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We previously designed the formulation containing minoxidil (MXD) nanoparticles (MXD-NPs), and found that the MXD-NPs can mainly deliver MXD into hair bulbs via hair follicles pathway, and that the therapeutic efficiency for hair growth is higher in comparison with the formulation containing dissolved MXD. In this study, we investigated whether the skin environmental changes by the treatment of steam towel, ethanol, l-menthol and commercially available (CA) carpronium affect the drug behavior in the MXD-NPs-applied mice. The steam towel, ethanol, l-menthol and CA-carpronium were pre-treated 3 min before MXD-NPs application, and the MXD content in the hair bulge, bulb, skin tissue and blood of mice were measured 4 h after MXD-NPs application. No significant difference of MXD levels in the blood was observed by the pre-treatment of steam towel, ethanol, l-menthol and CA-carpronium. On the other hand, the pre-treatment of steam towel and l-menthol enhanced the MXD levels in hair bulge and/or bulb. Although, the MXD levels in hair bulge and bulb were not changed by the pre-treatment of ethanol, the MXD levels in skin tissue was higher than that of saline-pre-treated group (control). The MXD levels in hair bulge, bulb and skin tissue of mice pre-treated with CA-carpronium were remarkably higher in comparison with control. In conclusion, we showed that the changes in skin environment by the steam towel, ethanol, l-menthol and CA-carpronium affected the absorption of MXD-NPs, and these increased MXD levels in the hair bulb and blood by the combination may enhance the therapeutic efficiency without side effects.

A 51-year-old man complained of continuous pain lasting about 3 weeks around his forehead and left orbit-locations where pain may indicate conjunctival injection and lacrimation. Upon arrival to our hospital, his neurological examination was normal, and brain MRI showed no abnormality. The headache disappeared with indomethacin treatment (75 mg/day), and a diagnosis of hemicrania continua (HC) was established according to the International Classification of Headache Disorders, 2nd Edition. The headache returned after reducing the dose of indomethacin. After adding pregabalin (150 mg/day) to his treatment regimen, we could reduce the dose of indomethacin from 75 mg/day to 25 mg/day, which the patient tolerated well. Although HC is one of the indomethacin-responsive headaches, continuous administration can cause side effects including gastrointestinal disorders. Such side effects can decrease the tolerability of indomethacin, and may eventually lead to its reduction or discontinuation. Pregabalin can be an alternative to indomethacin for treating HC.

Thirteen patients with metastatic colorectal cancer who suffered from oxaliplatin-induced sensory neuropathy were evaluated to determine the neuropathy Grade before and after the administration of pregabalin. All patients received oxaliplatin as adjuvant or first-line chemotherapy. The mFOLFOX6 and CapeOX groups included 3 and 10 cases, respectively, and the average treatment regimens were 8 and 5 doses, respectively. Before receiving pregabalin, sensory neuropathy was classified as Grade 3 in 2 patients, as Grade 2 in 8 patients, and as Grade 1 in 3 patient. The average amount of pregabalin administered to patients was 237 (range: 150-450) mg. After administering pregabalin, we observed improvements in 8 neuropathy cases (61. 5%)within approximately 2 weeks. All side effects were mild. In this study, pregabalin was shown to positively impact sensory neuropathy resulting from oxaliplatin treatment and to enable the long-term use of oxaliplatin-based chemotherapy.

This study included patients who were prescribed pregabalin, vitamin B12, amitriptyline, clonazepam, or carbamazepine to improve oxaliplatin(L-OHP)- or paclitaxel(PTX)-induced peripheral neuropathy at Iwate Medical University Hospital between April 2011 and July 2012. The efficacy and safety of pregabalin was evaluated by comparing 27 patients with L-OHP-induced peripheral neuropathy and 28 with PTX-induced peripheral neuropathy prescribed pregabalin(pregabalin group) with 20 patients with L-OHP-induced peripheral neuropathy and 25 with PTX-induced peripheral neuropathy prescribed other drugs(non-pregabalin group). Response was defined as a decrease in neuropathy of at least 1 grade from baseline. The response rates were 40.7% and 10.0% for L-OHP-induced peripheral neuropathy patients and 28.6% and 12.0% for PTX-induced peripheral neuropathy patients in the pregabalin and non-pregabalin groups, respectively. The severity of peripheral neuropathy before and after the administration of pregabalin differed significantly[L-OHP, 1.33±0.48(mean±SD) vs. 1.00±0.78 and PTX, 1.46±0.69 vs. 1.21±0.88]. In 28-37% of patients, pregabalin was associated with adverse events, with drowsiness and dizziness being frequently observed. In conclusion, pregabalin was efficacious in reducing the severity of L-OHP- and PTX-induced peripheral neuropathy.

Pregabalin has been available in Japan since June 2010 for neuropathic pain. The adverse effects of pregabalin might be serious, and one must start at minimal doses and increase gradually to effective doses with enough explanation to patients. Pregabalin is a derivative of y-aminobutyric acid (GABA), but it has no effects on GABA receptors. Pregabalin reduces allodynia and hyperalgesia that are main symptoms of neuropathic pain. There are reports about the supportive effects of pregabalin for perioperative analgesic action of opioids. In the spinal nerve ligation (SNL) model, mRNA of alpha2delta-1 subunit of voltage gated calcium channels (VGCCs) is increased in the dorsal root ganglion (DRG) and alpha2delta-1 subunit of the spinal dorsal horn is increased. The effects of pregabalin is to bind alpha2delta-1 subunit and normalize the numbers of VGCCs at neuron surface and decreases neurotransmission, especially by excitatory amino acid. The descending facilitating serotonergic system from rostral ventromedial medulla may have effects on the occurrence and maintenance for the chronic pain. New drugs with less adverse effects may be developed.

Cancer pain consists of continuous pain lasting almost all day and transient exacerbation of pain called breakthrough pain. Breakthrough pain is classified as somatic pain and visceral pain, neuropathic pain according to the character of pain. Although the immediate release opioid is used as the first treatment of choice to breakthrough pain, the effect is not enough when it shows the character of neuropathic pain. Pregabalin has become the first medicine for the treatment of neuropathic pain, and it sometimes reveals prompt analgesic effect based on its pharmacological profile. It has also been reported that pregabalin used with oxycodine reveals analgesic effect with smaller dosage than pregabalin alone. We experienced a young patient with lung cancer suffering from sudden exacerbation of symptomatic sciatica, whose pain was markedly reduced within 30 minutes by taking immediate release oxycodone 5 mg and pregabalin 75 mg simultaneously. Conclusions : Pregabalin with immediate release oxycodone simultaneously may be able to improve acute exacerbation of neuropathic cancer pain rapidly.

Were port a 51-year-old male left renal pelvic cancer patient with paclitaxel (PTX)-induced peripheral neuropathy, which was successfully treated with pregabalin. From June 2010, a gemcitabine/PTX (GP) regimen was used as third-line treatment. In order to relieve the PTX-induced peripheral neuropathy, pregabalin (75mg/day, at night) was administered from day 6 of the 16th course. Moreover, pregabalin was increased to 150mg/day from day 12 of the course. Sensory neurotoxicity after the administration of pregabalin was decreased from CTCAE (version 4. 0) grade 3 to 1 at day 19 of the course. Therefore, there is a possibility that the PTX -induced peripheral neuropathy may be improved by pregabalin administration. Further trials may be needed to confirm the value of pregabalin.

When performing R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)for diffuse large B-cell lymphoma(DLBCL), neurotoxicity of vincristine(VCR)is the serious dose-limiting factor.Pregabalin is one of the first-line treatments for painful diabetic peripheral neuropathy in many countries, and we have administered it to relieve the neurotoxicity associated with adverse effects of VCR in a DLBCL patient treated with the R-CHOP regimen.A 49-year-old man with kidney DLBCL had surgery performed.Afterward, the R-CHOP regimen was introduced.In order to relieve the neurotoxicity of VCR, pregabalin was used from day 8 in the second course.The severity of sensory neurotoxicity after the administration of pregabalin was improved from CTCAE(v4.0)grade 3 to grade 1.Therefore, there is a possibility that VCR-induced neurotoxicity is relieved by pregabalin.Further trials are needed to confirm the value of pregabalin.

Background: Evidence to support the use of pregabalin in combination with opioid analgesics for the treatment of cancer-related neuropathic pain is limited., Methods: We carried out a retrospective investigation on patients hospitalized in our department with cancer-related neuropathic pain and under pregabalin treatment. Patients were divided into two groups: A group (= < 300 mg pregabalin daily) and B group (> 300 mg pregabalin daily). The two groups were compared in terms of a suite of factors (e. g., age starting and maimtenance dose of pregabaline, adverse effect)., Results: Patient's age was significantly lower in the B group (> 300 mg pregabalin daily). Of the total number of patients involved in the study, 67% experienced mild and moderate somnolence., Conclusions: In this retrospective investigation, we conclude that the younger cancer patients may need lager doses of pregabalin to relieve cancer-related neuropathic pain. In addition, the mild and moderate somnolence occurs frequently when pregabalin is administered with opioid analgesics for the treatment of cancer-related neuropathic pain.

This paper presents the case of a man in his 60's with advanced esophageal cancer after the first course of 5-FU/CDDP therapy during follow-up visit, who had pain and numbness from right scapula to upper arm. MRI revealed bone metastasis in the first thoracic vertebra and lymph node metastasis to be diagnosed as neuropathic pain by brachial plexus invasion. Radiation therapy and medical treatment with lornoxicam and controlled-release oxycodone started. However, breakthrough pain in the night was remarkably severe and numerical rating scale was 9-10/10. Pregabalin as analgesic adjuvant was administrated from dose of 75mg/day to 300mg/day and the breakthrough pain in the night disappeared completely. The patient underwent the second course of 5-FU/CDDP therapy without the pain. In the present case, the combined therapy of medical treatment and radiation therapy provided complete relief of the neuropathic pain. We conclude that it is an option to select pregabalin as effective agent for neuropathic pain in medical treatment.

This paper presents a man in his 70's with non-small cell lung cancer (cT3N2M0, Stage III A) after chemoradiation therapy during follow-up visits. He was referred to the department of palliative care 1 month after the occurrence of herpes zoster, because of pain. Opioids (transdermal fentanyl patch and rapid-release oxycodone) were administered for his cancer pain previously. Additionally, gabapentin was given for neuropathic pain uncontrolled by opioids. However, this was replaced by pregabalin because he experienced somnolence. Although numbing improved remarkably with pregabalin, the pain was only slightly improved. The dose of rapid-release oxycodone was increased and controlled-release oxycodone was added. This provided for marked pain relief. We conclude that administration of pregabalin as an analgesic adjuvant, and oxycodone, which is an opioid, should be considered in the treatment of cancer patients without improvement of neuropathic pain from herpes zoster through use of the transdermal fentanyl patch.

Background: The efficacy of pregabalin was demonstrated in a randomized double-blind placebo-controlled 13-week trial in 371 Japanese patients with postherpetic neuralgia (PHN). In this study, we evaluated the long-term efficacy and safety of pregabalin for relief of PHN., Methods: 126 patients were enrolled from the preceding double-blind study into the 52-week open-label study. Patients were given pregabalin 150 to 600 mg x day(-1). Pain intensity was measured using the Short-Form McGill Pain Questionnaire (SF-MPQ: total score, visual analogue scale and present pain intensity)., Results: The efficacy parameter SF-MPQ showed a decrease over the treatment-term. The changes of visual analogue scale and present pain intensity at the endpoint were -28.3 mm and -1.1 score, respectively. The commonly reported adverse events were dizziness, somnolence, peripheral edema and weight gain, and most of them were mild to moderate in intensity. No new adverse events were observed due to long-term pregabalin administration., Conclusions: These results suggest that long-term treatment of pregabalin may be beneficial in patients with PHN.

Neuropathic pain has been known to be refractory to traditional analgesics, such as opioids and non-steroidal anti-inflammatoy drugs. Some mechanisms of the development of neuropathic pain have been proposed; 1) sprouting of A beta fibers to the superficial layer of the dorsal horn, 2) ectopic discharge in the dorsal root ganglion and/or in neuroma at the nerve stump, 3) spinal sensitization. Ectopic discharge has been reported to be inhibited by Na+ channel blocker, such as lidocaine, and anticonvulsant. Lidocaine and anticonvulsant are used in the management of neuropathic pain. Activation of NMDA receptor is usually involved in the development of spinal sensitization and NMDA receptor antagonist, such as ketamine, is used in the management of neuropathic pain. Recently, alpha2delta subunit blocker, new class of anticonvulsant, is introduced to the management of neuropathic pain. alpha2delta subunit is the subunit of Ca2+ channel and modulate the influx of Ca2+. This Ca2+ influx induces release of neurotransmitter in the neuron. alpha 2 delta subunit blockers, such as gabapentin and pregabalin, may reduce the release of neurotransmitter and elicit analgesic effect in the treatment of neuropathic pain.

The growing number of drugs used to treat various diseases and the growing number of invasive procedures used for diagnosis and therapy have generated many iatrogenic diseases. Elderly patients are more likely than the young to react adversely to drugs since the physiological functions of the organs, especially of the kidneys, decrease and pharmacokinetic characteristics altered. In addition, multiple disease states are common in the elderly, and multiple drugs are consequently prescribed. In the present study, adverse effects of so-called "cerebroactive drugs" and "cerebral vasodilators" are discussed. More than 30 kinds of these drugs are on the market in Japan and are widely prescribed for "chronic cerebrovascular diseases" and "dementia syndromes" in the elderly. In contrast, they are rarely used in Western Europe and not on the market in the United States. Among them, calcium hopantenate was the first of "cerebral activators" and was the most popular. In 1986, however, the first cases of toxic encephalopathy induced by calcium hopantenate were reported. It resembled Reye syndrome, showing coma, hepatic failure, lactic acidosis and hypoglycemia and was frequently fatal. More than 47 victims including 11 fatal cases have been reported since. Flunarizine, a cerebral vasodilator, produced high rates of parkinsonism and depression. Multicenter studies have revealed that these side effects occurred in 10-30% of the elderly patients who had taken it. These symptoms usually appeared several months after flunarizine was started. Some of the adverse effects of the drugs may be unpredictable and inevitable, but most of them can be prevented or reduced if physicians are more careful with their patients, and drugs and their adverse effects.2

A case with acute disturbance of consciousness associated with calcium hopanthenate (HOPA) administration was reported. He was a 3-year-old boy with autistic developmental delay, had orally taken 1.5 g of HOPA daily for 3 months. Clinical manifestations consisted of fever, vomiting and coma. Laboratory examination revealed severe hypoglycemia and metabolic acidosis, but there were no hepatic enzyme abnormalities. Analysis of urinary organic acid profile showed that very large amounts of medium and long chain dicarboxylic acids and omega-1 hydroxy-fatty acids were excreted. In particular, 2-hydroxysebacic acid, the accumulation of which has only been reported in the urine of patients with Zellweger syndrome and neonatal adrenoleukodystrophy (NALD), was observed. Analysis of urinary acylcarnitines showed that acetylcarnitine was predominant and C6-C10 dicarboxylic acylcarnitines were also excreted. He was treated with and rapidly responded to intravenous glucose and bicarbonate. After withdrawal of the drug he has had no problems and dicarboxylic aciduria disappeared. A CT scan showed symmetric, low density areas in periventricular white matter, especially around the posterior horns of the lateral ventricles. A T2-weighted MRI scan revealed high-intensity signal in the white matter corresponding to areas of low density on CT scan. We conclude that that a large amount of HOPA administration may cause encephalopathy by the inhibition of both mitochondrial and peroxisomal beta-oxidation.

The effects of idebenone and various nootropic drugs on lipid peroxidation in rat brain homogenate were examined. Idebenone inhibited lipoperoxide (LPO) production in brain homogenate in a concentration-dependent manner, with an IC50 of 38 microM. The inhibition was strongly enhanced (about 100-fold) by adding succinate, a substrate in the mitochondrial respiration. The optimal concentration of succinate was 0.5 mM. Inhibition of lipid peroxidation in brain homogenate by various nootropic drugs in the presence or absence of succinate was then examined. Drugs added to the brain homogenate at 100 microM in the absence of succinate inhibited LPO production in the order: idebenone greater than vinpocetine greater than bifemelane greater than indeloxazine greater than calcium hopantenate. However, when the drugs were added at 1 microM in the presence of succinate, only idebenone demonstrated inhibition. These results suggest that although almost all of the drugs tested inhibit lipid peroxidation in brain homogenate, only idebenone is activated by succinate, the other drugs being insensitive to this compound.

Effects of Y-8894 on learning and memory were studied using a radial maze task in intact and scopolamine-induced amnesic mice. The following results were obtained: 1) Repeated administration of Y-8894 (1, 2.5 and 5 mg/kg, i.p.) significantly increased the number of initial correct responses (ICR) in the training session in intact mice, facilitating the learning of the maze task. Dihydroergotoxine (5 mg/kg, i.p.) significantly facilitated the learning of this task in the initial stage of the training session, but non-specifically inhibited the performance in the late stage of training. Ca-hopantenate did not modify the learning of this task. 2) A single administration of Y-8894 (2.5 or 5 mg/kg, i.p.) showed an antagonistic effect on scopolamine (1 mg/kg, s.c.)-induced amnesic mice. Dihydroergotoxine (5 mg/kg, i.p.) and Ca-hopantenate (500 mg/kg, i.p.) also significantly antagonized the ICR-decreasing effect of scopolamine. These results suggest that Y-8894 has an ameliorative and/or facilitative effect on learning and memory in the radial maze task, and Y-8894 is more potent than dihydroergotoxine and Ca-hopantenate.

Calcium hopantenate (HOPA-Ca), which is obtained by substituting the beta-alanine of pantothenic acid for gamma-amino butyric acid (GABA), is a therapeutic drug for mental retardation and cerebrovascular dementia. HOPA-Ca is known to produce convulsive seizures in some patients although it is also true that this improves EEG abnormalities and suppresses epileptic seizures. Thus, clinical observations suggest that HOPA-Ca exerts a paradoxical influence on epilepsy. In order to gain further insight into the influence of HOPA-Ca on epilepsy, we examined its effects on the generalized seizure-triggering threshold (GST) of kindled amygdaloid (AM) seizure and on the rate of AM kindling in rats. Male Wistar rats weighing 200-250 g were used. Under pentobarbital anesthesia, a bipolar electrode, made of twisted stainless steel wire 0.2 mm in diameter, was stereotaxically implanted into the left AM. Daily electrical stimulation was given at the intensity of afterdischarge threshold (ADT). Electrical stimulation was continued until at least five consecutive generalized convulsions were evoked. Subsequently, the stimulus intensity was daily lowered by 20-microA steps and the last stimulus intensity for evoking generalized convulsion was designated as the GST. Experiment 1. Influence of HOPA-Ca on the GST; HOPA-Ca was dissolved in saline as a vehicle. Injections of 50, 100, 250, 500 mg/kg HOPA-Ca were given intraperitoneally 60 min before the stimulation at the GST. The GST never changed with vehicle injection. The GST increase was never observed with any amount of HOPA-Ca. However, the GST dropped flowing HOPA-Ca infection independent of its amount. The GST reduction was always 20-microA.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acetylcholine (ACh) and its reversed carboxy analogue, methyl N-trimethyl-gamma-aminobutyrate chloride (MTB), induced either by topical application to the skin surface around a transparent round table chamber (REC) that had been previously installed to the ear lobe or by intravenous injection on the micro- and macrocirculations were studied in the healthy male rabbit. The effects of both drugs on the cutaneous microcirculation within the REC were observed vital-microscopically under conscious conditions and the microcirculatory events were visualized with a microscope-closed TV system and microphotoelectric plethysmography. The results were as follows: (1) Topical application of 1% MTB cream caused an enhanced perfusion of rhythmic microvascular blood due to vasomotion for a period of 30 min or longer, while ACh did so to a much less extent, if any. On the other hand, no appreciable change developed in any systemic hemodynamic parameters. (2) Intravenous administration of MTB or ACh caused a very transient dilator effect on micro-and macrocirculatory blood vessels according to its cholinergic stimulation, which could be blocked by atropinization. Almost the same efficacy on vasomotion was observed for each drug. (3) These findings indicate that the topical application of MTB to the skin surface may cause a physiologically acceptable vasodilation accompanied by vasomotion, and it would facilitate the oxygen diffusion by the follicular circulation.

The effect of Y-8894 on the abnormal electrocorticogram (ECoG) of alcuronium-immobilized rats, induced by destruction of the internal capsule with heat, was compared with that produced by imipramine, amantadine and Ca-hopantenate. ECoG power in the delta + theta (1-7 Hz), alpha (7.5-12.5 Hz) and beta (13-30 Hz) bands was used as an index. Delta + theta power increased following destruction of the internal capsule with heat. The increased delta + theta power (abnormal ECoG) lasted for 60 min following the injection of saline at 60 degrees C for 3 min. Y-8894 (0.1-1 mg/kg, i.v.) apparently improved the abnormal ECoG dose-dependently by significantly reducing the increased delta + theta power. Similar results were obtained with amantadine (10 mg/kg, i.v.), but its potency was weaker than that of Y-8894. Imipramine (1 mg/kg, i.v.) and Ca-hopantenate (30 mg/kg, i.v.), however, both failed to modify the abnormal ECoG. All drugs, except Ca-hopantenate, decreased the magnitudes of the alpha and beta bands. The above results suggest that Y-8894 may be effective in ameliorating cerebral dysfunction induced experimentally by the lesion of the internal capsule.

With the increase in the aged population, it is expected that the number of debilitated aged people will increase and that the number of patients receiving many medications will increase. However, there have been few reports of clinical pharmacological studies on blood pharmacokinetics, metabolism, adverse effects, etc, of drugs used in debilitated aged people who have lowered physical and mental functions complicated by many diseases. Thus, for the large part, pharmacokinetics in these patients remains unelucidated. We experienced eight cases of marked hypoglycemia of unknown cause in patients who had not taken any hypoglycemic drugs or insulin and examined the relationships between the event and the physical features and medications of the patients. The eight patients included both males and females aged 66 to 88 years (mean: 78.5 years). The eight patients were all aged and showed cerebral infarction, reduced volition, etc. The onset of hypoglycemia was preceded by decreased appetite and an abrupt manifestation of severely disturbed consciousness a few days previously. Laboratory tests revealed marked hypoglycemia in 8 cases, leucocytosis in 7 cases (not examined in one case), metabolic acidosis in 3 cases, elevated GOT in 5 cases, elevated GPT in 2 cases, increased BUN in 1 case, and positive CRP in 4 cases. The patients had been taking an agent to activate brain metabolism/improve mental symptoms (Hopantene calcium: 7 cases; Idebenone: 1 case). The Idebenone-treated patient had received Hopantene calcium for eleven months prior to receiving Idebenone. Furthermore, the findings resembled those of Reye's syndrome often noted in children.(ABSTRACT TRUNCATED AT 250 WORDS)

The anti-anoxic effect of sufoxazine was investigated in various cerebral anoxia models with mice, in comparison with those of various cerebroactive drugs. Sufoxazine reduced dose-dependently the duration of coma induced by a sublethal dose of KCN (1.8 mg/kg, i.v.), significantly stimulating recovery from the coma at 5 mg/kg, i.p. and 30 mg/kg, p.o. It also protected against a lethal dose of KCN (2.5 mg/kg, i.v.). Sufoxazine prolonged the survival time of mice subjected to hypobaric and normobaric hypoxia. Dihydroergotoxin and ifenprodil gave similar protection in the KCN-induced anoxia models, but produced adverse effects in the hypoxia models. Calcium hopantenate exerted similar but weak protection only at a dose as high as 300 mg/kg, i.p. These findings suggest that sufoxazine has an anti-anoxic action superior to those of the other cerebroactive drugs used.

To predict the influence of MCI-2016 on cerebral energy metabolism, the activity of MCI-2016 on uptake of 2-deoxy-D-[14C]glucose ([14C]-DG) into the brain under normal or hypoxic conditions, formation of 14CO2 from 14C-glucose in the brain, and local cerebral glucose utilization (LCGU) were examined. Cerebral uptake of [14C]-DG in mice were significantly enhanced by 6 day repeated administration of MCI-2016 (25 mg/kg, i.p.) and Ca-hopantenate (100 mg/kg, i.p.). The two drugs showed a slight enhancing effect on [14C]-DG uptake after single administration. As an index of cerebral glucose metabolism, 14CO2 formation from 14C-glucose was also stimulated by 6 day repeated administration of MCI-2016 (100 mg/kg, p.o., mice and rats) and Ca-hopantenate (250 mg/kg, i.p., rats). MCI-2016 moderately attenuated the decreased [14C]-DG uptake under the hypoxic condition in rats after 6 day repeated administration (100 mg/kg, p.o.). In addition, local cerebral glucose utilization (LCGU) in rats was also significantly potentiated by MCI-2016 (100 mg/kg, p.o., 6 days) in the areas of the visual cortex, thalamus ventral nucleus and uvula. From these results, MCI-2016 may be suggested to have a moderate activating effect on cerebral energy metabolism.

Cerebral protective effect of MCI-2016 and influence of age on survival time in the cerebral ischemic model induced by bilateral-carotid-arterial ligation in male Mongolian gerbils were studied. Of all animals (6 to 40 weeks old), the mean survival time of the immature group (6 to 7 weeks) was long (3.6 hr), but variable, and that of the 10 to 40 weeks group was relatively stable (1.9-2.4 hr), but that of the older group (30-40 weeks) inclined to be reduced. Effects of drugs on this model were studied in 10 to 15 weeks old male Mongolian gerbils. The mean survival time in the control groups was 2.3-2.4 hr. After a single administration of MCI-2016 at doses of 25 mg/kg, i.p., and 100 mg/kg, p.o., the mean survival time were 8.1 and 6.4 hr, respectively. In these cases, some animals survived over 12 hr, while no animals surviving over 12 hr were observed in the control group. In this model, animals showed severe neurological symptoms. This, however, tended to be depressed by the administration of MCI-2016 at a dose of 25 mg/kg, i.p., which was observed early after ligation. A cerebral metabolic activator, Ca-hopantenate, slightly increased the survival time at a dose of 100 mg/kg, i.p., and a cerebral vasodilator, ifenprodil, was not effective. Subsequently, consecutive administration of MCI-2016 at a dose of 25 and 50 mg/kg, p.o., was more effective than a single administration of MCI-2016 at each dose. The mechanism for the cerebral protective effect of MCI-2016 was discussed.

A method for measuring the organic infarct focus induced by arachidonate infusion into rat brain was devised, and the statistical relationship between the measured values and stroke signs in the rat was studied. By the infusion of arachidonate, a high incidence of cerebral infarction was found in the live rats with uniformly necrotized foci. The size of these foci (infarction rate) were measured by transcripting them to a graduated brain sheet. The relationship between the independent parameter of the infarction rate and the dependent parameter of stroke signs was fully analyzed by multidimensional quantification. Many animals showed no stroke signs despite having lesions (false negative). By contract, no animal without any lesion showed stroke signs (false positive). When each parameter of these signs were quantified and normalized, the stumbling and abnormal posture signs showed a wide range of values, relatively accurately reflecting the infarction degree. Moreover, the highest partial correlation ratio between the various parameters was found to be that between the stumbling and abnormal posture stroke signs. Thus, it may be said that the stumbling and the abnormal posture stroke signs can be considered relatively good parameters for evaluating the degree of an infarction. These parameters should be useful for the testing of anti-infarction drugs.

The effect of Y-8894 (+/-) 2-[[o-(2-thenyl)phenoxy]methyl] morpholine maleate, which has been shown to improve experimentally induced learning and memory deficits, on cerebral monoamine uptake and turnover was studied in the mouse. The following results were obtained: 1) It inhibited in vitro norepinephrine (NE) uptake to the mouse cerebral synaptosomal fractions about 800 and 1250 times more potently than it did those of dopamine (DA) and serotonin (5-HT), respectively. 2) It dose-dependently inhibited in vivo NE uptake, but not DA or 5-HT uptake. 3) It reduced the accumulation of the NE metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), increased that of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and had no effect on that of the DA metabolite, homovanillic acid (HVA). These effects were compared with those of imipramine, calcium hopantenate (Ca-hopantenate) and dihydroergotoxine. Y-8894 appeared to act by stimulating the noradrenergic receptor, and it acts to a lesser extent by blocking the serotonergic receptor in the brain.

The behavioral pharmacological effects of Ca-4-(3,5-dihydroxy-3-methylpenthylamido) butyrate (mevalonic-GABA, MV-GABA), a new GABA derivative were studied in comparison with those of Ca-hopantenate (HOPA) in mice. MV-GABA had no effect on the general behavior and electric shock-induced fighting behavior. The dosage of MV-GABA which caused locomotor hypoactivity produced an impairment of the rotarod performance. MV-GABA inhibited the hyperactivity induced by a dopamine (DA) agonist (methamphetamine) and acetylcholine (ACh) antagonists (scopolamine and atropine) at a dose which did not affect locomotor activity in normal mice. MV-GABA prolonged the pentobarbital-Na-induced sleeping time, and it prolonged the latencies until convulsion and death after administration of strychnine. MV-GABA and HOPA antagonized the electroconvulsive shock-induced amnesia in the passive avoidance response of mice. These results suggest that MV-GABA has effects on the central nervous systems, in particular, ACh and DA neural systems. The actions of MV-GABA were qualitatively similar to those of HOPA except for the effect on the DA neural system.

SART-stressed (repeated cold-stressed) rats, experimental model animals for vagotonic-type dysautonomia, have been reported to show EEG with lower-amplitude fast waves during resting-arousal and higher-amplitude slow waves during slow-wave sleep compared to normal rats. In this report, the effects of certain drugs on EEG alterations were investigated using the power spectral analysis. EEG was measured 60 min after a single dose of drugs and on the day following the final dose of 6 administrations. Neurotropin, a sedative analgesic, slightly increased faster waves on resting-arousal EEG and slower waves on slow-wave sleep EEG in normal rats, and it prevented SART stress-induced EEG alterations during both resting-arousal and slow-wave sleep. Alprazolam, a minor tranquilizer, and GABOB, a GABA related compound, were also effective on SART stress-induced EEG alterations. Alprazolam produced remarkable but transient high-amplitude fast waves in the resting-arousal EEG of normal rats, and GABOB produced lasting low-amplitude fast waves in the slow-wave sleep EEG of normal rats. From the above results, it appears that Neurotropin may have an effect on EEG alterations caused by SART stress and that its action is likely due to mechanisms different from those of alprazolam and GABOB.

Effects of MCI-2016 on SMA changes were examined under several experimental conditions (normal conditions, hypoxia and head injury). Under normal conditions, MCI-2016 showed a significant increase of SMA after single administration of 12 mg/kg, i.p. Other doses (12.5-50 mg/kg, p.o. and 3-6 mg/kg, i.p.) of MCI-2016 were without significant effect. Under the same condition, MCI-2016 produced a dose-dependent increase of SMA after repeated doses of 12.5 to 50 mg/kg, p.o. (9-10 days administrations). After 5 days repeated administration, MCI-2016 significantly improved the decreased SMA due to hypoxia (rats) at 50 to 100 mg/kg, p.o. Furthermore, the drug also improved the decreased spontaneity due to head injury (mice) at 50 to 400 mg/kg, p.o. These improving effects of MCI-2016 were superior to those of Ca-hopantenate. The SMA increasing effect of MCI-2016 (12 mg/kg, i.p.) was antagonized more strongly by phenoxybenzamine than by haloperidol. In addition, the drug was shown to be rather antagonistic to the effects of anticholinergic agents. These effects may indicate the existence of qualitative differences between MCI-2016 and methamphetamine in the SMA increasing actions. It is also suggested that MCI-2016 may exhibit the above pharmacological effects through possible activation of noradrenergic and/or cholinergic mechanisms.

Calcium hopantenate (HOPA) has been widely used as an activator of cerebral metabolism in Japan. However, several cases of acute encephalopathy during HOPA administration were recently reported, which were characterized by marked metabolic acidosis and hypoglycemia. The encephalopathy in these patients was named Reye-like syndrome because of the similarity to Reye's syndrome in children. The purposes of this presentation are to report on 5 patients with acute encephalopathy developing during HOPA administration, to summarize their symptoms and clinical courses, and to discuss the pathogenesis of metabolic acidosis and hypoglycemia. Initial characteristics of the clinical course in all patients were loss of appetite, nausea and vomiting, followed by unconsciousness. Laboratory examinations revealed marked metabolic acidosis, severe hypoglycemia, hyperlactacidemia, leukocytosis, ketonuria, and increased Ht and BUN. A few days after development of the initial symptoms, mild renal and liver dysfunction, and elevation of serum amylase were observed in all patients. Hyperlactacidemia was present in 4 in the initial period. Blood concentration of HOPA was 2.131 micrograms/ml in patient 1 (8-10 hours after final administration), and 10.7 micrograms/ml in patient 5 (24 hours after final administration). These values are extremely high, because usually HOPA concentration is almost negligible 7 hours after the drug is taken. As the pathogenesis of acute encephalopathy due to HOPA administration, the failure of fatty acid beta-oxidation has been proposed by some investigators. However, the serum concentrations of CoA, pantothenic acid and carnitine during the initial stage were not reduced in our patients. Furthermore, it is very difficult to explain the severe hypoglycemia in terms of the beta-oxidation theory.(ABSTRACT TRUNCATED AT 250 WORDS)