Treatment of intestinal E. histolytica and G. lamblia with metronidazole, tinidazole and ornidazole: a comparative study

Metronidazole, tinidazole and ornidazole were compared in patients treated for Entamoeba histolytica or Giardia lamblia intestinal infections. Only patients with three positive stool specimens for trophozoites and/or cysts of E. histolytica or G. lamblia by the merthiolate iodine formaldehyde (MIFC) technique were included. Criteria for cure were at least 10 negative stool specimens over 3 weeks after completing therapy. Fifty-three male patients (aged 9-65 years) had E. histolytica infection. Seventeen received metronidazole (1.5 g daily for 10 days), 18 tinidazole (1.5 g daily for 10 days) and 18 ornidazole (1 g daily for 10 days). Metronidazole yielded 88%, tinidazole 67% and ornidazole 94% cure rates. Side reactions were minor. Eighty patients had G. lamblia infection, of whom 20 received metronidazole (0.5 g daily for 10 days), 30 tinidazole (single 2 g dose) and 30 ornidazole (single 1 g dose). Cure rates were 95% for metronidazole, 90% for tinidazole and 97% for ornidazole with no side reactions.     

Susceptibility of campylobacter species to metronidazole,its bioactive metabolites and tinidazole

Summary The susceptibilities of 115 campylobacters, belonging to five species, to metronidazole, its principal oxidative metabolites and tinidazole were determined by an agar dilution method. The activities of metronidazole and tinidazole were comparable. The hydroxy metabolite was more active than the parent drug against most species, particularlyCampylobacter jejuni andCampylobacter pyloridis. Although the acid derivative was less active againstC. jejuni andCampylobacter coli, it demonstrated an equivalent degree of activity to metronidazole against the remaining species. Inter-species differences existed with respect to the susceptibility of campylobacters and selected nitroimidazole antimicrobials.

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Empfindlichkeit von Campylobacter-Spezies gegenüber Metronidazol, dessen bioaktiven Metaboliten und Tinidazol

Zusammenfassung Mittels Agardilutionstest wurde die Empfindlichkeit von 115 Campylobacter-Stämmen aus fünf Spezies gegenüber Metronidazol, seinen durch oxydative Metabolisierung entstandenen Hauptmetaboliten und Tinidazol bestimmt. Metronidazol und Tinidazol zeigten vergleichbare Aktivität. Der Hydroxy-Metabolit wies gegenüber den meisten Spezies, insbesondere aber gegenCampylobacter jejuni undCampylobacter pyloridis höhere Aktivität auf als die Muttersubstanz. Bei geringerer Aktivität gegenC. jejuni undCampylobacter coli wies das Säurederivat gegenüber den restlichen untersuchten Spezies ebenso hohe Aktivität auf wie Metronidazol. Gegenüber ausgewählten Nitroimidazol-Antibiotika bestanden Empfindlichkeitsunterschiede bei verschiedenen Campylobacter-Spezies.

     

Treatment of non-invasive amoebiasis--a comparison between tinidazole and metronidazole

In a small pilot study the parasite cure rate (PCR) of non-invasive amoebiasis was compared after treatment with metronidazole 800 mg three times daily or tinidazole 600 mg twice daily for five days. Both treatment regimens were found to be highly unfavourable with PCRs of 44 and nil respectively, in contrast to previous published results showing PCR over 80%.     

Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy

A patient with acute myeloblastic leukemia received high-dose busulfan (1 mg/kg by mouth every 6 h for 4 days) as myelo-ablative therapy for autologous bone marrow transplantation. Rapid entry of busulfan into the cerebrospinal fluid (CSF) was observed. Plasma and CSF concentrations of busulfan were comparable during the 4 days of treatment. The elimination half-lives of busulfan in plasma and CSF were 2.6 h and 2.8 h respectively during the first 12 h after the last dose.     

Comparative pharmacokinetics of metronidazole and tinidazole and their tissue penetration

Since metronidazole and tinidazole are used prophylactically against infections after colorectal surgery, their pharmacokinetics and that of hydroxy-metronidazole were compared in 34 such patients. Seventeen patients received a single dose of 1.5 g (50-min infusion) of either agent 1 h before the operation. The concentrations of serum and tissue homogenates (subcutaneous fat, omentum, peritoneum, ileum, appendix, colon) were assayed by high-pressure liquid chromatography. The serum concentrations 1 h after start of infusion were 34.1 +/- 6.7 mg/l of metronidazole, 2.3 +/- 1.2 mg/l of OH-metronidazole, and 35.2 +/- 6.3 mg/l of tinidazole. OH-metronidazole and tinidazole were detectable for 72 h and metronidazole for 48 h. The ranges of serum and tissue concentrations (subcutaneous fat, omentum, peritoneum, ileum, appendix, colon) overlapped (within one single standard deviation). The tissue concentrations were high, particularly in intestinal tissues, except that the levels were low in subcutaneous tissue. The serum half-life of metronidazole was 9.0 +/- 1.6 h, of OH-metronidazole 14.8 +/- 7.4 h, and of tinidazole 16.4 +/- 3.8 h. The terminal-phase distribution volume was 35.8 +/- 10.01 for metronidazole and 40.6 +/- 9.91 for tinidazole, and the total body clearance 2.7 +/- 1.2 l/h and 1.8 +/- 0.5 l/h, respectively. The slower disposition of OH-metronidazole, which inhibits anaerobic bacteria, prolongs the duration of bioactivity in the body after metronidazole to that reached by tinidazole. OH-tinidazole was not detected in patient specimens (assay standards ensured that it could be assayed).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebrospinal fluid interleukin 8 concentrations and the subsequent development of postherpetic neuralgia

PURPOSE: Other than age, the risk factors for postherpetic neuralgia are not well established. We studied whether the concentration of interleukin 8 in the cerebrospinal fluid is associated with the risk of postherpetic neuralgia. METHODS: We enrolled 170 patients more than 50 years old who had a typical painful and nontrigeminal herpetic rash. Patients were treated with acyclovir; no corticosteroids were given. Cerebrospinal fluid was taken for analysis of interleukin 8 during and at full crusting of the herpetic rash. Age, sex, comorbid conditions, prodromal pain, localization and severity of herpetic rash, number of skin lesions, and degree of pain were recorded. We used multivariate logistic regression modeling to identify significant predictive factors. Receiver operating characteristic (ROC) curves were evaluated to determine the contribution of each factor. RESULTS: Six months after healing, 31 patients (18%) had postherpetic neuralgia; 27 patients still had it after 1 year. Only three variables-age (odds ratio [OR] = 2.7 per 10-year increase; 95% confidence interval [CI]: 1.2 to 6.2), acute pain (OR = 1.8 per unit increase in visual analog scale; 95% CI: 1.2 to 2.8), and interleukin 8 concentration in the cerebrospinal fluid at full crusting of the herpetic rash (OR = 1.6 per 20-microg/L increase; 95% CI: 1.3 to 2.0)-were significant predictors of postherpetic neuralgia at 1 year. Interleukin 8 concentration also had the highest area under the ROC curve at these evaluation points (P <0.001). CONCLUSION: Our results suggest that interleukin 8 concentration in the cerebrospinal fluid at full crusting of herpetic rash may be useful for identifying patients who are likely to develop intractable postherpetic neuralgia.     

Cerebrospinal fluid and plasma concentrations of leptin, NPY, and alpha-MSH in obese women and their relationship to negative energy balance

Leptin and its principal mediators, NPY and alpha-MSH are postulated to play a pivotal role in energy balance. To determine the possibility of the disturbance in neuropeptides in human obesity and their consequent changes in response to negative energy balance, we evaluated plasma and cerebrospinal fluid (CSF) leptin, NPY, and alpha-MSH levels in obese women before and after weight loss in comparison with normal control women. Subjects included 16 obese women [mean body mass index (BMI), 35.6 kg/m(2)] before and after weight loss induced by a 2-wk very low caloric diet (800 kcal/d) and 14 normal weight women (mean BMI, 20.4 kg/m(2)). The CSF to plasma leptin ratio in normal weight subjects was 2.3-fold higher than that in obese subjects. After weight loss in obese subjects, plasma leptin levels decreased by 40% and CSF levels decreased by 51%. There was a positive linear correlation between CSF and plasma leptin levels at baseline in obese subjects (r = 0.74, P < 0.05) and a positive logarithmic correlation in normal weight subjects (r = 0.89, P < 0.05) and in obese subjects after weight loss (r = 0.64, P < 0.05). The BMI was negatively correlated with the CSF to plasma leptin ratio (r = -0.86, P < 0.05) in all subjects. Neither the baseline plasma levels nor the baseline CSF levels of NPY were different between normal weight subjects and obese subjects. After weight loss, the CSF NPY level decreased significantly compared with baseline values in obese subjects. The alpha-MSH levels in plasma and CSF did not differ significantly from controls in obese subjects at baseline or after weight loss. Baseline CSF leptin level correlated with neither the baseline CSF NPY level nor the baseline CSF alpha-MSH level. In conclusion, this study demonstrated that the efficiency of brain leptin delivery is reduced in human obesity and central nervous system leptin uptake involves a combination of a saturable and an unsaturable mechanism. CSF NPY and alpha-MSH did not differ from controls in human obesity, and the CSF NPY level decreased significantly whereas alpha-MSH did not differ after weight loss in obese subjects compared with baseline. There was no significant correlation between CSF leptin and CSF NPY or alpha-MSH. This could be the result of leptin resistance present in human obesity and/or the more complex mechanisms involved in modulating appetite and regulating energy balance in human obesity.     

Cerebrospinal fluid cultures and analysis

Prompt and accurate diagnosis of acute central nervous system infections is of vital importance to the emergency physician. With the advent of modern antimicrobial therapy, the nearly uniformly fatal outcome of untreated bacterial meningitis can be reduced substantially. Proper test selection is crucial in arriving at a correct and timely diagnosis. A variety of tests are currently available for evaluation of the patient with an acute central nervous system infection. We review the current state of the art in central nervous system testing. Cost considerations and an algorithm for efficient selection of appropriate tests are presented.     

Single-dose metronidazole and tinidazole as therapy for giardiasis: success rates, side effects, and drug absorption and elimination

Eighty-five symptomatic patients with parasitologically confirmed, recently acquired giardiasis were treated in a comparative trial of 2.4 g of metronidazole either once or on two successive days or 2.0 g of tinidazole once. The follow-up period was eight weeks; the parasitological follow-up consisted of 871 stool and 30 duodenal specimens. Reinfections were unlikely. The rates of success were: metronidazole, single dose, 13 of 26; metronidazole, two doses, 24 of 31; and tinidazole, single dose, 26 of 28. Clinical and parasitological effects were parallel in nearly all cases. Tinidazole was more effective, produced fewer side effects, and was recommendable as the drug of choice in single-dose therapy. Pharmacokinetic explanations for therapeutic failure was sought with use of a bioassay of drug concentrations in serum. The outcome of therapy was not related to serum levels at 1hr or 24 hr, or to the rate of elimination. The mean serum half-lives of active metronidazole and tinidazole were 9.5 and 13.0 hr, respectively.     

Cerebrospinal fluid cachectin/tumor necrosis factor-alpha and platelet-activating factor concentrations and severity of bacterial meningitis in children

In prospective studies, tumor necrosis factor (TNF alpha) was detected in cerebrospinal fluid (CSF) of 33 of 38 children with bacterial meningitis (BM) but in none of 15 with viral meningitis/encephalitis (P less than .001). BM CSF TNF alpha (less than 35 to greater than 25,500 pg/ml) correlated with CSF bacterial density (P less than .01), CSF protein (P less than .001), endotoxin (LPS) in gram-negative disease (P less than .01), and consecutive febrile hospital days (P less than .001); initial CSF TNF alpha greater than 1000 pg/ml was associated with seizures (P less than .05). Only 5 children with BM (13%) had detectable plasma TNF alpha activity on admission. A higher proportion who died had detectable plasma TNF alpha activity compared with survivors (3/4 vs. 2/34, P less than .005). Platelet-activating factor (PAF) in CSF was higher in 19 children with Haemophilus influenzae meningitis than in 17 controls (P less than .01) and correlated with bacterial density (P less than .01), CSF LPS (P less than .01), CSF TNF alpha levels (P less than .01), and the Herson-Todd severity score (P less than .01). Elevated CSF TNF alpha and PAF are often present in children with BM and are associated with seizures and severity of disease. Detectable CSF TNF alpha appears to distinguish BM from viral meningitis.     

Cerebrospinal fluid lactate in meningitis and meningococcaemia

Cerebrospinal fluid (CSF) lactate values were measured in 26 children with meningitis (12 bacterial, 9 aseptic, 5 partially treated) and five children with meningococcaemia without meningitis. A reference range (0·5–3·2 mmol/l) was established from 100 control children. Amounts of lactate were significantly raised in bacterial meningitis (mean 6·5, range 4·5–10·2) compared with aseptic meningitis (mean 2·6, range 1·1–4·0) but this finding gave little practical help as the bacterial origin of the meningitis was clear from other CSF findings. High values (5·7) in a case of tuberculous meningitis (TBM) suggest that the test may be helpful when other CSF findings are inconclusive. Unless the CSF lactate is raised, the test is of minimal value in partially treated meningitis (mean 3·4, range 1·4–6·2). The previously unobserved finding of increased CSF lactate in meningococcaemia without meningitis (mean 3·9, range 3·1–5·0) supports the view that raised CSF lactate values in bacterial meningitis are not solely due to the presence of neutrophils. Literature relating to CSF lactate is reviewed.     

Cerebrospinal fluid and plasma HIV-1 RNA levels and lopinavir concentrations following lopinavir/ritonavir regimen

Our objective was to study the effect of lopinavir/ritonavir on cerebrospinal fluid (CSF) viral load as part of an antiretroviral combination treatment for HIV-1 infected individuals, and to determine the steady-state concentrations of lopinavir in CSF in relationship to plasma concentrations. Paired CSF and plasma samples from 12 antiretroviral-na?ve HIV-1 infected patients starting combination therapy containing lopinavir/ritonavir were collected at baseline, and during treatment at a first follow-up at median 3.0 months (range 2.6-6.0 months), and at a second follow-up at median 12.1 months (range 6.0-16.5 months). Levels of HIV-1 RNA, CD4+ T-cell count, beta2-microglobulin, neopterin, and lopinavir concentration were analysed. In addition, CSF and plasma lopinavir concentrations in 4 patients already on combination therapy including lopinavir/ritonavir were analysed. Nine of 11 patients had undetectable viral load in CSF and 5/11 in plasma at the first follow-up. At the second follow-up 7/7 had undetectable viral load in CSF and 9/9 in plasma. Intrathecal immunoactivation, measured by neopterin and beta2-microglobulin, decreased significantly both in CSF and serum. The total CSF concentrations of lopinavir were of the same order of magnitude as the unbound concentrations in plasma. Lopinavir mean (+/-SD) concentrations were 42.1 (+/-31.5) nM in CSF and 52.7 (+/-25.2) nM unbound in plasma. We found that antiretroviral combination therapy including lopinavir/ritonavir substantially decreases the viral load, both in CSF and plasma, as well as the intrathecal immunoactivation, measured by beta2-microglobulin and neopterin. CSF concentrations of lopinavir were low, but probably sufficient to have a virological effect.     

Cerebrospinal fluid and blood concentrations of luteinizing hormone, follicle stimulating hormone and prolactin following castration of adult male rats.

Comparative levels of LH, FSH, and PRL in the serum and cerebrospinal fluid (CSF) of adult male rats were studied at different periods following castration. Intact and sham-operated animals served as controls. Blood and CSF were collected at 1, 3, 7, 14, 21, 28, 35 and 46 days following castration. The CSF was collected via cisterna-magna puncture, while the blood was collected from abdominal aorta. Serum gonadotropins increased progressively beginning day 1 post-castration to reach maximum by day 35 or 46 post-castration. Sham operation and castration did not affect mean CSF, LH and FSH levels compared to intact controls. Analysis of the temporal pattern of serum and CSF gonadotropin levels following castration revealed significant positive correlation between CSF and serum LH (r = 0.58) and FSH (r = 0.64) levels respectively. The data suggest that CSF gonadotropins may be derived from systemic circulation. Serum PRL levels were not affected by castration, but CSF PRL levels were significantly reduced at days 28, 35 and 46 post-castration compared to intact controls. CSF PRL levels showed negative correlation with serum LH and FSH levels but failed to show a correlation with serum PRL levels. Hypothalamic norepinephrine turnover rate increased at days 28, 35 and 46 post-castration. Hypothalamic dopamine contents and turnover rates were reduced at days 21 and 28 post-castration. It is suggested that CSF PRL may have a role in the regulation of serum gonadotropins.