septal (VSD)
defects

midline (MD) defects

piroxicam

toxicity

intrauterine growth retardation

piroxicam

DFU

toxicity

piroxicam

DFU

DFU

piroxicam

ventricular septal and midline defects

ventricular septal
defects

midline defects