Epidemiology, risk factors and antimicrobial profile of Vulvovaginal Candidiasis (VVC): A study among women in the central region of Saudi Arabia.

BACKGROUND: Candida spp. is a fungal resident of the normal microbiota of gastrointestinal tract, reproductive mucosa and oral cavity. Hence, a majority of the healthy population may be prone to the most common fungal infection such as candidiasis that can be caused by any species of Candida. In women, vaginitis or vulvovaginal candidiasis (VVC) forms a significant part of urogenital infections with a high recurrence rate thus posing a public health issue worldwide. OBJECTIVES: The aim of this study was to determine the prevalence of VVC, its possible risk factors and the antifungal susceptibility of the species isolated from women attending a hospital in the central region of Saudi Arabia. METHODS: Samples of high vaginal swabs (HVS) were obtained from 208 women aged 15-64 years with signs and symptoms of VVC. The samples were cultured on Sabouraud agar plates (SDA) and incubated at 30°C for 10 days. Candida spp. were initially identified using morphologic characteristics, wet mount, germ tube test and finally confirmed with Vitek 2. RESULTS: Among the samples, 34% were culture positive. Out of the positive samples, 68% were Candida albicans, followed by C. tropicalis (27%) and C. glabrata (2.7%). Majority of the C. albicans (16%) were observed in women between ages of 21-30 years. All the isolates were sensitive to the antifungals tested. Also, the presence of Candida spp. did not correlate to risk factors such as pregnancy, diabetes and use of antibiotics. CONCLUSIONS: Prevalence of vulvovaginal candidiasis was observed in the central region of Saudi Arabia with the predominant organism as Candida albicans.

Efficacy of targeted therapy for metastatic renal cell carcinoma in the elderly patient population.

INTRODUCTION/BACKGROUND: Targeted therapy has become the mainstay of treatment for mRCC. The efficacy of this therapy in the older population is poorly understood. PATIENTS AND METHODS: Data from patients with mRCC treated with first-line anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. Patient characteristics, data on second-line therapy, and outcomes including treatment duration and overall survival, were evaluated using summary statistics and multivariate analysis. RESULTS: All patients (n = 1381) were treated with front-line targeted therapy; 144 (10%) were 75 years old or older. Six patients (4%) were favorable risk, 99 patients (69%) intermediate risk, and 39 patients (27%) poor risk according to Heng Journal of Clinical Oncology 2009 prognostic factors. The initial treatment for those ≥ 75 years of age was sunitinib (n = 98), sorafenib (n = 35), bevacizumab (n = 7), and AZD217 (n = 4). Twenty-three percent of older patients and 39% of the younger patients went on to receive second-line therapy (P < .0001). The overall response rate, median treatment duration, and overall survival for the older versus younger group were 18% versus 25% (P = .0975), 5.5 months versus 7.5 months (P = .1388), and 16.8 months versus 19.7 months (P = .3321), respectively. When adjusted for poor prognostic factors, age 75 years and older was not found to be associated with poorer overall survival (hazard ratio [HR], 1.002; 95% confidence interval [CI], 0.781-1.285) or shorter treatment duration (HR, 1.018; 95% CI, 0.827-1.252). The retrospective study design was the primary limitation. CONCLUSION: The use of advanced age as a selection criterion for targeted therapy requires further study, with data suggesting no clinically meaningful differences in overall response rate, treatment duration, and overall survival between older and younger age groups.

The role of vicinal tyrosine residues in the function of Haemophilus influenzae ferric-binding protein A.

The periplasmic FbpA (ferric-binding protein A) from Haemophilus influenzae plays a critical role in acquiring iron from host transferrin, shuttling iron from the outer-membrane receptor complex to the inner-membrane transport complex responsible for transporting iron into the cytoplasm. In the present study, we report on the properties of a series of site-directed mutants of two adjacent tyrosine residues involved in iron co-ordination, and demonstrate that, in contrast with mutation of equivalent residues in the N-lobe of human transferrin, the mutant FbpAs retain significant iron-binding affinity regardless of the nature of the replacement amino acid. The Y195A and Y196A FbpAs are not only capable of binding iron, but are proficient in mediating periplasm-to-cytoplasm iron transport in a reconstituted FbpABC pathway in a specialized Escherichia coli reporter strain. This indicates that their inability to mediate iron acquisition from transferrin is due to their inability to compete for iron with receptor-bound transferrin. Wild-type iron-loaded FbpA could be crystalized in a closed or open state depending upon the crystallization conditions. The synergistic phosphate anion was not present in the iron-loaded open form, suggesting that initial anchoring of iron was mediated by the adjacent tyrosine residues and that alternate pathways for iron and anion binding and release may be considered. Collectively, these results demonstrate that the presence of a twin-tyrosine motif common to many periplasmic iron-binding proteins is critical for initially capturing the ferric ion released by the outer-membrane receptor complex.

Family-focused cognitive behaviour therapy versus psycho-education for chronic fatigue syndrome in 11- to 18-year-olds: a randomized controlled treatment trial.

BACKGROUND: Only one previous randomized controlled trial (RCT) has examined the efficacy of cognitive behaviour therapy (CBT) for chronic fatigue syndrome (CFS) in children. The aim of this study was to compare family-focused CBT with psycho-education for CFS in adolescents. METHOD: Sixty-three 11- to 18-year-olds (43 girls, 20 boys) with CFS were randomly assigned to either family-focused CBT or psycho-education delivered over 6 months. School attendance was the main outcome, which was assessed at the end of treatment and at 3, 6 and 12 months follow-up. RESULTS: At the main outcome point (the 6-month follow-up) both groups had improved similarly. However, although those who received family-focused CBT were attending school for longer than those who received psycho-education, at discharge from treatment and at 3 months follow-up, they improved less quickly across the follow-up period. CONCLUSIONS: Adolescents with CFS get back to school more quickly after family-focused CBT. This is important as they are at a crucial stage of their development. However, the finding that psycho-education was as effective as family-focused CBT at 6 and 12 months follow-up has important implications for health service delivery.

Down-regulation of ventricular nitric oxide generating system in chronic alcohol-treated hypertensive rats.

Epidemiological studies show that low to moderate doses of alcohol consumption is beneficial to cardiac health. However, chronic high doses of alcohol ingestion cause cardiovascular complications including hypertension. The molecular and cellular mechanisms of chronic ethanol-induced increase in blood pressure (BP) are not completely understood. The purpose of this study was to investigate whether the increase in blood pressure following chronic ethanol exposure relates to cardiac endothelial nitric oxide levels and its generating system. Male Fisher rats were given 20% ethanol (4 g/kg, orally) through orogastric tube daily for 12 weeks and controls received 5% sucrose through orogastric tube daily for 12 weeks. The systolic, diastolic and mean BP was recorded through tail-cuff method. After 12 weeks, rats were sacrificed and heart dissected and left ventricle isolated and analyzed using enzyme linked immunosorbant assay (ELISA) and Western blotting. Results show that ethanol ingestion caused a significant increase in systolic, diastolic and mean BP (p<0.001) compared to control after 12 weeks. The levels of nitric oxide, its generating enzyme endothelial nitric oxide synthase (eNOS) protein expression and vascular endothelial growth factor (VEGF) gene (mRNA) and protein expressions were significantly down-regulated in the endothelium of left ventricles of ethanol-treated rats compared to controls. It is concluded that chronic ethanol ingestion causes an increase in blood pressure in rats via endothelial oxidative injury and the down-regulation of nitric oxide generating system in the left ventricles.

Vascular endothelial oxidative stress in alcohol-induced hypertension.

Epidemiological studies in humans and experimental studies in animals have shown the link between chronic alcohol consumption and the prevalence of hypertension. However, molecular mechanisms implicated with alcohol-induced increases in blood pressure (BP) remain elusive. The objective of this study was to investigate the relationship between BP and molecular as well as physiological changes in aortic endothelium in chronic ethanol treated rats. Male Fisher rats were given 20% ethanol (4 g/kg) orally and controls received 5% sucrose daily for 12 weeks. The BP was recorded weekly by tail-cuff method and after 12 weeks, rats were anesthetized with pentobarbital, thoracic aorta isolated and used for aortic reactivity using tissue bath and for biochemical analysis. The data show that ethanol ingestion significantly increased systolic, diastolic and mean BP after 12 weeks compared to control. The endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) expressions were down-regulated leading to depletion of aortic NO levels in ethanol treated rats compared to control. The aortic NADPH oxidase activity significantly enhanced with a concomitant increase in membrane lipid peroxidation and depressed ratio of reduced to oxidized glutathione in alcohol-treated rats compared to control. The aortic vasoconstriction was slightly enhanced in response to phenylephrine but vasorelaxation was significantly diminished in response to acetylcholine, adenosine and sodium nitroprusside in chronic ethanol treated rats. It is concluded that chronic ethanol ingestion induces aortic endothelial oxidative injury and the down regulation of nitric oxide generating system leading to impaired vasorelaxation and hypertension in rats.

Are investigations anxiolytic or anxiogenic? A randomised controlled trial of neuroimaging to provide reassurance in chronic daily headache.

OBJECTIVES: Aims were to investigate (a) whether neuroimaging in patients with chronic daily headache reassures patients or fails to reassure them and/or worsens outcome, impacting on service use, costs, health anxieties, and symptoms, and (b) whether this reassurance process occurs differentially in patients with different levels of psychological morbidity. DESIGN: randomised controlled trial; setting: headache clinic in secondary care, South London; participants: 150 patients fulfilling criteria for chronic daily headache, stratified using the Hospital Anxiety and Depression Scale (HADS); intervention: treatment as usual or the offer of an MRI brain scan; main outcome measures: use of services, costs, and health anxiety. RESULTS: Seventy six patients were randomised to the offer of a brain scan and 74 patients to treatment as usual. One hundred and thirty seven (91%) primary care case notes were examined at 1 year, 103 (69%) patients completed questionnaires at 3 months and 96 (64%) at 1 year. Sixty six (44%) patients were HADS positive (scored >11 on either subscale). Patients offered a scan were less worried about a serious cause of the headaches at 3 months (p = 0.004), but this was not maintained at 1 year; other health anxiety measures did not differ by scan status. However, at 1 year HADS positive patients offered a scan cost significantly less, by 465 pounds Sterling (95% confidence interval (CI): -1028 pounds Sterling to -104 pounds Sterling), than such patients not offered a scan, due to lower utilisation of medical resources. CONCLUSIONS: Neuroimaging significantly reduces costs for patients with high levels of psychiatric morbidity, possibly by changing subsequent referral patterns of the general practitioner.

Psychiatric morbidity and cognitive representations of illness in chronic daily headache.

OBJECTIVES: We studied patients with chronic daily headache (CDH) attending a headache clinic. Our hypothesis was that patients with anxiety or depression would have poorer functional status and differing cognitive representations of illness than would those without psychiatric morbidity. METHODS: The sample consisted of 144 consecutive new patients. Patients underwent a semistructured interview and completed a prospective headache diary, the Hospital Anxiety and Depression Scale (HADS) and other health-related questionnaires. RESULTS: Sixty patients (42%) were probable cases of anxiety or depression on the basis of their HADS score. These HADS-positive cases had longer, more severe headaches, were more worried about them, were more functionally impaired and believed that their illness would last longer. Principal components analysis revealed that the HADS-positive cases believed that psychological factors play a role in their headaches. CONCLUSIONS: Psychological morbidity is high amongst CDH patients who attend specialist clinics. In addition to identifying those with high levels of psychological distress, the HADS can be used to predict those likely to have worse headaches and poorer functional ability.

Time response of carboplatin-induced hearing loss in rat.

Carboplatin is currently being used as an anticancer drug against human cancers. However, high dose of carboplatin chemotherapy resulted in hearing loss in cancer patients. We have shown that carboplatin-induced hearing loss was related to dose-dependent oxidative injury to the cochlea in rat model. However, the time response of ototoxic dose of carboplatin on hearing loss and oxidative injury to cochlea has not been explored. The aim of the study was to evaluate the time response of carboplatin-induced hearing loss and oxidative injury to the cochlea of the rat. Male Wistar rats were divided into two groups of 30 animals each and treated as follows: (1) control (normal saline, i.p.) and (2) carboplatin (256 mg/kg, a single i.p. bolus injection). Auditory brain-evoked responses (ABRs) were recorded before and 1-5 days after treatments. The animals (n = 6) from each group were sacrificed on day 1, 2, 3, 4, and 5 and cochleae were isolated and analyzed. Carboplatin significantly elevated the hearing thresholds to clicks and to 2, 4, 8, 16, and 32 kHz tone burst stimuli only 3-5 days post-treatment. Carboplatin significantly increased nitric oxide (NO), malondialdehyde (MDA) levels and manganese superoxide dismutase (Mn-SOD) activity in the cochlea 4-5 and 3-5 days post-treatment, respectively, indicating enhanced influx of free radicals and oxidative injury to the cochlea. Carboplatin significantly depressed the reduced to oxidized glutathione (GSH/GSSG) ratio, antioxidant enzyme activities such as copper/zinc-superoxide dismutase (CuZn-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) as well as enzyme protein expressions in the cochlea 3-5 days after treatment. The data suggest that carboplatin-induced hearing loss involves oxidative injury to the cochlea of the rat in a time-dependent manner.

The role of revascularization in transmetatarsal amputations.

Data from 37 patients who underwent a transmetatarsal amputation from January 1993 to April 1996 were reviewed. The mean age and diabetes duration of the subjects were 54.9 (+/- 13.2) years and 16.6 (+/- 8.9) years, respectively. The follow-up period averaged 42.1 (+/- 11.2) months. At the time of follow-up, 29 (78.4%) of the 37 patients still had foot salvage, 8 (21.6%) had progressed to below-the-knee amputation, and 15 (40.5%) had undergone lower-extremity revascularization. Twelve (80%) of the 15 revascularized patients preserved their transmetatarsal amputation level at a follow-up of 36.4 months. The authors concluded that at a maximum of 3 years follow-up after initial amputation, transmetatarsal amputation was a successful amputation level.

Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study.

OBJECTIVE: This study evaluated the long-term outcome of cognitive behavior therapy versus relaxation therapy for patients with chronic fatigue syndrome. METHOD: Sixty patients who participated in a randomized controlled trial of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome were invited to complete self-rated measures and participate in a 5-year follow-up interview with an assessor who was blind to treatment type. RESULTS: Fifty-three patients (88%) participated in the follow-up study: 25 received cognitive behavior therapy and 28 received relaxation therapy. A total of 68% of the patients who received cognitive behavior therapy and 36% who received relaxation therapy rated themselves as "much improved" or "very much improved" at the 5-year follow-up. Significantly more patients receiving cognitive behavior therapy, in relation to those in relaxation therapy, met criteria for complete recovery, were free of relapse, and experienced symptoms that had steadily improved or were consistently mild or absent since treatment ended. Similar proportions were employed, but patients in the cognitive behavior therapy group worked significantly more mean hours per week. Few patients crossed the threshold for "normal" fatigue, despite achieving a good outcome on other measures. Cognitive behavior therapy was positively evaluated and was still used by over 80% of the patients. CONCLUSIONS: Cognitive behavior therapy for chronic fatigue syndrome can produce some lasting benefits but is not a cure. Once therapy ends, some patients have difficulty making further improvements. In the future, attention should be directed toward ensuring that gains are maintained and extended after regular treatment ends.

Chronic ethanol and nicotine interaction on rat tissue antioxidant defense system.

Ethanol consumption and cigarette smoking are common in societies worldwide and have been identified as injurious to human health. This study was undertaken to examine the interactive effects of chronic ethanol and nicotine consumption on the antioxidant defense system in different tissues of rat. Male Fisher-344 rats were divided into four groups of five animals each and treated for 6.5 weeks as follows: (1) Control rats were administered normal saline orally; (2) ethanol (20% [wt./vol.]) was given orally at a dose of 2 g/kg; (3) nicotine was administered subcutaneously at a dose of 0.1 mg/kg; and (4) a combination of ethanol plus nicotine was administered by the route and at the dose described above. The animals were killed 20 h after the last treatment, and liver, lung, kidney, and testes were isolated and analyzed. Chronic ingestion of ethanol resulted in a significant depletion of glutathione (GSH) content in liver, lung, and testes, whereas chronic administration of nicotine significantly depleted GSH content in liver and testes. The combination of ethanol plus nicotine resulted in a significant depletion of GSH content in liver, lung, and testes. Ethanol, nicotine, or a combination of ethanol plus nicotine significantly increased superoxide dismutase (SOD) activity in liver and decreased SOD activity in kidney. Ethanol, nicotine, or a combination of ethanol plus nicotine significantly decreased catalase (CAT) activity in liver and increased CAT activity in kidney and testes. Chronic ingestion of ethanol resulted in a significant decrease in glutathione peroxidase (GSH-Px) activity in liver and kidney, whereas a combination of ethanol plus nicotine increased GSH-Px activity in liver and decreased GSH-Px activity in kidney and testes. Ethanol, nicotine, or a combination of ethanol plus nicotine significantly increased lipid peroxidation, respectively, in liver. It is suggested that prolonged exposure to ethanol and nicotine produce similar, and in some cases additive, oxidative tissue injuries in rat.

Carboplatin-induced oxidative stress in rat cochlea.

Carboplatin is currently being used in the clinic against a variety of human cancers. However, high dose carboplatin chemotherapy resulted in ototoxicity in cancer patients. This is the first study to show carboplatin-induced oxidative stress response in the cochlea of rat. Male Wistar rats were divided into two groups of six animals each and treated as follows: (1) control (normal saline, i.p.) and (2) carboplatin (256 mg/kg, i.p.). Animals in both groups were sedated with ketamine/xylazine and auditory brainstem-evoked responses were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. A significant elevation of the hearing threshold shifts was noted at clicks, 8, 16, and 32 kHz tone burst stimuli following carboplatin administration. Carboplatin significantly increased nitric oxide and malondialdehyde levels, xanthine oxidase and manganese-superoxide dismutase activities in the cochlea indicating enhanced flux of free radicals. Cochlear glutathione levels, antioxidant enzyme activities such as copper zinc-superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase and enzyme protein levels were significantly depleted 4 days after carboplatin treatment. The data suggest that carboplatin induced free radical generation and antioxidant depletion, and caused oxidative injury in the cochleae of rats.

Interaction of pyridostigmine and physical stress on antioxidant defense system in skeletal muscle of mice.

Pyridostigmine bromide (PB), a reversible anticholinesterase drug, had been used against possible nerve gas exposure during the Persian Gulf War. The Gulf War veterans used PB and they were under physical stress. This study investigated the delayed and interactive effects of pyridostigmine and physical stress on the antioxidant defense system in triceps muscle of mice. Male NIH Swiss mice were divided into four groups and treated as follows: sedentary control; pyridostigmine (1.2 mg kg(-1) p.o.); exercise; and PB plus exercise. Mice were exercised for 10 weeks, but PB was administered daily during the 5th and 6th weeks. Mice were sacrificed 24 h after the last treatments and the triceps muscle was isolated and analyzed. There was a significant increase in total superoxide dismutase (CuZn-SOD + Mn-SOD) activity (141% of control) with PB plus exercise, suggesting that any influx of superoxide anions was scavenged efficiently. The Mn-SOD enzyme protein levels were reduced significantly (63% of control) by PB plus exercise. Catalase enzyme protein levels were increased significantly by exercise (132% of control) as well as by PB plus exercise (139% of control). Glutathione levels were increased significantly by exercise alone (123% of control). Pyridostigmine bromide plus exercise significantly increased the malondialdehyde concentration (124% of control) in the triceps muscle, indicating an oxidative stress response of the combination. The data indicate that a combination of PB ingestion and exercise training significantly altered the antioxidant enzyme activities, enzyme protein levels and lipid peroxidation, leading to oxidative injury. Physical stress amplified the delayed effects of PB in the skeletal muscle of mice.

Methyl chanofruticosinates from leaves of Kopsia flavida Blume.

Three new indole alkaloids with methyl chanofruticosinates skeletal system, viz., methyl 12-methoxy-N1-decarbomethoxychanofruticosinate, methyl 12-methoxychanofruticosinate and methyl 11,12-dimethoxychanofruticosinate, in addition to methyl 11,12-methylenedioxy-N1-decarbomethoxychanofruticosinate, have been isolated from the leaves of Kopsia flavida Blume. The structures of these three new indole alkaloids were assigned by NMR spectral data using various 2D-techniques.

Dose response of carboplatin-induced hearing loss in rats: antioxidant defense system.

Carboplatin, a platinum-containing anticancer drug, is currently being used against a variety of cancers. However, a single high dose of carboplatin is ototoxic in cancer patients. This is the first study to show carboplatin-induced hearing loss in a rat model. Male Wistar rats were divided into five groups and treated as follows: (1) control (saline, intraperitoneally (i.p.)); (2) carboplatin (64 mg/kg, i.p.); (3) carboplatin (128 mg/kg i.p.); (4) carboplatin (192 mg/kg, i.p.) and (5) carboplatin (256 mg/kg, i.p.). Animals in all groups were sedated with ketamine/xylazine and auditory brain-evoked responses (ABRs) were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. Carboplatin dose-dependently decreased body weight. However, at higher doses of carboplatin (192 and 256 mg/kg), there was a significant elevation of hearing threshold shifts at clicks, 4, 8, 16 and 32 kHz tone burst stimuli. The higher doses of carboplatin (192 and 256 mg/kg) significantly increased cochlear lipid peroxidation (132 and 146% of control) and depleted cochlear glutathione levels (66 and 63% of control), respectively. The antioxidant enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase (GST) depressed significantly at higher doses of carboplatin. The data suggest that higher doses of carboplatin (above 128 mg/kg) induce hearing loss as evidenced by significant changes in ABRs, lipid peroxidation and antioxidants in the cochlea of rats.

Delayed effects of pyridostigmine and exercise training on acetylcholinesterase and muscle tension in mouse lower extremity.

In this study, the interactive effects of pyridostigmine, a pretreatment drug against nerve agents, and exercise training on muscle tension were investigated in the mouse lower extremity anterior muscular compartment by dorsiflexion of the foot with stimulation of the peroneal nerve. Acetylcholinesterase (AChE), lipid peroxidation (in terms of the end-product malondialdehyde, MDA) and creatine phosphokinase (CPK) activity in the muscle were correlated with muscle tension. Male NIH Swiss mice were divided into four groups and treated as follows: (1) sedentary control; (2) pyridostigmine (1.2 mg/kg orally) daily for the 5th and 6th weeks; (3) exercise training for 10 weeks; and (4) pyridostigmine plus exercise training for 10 weeks. Experiments on muscle tension were conducted 4 weeks after the last dose of pyridostigmine or saline and 24 h after exercise. The muscle tension was measured in right and left legs using a tension transduction device connected to a polygraph. After muscle tension recording, mice were killed, blood and triceps muscle were isolated, and plasma CPK and muscle AChE activities, and MDA were determined. There was a significant increase in the muscle tension (P<0.05) in the group treated with pyridostigmine plus exercise as compared to the control and exercise groups. The pyridostigmine plus exercise group also showed a significant reduction in AChE activity (P<0.01) and enhanced MDA (P<0.05) in the triceps muscle. These results suggest that subchronic dosages of pyridostigmine and interaction with exercise training result in the delayed effects of reduction in muscle AChE activity and enhanced muscle tension.

Interactive and delayed effects of pyridostigmine and physical stress on biochemical and histological changes in peripheral tissues of mice.

Gulf War veterans were taking pyridostigmine orally against possible exposure to nerve agents as well as being under physical stress. This study was designed to investigate the delayed effects of pyridostigmine and treadmill exercise on cholinesterase activity, lipid peroxidation and histology of peripheral tissues of mice. Male NIH Swiss mice were divided into four groups of 15 animals each and treated as follows: sedentary control; exercise training for 10 weeks; pyridostigmine (1.2 mg kg(-1), p.o.) for 2 weeks during weeks 5 and 6; and pyridostigmine plus exercise training. The mice were sacrificed 24 h after the last exercise, and blood, triceps muscle and sciatic nerve were isolated and analyzed. The group treated with pyridostigmine alone showed decreased plasma butyrylcholinesterase (BChE) activity (87% of control), whereas pyridostigmine plus exercise significantly decreased the BChE activity (79% of control), indicating an interactive effect of the combination. Acetylcholinesterase (AChE) activity did not alter significantly in red blood cells, platelets or sciatic nerve with either of the treatments. However, AChE activity in triceps muscle decreased significantly (78% of control) in the group treated with pyridostigmine plus exercise. Creatine phosphokinase activity in plasma increased slightly (compared to control, pyridostigmine or exercise group) in mice treated with pyridostigmine plus exercise, which may be indicative of perturbation in the integrity of the skeletal muscle due to combination. However, there were no obvious histological abnormalities in the triceps muscle detected between experimental and control groups. Interaction of pyridostigmine and exercise significantly increased the concentration of the end product of lipid peroxidation (malondialdehyde) (124% of control) in triceps muscle, indicating an oxidative stress response of the combination. These results indicate that physical stress enhanced the delayed toxic effects of a subchronic oral dose of pyridostigmine primarily in the skeletal muscle of mice.

Effect of protective agents against cisplatin ototoxicity.

HYPOTHESIS: The goals of this investigation were to compare the efficacy of three protective agents against cisplatin-induced elevation of auditory brainstem response (ABR) thresholds and to examine whether these protective agents prevent cisplatin-induced alterations of the antioxidant defense system in the cochlea of the rat. BACKGROUND: Cisplatin is an ototoxic antitumor agent. Previous animal studies have shown that cisplatin administration causes an elevation of ABR thresholds. These auditory changes are accompanied by alterations in the concentration of glutathione and the antioxidant enzymes in the cochlea. The authors' previous work has indicated that the protective agent diethyldithiocarbamate (DDTC) prevents decrease in glutathione (GSH), alteration of antioxidant enzyme activity, and disruption of cochlear function with cisplatin administration. METHODS: Wistar rats were sedated and underwent pretreatment ABR testing using clicks and tone burst stimuli at 8, 16, and 32 kHz. Control rats received saline by intraperitoneal (i.p.) injection. Positive control rats were administered cisplatin 16 mg/kg i.p. Three groups of rats received protective agents in combination with cisplatin. The DDTC-protected rats were given 600 mg/kg of DDTC subcutaneously 1 hour after cisplatin. Animals protected by 4-methylthiobenzoic acid (MTBA) were given 250 mg/kg of this agent i.p. 30 minutes before cisplatin. Animals protected with ebselen were given 16 mg/kg i.p. one hour before cisplatin. The ABR thresholds were recorded 72 hours after cisplatin administration in all groups. Cochleas were removed, and extracts of the tissues were analyzed for GSH, activities of antioxidant enzymes (superoxide dismutase [SOD], catalase, glutathione peroxidase, and glutathione reductase) and malondialdehyde (MDA) (as an index of lipid peroxidation). RESULTS: Cisplatin-treated rats had significant ABR threshold shifts, ranging from 27 to 40 dB. Rats administered each of the three protective agents in combination with cisplatin had ABR threshold shifts of <10 dB. The cochleae of rats administered cisplatin alone had nearly a 50% depletion of glutathione and about a 50% reduction in the activities of SOD, glutathione peroxidase, and glutathione reductase, while catalase activity was reduced to 70% of control values. These changes were accompanied by a reciprocal elevation of MDA of 165%. These changes, namely, the depletion of GSH and antioxidant enzyme activity and the elevation of MDA in the cochlea, were largely attenuated by the administration of the protective agents tested. CONCLUSION: These findings suggest that cisplatin ototoxicity is related to lipid peroxidation and that the use of protective agents prevents hearing loss and lipid peroxidation by sparing the antioxidant system in the cochlea. These results suggest the possibility that the clinical use of protective agents could effectively reduce or prevent damage to the inner ear of patients receiving cisplatin chemotherapy, provided that the antitumor effect is not altered.

Dose-dependent protection by lipoic acid against cisplatin-induced nephrotoxicity in rats: antioxidant defense system.

This study was designed to investigate the role of graded doses of lipoic acid pretreatment against cisplatin-induced nephrotoxicity. Male Wistar rats were divided into six groups and treated as follows: 1) vehicle (saline) control; 2) cisplatin (16 mg/kg, intraperitoneally); 3) lipoic acid (100 mg/kg, intraperitoneally); 4) cisplatin plus lipoic acid (25 mg/kg); 5) cisplatin plus lipoic acid (50 mg/kg) and 6) cisplatin plus lipoic acid (100 mg/kg). Rats were sacrificed three days after treatment, and plasma as well as kidneys were isolated and analyzed. Plasma creatinine increased (677% of control) following cisplatin administration alone which was decreased by lipoic acid in a dose-dependent manner. Cisplatin-treated rats showed a depletion of renal glutathione (GSH), increased oxidized GSH and decreased GSH/GSH oxidized ratio (62%, 166% and 62% of control), respectively which were restored with lipoic acid pretreatment. Renal superoxide dismutase, catalase, glutathione peroxidase (GSH peroxidase) and glutathione reductase activities decreased (62%, 75%, 62% and 80% of control), respectively, and malondialdehyde content increased (204% of control) following cisplatin administration, which were restored with increasing doses of lipoic acid. The renal platinum concentration increased following cisplatin administration, which was possibly decreased by chelation with lipoic acid. The data suggest that the graded doses of lipoic acid effectively prevented a decrease in renal antioxidant defense system and prevented an increase in lipid peroxidation, platinum content and plasma creatinine concentrations in a dose-dependent manner.