Hyperlysinemia, an ultrarare inborn error of metabolism: Review and update.

Familial hyperlysinemia is a rare autosomal recessive disorder due to defects of the AASS (α-aminoadipate δ-semialdehyde synthase) gene, which encodes for a bifunctional enzyme. Two types of hyperlysinemia have been identified namely type 1, due to the deficit of the alfa-ketoglutarate activity, and type 2, due to the deficit of the saccharopine dehydrogenase activity. METHODS: To better characterize the phenotypic spectrum of familial hyperlysinemia type 1, we conducted a systematic review of cases in the literature following PRISMA guidelines. We selected 16 articles describing 23 patients with hyperlysinemia type 1, twelve of whom with homozygous or compound heterozygous mutations in AASS gene. We also included a novel patient with a homozygous c.799C>T; p.(Arg267Cys) mutation in AASS gene. We collected genetic, clinical, brain imaging and electroencephalogram (EEG) features when available. RESULTS: The phenotype of this disease is heterogeneous, ranging from more severe forms with spastic tetraparesis, intellectual disability and epilepsy and mild-moderate forms with only intellectual disability or behavioural problem and/or epilepsy to normal clinical conditions. Only our patient has neuropathy unrelated to infectious event. CONCLUSIONS: We described the heterogeneous phenotypic spectrum of familial hyperlysinemia type 1 and we identified a new symptom, axonal neuropathy, never before described in this condition.

Efficacy of vigabatrin intervention in a mild phenotypic expression of succinic semialdehyde dehydrogenase deficiency.

We report a patient with succinic semialdehyde dehydrogenase deficiency who presented a mild phenotype including developmental language delay, in association with the typical elevations of 4-hydroxybutyric acid (GHB) in biological fluids and MRI alterations. Two pathogenic mutations were identified one transversion (c.278 G>T) in exon 1 and another (c.1557 T>G) in exon 10. Both parents are carriers of one of the mutations, confirming compound-heterozygosity in their affected child. To reduce the GHB levels in body fluids, a treatment with vigabatrin at low dose (25 mg/kg per day) was started, monitoring its efficacy by clinical and neurochemical follow-up. After 9 months of therapy with vigabatrin, a significant reduction of GHB concentrations in urine and CSF was observed; after 36 months, a significant improvement of communicative skills, not previously reported, was referred. These results support the hypothesis that the clinical improvement is correlated to the reduction in the GHB levels and the importance of considering the SSADH deficiency in the differential diagnosis of patients with mental retardation and language delay.

Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene.

We describe the clinical and molecular features of a child harboring a novel mutation in SLC6A8 gene in association with a milder phenotype than other creatine transporter (CT1) deficient patients (OMIM 300352) [1-7]. The mutation c.757 G>C p.G253R in exon 4 of SLC6A8 was hemizygous in the child, aged 6 years and 6 months, who showed mild intellectual disability with severe speech and language delay. His carrier mother had borderline intellectual functioning. Although the neurochemical and biochemical parameters were fully consistent with those reported in the literature for subjects with CT1 deficit, in our patient within a general cognitive disability, a discrepancy between nonverbal and verbal skills was observed, confirming the peculiar vulnerability of language development under brain Cr depletion.

Treatment monitoring of brain creatine deficiency syndromes: a 1H- and 31P-MR spectroscopy study.

BACKGROUND AND PURPOSE: Brain creatine (Cr) deficiencies (BCr-d) are rare disorders of creatine biosynthesis and transport. We performed consecutive measures of total Cr (tCr) and of its phosphorylated fraction, phosphocreatine (PCr), in the brains of children affected by Cr synthesis defects during a long period of therapy. The aim was to identify the optimal treatment strategy for these disorders. MATERIALS AND METHODS: Two patients with guanidinoacetate methyltransferase defect (GAMT-d) were treated with different amounts of Cr and with diet restrictions aimed at reducing endogenous guanidinoacetate (GAA) synthesis. Three patients with arginine:glycine amidinotransferase defect (AGAT-d) were treated with different Cr intakes. The patients' treatments were monitored by means of (1)H- and (31)P-MR spectroscopy. RESULTS: Cr and PCr replenishment was lower in GAMT-d than in AGAT-d even when GAMT-d therapy was carried out with a very high Cr intake. Cr and especially PCr replenishment became more efficient only when GAA blood values were reduced. Adenosine triphosphate (ATP) was increased in the baseline phosphorous spectrum of GAMT-d, and it returned to a normal value with treatment. Brain pH and brain P(i) showed no significant change in the AGAT-d syndrome and at any Cr intake. However, 1 of the 2 GAMT-d patients manifested a lower brain pH level while consuming the GAA-lowering diet. CONCLUSIONS: AGAT-d treatment needs lower Cr intake than GAMT-d. Cr supplementation in GAMT-d treatment should include diet restrictions aimed at reducing GAA concentration in body fluids. (1)H- and especially (31)P-MR spectroscopy are the ideal tools for monitoring the therapy response to these disorders.

Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.

In humans, mutations in the alpha-synuclein gene or exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produce Parkinson's disease with loss of dopaminergic neurons and depletion of nigrostriatal dopamine. alpha-Synuclein is a vertebrate-specific component of presynaptic nerve terminals that may function in modulating synaptic transmission. To test whether MPTP toxicity involves alpha-synuclein, we generated alpha-synuclein-deficient mice by homologous recombination, and analyzed the effect of deleting alpha-synuclein on MPTP toxicity using these knockout mice. In addition, we examined commercially available mice that contain a spontaneous loss of the alpha-synuclein gene. As described previously, deletion of alpha-synuclein had no significant effects on brain structure or composition. In particular, the levels of synaptic proteins were not altered, and the concentrations of dopamine, dopamine metabolites, and dopaminergic proteins were unchanged. Upon acute MPTP challenge, alpha-synuclein knockout mice were partly protected from chronic depletion of nigrostriatal dopamine when compared with littermates of the same genetic background, whereas mice carrying the spontaneous deletion of the alpha-synuclein gene exhibited no protection. Furthermore, alpha-synuclein knockout mice but not the mice with the alpha-synuclein gene deletion were slightly more sensitive to methamphetamine than littermate control mice. These results demonstrate that alpha-synuclein is not obligatorily coupled to MPTP sensitivity, but can influence MPTP toxicity on some genetic backgrounds, and illustrate the need for extensive controls in studies aimed at describing the effects of mouse knockouts on MPTP sensitivity.

Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans.

Arginine:glycine amidinotransferase (AGAT) catalyzes the first step of creatine synthesis, resulting in the formation of guanidinoacetate, which is a substrate for creatine formation. In two female siblings with mental retardation who had brain creatine deficiency that was reversible by means of oral creatine supplementation and had low urinary guanidinoacetate concentrations, AGAT deficiency was identified as a new genetic defect in creatine metabolism. A homozygous G-A transition at nucleotide position 9297, converting a tryptophan codon (TGG) to a stop codon (TAG) at residue 149 (T149X), resulted in undetectable cDNA, as investigated by reverse-transcription PCR, as well as in undetectable AGAT activity, as investigated radiochemically in cultivated skin fibroblasts and in virus-transformed lymphoblasts of the patients. The parents were heterozygous for the mutant allele, with intermediate residual AGAT activities. Recognition and treatment with oral creatine supplements may prevent neurological sequelae in affected patients.

Similar increases in extracellular lactic acid in the limbic system during epileptic and/or olfactory stimulation.

Previous studies have shown that physiological stimulation of brain activity increases anaerobic glucose consumption, both in humans and in experimental animals. To investigate this phenomenon further, we measured extracellular lactate levels within different rat brain regions, using microdialysis. Experiments were performed comparing the effects of natural, physiological olfactory stimulation of the limbic system with experimental limbic seizures. Olfactory stimulation was carried out by using different odors (i.e. both conventional odors: 2-isobutyl-3-methoxypyrazine, green pepper essence; thymol; and 2-sec-butylthiazoline, a sexual pheromone). Limbic seizures were either induced by systemic injection of pilocarpine (200-400 mg/kg) or focally elicited by microinfusions of chemoconvulsants (bicuculline 118 pmol and cychlothiazide 1.2 nmol) within the anterior piriform cortex. Seizures induced by systemic pilocarpine tripled lactic acid within the hippocampus, whereas limbic seizures elicited by focal microinfusion of chemoconvulsants within the piriform cortex produced a less pronounced increase in extracellular lactic acid. Increases in extracellular lactate occurring during olfactory stimulation with the sexual pheromone (three times the baseline levels) were non-significantly different from those occurring after systemic pilocarpine. Increases in lactic acid following natural olfactory stimulation were abolished both by olfactory bulbectomy and by the focal microinfusion of tetrodotoxin, while they were significantly attenuated by the local application of the N-methyl-D-aspartate antagonist AP-5. Increases in hippocampal lactate induced by short-lasting stimuli (olfactory stimulation or microinfusion of subthreshold doses of chemoconvulsants, bicuculline 30 pmol) were reproducible after a short delay (1 h) and cumulated when applied sequentially. In contrast, limbic status epilepticus led to a long-lasting refractoriness to additional lactate-raising stimuli and there was no further increase in lactate levels when the olfactory stimulation was produced during status epilepticus. Increases in lactic acid following olfactory stimulation occurred with site specificity in the rhinencephalon (hippocampus, piriform and entorhinal cortex) but not in the dorsal striatum. Site specificity crucially relied on the quality of the stimulus. For instance, other natural stimuli (i.e. tail pinch) produced a similar increase in extracellular lactate in all brain areas under investigation. The major conclusion of this work is that the presentation of an odor known to be a rat pheromone results in lactate production as great as that induced by the systemic convulsant pylocarpine (maximum: 2.286+/-0.195 mM and 1.803+/-0.108 mM, respectively). This supports the notion that the great magnitude of lactate production known to accompany seizures can result from the intensified neural activity per se ("aerobic gycolysis"), not merely from local anoxia or other pathological changes.

Reversible brain creatine deficiency in two sisters with normal blood creatine level.

We describe a new creatine metabolism disorder in 2 young sisters who suffered from mental retardation and severe language delay. Blood examination, investigation of the most common neurometabolic disorders, and brain magnetic resonance imaging were normal. Diagnosis was established only by means of in vivo proton magnetic resonance spectroscopy, which disclosed generalized depletion of creatine in the brain. Creatine monohydrate oral administration led to almost complete brain creatine level restoration along with improvement of the patients' disabilities.

Modulation of dihydroxyphenylacetaldehyde extracellular levels in vivo in the rat striatum after different kinds of pharmacological treatment.

We recently identified the direct product of dopamine (DA) by monoamine-oxidase (MAO) activity, dihydroxyphenylacetaldehyde (DOPALD) in the trans-striatal dialysate. Based on these findings, in this work, we directly measured the variations in DOPALD levels after various kinds of pharmacological treatment in rat striatal extracellular fluid. Using both reversible and irreversible MAO inhibitors, we found that MAO-A inhibition suppressed, whereas MAO-B inhibition did not modify DOPALD levels in the dialysate. The vesicular DA uptake blocker Ro 4-1284 led to an increase in extracellular DA and DOPALD, whereas the increase in extracellular DA obtained after administration of the plasma membrane DA uptake blocker GBR-12909 occurred without concomitant changes in DOPALD extracellular levels. Microinfusions of DA through the dialysis probe or systemic administration of L-DOPA increased striatal DOPALD to a greater extent compared with other DA metabolites, both in intact and in 6-hydroxydopamine (6-OHDA)-lesioned striatum. This study indicates that the direct product of MAO activity within the rat striatum derives from the activity of the isoenzyme MAO-A. The assay of DOPALD, together with DOPAC, represents a reliable tool to measure directly, in freely moving animals, DA oxidative metabolism. As recent studies have shown that microinfusions of exogenous DOPALD might induce cell death, pharmacological modulation of DOPALD levels might also be relevant for an understanding of the mechanisms involved in DA neurotoxicity.

Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain dialysis study.

We have studied striatal dopamine (DA) metabolism in monoamine oxidase (MAO) B-deficient mice using brain microdialysis. Baseline DA levels were similar in wild-type and knock-out (KO) mice. Administration of a selective MAO A inhibitor, clorgyline (2 mg/kg), increased DA levels and decreased levels of its metabolites in all mice, but a selective MAO B inhibitor, l-deprenyl (1 mg/ kg), had no effect. Administration of 10 and 50 mg/kg L-DOPA, the precursor of DA, increased the levels of DA similarly in wild-type and KO mice. The highest dose of L-DOPA (100 mg/kg) produced a larger increase in DA in KO than wild-type mice. This difference was abolished by pretreating wild-type mice with l-deprenyl. These results suggest that in mice, DA is only metabolized by MAO A under basal conditions and by both MAO A and B at high concentrations. This is in contrast to the rat, where DA is always metabolized by MAO A regardless of concentration.

Effects of pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on methamphetamine pharmacokinetics and striatal dopamine losses.

We recently demonstrated that pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) exacerbates experimental parkinsonism induced by methamphetamine. The mechanism responsible for this effect remains to be elucidated. In this study, we investigated whether the exacerbation of chronic dopamine loss in DSP-4-pretreated animals is due to an impairment in the recovery of dopamine levels once the neurotoxic insult is generated or to an increased efficacy of the effects induced by methamphetamine. We administered different doses of methamphetamine either to DSP-4-pretreated or to intact Swiss-Webster mice and evaluated the methamphetamine-induced striatal dopamine loss at early and prolonged intervals. As a further step, we evaluated the striatal pharmacokinetics of methamphetamine, together with its early biochemical effects. We found that previous damage to norepinephrine terminals produced by DSP-4 did not modify the recovery of striatal dopamine levels occurring during several weeks after methamphetamine. By contrast, pretreatment with DSP-4 exacerbated early biochemical effects of methamphetamine, which were already detectable 1 h after methamphetamine administration. In addition, in norepinephrine-depleted animals, the clearance of striatal methamphetamine is prolonged, although the striatal concentration peak observed at 1 h is unmodified. These findings, together with the lack of a methamphetamine enhancement when DSP-4 was injected 12 h after methamphetamine administration, suggest that in norepinephrine-depleted animals, a more pronounced acute neuronal sensitivity to methamphetamine occurs.

Noradrenergic modulation of methamphetamine-induced striatal dopamine depletion.

Noradrenergic (NE) neurons belonging to the locus coeruleus (LC), much more than the A1 and A2 areas, are lost in Parkinson's disease (PD). In this study, we reproduced the selective pattern of NE loss involving axons arising from the LC using the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg). In these experimental conditions, we investigated whether NE loss potentiates methamphetamine-induced striatal dopamine (DA) depletion in mice and rats. Administration of a moderate dose of methamphetamine to C57B1/6N mice or Sprague-Dawley rats produced only a partial striatal DA depletion 7 days after drug administration. Pre-treatment with DSP-4, in both animal species, significantly enhanced methamphetamine-induced striatal DA depletion. Administration of a lower dose of methamphetamine did not decrease striatal DA levels when injected alone, but produced a significant decrease in striatal DA when given to DSP-4-pretreated rodents. Moreover, we found that agents reducing the noradrenergic activity (i.e., the alpha-2 agonist clonidine) enhanced, whereas alpha-2 antagonists decreased, methamphetamine toxicity. Enhancement of methamphetamine toxicity did not occur if the noradrenergic lesion was produced 12 hr after methamphetamine administration. By contrast, exacerbation of methamphetamine toxicity in NE-depleted animals was accompanied by increased extracellular DA levels measured with brain dialysis and by a more severe acute DA depletion measured in striatal homogenates.

Effects of noradrenergic lesions on MPTP/MPP+ kinetics and MPTP-induced nigrostriatal dopamine depletions.

Norepinephrine (NE) depletion caused by damage to locus ceruleus neurons was shown to worsen experimental Parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys and in rodents. However, it is not clear whether the lesion to the NE system enhances neurotoxicity in the nigrostriatal dopaminergic (DA) pathway and/or impairs the recovery of DA neurons once the neurotoxic insult is generated. In this study, we provide evidence that the lesion of NE terminals, induced by the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg), must occur before MPTP (30 mg/kg) administration in order to enhance MPTP toxicity. As a second step, we evaluated the acute effects of MPTP on the nigrostriatal DA pathway in NE-lesioned animals compared with intact animals. We observed a more marked acute DA depletion, persisting at 12 h, in DSP-4 + MPTP-treated mice compared with MPTP-injected controls. These findings, combined with the lack of an MPTP enhancement when NE depletion was induced 12 h after MPTP administration, suggest that in NE-depleted animals, a more pronounced acute neuronal sensitivity to MPTP occurs. In line with the hypothesis of an acute protective effect by NE axons, we evaluated whether the enhancement of MPTP toxicity in NE-lesioned animals is achieved through alterations to the kinetics of MPTP and its metabolite. Our findings indicate that despite the pivotal role of NE terminals in taking up and storing 1-methyl-4-phenylpyridinium (MPP+), MPTP enhancement does not depend on modifications in the striatal kinetics of MPTP/MPP+ measured at seven different time intervals after MPTP administration.

The influence of dosage, age, and comedication on steady state plasma lamotrigine concentrations in epileptic children: a prospective study with preliminary assessment of correlations with clinical response.

The effects of age, dosage, and type of comedication on plasma lamotrigine (LTG) concentrations and the relationship between plasma drug levels and clinical response were evaluated in a prospective study of 45 patients, aged 3 to 38 years, with epilepsy uncontrolled by conventional anticonvulsant therapy. Six of the 45 patients were on single-drug therapy, and 39 were on two to five concurrently administered antiepileptic drugs when LTG was added. Thirteen patients were assessed at three or more LTG dosage levels. Within individuals, steady state plasma LTG concentrations increased linearly with increasing daily dosage over the examined dose range (25 to 575 mg/day or 0.75 to 21 mg/kg.day). Among patients also receiving enzyme-inducing agents, such as carbamazepine, barbiturates, or phenytoin, plasma LTG concentrations normalized to a 1 mg/kg daily dose were lower in children aged 3 to 6 years (0.30 +/- 0.17 microgram/ml; n = 6) than in the older children (0.43 +/-0.18 microgram/ml; n = 12) and adolescents/adults (0.68 +/- 0.26 microgram/ml; n = 10). In patients treated with valproate, the age dependency of plasma LTG was less evident, possibly because of a smaller sample size and the confounding effect of comedication. Within any given age group, dose-normalized LTG concentrations were about five-fold higher in patients comedicated with valproic acid than in those comedicated with enzyme inducers. Twenty patients showed a favorable response (with a > or = 40% reduction in seizure frequency compared with the pre-LTG period) and continued on long-term treatment. Plasma drug concentrations in these apparent responders were highly variable and did not differ significantly from those observed in nonresponders (6.6 +/- 5.2 versus 4.8 +/- 3.3 microgram/ml). These findings show that plasma LTG concentrations exhibit a wide interindividual variability under the influence of age and type of comedication, but they are predictably related to dosage within individual patients. Although there was no apparent relationship between drug levels and clinical response in this difficult-to-treat population, further studies on the potential value of monitoring plasma LTG concentrations are indicated.

Region- and neurotransmitter-dependent species and strain differences in DSP-4-induced monoamine depletion in rodents.

The neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is commonly used as a chemical tool to induce selective denervation of noradrenergic terminals arising from the locus coeruleus and to study the molecular mechanisms underlying degeneration of central noradrenergic axons in rodents. Monoamine depletion in different rodent species after DSP-4 is generally assumed to occur with a similar pattern. To verify this assumption, in the present study we evaluated the different patterns of monoamine depletion produced by DSP-4 in different brain regions of two different strains of mice and rats 3, 7 and 14 days after DSP-4 administration. In this report, we show that there are evident species and strain differences concerning the pattern of norepinephrine depletion in various brain regions. Moreover, serotonin levels are fully preserved following DSP-4 in mice, whereas there is a significant serotonin decrease in specific brain regions after the same dose of DSP-4 in rats. Apart from disclosing species and strain variability among rodents in neurotoxin-induced monoamine depletion, these findings suggest that DSP-4 should be considered as a different neurotoxin, depending on the species and strain in which it is administered.

Clonidine suppresses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced reductions of striatal dopamine and tyrosine hydroxylase activity in mice.

Recent findings have shown that excitatory amino acid may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. At the same time, evidence is accumulating that the endogenous noradrenergic system plays a protective role in MPTP-induced striatal dopamine (DA) depletion and nigral dopaminergic cell death. Recently, alpha 2-adrenoceptors located on glutamatergic axons have been shown to inhibit glutamate overflow. In this study, we evaluated the effects of an alpha 2-agonist (clonidine) and an alpha 2-antagonist (yohimbine) on MPTP-induced striatal DA depletion and tyrosine hydroxylase activity reduction. We show that clonidine is able to prevent the neurotoxicity of MPTP in mice. To exert this effect, clonidine (0.5 mg/kg) must be administered at least twice (30 min before and 30 min after MPTP). Administration of another alpha 2-agonist (detomidine, 0.3 mg/kg) attenuated the neurotoxicity induced by MPTP. We provide evidence that the protective effect obtained with clonidine was not due to decreased striatal content of 1-methyl-4-phenylpyridinium (MPP+). We also show that yohimbine, which is a classic alpha 2-adrenoceptor antagonist with low affinity for imidazoline receptors, produced by itself an enhancement of MPTP toxicity and was able to block the protective effect of clonidine. These data raise the possibility that alpha 2-adrenoceptor may modulate the susceptibility of the nitrostriatal dopaminergic pathway to neurotoxicity.

beta,beta'-Iminodipropionitrile-induced persistent dyskinetic syndrome in mice is transiently modified by MPTP.

Chronic administration of iminodipropionitrile (IDPN) is known to produce a persistent dyskinetic syndrome. Recent neurochemical reports seem to point out the dopaminergic system as having an important role in mediating IDPN syndrome. In order to identify a possible role for the nigrostriatal dopaminergic pathway in determining at least some aspects of the IDPN-induced dyskinetic syndrome, we used the neurotoxin, 1-methyl, 4-phenyl,1,2,3,6-tetrahydropyridine (MPTP), as a tool for investigating which aspects of the IDPN-related syndrome could be due to enhanced dopaminergic activity in the neostriatum. In mice made permanently dyskinetic with IDPN, MPTP administration produced dramatic and biphasic effects on all behavioral patterns characteristic of the dyskinetic syndrome. Six weeks after the syndrome occurred, IDPN failed to produce any change in striatal DA levels with respect to controls. By contrast, IDPN seems to reduce striatal levels of extraneuronal metabolites of DA. These data suggest that the activity of the nigrostriatal dopaminergic pathway does not play a leading role in the maintenance of IDPN-related syndrome. The transient modification of all behavioral parameters immediately after MPTP administration could be explained by acute effects of MPTP on other dopaminergic areas which are not permanently lesioned by this neurotoxin, or by the acute effects of MPTP on the release of other neurotransmitters.

Plasma and tissue concentrations of coenzyme Q10 in the rat after intravenous, oral and topical administrations.

Coenzyme Q10 (CoQ10) distribution into rat liver, heart, kidney and plasma was investigated after intravenous and oral administrations in different vehicles. Moreover, CoQ10 skin levels following topical treatment were evaluated. The liver represented the target organ for this compound in all the cases examined. In the heart, high and persistent CoQ10 concentrations were achieved particularly after solution injection while, following oral treatment, high doses of the drug were needed to reach the same CoQ10 levels. High concentrations of CoQ10 may be achieved also in the skin by topical treatment.

Adriamycin, aclacinomycin and thepirubicin intracardiac distribution examined by fluorescence microscopy.

Male Wistar rats received adriamycin, aclacinomycin or thepirubicin at a dose of 4 mg/kg b.w. by slow infusion. Cardiac tissue sections were examined by fluorescence microscopy to evaluate the distribution of the three anthracyclines. The nuclei regularly exhibited a stronger coloring with respect to the cytoplasm for all three drugs. Adriamycin cytoplasm fluoresced intensely, unlike aclacinomycin and thepirubicin. Our results indicate a lower uptake of these last two molecules into cardiac tissue, thus suggesting a different pharmacokinetic profile which might account for their lower cardiotoxicity.

Aclacinomycin tissue distribution in the rat.

This study was undertaken to investigate aclacinomycin distribution in the rat, using a method based on the histofluorescence of tissues treated in vivo with anthracyclines. The target organs were the kidney, lung and pancreas; a fainter fluorescence was also detected in the heart compared with adriamycin due to a quantitatively different fixing of the two anthracyclines. Our findings revealed a preferential uptake into the cell nucleus in all tissues examined except the adrenal gland medulla where a slight fluorescence appeared only in the cytoplasm.