Long-term Valproate Treatment Research Articles

P.2.f.037 - Effect of long-term valproate treatment on bone metabolism in patients with bipolar disorder: a pilot study

P.2.f.037 - Effect of long-term valproate treatment on bone metabolism in patients with bipolar disorder: a pilot study

Seminal fluid analysis and testicular volume in adults with epilepsy receiving valproate

Epilepsy and its medications adversely affect reproductive and sexual functions and fertility. This study aimed to assess sperm parameters and testicular volume in men with epilepsy on valproate (VPA). Included were 55 patients with idiopathic epilepsy with a mean age of 31.86±standard deviation (SD) 6.55years, mean illness duration of 12.50±SD 5.10years, and a mean treatment time of 9.55±SD 0.85years. Sex hormone profile, semen analysis, testicular volume and total seminal plasma carnitine were determined. Compared to controls, patients had lower levels of free testosterone (p<0.01), sperm concentration (p<0.0001) and count (p<0.0001), carnitine (p<0.01), and testicular volume (p<0.01), and higher rates of immotile sperm (p<0.001) and abnormal forms (p<0.0001). Significant correlations were identified between sperm count, motility, immotile sperm, abnormal forms, testicular volume, carnitine levels and duration of illness, duration of treatment with VPA and VPA dose. Multivariable analysis demonstrated that duration of treatment with VPA, sperm count, motility and abnormal forms were significantly associated with seminal plasma carnitine. Long-term VPA treatment is adversely associated with reduced sperm count and motility, increased abnormal sperm count and reduced testicular volume. This may contribute to reduced fertility.

Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder.

Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder.

Long-Term Valproate Treatment Increases Brain Neuropeptide Y Expression and Decreases Seizure Expression in a Genetic Rat Model of Absence Epilepsy

The mechanisms by which valproate, one of the most widely prescribed anti-epileptic drugs, suppresses seizures have not been fully elucidated but may involve up-regulation of neuropeptide Y (NPY). We investigated the effects of valproate treatment in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) on brain NPY mRNA expression and seizure control. GAERS were administered either valproate (42 mg.kg−1 hr−1) or saline continuously for 5 days. Electroencephalograms were recorded for 24 hrs on treatment days 1, 3 and 5 and the percentage of time spent in seizure activity was analysed. NPY mRNA expression was measured in different brain regions using qPCR. Valproate treatment suppressed seizures by 80% in GAERS (p<0.05) and increased NPY mRNA expression in the thalamus (p<0.05) compared to saline treatment. These results demonstrate that long-term valproate treatment results in an upregulation of thalamic expression of NPY implicating this as a potential contributor to the mechanism by which valproate suppresses absence seizures.

Effect of Short- and Long-Term Treatment With Valproate on Carnitine Homeostasis in Humans

The aim of this study was to identify the mechanisms of hypocarnitinemia in patients treated with valproate. Plasma concentrations and urinary excretion of carnitine, acetylcarnitine, propionylcarnitine, valproylcarnitine, and butyrobetaine were determined in a patient starting valproate treatment and in 10 patients on long-term valproate treatment. Transport of carnitine and valproylcarnitine by the proximal tubular carnitine transporter OCTN2 was assessed in vitro. In the patient starting valproate, the plasma carnitine and acetylcarnitine levels dropped for 1-3 weeks and had recovered after 3-5 weeks, whereas the plasma levels of propionyl and valproylcarnitine increased steadily over 5 weeks. The renal excretion and excretion fractions (EFs) of carnitine, acetylcarnitine, propionylcarnitine, and butyrobetaine decreased substantially after starting valproate. Compared with controls, patients on long-term valproate treatment had similar plasma levels of carnitine, acetylcarnitine, and propionylcarnitine, whereas valproylcarnitine was found only in patients. Urinary excretion and renal clearance of carnitine, acetylcarnitine, propionylcarnitine, and butyrobetaine were decreased in valproate-treated compared with that in control patients, reaching statistical significance for carnitine. The EFs of carnitine, acetylcarnitine, and propionylcarnitine were <5% of the filtered load in controls and were lower in valproate-treated patients. In contrast, the EF for valproylcarnitine approached 100%, resulting from a low affinity of valproylcarnitine for the carnitine transporter OCTN2 and competition with concomitantly filtered carnitine. The initial drop in plasma carnitine levels of valproate-treated patients is most likely due to impaired carnitine biosynthesis, whereas the recovery of the plasma carnitine levels is explainable by an increased renal expression of OCTN2. Renally excreted valproylcarnitine does not affect renal handling of carnitine in vivo.

Fronto-striatal dysfunction in type 3 familial cortical myoclonic tremor epilepsy occurring during aging

The aim of this work is to study the cognition, progressive gait impairment, and neuroimaging findings in two patients over 65 years old of the previously described type 3 familial cortical myoclonic tremor with epilepsy (FCMTE3). We report investigations in two of these five FCMTE3 subjects over 65 and showing progressive gait disorders. They both had a pseudo-Parkinson's way of walking and visual intolerance to bright light and brightness contrast without EEG abnormalities exacerbating cortical myoclonus or triggering seizure. Case 1 had moderate gait impairment and a severe frontal syndrome. Case 2 had severe gait impairment and diffuse cognitive disorders. Both cases had cortical hypoperfusion (predominantly in the left frontal lobe) and no cerebellar abnormality on cerebral perfusion SPECT. DAT-SPECT showed dopaminergic depletion. These data indicate fronto-striatal dysfunction associated with gait impairment and cognitive disorders appearing after several decades of disease progression. This gives clues to understanding the pathogenesis and evolution of FCMTE3. Permanent myoclonic discharges or long-term valproate treatment may cause significant toxic effects on neurons (dopaminergic and frontal neurons). Further functional and molecular analyses are required in order to better understand this pathology and the consequences of chronic cortical myoclonus.

Investigation on sodium valproate induced germ cell damage, oxidative stress and genotoxicity in male Swiss mice

Sodium valproate (VPA) is the most widely used antiepileptic drug for the treatment of epilepsy, bipolar psychiatric disorders and migraine. However, long-term VPA treatment has several adverse effects on the reproductive system. The present study was aimed to investigate the possible germ cell toxicity of VPA in mice. Animals were treated with VPA intraperitoneally for 10 and 28 days at the doses of 500 mg/kg-d and 100, 200 and 400 mg/kg-d, respectively, and were sacrificed 24 h after the last dose. The germ cell toxicity of VPA was assessed using oxidative stress parameters, sperm count, sperm head morphology, sperm comet assay, 8-oxo-dG expression and histology. VPA treatment significantly decreased the sperm count, testes and epididymis weight and significantly increased the sperm head abnormality, sperm DNA damage, oxidative stress and 8-oxo-dG expression in the testes of mice. The present study illustrates that VPA induced germ cell toxicity in mice.

Evaluation of valproate effects on acylcarnitine in epileptic children by LC–MS/MS

Background: Valproate (VPA) is a simple fatty acid and a substrate for the fatty acid β-oxidation pathway. Previous data suggested that the toxicity of VPA may be provoked by carnitine deficiency and the inhibition of mitochondrial β-oxidation. Objective: The aim of the present study was to elucidate the effect of VPA treatment on carnitine and isomer-differentiated acylcarnitine disposition, and determined the relationships between acylcarnitines and blood VPA levels in long-term treated patients with VPA and/or other antiepileptic drugs. Methods: Serum samples were obtained from children aged 1–15 years old treated for at least 6 months with VPA alone ( n = 28) or VPA combined with other anticonvulsants ( n = 23) and untreated controls ( n = 23). Serum acylcarnitines were separated from their isomers and quantified using high-performance liquid chromatography–tandem mass spectrometry. Results: We found higher 3-hydroxyisovalerylcarnitine levels and trace amounts of valproylcarnitine in both VPA monotherapy and polytherapy patients. Other acylcarnitines, hexanoylcarnitine, C12, C14:1-carnitines and the ratio of long-chain acylcarnitine to free carnitine were also higher in VPA polytherapy individuals than in controls. VPA monotherapy does not result in decreases in free carnitine or in the accumulation of long-chain acylcarnitines. Blood VPA concentrations correlated positively with hexanoylcarnitine, C12, C14:1, C16:1, C18:1-carnitines in all VPA-treated children ( n = 51). Conclusion: Long-term VPA treatment in pediatric patients could affect some specific acylcarnitines, which is enhanced by the concomitant use of other anticonvulsants, and the formation of valproylcarnitine alone seems insufficient to develop severe carnitine deficiency at therapeutic doses of VPA.

Valproate-dependent transcriptional regulation of GLAST/EAAT1 expression: Involvement of Ying-Yang 1

Valproate, a widely used anti-epileptic drug also employed in the treatment of neurological diseases such as bipolar disorder and migraine, regulates the glutamatergic and GABAergic systems, although its effects in cell physiology have not been thoroughly characterized. High concentrations of glutamate reached during abnormal neurotransmission if not removed properly, become neurotoxic. Glutamate clearance is carried out by high affinity Na +-dependent glutamate transporter systems. The glutamate/aspartate transporter GLAST/EAAT1 plays the major role in glutamate removal and is regulated at different levels: transcription, post-translational modifications and cytoplasmic trafficking. The aim of this work was to gain insight into a plausible effect of valproate in GLAST function. Using cultured Bergmann glia cells from chick cerebellum we demonstrate here that valproate exposure elicits a dual regulatory effect on GLAST. In the short-term, valproate increases its Na +-dependent [ 3H]- d-aspartate uptake activity in a cytochalasin B-sensitive manner. Interestingly, a synergism between valproate and a histone deacetylase inhibitor was observed. Long-term valproate treatment up-regulates chglast promoter activity, GLAST mRNA levels, GLAST molecules at the plasma membrane and its uptake activity. Furthermore, valproate induces histone 3 lysine 14 acetylation and regulates Ying-Yang 1 (YY1) transcriptional repression on the chglast promoter. These results suggest that valproate elicits its effect through its histone deacetylase inhibitor properties.

Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy

Disturbances of reproductive endocrine hormones are more often found in men with epilepsy than in the general population. There is an ongoing debate whether this can be attributed to chronic use of antiepileptic drugs or to the epilepsy itself. The aim of the present study was to evaluate the degree of endocrine disturbances in men with epilepsy compared with healthy controls, and to investigate whether there was a drug-specific effect of valproate (VPA) or carbamazepine (CBZ). Men with epilepsy, 20-40 years old, having used either VPA (n = 16) or CBZ (n = 19) as monotherapy for >2 years were included and compared with age-matched controls. Men with epilepsy (VPA + CBZ) had significantly lower FSH values and higher C-peptide values compared with controls. Regarding possible drug-specific effects, the VPA treated patients had significantly higher dehydroepiandrosterone (DHEAS) levels and lower FSH and LH concentrations compared with the controls, whereas there were no differences in testosterone, testosterone/sexhormone-binding globulin (SHBG) ratio or androstenedione levels. Men on VPA also had significantly lower free carnitine/total carnitine, which may have implications for sperm motility, and also higher insulin and C-peptide concentrations. The CBZ treated patients had significantly lower testosterone/SHBG ratio than the controls. Compared with the CBZ treated patients, men on VPA had significantly higher DHEAS concentrations and lower levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) as well as a lower free carnitine/total carnitine ratio. A marked age dependency was found in all three groups regarding several of the endocrine hormones. In conclusion, drug-specific endocrine effects of VPA and CBZ were found in men with epilepsy. Long-term VPA treatment leads to significant changes in DHEAS, FSH, LH, insulin, C-peptide and carnitine ratio. Long-term CBZ treatment leads to significant lower testosterone/SHBG ratio. A strict age matching were found to be of importance in the evaluation of endocrine function in men.

Endocrine and metabolic responses to long-term monotherapy with the antiepileptic drug valproate in the normally cycling rhesus monkey.

An association between epilepsy and reproductive disturbances with an apparent increase in a polycystic ovarian syndrome (PCOS) has been reported. Whether this association can be attributed to epilepsy itself or is related to antiepileptic drug therapy, in particular valproate (VPA), remains controversial. We studied effects of a long-term VPA treatment on cycling monkeys, postulating that, if VPA monotherapy were to promote abnormal endocrine and metabolic parameters that are characteristic of PCOS, changes in cyclicity would be readily demonstrated. After a 2-month control, a 12- to 15-month VPA monotherapy was initiated in 7 regularly cycling rhesus monkeys. Overall mean levels of VPA were 88.7 +/- 4.0 (SE) microg/ml. Mean body weight increased progressively during VPA treatment from 8.5 +/- 0.5 kg before treatment to 9.6 +/- 0.7 kg in the last week of treatment (P < 0.05). Monkeys continued to have regular ovulatory menstrual cycles throughout VPA monotherapy. Length of the cycles was 28 +/- 0.58 d in control and 28.4 +/- 1.18 d in the last 3 months of VPA treatment. Follicular and luteal lengths and peak preovulatory estradiol and integrated luteal progesterone levels did not differ between control and treatment. Ovaries from VPA-treated monkeys showed histological evidence of ovulation, and none had characteristic features of PCOS. Endocrine PCOS markers, such as increased early follicular LH/FSH ratio and androgen levels were not different in control and VPA treatment cycles. LH and 17-hydroxyprogesterone responses to GnRH agonist challenges and the insulin response to glucose tolerance tests were similar in control and VPA groups. Lipid profiles were not affected by VPA treatment. The data indicate that a 12- to 15-month therapeutic exposure to VPA does not induce cyclic hormonal or morphological ovarian abnormalities or characteristics of the PCOS when administered to nonepileptic normally cycling nonhuman primates.

Morphological changes in the testis after long-term valproate treatment in male Wistar rats

Uncertainty exists about the effect of antiepileptic drugs on gonadal function. In females, long-term valproate treatment has been shown to induce endocrine disturbances and an increased number of ovarian cysts. The aim of the present study was to investigate whether valproate can also induce morphological changes in the testis of male animals. In addition, possible morphological changes in the liver, heart, lungs, lymphatic nodes, pancreas, kidney or brain were studied. The carcinogenic implications were evaluated by the measurement of p53. Male Wistar rats were fed perorally with valproate mixture 200 mg kg−1(n= 15) or 400 mg kg−1(n= 20), or control solution (n= 15) twice daily for 90 days. Serum concentrations measured 4–6 hours after the last dose were 105 and 404 μ mol l−1in low- and high-dose valproate treated animals respectively. There was a highly significant, 51% decrease (P< 0.001) in testicular weight in the high-dose treated valproate rats with no changes in the other groups. There was widespread testicular atrophy with histologically verified spermatogenic arrest in 15/20 of the high-dose valproate treated animals. No changes in the testis were seen in the low-dose valproate treated rats, nor in the control rats. There were no morphological changes in the other investigated organs. None of the groups showed over-expression of p53. In conclusion, a dose-dependent effect of chronic valproate treatment was found on testicular morphology in rats. Caution must be taken before these results can be applied to humans.

Long-term valproate treatment induces changes in ovarian morphology and serum sex steroid hormone levels in female Wistar rats

Long-term valproate treatment is associated with polycystic ovaries and endocrine disorders in women with epilepsy. The mechanisms responsible for these effects are unknown, but both the epilepsy itself and the drug per se may be of importance. The aim of this study was to investigate possible effects of the drug on gonadal structure and function in animals with no epileptic disorders. Three groups, each of 15 female Wistar rats, were fed perorally with a valproate mixture (50 mg /kg or 200 mg /kg) or control solution once daily for 90 days, giving mean valproate concentrations within the normal human range. A significant, 20% increase in ovary weight was found in both low- (P= 0.027) and high- (P< 0.001) dose animals together with a significantly increased number of ovarian follicular cysts. Mean serum testosterone concentration was significantly reduced in both low- and high-dose animals. There was a non-significant trend towards reduced estrogen levels, while progesterone levels were unchanged. Even if the hormonal changes are somewhat different from those in humans, the findings demonstrate that changes in gonadal structure and endocrine function also occur in intact animals indicating a drug-specific effect. Our findings encourages further studies using animal models to elucidate possible mechanisms involved in the endocrine side-effects of antiepileptic drugs.

Valproate treatment and platelet function: the role of arachidonate metabolites.

Valproate (VPA) is an extensively used drug in the therapy of epilepsies. One of the most frequently reported side effects of VPA is hemorrhagic diathesis. Some authors emphasized the decreased platelet count as the basis of VPA-induced hemorrhagic diathesis, but some reports suggested that a significant proportion of patients with normal platelet count may still have an altered platelet function. The mechanism of the VPA-induced platelet dysfunction has not yet been elucidated. A determining element of platelet functions is the arachidonate cascade. Present ex vivo experiments were designed to determine whether a relation exists between the incidence of hemostasis caused by VPA and the effect of this drug on the arachidonate cascade of platelets. Platelets were isolated from patients receiving long-term VPA treatment (serum level, 36.04+/-16.12 microg/ml; n = 10) or carbamazepine (CBZ) treatment (serum level, 5.24+/-2.67 microg/ml; n = 10) and were labeled with [14C]arachidonic acid. (CBZ-treated patients were chosen as a control group, because CBZ causes blood dyscrasias similar to those elicited by VPA, but there has been no report that CBZ induces a platelet dysfunction.) The 14C-eicosanoids were separated by means of overpressure thin-layer chromatography and determined quantitatively by liquid scintillation. Even when the mean plasma concentration of the drug was low, VPA treatment reduced the activity of the arachidonate cascade in platelets. VPA effectively inhibited the cyclooxygenase pathway and the synthesis of the strong platelet aggregator thromboxane A2. Inhibition of the platelet arachidonate cascade may contribute to the platelet-function alterations caused by VPA.

Long-term treatment with sodium valproate: monitoring of venous ammonia concentrations and adverse effects.

Adverse effects and venous blood ammonia concentrations were monitored over a period of 7 months in patients with epilepsy treated with valproate (VPA). During the 1st, 4th, 12th, 20th, and 28th weeks of therapy, blood samples for analysis of ammonia and anticonvulsants were taken immediately before the morning dose of VPA as well as 2 h after dosing. In all, 40 patients completed the follow-up; 16 of these (Group 1) received VPA alone, while the remaining 24 (Group 2) were treated simultaneously with VPA and other anticonvulsants (phenobarbital, phenytoin, and/or carbamazepine). In Group 1 patients, a slight though significant increase in ammonia concentrations was found during long-term VPA treatment; this trend was even more pronounced in Group 2 patients. The difference between postdose and predose ammonia levels in Group 2 patients was significant at each of the five follow-up examinations. In contrast, no such difference was demonstrated in patients of Group 1. VPA concentrations were found to be consistently higher in Group 2 patients than in Group 1. Twenty-three patients complained of various long-term adverse effects, while the other 17 remained symptom-free. The adverse effects reported included drowsiness, tremors, weight gain, hair loss, and gastrointestinal symptoms. Our data confirm the previously suggested hypothesis that changes in venous blood ammonia are particularly evident in patients taking VPA in combination with other antiepileptic drugs, such as phenobarbital and phenytoin.