Incidence of diabetes among postmenopausal breast cancer survivors.

AIMS/HYPOTHESIS: Evidence is emerging of an association between breast cancer and diabetes; however, it is uncertain whether diabetes incidence is increased in postmenopausal breast cancer survivors compared with women without breast cancer. The objective of this study was to determine whether postmenopausal women who develop breast cancer have a higher incidence of diabetes than those who do not develop breast cancer. METHODS: We used population-based data from Ontario, Canada to compare the incidence of diabetes among women with breast cancer, aged 55 years or older, from 1996 to 2008, with that of age-matched women without breast cancer. We used Cox proportional hazard models to estimate the effect of breast cancer on the cause-specific hazard of developing diabetes overall and in the subgroup of women who received adjuvant chemotherapy. RESULTS: Of 24,976 breast cancer survivors and 124,880 controls, 9.7% developed diabetes over a mean follow-up of 5.8 years. The risk of diabetes among breast cancer survivors compared with women without breast cancer began to increase 2 years after diagnosis (HR 1.07 [95% CI, 1.02, 1.12]), and rose to an HR of 1.21 (95% CI, 1.09, 1.35) after 10 years. Among those who received adjuvant chemotherapy (n = 4,404), risk was highest in the first 2 years after diagnosis (HR 1.24 [95% CI 1.12, 1.38]) and then declined. CONCLUSIONS/INTERPRETATION: We found a modest increase in the incidence of diabetes among postmenopausal breast cancer survivors that varied over time. In most women the risk began to increase 2 years after cancer diagnosis but the highest risk was in the first 2 years in those who received adjuvant therapy. Our study suggests that greater diabetes screening and prevention strategies among breast cancer survivors may be warranted.

Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure.

INTRODUCTION: Acquired resistance to TKI is an important unmet need in the management of EGFR mutated lung cancer. Recent clinical trial IMPower150 suggested that combination approach with VEGF inhibitor, check point inhibitor immunotherapy and platinum-based chemotherapy was effective in oncogene driven lung cancer. The current trial examined the efficacy of a modified regimen in an EGFR mutated cohort. METHODS: An open-labelled, single arm, phase II study was conducted in patients with EGFR mutated NSCLC who had progressed on at least one EGFR TKI. For those with T790M mutation, radiological progression on osimertinib was required for enrolment. Patients were treated with combination atezolizumab (1200 mg), bevacizumab (7.5 mg/kg), pemetrexed (500 mg/m2) and carboplatin (AUC 5) given once every 3 weeks until progression. RESULTS: Forty patients were enrolled. Median age was 62 (range 45-76) years. More than one half (23/40, 57.5%) had progressed on osimertinib. PD-L1 expression was < 1% in 52.5%. Median follow-up time was 17.8 months. ORR was 62.5%. Median PFS was 9.4 months (95% CI: 7.6 - 12.1). One year OS was 72.5% (95% CI: 0.56-0.83). Treatment related grade 3 or above adverse events (AE) occurred in 37.5% (15/40). Immune-related AE occurred in 32.5% (13/40) patients. Quality of life measures of function and symptoms did not change significantly throughout the course of treatments. Post-trial rechallenge with EGFR TKI containing regimen resulted in PFS of 5.8 months (95% CI 3.9-10.0 months). CONCLUSION: Combination approach of atezolizumab, bevacizumab, pemetrexed and carboplatin achieved promising efficacy in metastatic EGFR mutated NSCLC after TKI failure. The results were comparable with taxane based regimen of IMPower150 while toxicity profile was improved.

Bisphosphonates and osteoporotic fractures: a cross-design synthesis of results among compliant/persistent postmenopausal women in clinical practice versus randomized controlled trials.

UNLABELLED: In a cross-design synthesis, total fractures were similarly reduced by bisphosphonates among postmenopausal women in randomized trials (23.8%) and highly compliant/persistent patients in observational studies of large databases from routine practice (20.3%). Bisphosphonates also reduced nonvertebral, vertebral and hip fractures in randomized trials and observational studies. In the real-word setting, compliant/persistent patients can gain a benefit from bisphosphonates comparable to that of randomized trial participants. INTRODUCTION: The purpose of the study was to determine whether clinical fracture risk reduction by bisphosphonate treatment in women with postmenopausal osteoporosis differs between randomized controlled trials and routine practice. METHODS: Randomized trials comparing bisphosphonate with placebo and observational studies comparing highly compliant/persistent with less compliant/persistent patients were sought by electronic searches and ancillary methods. Clinical fracture data were extracted from the study reports and quantitatively combined by random effects metaanalysis. RESULTS: The odds ratio (OR) for all clinical fractures in randomized trials of 0.762, with a 95% confidence interval (CI) of 0.680-0.855, was closely similar to that in the observational studies (OR, 0.797; CI, 0.748-0.850). Pooled clinical fracture reduction across both study designs was 22%. Nonvertebral, vertebral, and hip fractures were also significantly reduced by bisphosphonate treatment in both randomized trials and observational studies. CONCLUSIONS: Compliant/persistent patients in the "real-world" setting benefit from bisphosphonate treatment to a similar extent as patients in randomized trials.

A nonpeptidyl growth hormone secretagogue.

A nonpeptidyl secretagogue for growth hormone of the structure 3-amino-3-methyl-N-(2,3,4,5-tetrahydro-2-oxo-1-([2'-(1H-tetrazol-5 -yl) (1,1'-biphenyl)-4-yl]methyl)-1H-1-benzazepin-3(R)-yl)-butanamid e (L-692,429) has been identified. L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway. The mechanism of action of L-692,429 and studies with peptidyl and nonpeptidyl antagonists suggest that this molecule is a mimic of the growth hormone-releasing hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6). L-692,429 is an example of a nonpeptidyl specific secretagogue for growth hormone.

Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry.

Nonpeptide agonists of each of the five somatostatin receptors were identified in combinatorial libraries constructed on the basis of molecular modeling of known peptide agonists. In vitro experiments using these selective compounds demonstrated the role of the somatostatin subtype-2 receptor in inhibition of glucagon release from mouse pancreatic alpha cells and the somatostatin subtype-5 receptor as a mediator of insulin secretion from pancreatic beta cells. Both receptors regulated growth hormone release from the rat anterior pituitary gland. The availability of high-affinity, subtype-selective agonists for each of the somatostatin receptors provides a direct approach to defining their physiological functions.

Penetrating head injury caused by a dart.

In paediatric practice, head injury is a major public health hazard that places considerable demand on health services. It accounts for almost one third of all accidental deaths and for up to two thirds of all trauma deaths in hospital. Common house-hold objects are at times a source of penetrating head injuries in children. These include electric plugs, golf clubs, toys, nails, etc. Fortunately less than 10% of these eventually lead to permanent brain injury. We report a rare case of penetrating head injury caused by a dart.

Lung disease severity in idiopathic pulmonary fibrosis is more strongly associated with impedance measures of bolus reflux than pH parameters of acid reflux alone.

BACKGROUND: Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF). Pathogenesis may be related to chronic micro-aspiration. We aimed to assess objective measures of GER on multichannel intraluminal impedance and pH study (MII-pH) and their relationship with pulmonary function testing (PFT) results, and to compare the performance of pH/acid reflux parameters vs corresponding MII/bolus parameters in predicting pulmonary dysfunction in IPF. METHODS: This was a retrospective cohort study of IPF patients undergoing prelung transplant evaluation with MII-pH off acid suppression, and having received PFT within 3 months. Patients with prior fundoplication were excluded. Severe pulmonary dysfunction was defined using diffusion capacity of the lung for carbon monoxide (DLCO) ≤40%. Six pH/acid reflux parameters with corresponding MII/bolus reflux measures were specified a priori. Multivariate analyses were applied using forward stepwise logistic regression. Predictive value of each parameter for severe pulmonary dysfunction was calculated by area-under-the-receiver-operating-characteristic-curve or c-statistic. KEY RESULTS: Forty-five subjects (67% M, age 59, 15 mild-moderate vs 30 severe) met criteria for inclusion. Patient demographics and clinical characteristics were similar between pulmonary dysfunction groups. Abnormal total reflux episodes and prolonged bolus clearance time were significantly associated with pulmonary dysfunction severity on univariate and multivariate analyses. No pH parameters were significant. The c-statistic of each pH parameter was lower than its MII counterpart in predicting pulmonary dysfunction. CONCLUSIONS & INFERENCES: MII/bolus reflux, but not pH/acid reflux, was associated with pulmonary dysfunction in prelung transplant patients with IPF. MII-pH may be more valuable than pH testing alone in characterizing GER in IPF.

Increased proximal acid reflux is associated with early readmission following lung transplantation.

BACKGROUND: Gastroesophageal reflux disease has been associated with poor outcomes following lung transplantation. However, the association between pretransplant reflux and post-transplant readmission, an indicator of early clinical outcome, has not been previously assessed. METHODS: This was a retrospective cohort study of lung transplant recipients undergoing pretransplant multichannel intraluminal impedance and pH (MII-pH) study off acid suppression at a tertiary care center since 2007. Subjects with pretransplant fundoplication were excluded. Time to readmission was defined as duration from post-transplant discharge to next hospital admission for any reason. Subgroup analysis was performed to exclude elective readmissions. Time-to-event analysis was performed using Cox proportional hazards model, with appropriate censoring. KEY RESULTS: Forty-three subjects (60% men, mean age: 57, median follow-up: 1.7 years) met inclusion criteria for the study. Patient demographics and pretransplant cardiopulmonary function were similar between readmission cohorts. Time to all-cause readmission was associated with increased distal acid episodes (HR: 3.15, p = 0.04) and proximal acid episodes (HR: 3.61, p = 0.008) on impedance, increased acid exposure on pH (HR: 2.22, p = 0.04), and elevated Demeester score (HR: 2.26, p = 0.03). When elective readmissions were excluded, early readmission remained significantly associated with increased proximal acid reflux episodes (HR: 2.49, p = 0.04). All findings were confirmed on Kaplan-Meier analysis. CONCLUSIONS & INFERENCES: Elevated proximal acid reflux on pretransplant MII-pH testing was associated with early readmission following lung transplantation, even after excluding elective readmissions. Exposure to severe acid reflux has measurable effects on early postoperative outcomes such as readmission, and aggressive early antireflux therapy should be considered.

GERD phenotypes from pH-impedance monitoring predict symptomatic outcomes on prospective evaluation.

BACKGROUND: Combinations of reflux parameters (acid exposure time, AET; symptom association probability, SAP) on pH-impedance monitoring describe varying confidence in reflux evidence. We compared outcomes between phenotypes with distinct pre-identified reflux parameters. METHODS: In this observational cohort study, patients undergoing pH-impedance testing over a 5-year period were phenotyped by strength of reflux evidence as strong (abnormal AET, positive SAP), good (abnormal AET, negative SAP), reflux hypersensitivity (RH, normal AET, positive SAP), and equivocal evidence of reflux, and compared to two historical institutional pH monitoring cohorts. Symptom burden (dominant symptom intensity, DSI; global symptom severity, GSS) was assessed by questionnaire at baseline and on prospective follow-up and compared between phenotypes. KEY RESULTS: Of 94 patients tested off proton pump inhibitor (PPI) therapy, baseline symptom burden was highest with strong reflux evidence and lowest when equivocal (DSI: p = 0.01; GSS: p = 0.03 across groups). After 3.1 ± 0.2 years follow-up, symptomatic improvement with surgical or medical therapy was highest with strong or good evidence, and lowest when equivocal (DSI: p = 0.008; GSS: p = 0.005 across groups). This was most pronounced for typical symptoms (DSI: p = 0.001; GSS: 0.016 across groups), but not atypical symptoms (DSI: p = 0.6; GSS: p = 0.2). For testing on PPI therapy, only GSS followed a similar trend (GSS: p = 0.057, DSI: p = 0.3). Compared to historical cohorts with pH monitoring alone, equivocal evidence for reflux was partly replaced by RH, especially off PPI (p < 0.0001). CONCLUSIONS & INFERENCES: Phenotyping gastroesophageal reflux disease by the strength of reflux evidence on pH-impedance testing off PPI efficiently stratifies symptomatic outcome, especially for typical symptoms, and could be useful in planning management.

Dissociation of phosphohistone phosphatases from canine heart.

Phosphohistone phosphatase (phosphoprotein phosphohydrolase, EC 3.1.3.16) of canine heart extract has been separated by DEAE-cellulose chromatography into 4 molecular forms, namely phosphatases A (Mr = 156 000), B (Mr = 161 000), C (Mr = 95 600) and U (Mr = 61 000). ATP inhibited phosphatase A, stimulated phosphatase B and did not significantly affect phosphatase C activity. Phosphatase U requires Mn2+ for activity, under which condition ATP is inhibitory. Phosphatases A, B and C, but not phosphatase U, were dissociated by ethanol into catalytic subunits that were inhibited by ATP, insensitive to Mn2+, and had a common molecular weight of 34 800 (phosphatase S). The dissociation was accompanied by an increase of enzymic activity. Chromatography of the ethanol-treated 55% (NH4)2SO4 fraction of canine heart extract on DEAE-cellulose demonstrated that the multiple forms of phosphohistone phosphatase could be reduced to two forms: phosphatase U and phosphatase S, which may represent two basic constituents of the multiple forms of phosphohistone phosphatase in canine heart.

Idiopathic pulmonary fibrosis is associated with increased impedance measures of reflux compared to non-fibrotic disease among pre-lung transplant patients.

BACKGROUND: Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF), although the mechanism remains unclear. Gastroesophageal reflux/microaspiration may lead to lung fibrosis, while increased pulmonary workload may also worsen GER. Comparing the GER profile of IPF patients to chronic obstructive pulmonary disease (COPD) patients with similar lung function may help delineate the role of GER in IPF pathogenesis. METHODS: This was a retrospective cohort study of IPF and COPD patients undergoing pre-lung transplant multichannel intraluminal impedance and pH study (MII-pH) off acid suppression at a tertiary center in 2008-2014. Patients with prior fundoplication were excluded. Baseline demographics, pulmonary function test, and MII-pH results were recorded. Univariate analyses were performed using Fisher's exact (binary variables) and Student's t (continuous variables) tests. Logistic regression was performed to adjust for potential confounders. KEY RESULTS: A total of 90 subjects (54 IPF, 36 COPD) met inclusion criteria. Compared to COPD, IPF patients had increased total reflux episodes (65.9 vs 46.1, p = 0.02), proximal reflux episodes (30.3 vs 20.3, p = 0.04), and prevalence of abnormal total reflux episodes (38.9% vs 16.7%, p = 0.02). On multivariate analyses, abnormal total reflux episodes (OR: 4.9, p = 0.05) and bolus reflux exposure time (OR: 4, p = 0.04) remained significantly associated with IPF. CONCLUSIONS & INFERENCES: Abnormal reflux was significantly more prevalent among IPF patients after controlling for lung disease severity. Gastroesophageal reflux/microaspiration likely plays a role in fibrosis in IPF. A significant portion of IPF patients had increased non-acid reflux. Therapies aiming to prevent reflux of gastric contents may be more beneficial than antisecretory medications alone in these patients.

The synergistic effects of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on growth hormone (GH)-releasing factor-stimulated GH release and intracellular adenosine 3',5'-monophosphate accumulation in rat primary pituitary cell culture.

His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6) stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner. Stimulation was observed after a 15-min, but not a 4-h, incubation. The concentrations of GHRP-6 required for half-maximal and maximal stimulation were 7 x 10(-9) and 10(-7) M, respectively. GH release induced by GHRP-6 was not affected by the addition of either naloxone or the GRF antagonist [N-Ac-Tyr1,D-Arg2]GRF-(1-29)-NH2. The latter inhibited GRF-stimulated GH release by shifting the dose-response curve to the right. His-D-Trp-D-Lys-Trp-D-Phe-Lys-NH2, an analog of GHRP-6, inhibited GH release stimulated by GHRP-6 without affecting that induced by GRF. When present together at maximal concentrations, GHRP-6 and GRF produced a synergistic effect on GH release. GHRP-6 had no effect on intracellular cAMP levels, whereas GRF increased intracellular cAMP concentrations by 3-fold. Combined treatment of pituitary cells with GRF and GHRP-6 resulted in a potentiation of the GRF-induced increase in cAMP levels. Basal GH release was reduced by 30% after pretreatment with GHRP-6 (10(-7) M) for 1 h. Pretreatment with GHRP-6 also decreased the subsequent response to GHRP-6, but not GRF. In contrast, pretreatment with GRF for 1 h had no effect on the subsequent action of GHRP-6 or GRF on GH release. The desensitization induced by GHRP-6 was completely reversed within 1 h after removal of the peptide. Results from this study indicate that GHRP-6 and GRF stimulated GH release from somatotrophs via different receptors and through discrete mechanisms.

Evidence for a role of protein kinase-C in His-D-Trp-Ala-Trp-D-Phe-Lys-NH2-induced growth hormone release from rat primary pituitary cells.

We have recently reported that His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6) synergizes with GH-releasing factor (GRF) to increase GH release and cAMP accumulation in rat pituitary cells in vitro. This study was undertaken to further investigate the mechanism of action of GHRP-6 on GH release, particularly the involvement of protein kinase-C. Forskolin (10(-5) M), A23187 (10(-6) M), and phorbol 12-myristate 13-acetate (PMA; 10(-7) M) all stimulated GH release. However, only PMA can mimic the synergistic effects of GHRP-6 on GRF-stimulated GH release and intracellular cAMP accumulation. 4 alpha-Phorbol 12,13-didecanoate, an inactive phorbol ester, was unable to stimulate GH release or potentiate the effect of GRF. Extracellularly added phospholipase-C not only stimulated GH release in a dose-dependent manner, but also potentiated GRF-induced GH release. Phloretin, a protein kinase-C inhibitor, in a concentration range of 10-250 microM had very little or no effect on basal and GRF-stimulated GH release, but markedly inhibited the stimulatory effects induced by either PMA or GHRP-6. Incubation of rat pituitary cells with 10(-6) M PMA for 24 h completely down-regulated protein kinase-C, since such PMA-pretreated cells did not release GH in response to a second dose of PMA. The protein kinase-C-depleted cells had an attenuated GHRP-6 response, but they responded normally to GRF. Moreover, the synergistic effects of GHRP-6 and GRF on GH release and cAMP accumulation were also greatly inhibited by protein kinase-C down-regulation. These data suggest that the effects of GHRP-6 on GH release, either alone or together with GRF, are at least partially mediated via the activation of protein kinase-C.

Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue.

L-692,429, a benzolactam derivative, stimulated GH release from rat primary pituitary cells in a dose-dependent manner. The concentration of L-692,429 required for half-maximal stimulation were 59.6 +/- 7.3 nM. Under the same conditions, GHRP-6 and GRF had EC50 values of 10.3 +/- 1.9 nM and 0.47 +/- 0.09 nM, respectively. L-692,428, the enantiomer of L-692,429, was inactive at a concentration as high as 2 microM. Like GHRP-6, L-692,429 had no effect on intracellular cAMP level; however, it synergized with GRF to further increase not only the accumulation of cAMP but also the release of GH. The magnitude of GH release stimulated by maximal concentrations of L-692,429 and GHRP-6 was comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause additional GH release when compared with either secretagogue alone. The L-692,429-stimulated GH release was completely inhibited by 20 nM somatostatin. To our knowledge, L-692,429 is the first non-peptidyl GH secretagogue which has a direct effect on the release of growth hormone from rat primary pituitary cells. Its effect is most likely mediated through a mechanism which is similar to that of GHRP-6.

Phosphorus-containing inhibitors of aspartate transcarbamoylase from Escherichia coli.

A tetrahedral intermediate is the prominent feature of the generally accepted mechanism for aspartate transcarbamoylase. We have synthesized N-pyrophosphoryl-L-aspartate as a charged analogue of the postulated intermediate. Surprisingly, its affinity for the enzyme from Escherichia coli was substantially lower than that of the previously known inhibitor phosphonoacetyl-L-aspartate which contained a trigonal carbonyl group. Similar results were obtained with the corresponding mercaptosuccinate derivatives. We also tested a number of new pyrophosphate analogues as inhibitors. Our results cast doubt on some aspects of the current model for the mechanism of this enzyme.

A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429).

The 3-substituted benzazepinone, L-692,429 (compound 1), is the prototype compound of a novel class of compounds that stimulate release of growth hormone (GH). The molecule evolved from efforts to identify a non-peptide mimic of the growth hormone-releasing hexapeptide, GHRP-6. Compound 1 is prepared by sequential attachment of dimethyl-beta-alanine and 2'-biphenylyltetrazole side chains to a chiral 3-aminobenzolactam nucleus. Comparison of the biological activity of 1 with the corresponding six- and eight-membered lactam analogs shows the seven-membered benzazepinone skeleton to be preferred. Molecular modeling of the structurally diverse GH secretagogues, L-692,429 and GHRP-6, was performed.

A potent, orally bioavailable benzazepinone growth hormone secretagogue.

The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the neutral and potency enhancing 2'-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release of growth hormone in beagle dogs at doses as low as 0.5 mg/kg. Oral bioavailability in dogs of 8b is 24% at a dose of 2 mg/kg with a mean drug Cmax of 145 +/- 46 ng/mL. L-739,943 represents a significant breakthrough in terms of both potency and oral bioavailability as compared to the prototype benzolactam L-692,429.

Inhibition of L-692,429-stimulated rat growth hormone release by a weak substance P antagonist: L-756,867.

H2N,D-Arg,Pro,Lys,Pro,D-Phe,Gln,D-Trp,Phe,D-Trp,Leu, Leu,NH2 (L-756,867), a weak substance P antagonist, inhibited L-692,429-stimulated GH release from rat primary pituitary cells in a dose-dependent manner. At a concentration of 50 nM, L-756,867 shifted the dose-response curve of L-692,429-induced GH release to the right by about tenfold. It also impaired the ability of L-692,429 to potentiate the effect of growth hormone-releasing factor (GRF) on GH release. Substance P (1 microM) had no effect on basal or L-692,429-stimulated GH release. When tested in anesthetized rats, L-756,867 inhibited L-692,429- and growth hormone-releasing hexapeptide- (GHRP-6)-stimulated GH secretion in a dose-dependent manner. Complete inhibition was observed at an i.v. dose of 100 micrograms/kg of L-756,867. However, at the same concentration, it had no effect on GRF-induced GH secretion D-Lys3-GHRP-6, a GHRP-6 antagonist, had no effect on GHRP-6 or L-692,429-induced GH secretion even at an i.v. dose of 2 mg/kg. These results indicate that L-692,429 and GHRP-6 stimulate GH release both in vitro and in vivo via a common receptor and signaling pathway which is different from that of substance P in spite of the fact that their effects are inhibited by a weak substance P antagonist.

Effect of lipoic acid on redox state of coenzyme Q in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and diethyldithiocarbamate.

We investigated the effects of a combined treatment of male C57Bl/6 mice with diethyldithiocarbamate and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the absence or presence of different forms of lipoic acid (Thioctacid TR; commonly used for treatment of diabetic polyneuropathies) on levels and redox states of alpha-tocopherol and coenzyme Q in vivo and on activities of various enzymes of energy metabolism ex vivo. Treatment of mice with diethyldithiocarbamate plus MPTP resulted in a decrease in dopamine (67%) and its major metabolites dihydroxyphenylacetic acid (38%) and homovanillic acid (37%) in striatum. alpha-Tocopherol levels were unaltered in striatum; however, the reduced forms of coenzyme Q were decreased in frontal cortex and hippocampus following diethyldithiocarbamate plus MPTP. In frontal cortex activity of NADH dehydrogenase was significantly inhibited by diethyldithiocarbamate plus MPTP ex vivo, suggesting that the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium ion, is acting in brain regions other than striatum as well. Lipoic acid, administered 6 times, each at 90 min prior to MPTP, could not restore dopamine in striatum but in contrast maintained a normal ratio of the reduced form to the oxidized form of coenzyme Q, suggesting an interaction of lipoic acid with energy metabolism which seems, however, not only to be due to an activation of pyruvate dehydrogenase.