Age and renal clearance of cimetidine.

In 35 patients (ages 20 to 86 yr) receiving cimetidine therapeutically two serum samples and all urine formed in the interim were collected for analysis of cimetidine by high-pressure liquid chromatography and for creatinine. Cimetidine clearance decreased with age. The extrapolated 6-hr serum concentration of cimetidine per unit dose, after intravenous cimetidine, increased with age of the patients. The ratio of cimetidine clearance to creatinine clearance (Rc) averaged 4.8 +/- 2.0, indicating net tubular secretion for cimetidine. Rc seemed to be independent of age and decreased with increasing serum concentration of cimetidine, suggesting that secretion of cimetidine is a saturable process. There was only one case of dementia possibly due to cimetidine (with a drug level of 1.9 microgram/ml 6 hr after a dose) in a group of 13 patients without liver or kidney disease who had cimetidine levels above 1.25 microgram/ml. Thus, high cimetidine levels alone do not always induce dementia.

cimetidine

cimetidine

cimetidine

creatinine

Cimetidine

cimetidine

cimetidine

cimetidine

creatinine

cimetidine

cimetidine

cimetidine

dementia

cimetidine

liver or kidney disease

liver disease

kidney disease

cimetidine

cimetidine

dementia


Development of clear cell adenocarcinoma in DES-exposed offspring under observation.

Two cases of clear cell adenocarcinoma of the vagina detected at follow-up in young women exposed in utero to diethylstilbestrol are reported. One patient, aged 23, had been followed for 2 years before carcinoma was diagnosed; the second patient, aged 22, had been seen on a regular basis for 5 years, 8 months. In both instances, suspicion of the presence of carcinoma was aroused by the palpation of a small nodule in the vaginal fornix. Hysterosalpingography was performed on both patients and, in 1 instance, an abnormal x-ray film was reflected by the gross appearance of the uterine cavity found in the surgical specimen.

clear cell adenocarcinoma

DES

clear cell adenocarcinoma of the vagina

clear cell adenocarcinoma

adenocarcinoma of the vagina

diethylstilbestrol

carcinoma

carcinoma


Phenobarbitone-induced enlargement of the liver in the rat: its relationship to carbon tetrachloride-induced cirrhosis.

The yield of severe cirrhosis of the liver (defined as a shrunken finely nodular liver with micronodular histology, ascites greater than 30 ml, plasma albumin less than 2.2 g/dl, splenomegaly 2-3 times normal, and testicular atrophy approximately half normal weight) after 12 doses of carbon tetrachloride given intragastrically in the phenobarbitone-primed rat was increased from 25% to 56% by giving the initial "calibrating" dose of carbon tetrachloride at the peak of the phenobarbitone-induced enlargement of the liver. At this point it was assumed that the cytochrome P450/CCl4 toxic state was both maximal and stable. The optimal rat size to begin phenobarbitone was determined as 100 g, and this size as a group had a mean maximum relative liver weight increase 47% greater than normal rats of the same body weight. The optimal time for the initial dose of carbon tetrachloride was after 14 days on phenobarbitone.

Phenobarbitone

enlargement of the liver

carbon tetrachloride

cirrhosis

cirrhosis of the liver

ascites

splenomegaly

atrophy

carbon tetrachloride

phenobarbitone

carbon tetrachloride

phenobarbitone

enlargement of the liver

phenobarbitone

carbon tetrachloride

phenobarbitone


Attenuation of the lithium-induced diabetes-insipidus-like syndrome by amiloride in rats.

The effect of amiloride on lithium-induced polydipsia and polyuria and on the lithium concentration in the plasma, brain, kidney, thyroid and red blood cells was investigated in rats, chronically treated with LiCl. Amiloride reduced the drinking and urine volume of rats in an acute (6 or 12 h) and a subacute (3 days) experiment. 6 h after the administration of amiloride, a reduction was observed in the lithium content of the renal medulla but not in the other organs studied. At 12 h, all the tissues showed a slight increase in lithium levels. After 3 days of combined treatment, a marked elevation in plasma and tissue lithium levels accompanied a reduction in water intake. In all the experiments, the attenuation of the lithium-induced diabetes-insipidus-like syndrome by amiloride was accompanied by a reduction of the ratio between the lithium concentration in the renal medulla and its levels in the blood and an elevation in the plasma potassium level. It is concluded that acute amiloride administration to lithium-treated patients suffering from polydipsia and polyuria might relieve these patients but prolonged amiloride supplementation would result in elevated lithium levels and might be hazardous.

lithium

diabetes-insipidus-like syndrome

amiloride

amiloride

lithium

polydipsia

polyuria

lithium

LiCl

Amiloride

amiloride

lithium

lithium

lithium

lithium

diabetes-insipidus-like syndrome

amiloride

lithium

potassium

amiloride

lithium

polydipsia

polyuria

amiloride

lithium


Safety and side-effects of alprazolam. Controlled study in agoraphobia with panic disorder.

BACKGROUND: The widespread use of benzodiazepines has led to increasing recognition of their unwanted effects. The efficacy of alprazolam and placebo in panic disorder with agoraphobia, and the side-effect and adverse effect profiles of both drug groups were measured. METHOD: In London and Toronto 154 patients who met DSM-III criteria for panic disorder with agoraphobia were randomised to alprazolam or placebo. Subjects in each drug group also received either exposure or relaxation. Treatment was from weeks 0 to 8 and was then tapered from weeks 8 to 16. RESULTS: Mean alprazolam dose was 5 mg daily. Compared with placebo subjects, alprazolam patients developed more adverse reactions (21% v. 0%) of depression, enuresis, disinhibition and aggression; and more side-effects, particularly sedation, irritability, impaired memory, weight loss and ataxia. Side-effects tended to diminish during treatment but remained significant at week 8. Despite this, the drop-out rate was low. CONCLUSIONS: Alprazolam caused side-effects and adverse effects during treatment but many patients were willing to accept these.

alprazolam

agoraphobia

panic disorder

benzodiazepines

alprazolam

panic disorder

agoraphobia

panic disorder

agoraphobia

alprazolam

alprazolam

alprazolam

depression

enuresis

aggression

irritability

impaired memory

weight loss

ataxia

Alprazolam


Dup 753 prevents the development of puromycin aminonucleoside-induced nephrosis.

The appearance of nephrotic syndromes such as proteinuria, hypoalbuminemia, hypercholesterolemia and increase in blood nitrogen urea, induced in rats by injection of puromycin aminonucleoside was markedly inhibited by oral administration of Dup 753 (losartan), a novel angiotensin II receptor antagonist, at a dose of 1 or 2 mg/kg per day. The results suggest a possible involvement of the renin-angiotensin system in the development of puromycin aminonucleoside-induced nephrosis.

Dup 753

puromycin aminonucleoside

nephrosis

nephrotic syndromes

proteinuria

hypoalbuminemia

hypercholesterolemia

blood nitrogen urea

puromycin aminonucleoside

Dup 753

losartan

angiotensin II

angiotensin

puromycin aminonucleoside

nephrosis


Sodium bicarbonate alleviates penile pain induced by intracavernous injections for erectile dysfunction.

In an attempt to determine whether penile pain associated with intracorporeal injections could be due to the acidity of the medication, we performed a randomized study comparing the incidence of penile pain following intracorporeal injections with or without the addition of sodium bicarbonate to the intracorporeal medications. A total of 38 consecutive patients who presented to our clinic with impotence received 0.2 ml. of a combination of 3 drugs: 6 mg. papaverine, 100 micrograms. phentolamine and 10 micrograms. prostaglandin E1 with (pH 7.05) or without (pH 4.17) the addition of sodium bicarbonate (0.03 mEq.). Of the 19 patients without sodium bicarbonate added to the medication 11 (58%) complained of penile pain due to the medication, while only 1 of the 19 men (5%) who received sodium bicarbonate complained of penile pain. From these data we conclude that the penile pain following intracorporeal injections is most likely due to the acidity of the medication, which can be overcome by elevating the pH to a neutral level.

Sodium bicarbonate

penile pain

erectile dysfunction

penile pain

penile pain

sodium bicarbonate

impotence

papaverine

phentolamine

prostaglandin E1

sodium bicarbonate

sodium bicarbonate

penile pain

sodium bicarbonate

penile pain

penile pain


Prospective study of the long-term effects of somatostatin analog (octreotide) on gallbladder function and gallstone formation in Chinese acromegalic patients.

This article reports the changes in gallbladder function examined by ultrasonography in 20 Chinese patients with active acromegaly treated with sc injection of the somatostatin analog octreotide in dosages of 300-1500 micrograms/day for a mean of 24.2 +/- 13.9 months. During treatment with octreotide, 17 patients developed sludge, 10 had gallstones, and 1 developed acute cholecystitis requiring surgery. In all of 7 patients examined acutely, gallbladder contractility was inhibited after a single 100-micrograms injection. In 8 patients followed for 24 weeks, gallbladder contractility remained depressed throughout therapy. After withdrawal of octreotide in 10 patients without gallstones, 8 patients assessed had return of normal gallbladder contractility within 1 month. In 8 of the remaining 10 patients who developed gallstones during treatment, gallbladder contractility normalized in 5 patients (3 of whom has disappearance of their stones within 3 weeks), and remained depressed in 3 (2 of whom had stones present at 6 months). Our results suggest that the suppression of gallbladder contractility is the cause of the successive formation of bile sludge, gallstones, and cholecystitis during octreotide therapy in Chinese acromegalic patients. It is therefore very important to follow the changes of gallbladder function during long-term octreotide therapy of acromegalic patients.

octreotide

gallstone

acromegalic

acromegaly

octreotide

octreotide

gallstones

acute cholecystitis

depressed

octreotide

gallstones

gallstones

depressed

gallstones

cholecystitis

octreotide

acromegalic

octreotide

acromegalic


Improvement of levodopa-induced dyskinesia by propranolol in Parkinson's disease.

Seven patients suffering from Parkinson's disease (PD) with severely disabling dyskinesia received low-dose propranolol as an adjunct to the currently used medical treatment. There was a significant 40% improvement in the dyskinesia score without increase of parkinsonian motor disability. Ballistic and choreic dyskinesia were markedly ameliorated, whereas dystonia was not. This study suggests that administration of low doses of beta-blockers may improve levodopa-induced ballistic and choreic dyskinesia in PD.

levodopa

dyskinesia

propranolol

Parkinson's disease

Parkinson's disease

PD

dyskinesia

propranolol

dyskinesia

parkinsonian

motor disability

dyskinesia

dystonia

levodopa

dyskinesia

PD


Morphological features of encephalopathy after chronic administration of the antiepileptic drug valproate to rats. A transmission electron microscopic study of capillaries in the cerebellar cortex.

Long-term intragastric application of the antiepileptic drug sodium valproate (Vupral "Polfa") at the effective dose of 200 mg/kg b. w. once daily to rats for 1, 3, 6, 9 and 12 months revealed neurological disorders indicating cerebellum damage ("valproate encephalopathy"). The first ultrastructural changes in structural elements of the blood-brain-barrier (BBB) in the cerebellar cortex were detectable after 3 months of the experiment. They became more severe in the later months of the experiment, and were most severe after 12 months, located mainly in the molecular layer of the cerebellar cortex. Lesions of the capillary included necrosis of endothelial cells. Organelles of these cells, in particular the mitochondria (increased number and size, distinct degeneration of their matrix and cristae) and Golgi apparatus were altered. Reduced size of capillary lumen and occlusion were caused by swollen endothelial cells which had luminal protrusions and swollen microvilli. Pressure on the vessel wall was produced by enlarged perivascular astrocytic processes. Fragments of necrotic endothelial cells were in the vascular lumens and in these there was loosening and breaking of tight cellular junctions. Damage to the vascular basement lamina was also observed. Damage to the capillary was accompanied by marked damage to neuroglial cells, mainly to perivascular processes of astrocytes. The proliferation of astrocytes (Bergmann's in particular) and occasionally of oligodendrocytes was found. Alterations in the structural elements of the BBB coexisted with marked lesions of neurons of the cerebellum (Purkinje cells are earliest). In electron micrographs both luminal and antiluminal sides of the BBB of the cerebellar cortex had similar lesions. The possible influence of the hepatic damage, mainly hyperammonemia, upon the development of valproate encephalopathy is discussed.

encephalopathy

valproate

sodium valproate

neurological disorders

cerebellum damage

valproate

encephalopathy

necrosis

luminal

necrotic

luminal

hepatic damage

hyperammonemia

valproate

encephalopathy


Macula toxicity after intravitreal amikacin.

BACKGROUND: Although intravitreal aminoglycosides have substantially improved visual prognosis in endophthalmitis, macular infarction may impair full visual recovery. METHODS: We present a case of presumed amikacin retinal toxicity following treatment with amikacin and vancomycin for alpha-haemolytic streptococcal endophthalmitis. RESULTS: Endophthalmitis resolved with improvement in visual acuity to 6/24 at three months. Fundus fluorescein angiography confirmed macular capillary closure and telangiectasis. CONCLUSIONS: Currently accepted intravitreal antibiotic regimens may cause retinal toxicity and macular ischaemia. Treatment strategies aimed at avoiding retinal toxicity are discussed.

toxicity

amikacin

aminoglycosides

endophthalmitis

infarction

amikacin

retinal toxicity

amikacin

vancomycin

streptococcal endophthalmitis

Endophthalmitis

fluorescein

telangiectasis

retinal toxicity

ischaemia

retinal toxicity


Iatrogenically induced intractable atrioventricular reentrant tachycardia after verapamil and catheter ablation in a patient with Wolff-Parkinson-White syndrome and idiopathic dilated cardiomyopathy.

In a patient with WPW syndrome and idiopathic dilated cardiomyopathy, intractable atrioventricular reentrant tachycardia (AVRT) was iatrogenically induced. QRS without preexcitation, caused by junctional escape beats after verapamil or unidirectional antegrade block of accessory pathway after catheter ablation, established frequent AVRT attack.

atrioventricular reentrant tachycardia

verapamil

Wolff-Parkinson-White syndrome

idiopathic dilated cardiomyopathy

WPW syndrome

idiopathic dilated cardiomyopathy

atrioventricular reentrant tachycardia

AVRT

verapamil

AVRT


Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons.

BACKGROUND: Hydrochlorofluorocarbons (HCFCs) are used increasingly in industry as substitutes for ozone-depleting chlorofluorocarbons (CFCs). Limited studies in animals indicate potential hepatotoxicity of some of these compounds. We investigated an epidemic of liver disease in nine industrial workers who had had repeated accidental exposure to a mixture of 1,1-dichloro-2,2,2-trifluoroethane (HCFC 123) and 1-chloro-1,2,2,2-tetrafluoroethane (HCFC 124). All nine exposed workers were affected to various degrees. Both compounds are metabolised in the same way as 1-bromo-1-chloro-2,2,2-trifluoroethane (halothane) to form reactive trifluoroacetyl halide intermediates, which have been implicated in the hepatotoxicity of halothane. We aimed to test whether HCFCs 123 and 124 can result in serious liver disease. METHODS: For one severely affected worker liver biopsy and immunohistochemical stainings for the presence of trifluoroacetyl protein adducts were done. The serum of six affected workers and five controls was tested for autoantibodies that react with human liver cytochrome-P450 2E1 (P450 2E1) and P58 protein disulphide isomerase isoform (P58). FINDINGS: The liver biopsy sample showed hepatocellular necrosis which was prominent in perivenular zone three and extended focally from portal tracts to portal tracts and centrilobular areas (bridging necrosis). Trifluoroacetyl-adducted proteins were detected in surviving hepatocytes. Autoantibodies against P450 2E1 or P58, previously associated with halothane hepatitis, were detected in the serum of five affected workers. INTERPRETATION: Repeated exposure of human beings to HCFCs 123 and 124 can result in serious liver injury in a large proportion of the exposed population. Although the exact mechanism of hepatotoxicity of these agents is not known, the results suggest that trifluoroacetyl-altered liver proteins are involved. In view of the potentially widespread use of these compounds, there is an urgent need to develop safer alternatives.

liver disease

hydrochlorofluorocarbons

ozone

chlorofluorocarbons

Hydrochlorofluorocarbons

HCFCs

ozone

chlorofluorocarbons

CFCs

hepatotoxicity

liver disease

HCFC 123

HCFC 124

halothane

trifluoroacetyl

hepatotoxicity

halothane

HCFCs 123 and 124

HCFCs 123

HCFCs

liver disease

trifluoroacetyl

necrosis

necrosis

Trifluoroacetyl

halothane hepatitis

HCFCs 123 and 124

HCFCs 123

HCFCs

liver injury

hepatotoxicity

trifluoroacetyl


The effect of different anaesthetic agents in hearing loss following spinal anaesthesia.

The cause of hearing loss after spinal anaesthesia is unknown. Up until now, the only factor studied has been the effect of the diameter of the spinal needle on post-operative sensorineural hearing loss. The aim of this study was to describe this hearing loss and to investigate other factors influencing the degree of hearing loss. Two groups of 22 similar patients were studied: one group received 6 mL prilocaine 2%; and the other received 3 mL bupivacaine 0.5%. Patients given prilocaine were more likely to develop hearing loss (10 out of 22) than those given bupivacaine (4 out of 22) (P < 0.05). The average hearing loss for speech frequencies was about 10 dB after prilocaine and 15 dB after bupivacaine. None of the patients complained of subjective hearing loss. Long-term follow-up of the patients was not possible.

hearing loss

hearing loss

sensorineural hearing loss

hearing loss

hearing loss

prilocaine

bupivacaine

prilocaine

hearing loss

bupivacaine

hearing loss

prilocaine

bupivacaine

hearing loss


A transient neurological deficit following intrathecal injection of 1% hyperbaric bupivacaine for unilateral spinal anaesthesia.

We describe a case of transient neurological deficit that occurred after unilateral spinal anaesthesia with 8 mg of 1% hyperbaric bupivacaine slowly injected through a 25-gauge pencil-point spinal needle. The surgery and anaesthesia were uneventful, but 3 days after surgery, the patient reported an area of hypoaesthesia over L3-L4 dermatomes of the leg which had been operated on (loss of pinprick sensation) without reduction in muscular strength. Sensation in this area returned to normal over the following 2 weeks. Prospective multicentre studies with a large population and a long follow-up should be performed in order to evaluate the incidence of this unusual side effect. However, we suggest that a low solution concentration should be preferred for unilateral spinal anaesthesia with a hyperbaric anaesthetic solution (if pencil-point needle and slow injection rate are employed), in order to minimize the risk of a localized high peak anaesthetic concentration, which might lead to a transient neurological deficit.

neurological deficit

bupivacaine

neurological deficit

bupivacaine

loss of pinprick sensation

neurological deficit


Pethidine-associated seizure in a healthy adolescent receiving pethidine for postoperative pain control.

A healthy 17-year-old male received standard intermittent doses of pethidine via a patient-controlled analgesia (PCA) pump for management of postoperative pain control. Twenty-three h postoperatively he developed a brief self-limited seizure. Both plasma pethidine and norpethidine were elevated in the range associated with clinical manifestations of central nervous system excitation. No other risk factors for CNS toxicity were identified. This method allowed frequent self-dosing of pethidine at short time intervals and rapid accumulation of pethidine and norpethidine. The routine use of pethidine via PCA even for a brief postoperative analgesia should be reconsidered.

Pethidine

seizure

pethidine

postoperative pain

pethidine

postoperative pain

seizure

pethidine

norpethidine

toxicity

pethidine

pethidine

norpethidine

pethidine


Drug-associated acute-onset vanishing bile duct and Stevens-Johnson syndromes in a child.

Acute vanishing bile duct syndrome is a rare but established cause of progressive cholestasis in adults, is most often drug or toxin related, and is of unknown pathogenesis. It has not been reported previously in children. Stevens-Johnson syndrome is a well-recognized immune complex-mediated hypersensitivity reaction that affects all age groups, is drug or infection induced, and has classic systemic, mucosal, and dermatologic manifestations. A previously healthy child who developed acute, severe, rapidly progressive vanishing bile duct syndrome shortly after Stevens-Johnson syndrome is described; this was temporally associated with ibuprofen use. Despite therapy with ursodeoxycholic acid, prednisone, and then tacrolimus, her cholestatic disease was unrelenting, with cirrhosis shown by biopsy 6 months after presentation. This case documents acute drug-related vanishing bile duct syndrome in the pediatric age group and suggests shared immune mechanisms in the pathogenesis of both Stevens-Johnson syndrome and vanishing bile duct syndrome.

vanishing bile duct

Stevens-Johnson syndromes

vanishing bile duct

cholestasis

Stevens-Johnson syndrome

hypersensitivity

infection

vanishing bile duct syndrome

Stevens-Johnson syndrome

ibuprofen

ursodeoxycholic acid

prednisone

tacrolimus

cholestatic disease

cirrhosis

vanishing bile duct syndrome

Stevens-Johnson syndrome

vanishing bile duct syndrome


High incidence of primary pulmonary hypertension associated with appetite suppressants in Belgium.

Primary pulmonary hypertension is a rare, progressive and incurable disease, which has been associated with the intake of appetite suppressant drugs. The importance of this association was evaluated in Belgium while this country still had no restriction on the prescription of appetite suppressants. Thirty-five patients with primary pulmonary hypertension and 85 matched controls were recruited over 32 months (1992-1994) in Belgium. Exposure to appetite-suppressants was assessed on the basis of hospital records and standardized interview. Twenty-three of the patients had previously taken appetite suppressants, mainly fenfluramines, as compared with only 5 of the controls (66 versus 6%, p<0.0001). Five patients died before the interview, all of them had taken appetite suppressants. In 8 patients the diagnosis of primary pulmonary hypertension was uncertain, 5 of them had taken appetite suppressants. The patients who had been exposed to appetite suppressants tended to be on average more severely ill, and to have a shorter median delay between onset of symptoms and diagnosis. A policy of unrestricted prescription of appetite suppressants may lead to a high incidence of associated primary pulmonary hypertension. Intake of appetite suppressants may accelerate the progression of the disease.

primary pulmonary hypertension

appetite suppressants

Primary pulmonary hypertension

appetite suppressant

appetite suppressants

primary pulmonary hypertension

appetite-suppressants

appetite suppressants

fenfluramines

appetite suppressants

primary pulmonary hypertension

appetite suppressants

appetite suppressants

appetite suppressants

primary pulmonary hypertension

appetite suppressants


Choreoathetoid movements associated with rapid adjustment to methadone.

Choreatiform hyperkinesias are known to be occasional movement abnormalities during intoxications with cocaine but not opiates. This is a case report of euphoria and choreoathetoid movements both transiently induced by rapid adjustment to the selective mu-opioid receptor agonist methadone in an inpatient previously abusing heroine and cocaine. In addition, minor EEG abnormalities occurred. Possible underlying neurobiological phenomena are discussed.

Choreoathetoid movements

methadone

Choreatiform hyperkinesias

Choreatiform

hyperkinesias

movement abnormalities

cocaine

choreoathetoid movements

methadone

heroine

cocaine


Cocaine-induced mood disorder: prevalence rates and psychiatric symptoms in an outpatient cocaine-dependent sample.

This paper attempts to examine and compare prevalence rates and symptom patterns of DSM substance-induced and other mood disorders. 243 cocaine-dependent outpatients with cocaine-induced mood disorder (CIMD), other mood disorders, or no mood disorder were compared on measures of psychiatric symptoms. The prevalence rate for CIMD was 12% at baseline. Introduction of the DSM-IV diagnosis of CIMD did not substantially affect rates of the other depressive disorders. Patients with CIMD had symptom severity levels between those of patients with and without a mood disorder. These findings suggest some validity for the new DSM-IV diagnosis of CIMD, but also suggest that it requires further specification and replication.

Cocaine

mood disorder

psychiatric

cocaine

mood disorders

cocaine

cocaine

mood disorder

CIMD

mood disorders

mood disorder

psychiatric

CIMD

CIMD

depressive disorders

CIMD

mood disorder

CIMD


Hemolysis of human erythrocytes induced by tamoxifen is related to disruption of membrane structure.

Tamoxifen (TAM), the antiestrogenic drug most widely prescribed in the chemotherapy of breast cancer, induces changes in normal discoid shape of erythrocytes and hemolytic anemia. This work evaluates the effects of TAM on isolated human erythrocytes, attempting to identify the underlying mechanisms on TAM-induced hemolytic anemia and the involvement of biomembranes in its cytostatic action mechanisms. TAM induces hemolysis of erythrocytes as a function of concentration. The extension of hemolysis is variable with erythrocyte samples, but 12.5 microM TAM induces total hemolysis of all tested suspensions. Despite inducing extensive erythrocyte lysis, TAM does not shift the osmotic fragility curves of erythrocytes. The hemolytic effect of TAM is prevented by low concentrations of alpha-tocopherol (alpha-T) and alpha-tocopherol acetate (alpha-TAc) (inactivated functional hydroxyl) indicating that TAM-induced hemolysis is not related to oxidative membrane damage. This was further evidenced by absence of oxygen consumption and hemoglobin oxidation both determined in parallel with TAM-induced hemolysis. Furthermore, it was observed that TAM inhibits the peroxidation of human erythrocytes induced by AAPH, thus ruling out TAM-induced cell oxidative stress. Hemolysis caused by TAM was not preceded by the leakage of K(+) from the cells, also excluding a colloid-osmotic type mechanism of hemolysis, according to the effects on osmotic fragility curves. However, TAM induces release of peripheral proteins of membrane-cytoskeleton and cytosol proteins essentially bound to band 3. Either alpha-T or alpha-TAc increases membrane packing and prevents TAM partition into model membranes. These effects suggest that the protection from hemolysis by tocopherols is related to a decreased TAM incorporation in condensed membranes and the structural damage of the erythrocyte membrane is consequently avoided. Therefore, TAM-induced hemolysis results from a structural perturbation of red cell membrane, leading to changes in the framework of the erythrocyte membrane and its cytoskeleton caused by its high partition in the membrane. These defects explain the abnormal erythrocyte shape and decreased mechanical stability promoted by TAM, resulting in hemolytic anemia. Additionally, since membrane leakage is a final stage of cytotoxicity, the disruption of the structural characteristics of biomembranes by TAM may contribute to the multiple mechanisms of its anticancer action.

Hemolysis

tamoxifen

Tamoxifen

TAM

breast cancer

hemolytic anemia

TAM

TAM

hemolytic anemia

TAM

hemolysis

hemolysis

TAM

hemolysis

TAM

hemolytic

TAM

alpha-tocopherol

alpha-T

alpha-tocopherol acetate

alpha-TAc

hydroxyl

TAM

hemolysis

oxygen

TAM

hemolysis

TAM

AAPH

TAM

Hemolysis

TAM

K

hemolysis

TAM

alpha-T

alpha-TAc

TAM

hemolysis

tocopherols

TAM

TAM

hemolysis

TAM

hemolytic anemia

TAM


Changes of sodium and ATP affinities of the cardiac (Na,K)-ATPase during and after nitric oxide deficient hypertension.

In the cardiovascular system, NO is involved in the regulation of a variety of functions. Inhibition of NO synthesis induces sustained hypertension. In several models of hypertension, elevation of intracellular sodium level was documented in cardiac tissue. To assess the molecular basis of disturbances in transmembraneous transport of Na+, we studied the response of cardiac (Na,K)-ATPase to NO-deficient hypertension induced in rats by NO-synthase inhibition with 40 mg/kg/day N(G)-nitro-L-arginine methyl ester (L-NAME) for 4 four weeks. After 4-week administration of L-NAME, the systolic blood pressure (SBP) increased by 36%. Two weeks after terminating the treatment, the SBP recovered to control value. When activating the (Na,K)-ATPase with its substrate ATP, no changes in Km and Vmax values were observed in NO-deficient rats. During activation with Na+, the Vmax remained unchanged, however the K(Na) increased by 50%, indicating a profound decrease in the affinity of the Na+-binding site in NO-deficient rats. After recovery from hypertension, the activity of (Na,K)-ATPase increased, due to higher affinity of the ATP-binding site, as revealed from the lowered Km value for ATP. The K(Na) value for Na+ returned to control value. Inhibition of NO-synthase induced a reversible hypertension accompanied by depressed Na+-extrusion from cardiac cells as a consequence of deteriorated Na+-binding properties of the (Na,K)-ATPase. After recovery of blood pressure to control values, the extrusion of Na+ from cardiac cells was normalized, as revealed by restoration of the (Na,K)-ATPase activity.

sodium

ATP

K

nitric oxide

hypertension

NO

NO

hypertension

hypertension

sodium

K

NO

hypertension

NO

N(G)-nitro-L-arginine methyl ester

L-NAME

L-NAME

K

ATP

NO

K

NO

hypertension

K

ATP

ATP

K

NO

hypertension

depressed

K

K


Effects of long-term pretreatment with isoproterenol on bromocriptine-induced tachycardia in conscious rats.

It has been shown that bromocriptine-induced tachycardia, which persisted after adrenalectomy, is (i) mediated by central dopamine D2 receptor activation and (ii) reduced by 5-day isoproterenol pretreatment, supporting therefore the hypothesis that this effect is dependent on sympathetic outflow to the heart. This study was conducted to examine whether prolonged pretreatment with isoproterenol could abolish bromocriptine-induced tachycardia in conscious rats. Isoproterenol pretreatment for 15 days caused cardiac hypertrophy without affecting baseline blood pressure and heart rate. In control rats, intravenous bromocriptine (150 microg/kg) induced significant hypotension and tachycardia. Bromocriptine-induced hypotension was unaffected by isoproterenol pretreatment, while tachycardia was reversed to significant bradycardia, an effect that was partly reduced by i.v. domperidone (0.5 mg/kg). Neither cardiac vagal nor sympathetic tone was altered by isoproterenol pretreatment. In isolated perfused heart preparations from isoproterenol-pretreated rats, the isoproterenol-induced maximal increase in left ventricular systolic pressure was significantly reduced, compared with saline-pretreated rats (the EC50 of the isoproterenol-induced increase in left ventricular systolic pressure was enhanced approximately 22-fold). These results show that 15-day isoproterenol pretreatment not only abolished but reversed bromocriptine-induced tachycardia to bradycardia, an effect that is mainly related to further cardiac beta-adrenoceptor desensitization rather than to impairment of autonomic regulation of the heart. They suggest that, in normal conscious rats, the central tachycardia of bromocriptine appears to predominate and to mask the bradycardia of this agonist at peripheral dopamine D2 receptors.

isoproterenol

bromocriptine

tachycardia

bromocriptine

tachycardia

dopamine

isoproterenol

isoproterenol

bromocriptine

tachycardia

Isoproterenol

cardiac hypertrophy

bromocriptine

hypotension

tachycardia

Bromocriptine

hypotension

isoproterenol

tachycardia

bradycardia

domperidone

isoproterenol

isoproterenol

isoproterenol

isoproterenol

isoproterenol

bromocriptine

tachycardia

bradycardia

tachycardia

bromocriptine

bradycardia

dopamine


A developmental analysis of clonidine's effects on cardiac rate and ultrasound production in infant rats.

Under controlled conditions, infant rats emit ultrasonic vocalizations during extreme cold exposure and after administration of the alpha(2) adrenoceptor agonist, clonidine. Previous investigations have determined that, in response to clonidine, ultrasound production increases through the 2nd-week postpartum and decreases thereafter. Given that sympathetic neural dominance exhibits a similar developmental pattern, and given that clonidine induces sympathetic withdrawal and bradycardia, we hypothesized that clonidine's developmental effects on cardiac rate and ultrasound production would mirror each other. Therefore, in the present experiment, the effects of clonidine administration (0.5 mg/kg) on cardiac rate and ultrasound production were examined in 2-, 8-, 15-, and 20-day-old rats. Age-related changes in ultrasound production corresponded with changes in cardiovascular variables, including baseline cardiac rate and clonidine-induced bradycardia. This experiment is discussed with regard to the hypothesis that ultrasound production is the acoustic by-product of a physiological maneuver that compensates for clonidine's detrimental effects on cardiovascular function.

clonidine

clonidine

clonidine

clonidine

bradycardia

clonidine

clonidine

clonidine

bradycardia

clonidine


Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans.

We have examined the effect of systemic administration of ketamine and lidocaine on brush-evoked (dynamic) pain and punctate-evoked (static) hyperalgesia induced by capsaicin. In a randomized, double-blind, placebo-controlled, crossover study, we studied 12 volunteers in three experiments. Capsaicin 100 micrograms was injected intradermally on the volar forearm followed by an i.v. infusion of ketamine (bolus 0.1 mg kg-1 over 10 min followed by infusion of 7 micrograms kg-1 min-1), lidocaine 5 mg kg-1 or saline for 50 min. Infusion started 15 min after injection of capsaicin. The following were measured: spontaneous pain, pain evoked by punctate and brush stimuli (VAS), and areas of brush-evoked and punctate-evoked hyperalgesia. Ketamine reduced both the area of brush-evoked and punctate-evoked hyperalgesia significantly and it tended to reduce brush-evoked pain. Lidocaine reduced the area of punctate-evoked hyperalgesia significantly. It tended to reduce VAS scores of spontaneous pain but had no effect on evoked pain. The differential effects of ketamine and lidocaine on static and dynamic hyperalgesia suggest that the two types of hyperalgesia are mediated by separate mechanisms and have a distinct pharmacology.

ketamine

lidocaine

hyperalgesia

capsaicin

ketamine

lidocaine

pain

hyperalgesia

capsaicin

Capsaicin

ketamine

lidocaine

capsaicin

pain

pain

hyperalgesia

Ketamine

hyperalgesia

pain

Lidocaine

hyperalgesia

pain

pain

ketamine

lidocaine

hyperalgesia

hyperalgesia


Cyclosporine and tacrolimus-associated thrombotic microangiopathy.

The development of thrombotic microangiopathy (TMA) associated with the use of cyclosporine has been well documented. Treatments have included discontinuation or reduction of cyclosporine dose with or without concurrent plasma exchange, plasma infusion, anticoagulation, and intravenous immunoglobulin G infusion. However, for recipients of organ transplantation, removing the inciting agent is not without the attendant risk of precipitating acute rejection and graft loss. The last decade has seen the emergence of tacrolimus as a potent immunosuppressive agent with mechanisms of action virtually identical to those of cyclosporine. As a result, switching to tacrolimus has been reported to be a viable therapeutic option in the setting of cyclosporine-induced TMA. With the more widespread application of tacrolimus in organ transplantation, tacrolimus-associated TMA has also been recognized. However, literature regarding the incidence of the recurrence of TMA in patients exposed sequentially to cyclosporine and tacrolimus is limited. We report a case of a living donor renal transplant recipient who developed cyclosporine-induced TMA that responded to the withdrawal of cyclosporine in conjunction with plasmapheresis and fresh frozen plasma replacement therapy. Introduction of tacrolimus as an alternative immunosuppressive agent resulted in the recurrence of TMA and the subsequent loss of the renal allograft. Patients who are switched from cyclosporine to tacrolimus or vice versa should be closely monitored for the signs and symptoms of recurrent TMA.

Cyclosporine

tacrolimus

thrombotic microangiopathy

thrombotic microangiopathy

TMA

cyclosporine

cyclosporine

tacrolimus

cyclosporine

tacrolimus

cyclosporine

TMA

tacrolimus

tacrolimus

TMA

TMA

cyclosporine

tacrolimus

cyclosporine

TMA

cyclosporine

tacrolimus

TMA

cyclosporine

tacrolimus

TMA


Repeated transient anuria following losartan administration in a patient with a solitary kidney.

We report the case of a 70-year-old hypertensive man with a solitary kidney and chronic renal insufficiency who developed two episodes of transient anuria after losartan administration. He was hospitalized for a myocardial infarction with pulmonary edema, treated with high-dose diuretics. Due to severe systolic dysfunction losartan was prescribed. Surprisingly, the first dose of 50 mg of losartan resulted in a sudden anuria, which lasted eight hours despite high-dose furosemide and amine infusion. One week later, by mistake, losartan was prescribed again and after the second dose of 50 mg, the patient developed a second episode of transient anuria lasting 10 hours. During these two episodes, his blood pressure diminished but no severe hypotension was noted. Ultimately, an arteriography showed a 70-80% renal artery stenosis. In this patient, renal artery stenosis combined with heart failure and diuretic therapy certainly resulted in a strong activation of the renin-angiotensin system (RAS). Under such conditions, angiotensin II receptor blockade by losartan probably induced a critical fall in glomerular filtration pressure. This case report highlights the fact that the angiotensin II receptor antagonist losartan can cause serious unexpected complications in patients with renovascular disease and should be used with extreme caution in this setting.

anuria

losartan

hypertensive

chronic renal insufficiency

anuria

losartan

myocardial infarction

pulmonary edema

systolic dysfunction

losartan

losartan

anuria

furosemide

amine

losartan

anuria

hypotension

renal artery stenosis

renal artery stenosis

heart failure

angiotensin

angiotensin II

losartan

angiotensin II

losartan

renovascular disease


In vivo protection of dna damage associated apoptotic and necrotic cell deaths during acetaminophen-induced nephrotoxicity, amiodarone-induced lung toxicity and doxorubicin-induced cardiotoxicity by a novel IH636 grape seed proanthocyanidin extract.

Grape seed extract, primarily a mixture of proanthocyanidins, has been shown to modulate a wide-range of biological, pharmacological and toxicological effects which are mainly cytoprotective. This study assessed the ability of IH636 grape seed proanthocyanidin extract (GSPE) to prevent acetaminophen (AAP)-induced nephrotoxicity, amiodarone (AMI)-induced lung toxicity, and doxorubicin (DOX)-induced cardiotoxicity in mice. Experimental design consisted of four groups: control (vehicle alone), GSPE alone, drug alone and GSPE+drug. For the cytoprotection study, animals were orally gavaged 100 mg/Kg GSPE for 7-10 days followed by i.p. injections of organ specific three drugs (AAP: 500 mg/Kg for 24 h; AMI: 50 mg/Kg/day for four days; DOX: 20 mg/Kg for 48 h). Parameters of study included analysis of serum chemistry (ALT, BUN and CPK), and orderly fragmentation of genomic DNA (both endonuclease-dependent and independent) in addition to microscopic evaluation of damage and/or protection in corresponding PAS stained tissues. Results indicate that GSPE preexposure prior to AAP, AMI and DOX, provided near complete protection in terms of serum chemistry changes (ALT, BUN and CPK), and significantly reduced DNA fragmentation. Histopathological examination of kidney, heart and lung sections revealed moderate to massive tissue damage with a variety of morphological aberrations by all the three drugs in the absence of GSPE preexposure than in its presence. GSPE+drug exposed tissues exhibited minor residual damage or near total recovery. Additionally, histopathological alterations mirrored both serum chemistry changes and the pattern of DNA fragmentation. Interestingly, all the drugs, such as, AAP, AMI and DOX induced apoptotic death in addition to necrosis in the respective organs which was very effectively blocked by GSPE. Since AAP, AMI and DOX undergo biotransformation and are known to produce damaging radicals in vivo, the protection by GSPE may be linked to both inhibition of metabolism and/or detoxification of cytotoxic radicals. In addition, its' presumed contribution to DNA repair may be another important attribute, which played a role in the chemoprevention process. Additionally, this may have been the first report on AMI-induced apoptotic death in the lung tissue. Taken together, these events undoubtedly establish GSPE's abundant bioavailability, and the power to defend multiple target organs from toxic assaults induced by structurally diverse and functionally different entities in vivo.

necrotic

acetaminophen

nephrotoxicity

amiodarone

lung toxicity

doxorubicin

cardiotoxicity

Grape seed extract

proanthocyanidins

GSPE

acetaminophen

AAP

nephrotoxicity

amiodarone

AMI

lung toxicity

doxorubicin

DOX

cardiotoxicity

GSPE

GSPE

GSPE

AAP

AMI

DOX

GSPE

AAP

AMI

DOX

tissue damage

GSPE

GSPE

AAP

AMI

DOX

necrosis

GSPE

AAP

AMI

DOX

GSPE

AMI

GSPE


Palpebral twitching in a depressed adolescent on citalopram.

Current estimates suggest that between 0.4% and 8.3% of children and adolescents are affected by major depression. We report a favorable response to treatment with citalopram by a 15-year-old boy with major depression who exhibited palpebral twitching during his first 2 weeks of treatment. This may have been a side effect of citalopram as it remitted with redistribution of doses.

Palpebral twitching

depressed

citalopram

major depression

citalopram

major depression

palpebral twitching

citalopram


Metamizol potentiates morphine antinociception but not constipation after chronic treatment.

This work evaluates the antinociceptive and constipating effects of the combination of 3.2 mg/kg s.c. morphine with 177.8 mg/kg s.c. metamizol in acutely and chronically treated (once a day for 12 days) rats. On the 13th day, antinociceptive effects were assessed using a model of inflammatory nociception, pain-induced functional impairment model, and the charcoal meal test was used to evaluate the intestinal transit. Simultaneous administration of morphine with metamizol resulted in a markedly antinociceptive potentiation and an increasing of the duration of action after a single (298+/-7 vs. 139+/-36 units area (ua); P<0.001) and repeated administration (280+/-17 vs. 131+/-22 ua; P<0.001). Antinociceptive effect of morphine was reduced in chronically treated rats (39+/-10 vs. 18+/-5 au) while the combination-induced antinociception was remained similar as an acute treatment (298+/-7 vs. 280+/-17 au). Acute antinociceptive effects of the combination were partially prevented by 3.2 mg/kg naloxone s.c. (P<0.05), suggesting the partial involvement of the opioidergic system in the synergism observed. In independent groups, morphine inhibited the intestinal transit in 48+/-4% and 38+/-4% after acute and chronic treatment, respectively, suggesting that tolerance did not develop to the constipating effects. The combination inhibited intestinal transit similar to that produced by morphine regardless of the time of treatment, suggesting that metamizol did not potentiate morphine-induced constipation. These findings show a significant interaction between morphine and metamizol in chronically treated rats, suggesting that this combination could be useful for the treatment of chronic pain.

Metamizol

morphine

constipation

constipating

morphine

metamizol

pain

charcoal

morphine

metamizol

morphine

naloxone

morphine

constipating

morphine

metamizol

morphine

constipation

morphine

metamizol

chronic pain


Ifosfamide encephalopathy presenting with asterixis.

CNS toxic effects of the antineoplastic agent ifosfamide (IFX) are frequent and include a variety of neurological symptoms that can limit drug use. We report a case of a 51-year-old man who developed severe, disabling negative myoclonus of the upper and lower extremities after the infusion of ifosfamide for plasmacytoma. He was awake, revealed no changes of mental status and at rest there were no further motor symptoms. Cranial magnetic resonance imaging and extensive laboratory studies failed to reveal structural lesions of the brain and metabolic abnormalities. An electroencephalogram showed continuous, generalized irregular slowing with admixed periodic triphasic waves indicating symptomatic encephalopathy. The administration of ifosfamide was discontinued and within 12 h the asterixis resolved completely. In the patient described, the presence of asterixis during infusion of ifosfamide, normal laboratory findings and imaging studies and the resolution of symptoms following the discontinuation of the drug suggest that negative myoclonus is associated with the use of IFX.

Ifosfamide

encephalopathy

asterixis

ifosfamide

IFX

myoclonus

ifosfamide

plasmacytoma

structural lesions of the brain

metabolic abnormalities

encephalopathy

ifosfamide

asterixis

asterixis

ifosfamide

myoclonus

IFX


Sub-chronic low dose gamma-vinyl GABA (vigabatrin) inhibits cocaine-induced increases in nucleus accumbens dopamine.

RATIONALE: gamma-Vinyl GABA (GVG) irreversibly inhibits GABA-transaminase. This non-receptor mediated inhibition requires de novo synthesis for restoration of functional GABA catabolism. OBJECTIVES: Given its preclinical success for treating substance abuse and the increased risk of visual field defects (VFD) associated with cumulative lifetime exposure, we explored the effects of sub-chronic low dose GVG on cocaine-induced increases in nucleus accumbens (NAcc) dopamine (DA). METHODS: Using in vivo microdialysis, we compared acute exposure (450 mg/kg) to an identical sub-chronic exposure (150 mg/kg per day for 3 days), followed by 1- or 3-day washout. Finally, we examined the low dose of 150 mg/kg (50 mg/kg per day) using a similar washout period. RESULTS: Sub-chronic GVG exposure inhibited the effect of cocaine for 3 days, which exceeded in magnitude and duration the identical acute dose. CONCLUSIONS: Sub-chronic low dose GVG potentiates and extends the inhibition of cocaine-induced increases in dopamine, effectively reducing cumulative exposures and the risk for VFDS.

gamma-vinyl GABA

vigabatrin

cocaine

dopamine

gamma-Vinyl GABA

GVG

GABA

GABA

substance abuse

visual field defects

VFD

GVG

cocaine

dopamine

DA

GVG

cocaine

GVG

cocaine

dopamine


Amount of bleeding and hematoma size in the collagenase-induced intracerebral hemorrhage rat model.

The aggravated risk on intracerebral hemorrhage (ICH) with drugs used for stroke patients should be estimated carefully. We therefore established sensitive quantification methods and provided a rat ICH model for detection of ICH deterioration. In ICH intrastriatally induced by 0.014-unit, 0.070-unit, and 0.350-unit collagenase, the amount of bleeding was measured using a hemoglobin assay developed in the present study and was compared with the morphologically determined hematoma volume. The blood amounts and hematoma volumes were significantly correlated, and the hematoma induced by 0.014-unit collagenase was adequate to detect ICH deterioration. In ICH induction using 0.014-unit collagenase, heparin enhanced the hematoma volume 3.4-fold over that seen in control ICH animals and the bleeding 7.6-fold. Data suggest that this sensitive hemoglobin assay is useful for ICH detection, and that a model with a small ICH induced with a low-dose collagenase should be used for evaluation of drugs that may affect ICH.

bleeding

hematoma

intracerebral hemorrhage

intracerebral hemorrhage

ICH

stroke

ICH

ICH

ICH

bleeding

hematoma

hematoma

hematoma

ICH

ICH

heparin

hematoma

ICH

bleeding

ICH

ICH

ICH


Estradiol reduces seizure-induced hippocampal injury in ovariectomized female but not in male rats.

Estrogens protect ovariectomized rats from hippocampal injury induced by kainic acid-induced status epilepticus (SE). We compared the effects of 17beta-estradiol in adult male and ovariectomized female rats subjected to lithium-pilocarpine-induced SE. Rats received subcutaneous injections of 17beta-estradiol (2 microg/rat) or oil once daily for four consecutive days. SE was induced 20 h following the second injection and terminated 3 h later. The extent of silver-stained CA3 and CA1 hippocampal neurons was evaluated 2 days after SE. 17beta-Estradiol did not alter the onset of first clonus in ovariectomized rats but accelerated it in males. 17beta-Estradiol reduced the argyrophilic neurons in the CA1 and CA3-C sectors of ovariectomized rats. In males, estradiol increased the total damage score. These findings suggest that the effects of estradiol on seizure threshold and damage may be altered by sex-related differences in the hormonal environment.

Estradiol

seizure

hippocampal injury

hippocampal injury

kainic acid

status epilepticus

SE

lithium

pilocarpine

SE

SE

silver

SE

estradiol

estradiol

seizure


Delirium during clozapine treatment: incidence and associated risk factors.

BACKGROUND: Incidence and risk factors for delirium during clozapine treatment require further clarification. METHODS: We used computerized pharmacy records to identify all adult psychiatric inpatients treated with clozapine (1995-96), reviewed their medical records to score incidence and severity of delirium, and tested associations with potential risk factors. RESULTS: Subjects (n = 139) were 72 women and 67 men, aged 40.8 +/- 12.1 years, hospitalized for 24.9 +/- 23.3 days, and given clozapine, gradually increased to an average daily dose of 282 +/- 203 mg (3.45 +/- 2.45 mg/kg) for 18.9 +/- 16.4 days. Delirium was diagnosed in 14 (10.1 % incidence, or 1.48 cases/person-years of exposure); 71.4 % of cases were moderate or severe. Associated factors were co-treatment with other centrally antimuscarinic agents, poor clinical outcome, older age, and longer hospitalization (by 17.5 days, increasing cost); sex, diagnosis or medical co-morbidity, and daily clozapine dose, which fell with age, were unrelated. CONCLUSIONS: Delirium was found in 10 % of clozapine-treated inpatients, particularly in older patients exposed to other central anticholinergics. Delirium was inconsistently recognized clinically in milder cases and was associated with increased length-of-stay and higher costs, and inferior clinical outcome.

Delirium

clozapine

delirium

clozapine

psychiatric

clozapine

delirium

clozapine

Delirium

clozapine

Delirium

clozapine

Delirium


Ketoconazole-induced neurologic sequelae.

A 77-y-old patient developed weakness of extremities, legs paralysis, dysarthria and tremor 1 h after ingestion of 200 mg ketoconazole for the first time in his life. All complaints faded away within 24 h. Few days later, the patient used another 200 mg ketoconazole tablet, and within an hour experienced a similar clinical picture, which resolved again spontaneously within hours. Laboratory evaluations, including head CT scan, were normal. This case illustrates the need for close vigilance in adverse drug reactions, particularly in the elderly.

Ketoconazole

neurologic sequelae

weakness of extremities

legs paralysis

dysarthria

tremor

ketoconazole

ketoconazole

adverse drug reactions


Noxious chemical stimulation of rat facial mucosa increases intracranial blood flow through a trigemino-parasympathetic reflex--an experimental model for vascular dysfunctions in cluster headache.

Cluster headache is characterized by typical autonomic dysfunctions including facial and intracranial vascular disturbances. Both the trigeminal and the cranial parasympathetic systems may be involved in mediating these dysfunctions. An experimental model was developed in the rat to measure changes in lacrimation and intracranial blood flow following noxious chemical stimulation of facial mucosa. Blood flow was monitored in arteries of the exposed cranial dura mater and the parietal cortex using laser Doppler flowmetry. Capsaicin (0.01-1 mm) applied to oral or nasal mucosa induced increases in dural and cortical blood flow and provoked lacrimation. These responses were blocked by systemic pre-administration of hexamethonium chloride (20 mg/kg). The evoked increases in dural blood flow were also abolished by topical pre-administration of atropine (1 mm) and [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP (0.1 mm), a vasoactive intestinal polypeptide (VIP) antagonist, onto the exposed dura mater. We conclude that noxious stimulation of facial mucosa increases intracranial blood flow and lacrimation via a trigemino-parasympathetic reflex. The blood flow responses seem to be mediated by the release of acetylcholine and VIP within the meninges. Similar mechanisms may be involved in the pathogenesis of cluster headache.

vascular dysfunctions

cluster headache

Cluster headache

intracranial vascular disturbances

Capsaicin

hexamethonium chloride

increases in dural blood flow

atropine

acetylcholine

cluster headache


Recurrent excitation in the dentate gyrus of a murine model of temporal lobe epilepsy.

Similar to rats, systemic pilocarpine injection causes status epilepticus (SE) and the eventual development of spontaneous seizures and mossy fiber sprouting in C57BL/6 and CD1 mice, but the physiological correlates of these events have not been identified in mice. Population responses in granule cells of the dentate gyrus were examined in transverse slices of the ventral hippocampus from pilocarpine-treated and untreated mice. In Mg(2+)-free bathing medium containing bicuculline, conditions designed to increase excitability in the slices, electrical stimulation of the hilus resulted in a single population spike in granule cells from control mice and pilocarpine-treated mice that did not experience SE. In SE survivors, similar stimulation resulted in a population spike followed, at a variable latency, by negative DC shifts and repetitive afterdischarges of 3-60 s duration, which were blocked by ionotropic glutamate receptor antagonists. Focal glutamate photostimulation of the granule cell layer at sites distant from the recording pipette resulted in population responses of 1-30 s duration in slices from SE survivors but not other groups. These data support the hypothesis that SE-induced mossy fiber sprouting and synaptic reorganization are relevant characteristics of seizure development in these murine strains, resembling rat models of human temporal lobe epilepsy.

temporal lobe epilepsy

pilocarpine

status epilepticus

SE

seizures

pilocarpine

Mg

bicuculline

pilocarpine

SE

SE

glutamate

glutamate

SE

SE

seizure

temporal lobe epilepsy


The alpha3 and beta4 nicotinic acetylcholine receptor subunits are necessary for nicotine-induced seizures and hypolocomotion in mice.

Binding of nicotine to nicotinic acetylcholine receptors (nAChRs) elicits a series of dose-dependent behaviors that go from altered exploration, sedation, and tremors, to seizures and death. nAChRs are pentameric ion channels usually composed of alpha and beta subunits. A gene cluster comprises the alpha3, alpha5 and beta4 subunits, which coassemble to form functional receptors. We examined the role of the beta4 subunits in nicotine-induced seizures and hypolocomotion in beta4 homozygous null (beta4 -/-) and alpha3 heterozygous (+/-) mice. beta4 -/- mice were less sensitive to the effects of nicotine both at low doses, measured as decreased exploration in an open field, and at high doses, measured as sensitivity to nicotine-induced seizures. Using in situ hybridization probes for the alpha3 and alpha5 subunits, we showed that alpha5 mRNA levels are unchanged, whereas alpha3 mRNA levels are selectively decreased in the mitral cell layer of the olfactory bulb, and the inferior and the superior colliculus of beta4 -/- brains. alpha3 +/- mice were partially resistant to nicotine-induced seizures when compared to wild-type littermates. mRNA levels for the alpha5 and the beta4 subunits were unchanged in alpha3 +/- brains. Together, these results suggest that the beta4 and the alpha3 subunits are mediators of nicotine-induced seizures and hypolocomotion.

acetylcholine

nicotine

seizures

hypolocomotion

nicotine

acetylcholine

tremors

seizures

death

nicotine

seizures

hypolocomotion

nicotine

nicotine

seizures

nicotine

seizures

nicotine

seizures

hypolocomotion


Recurrent acute interstitial nephritis induced by azithromycin.

A 14-year-old girl is reported with recurrent, azithromycin-induced, acute interstitial nephritis. The second episode was more severe than the first; and although both were treated with intensive corticosteroid therapy, renal function remained impaired. Although most cases of antibiotic induced acute interstitial nephritis are benign and self-limited, some patients are at risk for permanent renal injury.

interstitial nephritis

azithromycin

azithromycin

interstitial nephritis

interstitial nephritis

renal injury


Valproate-induced encephalopathy.

Valproate-induced encephalopathy is a rare syndrome that may manifest in otherwise normal epileptic individuals. It may even present in patients who have tolerated this medicine well in the past. It is usually but not necessarily associated with hyperammonemia. The EEG shows characteristic triphasic waves in most patients with this complication. A case of valproate-induced encephalopathy is presented. The problems in diagnosing this condition are subsequently discussed.

Valproate

encephalopathy

Valproate

encephalopathy

epileptic

hyperammonemia

valproate

encephalopathy


Nitro-L-arginine methyl ester: a potential protector against gentamicin ototoxicity.

The nitric oxide (NO) inhibitor nitro-L-arginine methyl ester (L-NAME) may act as an otoprotectant against high-frequency hearing loss caused by gentamicin, but further studies are needed to confirm this.Aminoglycoside antibiotics are still widely used by virtue of their efficacy and low cost. Their ototoxicity is a serious health problem and, as their ototoxic mechanism involves the production of NO, we need to assess the use of NO inhibitors for the prevention of aminoglycoside-induced sensorineural hearing loss. In this experimental study we used 30 Sprague-Dawley rats, 27 of which had gentamicin instilled into the middle ear. The otoprotectant L-NAME was administered topically to 12/27 animals. Its effect was determined in terms of attenuation of hearing loss, measured by shifts in the auditory brainstem response threshold. L-NAME reduced gentamicin-induced hearing loss in the high-frequency range, but gave no protection in the middle or low frequencies.

Nitro-L-arginine methyl ester

gentamicin

ototoxicity

nitric oxide

NO

nitro-L-arginine methyl ester

L-NAME

high-frequency hearing loss

gentamicin

Aminoglycoside

ototoxicity

ototoxic

NO

NO

aminoglycoside

sensorineural hearing loss

gentamicin

L-NAME

hearing loss

L-NAME

gentamicin

hearing loss


Cerebral vasculitis following oral methylphenidate intake in an adult: a case report.

Methylphenidate is structurally and functionally similar to amphetamine. Cerebral vasculitis associated with amphetamine abuse is well documented, and in rare cases ischaemic stroke has been reported after methylphenidate intake in children. We report the case of a 63-year-old female who was treated with methylphenidate due to hyperactivity and suffered from multiple ischaemic strokes. We consider drug-induced cerebral vasculitis as the most likely cause of recurrent ischaemic strokes in the absence of any pathological findings during the diagnostic work-up. We conclude that methylphenidate mediated vasculitis should be considered in patients with neurological symptoms and a history of methylphenidate therapy. This potential side-effect, though very rare, represents one more reason to be very restrictive in the use of methylphenidate.

Cerebral vasculitis

methylphenidate

Methylphenidate

amphetamine

Cerebral vasculitis

amphetamine abuse

ischaemic stroke

methylphenidate

methylphenidate

hyperactivity

ischaemic strokes

cerebral vasculitis

ischaemic strokes

methylphenidate

vasculitis

methylphenidate

methylphenidate


Cerebral haemorrhage induced by warfarin - the influence of drug-drug interactions.

PURPOSE: To evaluate the frequency, severity and preventability of warfarin-induced cerebral haemorrhages due to warfarin and warfarin-drug interactions in patients living in the county of Osterg  tland, Sweden. METHODS: All patients with a diagnosed cerebral haemorrhage at three hospitals during the period 2000-2002 were identified. Medical records were studied retrospectively to evaluate whether warfarin and warfarin-drug interactions could have caused the cerebral haemorrhage. The proportion of possibly avoidable cases due to drug interactions was estimated. RESULTS: Among 593 patients with cerebral haemorrhage, 59 (10%) were assessed as related to warfarin treatment. This imply an incidence of 1.7/100,000 treatment years. Of the 59 cases, 26 (44%) had a fatal outcome, compared to 136 (25%) among the non-warfarin patients (p < 0.01). A warfarin-drug interaction could have contributed to the haemorrhage in 24 (41%) of the warfarin patients and in 7 of these (12%) the bleeding complication was considered being possible to avoid. CONCLUSIONS: Warfarin-induced cerebral haemorrhages are a major clinical problem with a high fatality rate. Almost half of the cases was related to a warfarin-drug interaction. A significant proportion of warfarin-related cerebral haemorrhages might have been prevented if greater caution had been taken when prescribing drugs known to interact with warfarin.

Cerebral haemorrhage

warfarin

warfarin

cerebral haemorrhages

warfarin

warfarin

cerebral haemorrhage

warfarin

warfarin

cerebral haemorrhage

cerebral haemorrhage

warfarin

warfarin

warfarin

haemorrhage

warfarin

bleeding

Warfarin

cerebral haemorrhages

warfarin

warfarin

cerebral haemorrhages

warfarin


Side effects of postoperative administration of methylprednisolone and gentamicin into the posterior sub-Tenon's space.

PURPOSE: To assess the incidence of postoperative emetic side effects after the administration of methylprednisolone and gentamicin into the posterior sub-Tenon's space at the end of routine cataract surgery. SETTING: St. Luke's Hospital, Gwardamangia, Malta. METHODS: A double-blind double-armed prospective study comprised 40 patients who had uneventful sutureless phacoemulsification under sub-Tenon's local infiltration of 3 mL of plain lignocaine. At the end of the procedure, Group A (n = 20) had 20 mg/0.5 mL of methylprednisolone and 10 mg/0.5 mL of gentamicin injected into the posterior sub-Tenon's space and Group B (n = 20) had the same combination injected into the anterior sub-Tenon's space. Postoperatively, all patients were assessed for symptoms of nausea, vomiting, and headache. A chi-square test was used to assess the statistical significance of results. RESULTS: Sixty percent in Group A developed postoperative emetic symptoms, headache, or both; 1 patient in Group B developed symptoms. CONCLUSIONS: The administration of methylprednisolone and gentamicin in the posterior sub-Tenon's space was related to a high incidence of side effects including nausea, vomiting, and headache. All adverse effects were self-limiting.

methylprednisolone

gentamicin

methylprednisolone

gentamicin

cataract

lignocaine

methylprednisolone

gentamicin

nausea, vomiting

headache

postoperative emetic symptoms

headache

methylprednisolone

gentamicin

nausea, vomiting

headache


Cardiac Angiography in Renally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease.

BACKGROUND: No direct comparisons exist of the renal tolerability of the low-osmolality contrast medium iopamidol with that of the iso-osmolality contrast medium iodixanol in high-risk patients. METHODS AND RESULTS: The present study is a multicenter, randomized, double-blind comparison of iopamidol and iodixanol in patients with chronic kidney disease (estimated glomerular filtration rate, 20 to 59 mL/min) who underwent cardiac angiography or percutaneous coronary interventions. Serum creatinine (SCr) levels and estimated glomerular filtration rate were assessed at baseline and 2 to 5 days after receiving medications. The primary outcome was a postdose SCr increase > or = 0.5 mg/dL (44.2 micromol/L) over baseline. Secondary outcomes were a postdose SCr increase > or = 25%, a postdose estimated glomerular filtration rate decrease of > or = 25%, and the mean peak change in SCr. In 414 patients, contrast volume, presence of diabetes mellitus, use of N-acetylcysteine, mean baseline SCr, and estimated glomerular filtration rate were comparable in the 2 groups. SCr increases > or = 0.5 mg/dL occurred in 4.4% (9 of 204 patients) after iopamidol and 6.7% (14 of 210 patients) after iodixanol (P=0.39), whereas rates of SCr increases > or = 25% were 9.8% and 12.4%, respectively (P=0.44). In patients with diabetes, SCr increases > or = 0.5 mg/dL were 5.1% (4 of 78 patients) with iopamidol and 13.0% (12 of 92 patients) with iodixanol (P=0.11), whereas SCr increases > or = 25% were 10.3% and 15.2%, respectively (P=0.37). Mean post-SCr increases were significantly less with iopamidol (all patients: 0.07 versus 0.12 mg/dL, 6.2 versus 10.6 micromol/L, P=0.03; patients with diabetes: 0.07 versus 0.16 mg/dL, 6.2 versus 14.1 micromol/L, P=0.01). CONCLUSIONS: The rate of contrast-induced nephropathy, defined by multiple end points, is not statistically different after the intraarterial administration of iopamidol or iodixanol to high-risk patients, with or without diabetes mellitus. Any true difference between the agents is small and not likely to be clinically significant.

nephropathy

chronic kidney disease

contrast medium

iopamidol

contrast medium

iodixanol

iopamidol

iodixanol

chronic kidney disease

creatinine

diabetes mellitus

N-acetylcysteine

iopamidol

iodixanol

diabetes

iopamidol

iodixanol

iopamidol

diabetes

nephropathy

iopamidol

iodixanol

diabetes mellitus


A novel compound, maltolyl p-coumarate, attenuates cognitive deficits and shows neuroprotective effects in vitro and in vivo dementia models.

To develop a novel and effective drug that could enhance cognitive function and neuroprotection, we newly synthesized maltolyl p-coumarate by the esterification of maltol and p-coumaric acid. In the present study, we investigated whether maltolyl p-coumarate could improve cognitive decline in scopolamine-injected rats and in amyloid beta peptide(1-42)-infused rats. Maltolyl p-coumarate was found to attenuate cognitive deficits in both rat models using passive avoidance test and to reduce apoptotic cell death observed in the hippocampus of the amyloid beta peptide(1-42)-infused rats. We also examined the neuroprotective effects of maltolyl p-coumarate in vitro using SH-SY5Y cells. Cells were pretreated with maltolyl p-coumarate, before exposed to amyloid beta peptide(1-42), glutamate or H2O2. We found that maltolyl p-coumarate significantly decreased apoptotic cell death and reduced reactive oxygen species, cytochrome c release, and caspase 3 activation. Taking these in vitro and in vivo results together, our study suggests that maltolyl p-coumarate is a potentially effective candidate against Alzheimer's disease that is characterized by wide spread neuronal death and progressive decline of cognitive function.

maltolyl p-coumarate

cognitive deficits

dementia

maltolyl p-coumarate

maltol

p-coumaric acid

maltolyl p-coumarate

cognitive decline

scopolamine

amyloid beta peptide(1-42)

Maltolyl p-coumarate

cognitive deficits

amyloid beta peptide(1-42)

maltolyl p-coumarate

maltolyl p-coumarate

amyloid beta peptide(1-42)

glutamate

maltolyl p-coumarate

maltolyl p-coumarate

Alzheimer's disease

neuronal death

decline of cognitive function


Interaction between warfarin and levofloxacin: case series.

Warfarin is the most widely used oral anticoagulant and is indicated for many clinical conditions. Levofloxacin, a fluoroquinolone, is one of the most commonly prescribed antibiotics in clinical practice and is effective against Gram-positive, Gram-negative, and atypical bacteria. While small prospective studies have not revealed any significant drug-drug interaction between warfarin and levofloxacin, several case reports have indicated that levofloxacin may significantly potentiate the anticoagulation effect of warfarin. We report 3 cases of serious bleeding complications that appear to be the result of the interaction between warfarin and levofloxacin. Physicians should be aware of this potential interaction and use caution when prescribing levofloxacin to patients taking warfarin.

warfarin

levofloxacin

Warfarin

Levofloxacin

fluoroquinolone

warfarin

levofloxacin

levofloxacin

warfarin

bleeding

warfarin

levofloxacin

levofloxacin

warfarin


Mutations associated with lamivudine-resistance in therapy-na  ve hepatitis B virus (HBV) infected patients with and without HIV co-infection: implications for antiretroviral therapy in HBV and HIV co-infected South African patients.

This was an exploratory study to investigate lamivudine-resistant hepatitis B virus (HBV) strains in selected lamivudine-na  ve HBV carriers with and without human immunodeficiency virus (HIV) co-infection in South African patients. Thirty-five lamivudine-na  ve HBV infected patients with or without HIV co-infection were studied: 15 chronic HBV mono-infected patients and 20 HBV-HIV co-infected patients. The latter group was further sub-divided into 13 occult HBV (HBsAg-negative) and 7 overt HBV (HBsAg- positive) patients. HBsAg, anti-HBs, anti-HBc, and anti-HIV 1/2 were determined as part of routine diagnosis using Axsym assays (Abbott Laboratories, North Chicago, IL). Serum samples were PCR amplified with HBV reverse transcriptase (RT) primers, followed by direct sequencing across the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the major catalytic region in the C domain of the HBV RT enzyme. HBV viral load was performed with Amplicor HBV Monitor test v2.0 (Roche Diagnostics, Penzberg, Germany). HBV lamivudine-resistant strains were detected in 3 of 15 mono-infected chronic hepatitis B patients and 10 of 20 HBV-HIV co-infected patients. To the best of our knowledge, this constitutes the first report of HBV lamivudine-resistant strains in therapy-na  ve HBV-HIV co-infected patients. The HBV viral loads for mono-infected and co-infected patients ranged from 3.32 x 10(2) to 3.82 x 10(7) and <200 to 4.40 x 10(3) copies/ml, respectively. It remains to be seen whether such pre-existing antiviral mutations could result in widespread emergence of HBV resistant strains when lamivudine-containing highly active antiretroviral (ARV) treatment (HAART) regimens become widely applied in South Africa, as this is likely to have potential implications in the management of HBV-HIV co-infected patients.

lamivudine

hepatitis B virus (HBV) infected

HIV co-infection

HBV and HIV co-infected

HBV infected

HIV infected

lamivudine

hepatitis B

lamivudine

lamivudine

HBV infected

HIV co-infection

HBV mono-infected

HBV-HIV co-infected

HBV infected

HIV infected

HBsAg

HBsAg

HBsAg

tyrosine

methionine

aspartate

aspartate

lamivudine

hepatitis B

HBV-HIV co-infected

HBV infected

HIV infected

lamivudine

HBV-HIV co-infected

HBV infected

HIV infected

lamivudine

HBV-HIV co-infected

HBV infected

HIV infected


Sex differences in NMDA antagonist enhancement of morphine antihyperalgesia in a capsaicin model of persistent pain: comparisons to two models of acute pain.

In acute pain models, N-methyl-D-aspartate (NMDA) antagonists enhance the antinociceptive effects of morphine to a greater extent in males than females. The purpose of this investigation was to extend these findings to a persistent pain model which could be distinguished from acute pain models on the basis of the nociceptive fibers activated, neurochemical substrates, and duration of the nociceptive stimulus. To this end, persistent hyperalgesia was induced by administration of capsaicin in the tail of gonadally intact F344 rats, following which the tail was immersed in a mildly noxious thermal stimulus, and tail-withdrawal latencies measured. For comparison, tests were conducted in two acute pain models, the hotplate and warm water tail-withdrawal procedures. In males, the non-competitive NMDA antagonist dextromethorphan enhanced the antihyperalgesic effect of low to moderate doses of morphine in a dose-and time-dependent manner. Across the doses and pretreatment times examined, enhancement was not observed in females. Enhancement of morphine antinociception by dextromethorphan was seen in both males and females in the acute pain models, with the magnitude of this effect being greater in males. These findings demonstrate a sexually-dimorphic interaction between NMDA antagonists and morphine in a persistent pain model that can be distinguished from those observed in acute pain models.

NMDA

morphine

capsaicin

pain

acute pain

acute pain

N-methyl-D-aspartate

NMDA

morphine

pain

acute pain

hyperalgesia

capsaicin

acute pain

NMDA

dextromethorphan

morphine

morphine

dextromethorphan

acute pain

NMDA

morphine

pain

acute pain


Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients.

Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil +/- steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0-5.7) preswitch to 0.23 g/day (0-9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.

proteinuria

sirolimus

renal dysfunction

sirolmus

Srl

nephrotoxic

proteinuria

Srl

proteinuria

Srl

cyclosporine

Srl

mycophenolate mofetil

steroids

proteinuria

ACE inhibitor

angiotensin-releasing blocker

ARB

proteinuria

proteinuria

proteinuria

proteinuria

Srl

Srl

ACEi

ARB

proteinuria

renal dysfunction


Synthesis of N-pyrimidinyl-2-phenoxyacetamides as adenosine A2A receptor antagonists.

A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.

adenosine

adenosine

haloperidol

catalepsy

Parkinson's disease


Methamphetamine-induced neurotoxicity and microglial activation are not mediated by fractalkine receptor signaling.

Methamphetamine (METH) damages dopamine (DA) nerve endings by a process that has been linked to microglial activation but the signaling pathways that mediate this response have not yet been delineated. Cardona et al. [Nat. Neurosci. 9 (2006), 917] recently identified the microglial-specific fractalkine receptor (CX3CR1) as an important mediator of MPTP-induced neurodegeneration of DA neurons. Because the CNS damage caused by METH and MPTP is highly selective for the DA neuronal system in mouse models of neurotoxicity, we hypothesized that the CX3CR1 plays a role in METH-induced neurotoxicity and microglial activation. Mice in which the CX3CR1 gene has been deleted and replaced with a cDNA encoding enhanced green fluorescent protein (eGFP) were treated with METH and examined for striatal neurotoxicity. METH depleted DA, caused microglial activation, and increased body temperature in CX3CR1 knockout mice to the same extent and over the same time course seen in wild-type controls. The effects of METH in CX3CR1 knockout mice were not gender-dependent and did not extend beyond the striatum. Striatal microglia expressing eGFP constitutively show morphological changes after METH that are characteristic of activation. This response was restricted to the striatum and contrasted sharply with unresponsive eGFP-microglia in surrounding brain areas that are not damaged by METH. We conclude from these studies that CX3CR1 signaling does not modulate METH neurotoxicity or microglial activation. Furthermore, it appears that striatal-resident microglia respond to METH with an activation cascade and then return to a surveying state without undergoing apoptosis or migration.

Methamphetamine

neurotoxicity

Methamphetamine

METH

dopamine

DA

MPTP

neurodegeneration

DA

CNS damage

METH

MPTP

DA

neurotoxicity

METH

neurotoxicity

METH

neurotoxicity

METH

DA

METH

METH

METH

METH

neurotoxicity

METH


Recovery of tacrolimus-associated brachial neuritis after conversion to everolimus in a pediatric renal transplant recipient--case report and review of the literature.

TAC has been shown to be a potent immunosuppressive agent for solid organ transplantation in pediatrics. Neurotoxicity is a potentially serious toxic effect. It is characterized by encephalopathy, headaches, seizures, or neurological deficits. Here, we describe an eight-and-a-half-yr-old male renal transplant recipient with right BN. MRI demonstrated hyperintense T2 signals in the cervical cord and right brachial plexus roots indicative of both myelitis and right brachial plexitis. Symptoms persisted for three months despite TAC dose reduction, administration of IVIG and four doses of methylprednisolone pulse therapy. Improvement and eventually full recovery only occurred after TAC was completely discontinued and successfully replaced by everolimus.

tacrolimus

brachial neuritis

everolimus

TAC

Neurotoxicity

encephalopathy

headaches

seizures

neurological deficits

myelitis

brachial plexitis

TAC

methylprednisolone

TAC

everolimus


Valvular heart disease in patients with Parkinson's disease treated with pergolide. Course following treatment modifications.

Valvular heart abnormalities have been reported in patients with Parkinson's disease (PD) treated with pergolide. However, the incidence and severity of these abnormalities vary from study to study and their course after drug withdrawal has not been systematically assessed. OBJECTIVES: To estimate the frequency and severity of valvular heart abnormality and its possible reversibility after drug withdrawal in a case-control study. METHODS: All PD patients in the Amiens area treated with pergolide were invited to attend a cardiologic assessment including transthoracic echocardiography. Thirty PD patients participated in the study. A second echocardiography was performed (median interval: 13 months) after pergolide withdrawal (n=10 patients). Controls were age- and sex-matched non-PD patients referred to the cardiology department. RESULTS: Compared to controls, aortic regurgitation (OR: 3.1; 95% IC: 1.1-8.8) and mitral regurgitation (OR: 10.7; 95% IC: 2.1-53) were more frequent in PD patients (tricuspid: NS). The number of affected valves (n=2.4+/-0.7) and the sum of regurgitation grades (n=2.8+/-1.09) were higher (p=0.008 and p=0.006, respectively) in the pergolide group. Severity of regurgitation was not correlated with pergolide cumulative dose. A restrictive pattern of valvular regurgitation, suggestive of the role of pergolide, was observed in 12/30 (40%) patients including two with heart failure. Pergolide was discontinued in 10 patients with valvular heart disease, resulting in a lower regurgitation grade (p=0.01) at the second transthoracic echocardiography and the two patients with heart failure returned to nearly normal clinical examination. This study supports the high frequency of restrictive valve regurgitation in PD patients treated with pergolide and reveals that a significant improvement is usual when the treatment is converted to non-ergot dopamine agonists.

Valvular heart disease

Parkinson's disease

pergolide

Valvular heart abnormalities

Parkinson's disease

PD

pergolide

valvular heart abnormality

PD

pergolide

PD

pergolide

PD

aortic regurgitation

mitral regurgitation

PD

pergolide

pergolide

valvular regurgitation

pergolide

heart failure

Pergolide

valvular heart disease

heart failure

valve regurgitation

PD

pergolide

dopamine


Adverse effects of topical papaverine on auditory nerve function.

BACKGROUND: Papaverine hydrochloride is a direct-acting vasodilator used to manage vasospasm during various neurosurgical operations. Transient cranial nerve dysfunction has been described in a few cases with topical papaverine. This study supports previous reports and provides neurophysiological evidence of an adverse effect on the auditory nerve. METHODS: We conducted a retrospective review of 70 consecutive microvascular decompression operations and studied those patients who received topical papaverine for vasospasm. Topical papaverine was used as a direct therapeutic action to manage vasospasm in a total of 11 patients. The timing of papaverine application and ongoing operative events was reviewed relative to changes in neurophysiological recordings. Brainstem auditory evoked potentials (BAEPs) were routinely used to monitor cochlear nerve function during these operations. FINDINGS: A temporal relationship was found between topical papaverine and BAEP changes leading to complete waveform loss. The average temporal delay between papaverine and the onset of an adverse BAEP change was 5 min. In 10 of 11 patients, BAEP waves II/III-V completely disappeared within 2 to 25 min after papaverine. Eight of these 10 patients had complete loss of BAEP waveforms within 10 min. One patient showed no recovery of later waves and a delayed profound sensorineural hearing loss. The average recovery time of BAEP waveforms to pre-papaverine baseline values was 39 min. CONCLUSIONS: Topical papaverine for the treatment of vasospasm was associated with the onset of a transient disturbance in neurophysiological function of the ascending auditory brainstem pathway. The complete disappearance of BAEP waveforms with a consistent temporal delay suggests a possible adverse effect on the proximal eighth nerve. Recommendations to avoid potential cranial nerve deficits from papaverine are provided.

papaverine

Papaverine hydrochloride

vasospasm

cranial nerve dysfunction

papaverine

papaverine

vasospasm

papaverine

vasospasm

papaverine

papaverine

papaverine

papaverine

sensorineural hearing loss

papaverine

papaverine

vasospasm

cranial nerve deficits

papaverine


Massive proteinuria and acute renal failure after oral bisphosphonate (alendronate) administration in a patient with focal segmental glomerulosclerosis.

A 61-year-old Japanese man with nephrotic syndrome due to focal segmental glomerulosclerosis was initially responding well to steroid therapy. The amount of daily urinary protein decreased from 15.6 to 2.8 g. Within 14 days of the oral bisphosphonate (alendronate sodium) administration, the amount of daily urinary protein increased rapidly up to 12.8 g with acute renal failure. After discontinuing the oral alendronate, the patient underwent six cycles of hemodialysis and four cycles of LDL apheresis. Urinary volume and serum creatinine levels recovered to the normal range, with urinary protein disappearing completely within 40 days. This report demonstrates that not only intravenous, but also oral bisphosphonates can aggravate proteinuria and acute renal failure.

proteinuria

acute renal failure

bisphosphonate

alendronate

focal segmental glomerulosclerosis

nephrotic syndrome

focal segmental glomerulosclerosis

steroid

bisphosphonate

alendronate sodium

acute renal failure

alendronate

creatinine

bisphosphonates

proteinuria

acute renal failure


Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome.

Doxorubicin-induced nephropathy leads to epithelial sodium channel (ENaC)-dependent volume retention and renal fibrosis. The aldosterone-sensitive serum- and glucocorticoid-inducible kinase SGK1 has been shown to participate in the stimulation of ENaC and to mediate renal fibrosis following mineralocorticoid and salt excess. The present study was performed to elucidate the role of SGK1 in the volume retention and fibrosis during nephrotic syndrome. To this end, doxorubicin (15 mug/g body wt) was injected intravenously into gene-targeted mice lacking SGK1 (sgk1(-/-)) and their wild-type littermates (sgk1(+/+)). Doxorubicin treatment resulted in heavy proteinuria (>100 mg protein/mg crea) in 15/44 of sgk1(+/+) and 15/44 of sgk1(-/-) mice leading to severe nephrotic syndrome with ascites, lipidemia, and hypoalbuminemia in both genotypes. Plasma aldosterone levels increased in nephrotic mice of both genotypes and was followed by increased SGK1 protein expression in sgk1(+/+) mice. Urinary sodium excretion reached signficantly lower values in sgk1(+/+) mice (15 +/- 5 mumol/mg crea) than in sgk1(-/-) mice (35 +/- 5 mumol/mg crea) and was associated with a significantly higher body weight gain in sgk1(+/+) compared with sgk1(-/-) mice (+6.6 +/- 0.7 vs. +4.1 +/- 0.8 g). During the course of nephrotic syndrome, serum urea concentrations increased significantly faster in sgk1(-/-) mice than in sgk1(+/+) mice leading to uremia and a reduced median survival in sgk1(-/-) mice (29 vs. 40 days in sgk1(+/+) mice). In conclusion, gene-targeted mice lacking SGK1 showed blunted volume retention, yet were not protected against renal fibrosis during experimental nephrotic syndrome.

doxorubicin

nephrotic syndrome

Doxorubicin

nephropathy

sodium

volume retention

fibrosis

aldosterone

fibrosis

volume retention

fibrosis

nephrotic syndrome

doxorubicin

Doxorubicin

proteinuria

nephrotic syndrome

ascites

lipidemia

hypoalbuminemia

aldosterone

nephrotic

sodium

weight gain

nephrotic syndrome

urea

uremia

volume retention

fibrosis

nephrotic syndrome


Severe and long lasting cholestasis after high-dose co-trimoxazole treatment for Pneumocystis pneumonia in HIV-infected patients--a report of two cases.

Pneumocystis pneumonia (PCP), a common opportunistic infection in HIV-infected individuals, is generally treated with high doses of co-trimoxazole. However, treatment is often limited by adverse effects. Here, we report two cases of severely immunocompromised HIV-infected patients who developed severe intrahepatic cholestasis, and in one patient lesions mimicking liver abscess formation on radiologic exams, during co-trimoxazole treatment for PCP. Whereas patient 1 showed lesions of up to 1 cm readily detectable on magnetic resonance imaging under prolonged co-trimoxazole treatment, therapy of patient 2 was switched early.

cholestasis

co-trimoxazole

Pneumocystis pneumonia

HIV-infected

Pneumocystis pneumonia

PCP

opportunistic infection

HIV-infected

co-trimoxazole

HIV-infected

intrahepatic cholestasis

liver abscess

co-trimoxazole

PCP

co-trimoxazole


Clinically significant proteinuria following the administration of sirolimus to renal transplant recipients.

BACKGROUND: Sirolimus is the latest immunosuppressive agent used to prevent rejection, and may have less nephrotoxicity than calcineurin inhibitor (CNI)-based regimens. To date there has been little documentation of clinically significant proteinuria linked with the use of sirolimus. We have encountered several patients who developed substantial proteinuria associated with sirolimus use. In each patient, the close temporal association between the commencement of sirolimus therapy and proteinuria implicated sirolimus as the most likely etiology of the proteinuria. METHODS: We analyzed the clinical and laboratory information available for all 119 patients transplanted at the Washington Hospital Center between 1999-2003 for whom sirolimus was a component of their immunosuppressant regimen. In these patients, the magnitude of proteinuria was assessed on morning urine samples by turbidometric measurement or random urine protein:creatinine ratios, an estimate of grams of proteinuria/day. Laboratory results were compared between prior, during and following sirolimus use. RESULTS: Twenty-eight patients (24%) developed increased proteinuria from baseline during their post-transplantation course. In 21 patients an alternative cause of proteinuria was either obvious or insufficient data was available to be conclusive. In 7 of the 28 patients there was a striking temporal association between the initiation of sirolimus and the development of nephrotic-range proteinuria. Proteinuria correlated most strongly with sirolimus therapy when compared to other demographic and clinical variables. In most patients, discontinuation of sirolimus resulted in a decrease, but not resolution, of proteinuria. CONCLUSIONS: Sirolimus induces or aggravates pre-existing proteinuria in an unpredictable subset of renal allograft recipients. Proteinuria may improve, but does not resolve, when sirolimus is withdrawn.

proteinuria

sirolimus

Sirolimus

nephrotoxicity

proteinuria

sirolimus

proteinuria

sirolimus

sirolimus

proteinuria

sirolimus

proteinuria

sirolimus

proteinuria

creatinine

proteinuria

sirolimus

proteinuria

proteinuria

sirolimus

nephrotic

proteinuria

Proteinuria

sirolimus

sirolimus

proteinuria

Sirolimus

proteinuria

Proteinuria

sirolimus


Comparative cognitive and subjective side effects of immediate-release oxycodone in healthy middle-aged and older adults.

This study measured the objective and subjective neurocognitive effects of a single 10-mg dose of immediate-release oxycodone in healthy, older (> 65 years), and middle-aged (35 to 55 years) adults who were not suffering from chronic or significant daily pain. Seventy-one participants completed 2 separate study days and were blind to medication condition (placebo, 10-mg oxycodone). Plasma oxycodone concentration peaked between 60 and 90 minutes postdose (P < .01) and pupil size, an indication of physiological effects of the medication, peaked at approximately 90 to 120 minutes postdose (P < .01). Significant declines in simple and sustained attention, working memory, and verbal memory were observed at 1 hour postdose compared to baseline for both age groups with a trend toward return to baseline by 5 hours postdose. For almost all cognitive measures, there were no medication by age-interaction effects, which indicates that the 2 age groups exhibited similar responses to the medication challenge. This study suggests that for healthy older adults who are not suffering from chronic pain, neurocognitive and pharmacodynamic changes in response to a 10-mg dose of immediate-release oxycodone are similar to those observed for middle-aged adults. PERSPECTIVE: Study findings indicate that the metabolism, neurocognitive effects, and physical side effects of oral oxycodone are similar for healthy middle-aged and older adults. Therefore, clinicians should not avoid prescribing oral opioids to older adults based on the belief that older adults are at higher risk for side effects than younger adults.

oxycodone

oxycodone

pain

oxycodone

oxycodone

declines in
working memory, and verbal memory

chronic pain

oxycodone

oxycodone


Normalizing effects of modafinil on sleep in chronic cocaine users.

OBJECTIVE: The purpose of the present study was to determine the effect of morning-dosed modafinil on sleep and daytime sleepiness in chronic cocaine users. METHOD: Twenty cocaine-dependent participants were randomly assigned to receive modafinil, 400 mg (N=10), or placebo (N=10) every morning at 7:30 a.m. for 16 days in an inpatient, double-blind randomized trial. Participants underwent polysomnographic sleep recordings on days 1 to 3, 7 to 9, and 14 to 16 (first, second, and third weeks of abstinence). The Multiple Sleep Latency Test was performed at 11:30 a.m., 2:00 p.m., and 4:30 p.m. on days 2, 8, and 15. For comparison of sleep architecture variables, 12 healthy comparison participants underwent a single night of experimental polysomnography that followed 1 night of accommodation polysomnography. RESULTS: Progressive abstinence from cocaine was associated with worsening of all measured polysomnographic sleep outcomes. Compared with placebo, modafinil decreased nighttime sleep latency and increased slow-wave sleep time in cocaine-dependent participants. The effect of modafinil interacted with the abstinence week and was associated with longer total sleep time and shorter REM sleep latency in the third week of abstinence. Comparison of slow-wave sleep time, total sleep time, and sleep latency in cocaine-dependent and healthy participants revealed a normalizing effect of modafinil in cocaine-dependent participants. Modafinil was associated with increased daytime sleep latency, as measured by the Multiple Sleep Latency Test, and a nearly significant decrease in subjective daytime sleepiness. CONCLUSIONS: Morning-dosed modafinil promotes nocturnal sleep, normalizes sleep architecture, and decreases daytime sleepiness in abstinent cocaine users. These effects may be relevant in the treatment of cocaine dependence.

modafinil

cocaine

modafinil

daytime sleepiness

cocaine

cocaine

modafinil

cocaine

modafinil

cocaine

modafinil

cocaine

modafinil

cocaine

Modafinil

daytime sleepiness

modafinil

daytime sleepiness

cocaine

cocaine


Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia.

Asenapine is approved by the Food and Drugs Administration in adults for acute treatment of schizophrenia or of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. In a double-blind 6-week trial, 458 patients with acute schizophrenia were randomly assigned to fixed-dose treatment with asenapine at 5 mg twice daily (BID), asenapine at 10 mg BID, placebo, or haloperidol at 4 mg BID (to verify assay sensitivity). With last observations carried forward (LOCF), mean Positive and Negative Syndrome Scale total score reductions from baseline to endpoint were significantly greater with asenapine at 5 mg BID (-16.2) and haloperidol (-15.4) than placebo (-10.7; both P < 0.05); using mixed model for repeated measures (MMRM), changes at day 42 were significantly greater with asenapine at 5 and 10 mg BID (-21.3 and -19.4, respectively) and haloperidol (-20.0) than placebo (-14.6; all P < 0.05). On the Positive and Negative Syndrome Scale positive subscale, all treatments were superior to placebo with LOCF and MMRM; asenapine at 5 mg BID was superior to placebo on the negative subscale with MMRM and on the general psychopathology subscale with LOCF and MMRM. Treatment-related adverse events (AEs) occurred in 44% and 52%, 57%, and 41% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Extrapyramidal symptoms reported as AEs occurred in 15% and 18%, 34%, and 10% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Across all groups, no more than 5% of patients had clinically significant weight change. Post hoc analyses indicated that efficacy was similar with asenapine and haloperidol; greater contrasts were seen in AEs, especially extrapyramidal symptoms.

asenapine

haloperidol

schizophrenia

Asenapine

schizophrenia

manic

bipolar I disorder

psychotic

schizophrenia

asenapine

asenapine

haloperidol

asenapine

haloperidol

asenapine

haloperidol

asenapine

asenapine

haloperidol

Extrapyramidal symptoms

asenapine

haloperidol

asenapine

haloperidol

extrapyramidal symptoms