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1.  Contribution of Moxifloxacin or Levofloxacin in Second-Line Regimens with or without Continuation of Pyrazinamide in Murine Tuberculosis 
Rationale: High-dose levofloxacin (L) (1,000 mg) was as active as moxifloxacin (M) (400 mg) in an early bactericidal activity trial, suggesting these fluoroquinolones could be used interchangeably. Whether pyrazinamide (Z) contributes sterilizing activity beyond the first 2 months in fluoroquinolone-containing second-line regimens remains unknown.
Objectives: We compared the efficacy of M and high-dose L alone or in combination with ethionamide (Et), amikacin (A), and Z given for 2 or 7 months.
Methods: A pharmacokinetic study was performed to determine the L dose equivalent to 1,000 mg in humans. Treatment started 2 weeks after aerosol infection with Mycobacterium tuberculosis H37Rv. Mice received M or L alone or in combination with 2 months of EtZA followed by 5 months of Et or EtZ.
Measurements and Main Results: After 2 months of treatment, lung colony-forming unit (CFU) counts were similar in mice receiving either fluoroquinolone alone, but, after 4 and 5 months, CFU counts were 2 log10 lower in mice receiving M. Mice receiving 2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log10 lung CFUs, respectively. When Z was given throughout, both regimens rendered mice culture negative by 5 months, and most mice did not relapse after 7 months of treatment, with fewer relapses observed in the M group after 6 and 7 months of treatment.
Conclusions: In murine tuberculosis, M had superior efficacy compared with L despite lower serum drug exposures and may remain the fluoroquinolone of choice for second-line regimens. Z contributed substantial sterilizing activity beyond 2 months in fluoroquinolone-containing second-line regimens, largely compensating for L’s weaker activity.
PMCID: PMC3735243  PMID: 23593945
moxifloxacin; levofloxacin; MDR-TB; pharmacokinetics; mouse model
2.  Multiple Cranial Nerve Palsies as the First Presentation of Sarcoidosis 
Case Reports in Otolaryngology  2014;2014:592510.
Sarcoidosis is a disease process which predominantly affects the lungs but can involve virtually any organ in the human body. Neurosarcoidosis is a rare manifestation which can present in a variety of ways. There is no single diagnostic test for sarcoidosis; hence, the diagnosis is based on combined clinical, laboratorial, and radiological grounds. We describe a rare case where a patient presented with dysphagia, hoarseness, hearing loss, and unsteadiness.
PMCID: PMC3984804  PMID: 24790763
3.  Activity of 5-chloro-pyrazinamide in mice infected with Mycobacterium tuberculosis or Mycobacterium bovis 
Background & objectives:
Pyrazinamide is an essential component of first line anti-tuberculosis regimen as well as most of the second line regimens. This drug has a unique sterilizing activity against Mycobacterium tuberculosis. Its unique role in tuberculosis treatment has lead to the search and development of its structural analogues. One such analogue is 5-chloro-pyrazinamide (5-Cl-PZA) that has been tested under in vitro conditions against M. tuberculosis. The present study was designed with an aim to assess the activity of 5-Cl-PZA, alone and in combination with first-line drugs, against murine tuberculosis.
The minimum inhibitory concentration (MIC) of 5-Cl-PZA in Middlebrook 7H9 broth (neutral pH) and the inhibitory titre of serum from mice that received a 300 mg/kg oral dose of 5-Cl-PZA 30 min before cardiac puncture were determined. To test the tolerability of orally administered 5-Cl-PZA, uninfected mice received doses up to 300 mg/kg for 2 wk. Four weeks after low-dose aerosol infection either with M. tuberculosis or M. bovis, mice were treated 5 days/wk with 5-Cl-PZA, at doses ranging from 37.5 to 150 mg/kg, either alone or in combination with isoniazid and rifampicin. Antimicrobial activity was assessed by colony-forming unit counts in lungs after 4 and 8 wk of treatment.
The MIC of 5-Cl-PZA against M. tuberculosis was between 12.5 and 25 μg/ml and the serum inhibitory titre was 1:4. Under the same experimental conditions, the MIC of pyrazinamide was >100 μg/ml and mouse serum had no inhibitory activity after a 300 mg/kg dose; 5-Cl-PZA was well tolerated in uninfected and infected mice up to 300 and 150 mg/kg, respectively. While PZA alone and in combination exhibited its usual antimicrobial activity in mice infected with M. tuberculosis and no activity in mice infected with M. bovis, 5-Cl-PZA exhibited antimicrobial activity neither in mice infected with M. tuberculosis nor in mice infected with M. bovis.
Interpretation & conclusion:
Our findings showed that 5-Cl-PZA at doses up to 150 mg/kg was not active in chronic murine TB model. Further studies need to be done to understand the mechanism and mode of inactivation in murine model of tuberculosis.
PMCID: PMC3573602  PMID: 23287128
Experimental chemotherapy; mouse; pyrazinamide; tuberculosis
4.  Effectiveness of tuberculosis chemotherapy correlates with resistance to Mycobacterium tuberculosis infection in animal models 
It is widely believed that persistent Mycobacterium tuberculosis inhabits necrotic lung granulomas in humans and that the microenvironmental conditions encountered therein render the bacilli phenotypically tolerant to antibiotics, accounting for the long duration required for successful treatment of tuberculosis (TB). To validate this belief, we directly compared the activity of rifampicin/isoniazid/pyrazinamide (RHZ) against chronic TB infection in guinea pigs, which exhibit caseous granulomas histologically resembling human caseous foci, and in mice, which lack necrotic granulomas.
Guinea pigs and mice were aerosol-infected with M. tuberculosis CDC1551 and twice weekly treatment with RHZ was started 4 weeks later. Culture-positive relapse was assessed in subgroups of guinea pigs after 3 months and 4 months of treatment.
All guinea pig lungs exhibited histological evidence of granulomas with central caseation, while mouse lungs exhibited cellular lesions at the initiation of antibiotic treatment. Guinea pig lungs became culture-negative after 2 months of RHZ given twice weekly at human-equivalent doses. Relapse rates in guinea pigs were 0% (0/10) both after 3 months and 4 months of treatment. In contrast, all mouse lungs remained culture-positive after 4 months of equivalent RHZ exposures.
Caseous necrosis does not reduce the sterilizing activity of the standard antituberculosis regimen of RHZ. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.
PMCID: PMC3112031  PMID: 21602551
chronic tuberculosis; guinea pig; mouse; antibiotics; chemotherapy; caseous necrosis; hypoxia; granuloma; persistence
5.  Treatment of Tuberculosis with Rifamycin-containing Regimens in Immune-deficient Mice 
Rationale: Daily rifapentine plus isoniazid-pyrazinamide in mice infected with Mycobacterium tuberculosis produces cure in 3 months. Whether cure corresponds to latent infection contained by host immunity or true tissue sterilization is unknown.
Objectives: To determine the length of treatment with rifapentine-isoniazid-pyrazinamide or rifampin-isoniazid-pyrazinamide needed to prevent relapse in immune-deficient mice.
Methods: Aerosol-infected BALB/c and nude mice were treated 5 days per week with either 2 months of the rifapentine-based regimen followed by rifapentine-isoniazid up to 12 months or the same regimen with rifampin instead of rifapentine. Cultures of lung homogenates were performed during the first 3 months and then every 3 months. Relapse rates were assessed after 3, 6, 9, and 12 months of treatment in BALB/c (± 1 mo of cortisone) and nude mice.
Measurements and Main Results: All rifapentine-treated mice were lung culture–negative at 3 months but 13% of BALB/c that received cortisone and 73% of nude mice relapsed. After 6, 9, and 12 months of treatment no mouse relapsed. Rifampin-treated BALB/c mice remained culture positive at 3 months. All were culture negative at 6, 9, and 12 months. None, including those receiving cortisone, relapsed. Rifampin-treated nude mice harbored more than 4 log10 lung cfu at Month 2 and approximately 6 log10 cfu with isoniazid resistance at Month 3. A supplementary experiment demonstrated that 7 days a week treatment did not prevent isoniazid resistance, whereas addition of ethambutol did.
Conclusions: In nude mice, sterilization of tuberculosis is obtained with rifapentine-containing treatment, whereas failure with development of isoniazid resistance is obtained with rifampin-containing treatment.
PMCID: PMC3114054  PMID: 21330452
tuberculosis; immune-deficient mice; rifapentine; rifampin; drug resistance
6.  The potent bactericidal activity of streptomycin in the guinea pig model of tuberculosis ceases due to the presence of persisters 
Journal of Antimicrobial Chemotherapy  2010;65(10):2172-2175.
The biphasic kill curve of isoniazid against Mycobacterium tuberculosis in guinea pigs is due to the presence of persisters rather than selection of isoniazid-resistant mutants. To determine whether this phenomenon is common to other bactericidal drugs, we studied the activity of streptomycin and its ability to select for streptomycin-resistant mutants in the guinea pig model of tuberculosis.
Pharmacokinetic studies were performed to establish the human-equivalent dose of streptomycin. Guinea pigs were aerosol-infected with M. tuberculosis and 2 weeks later streptomycin was given for 5 days/week via intramuscular injection. Bactericidal activity was assessed by homogenizing and plating lungs for cfu until 10 weeks of treatment. At each timepoint, cfu were isolated, suspended in normal saline and re-plated on plates containing 0.5, 1.0, 2.0 or 10.0 mg/L streptomycin.
The human-equivalent dose of streptomycin was determined to be 70 mg/kg. Streptomycin showed potent activity during the first 14 days of treatment, rescuing all animals from acute tuberculosis-related death and reducing lung cfu by ∼4 log10. However, streptomycin activity was dramatically reduced thereafter, as lung cfu declined by only ∼1 log10 over the next 56 days of treatment. Although streptomycin-resistant mutants were detectable, their frequency of isolation was identical at treatment initiation and after 70 days of treatment.
The reduced activity of streptomycin during the second phase of monotherapy is not associated with the selection of streptomycin-resistant mutants but, rather, with the presence of phenotypically tolerant ‘persisters’.
PMCID: PMC2941674  PMID: 20693172
Mycobacterium tuberculosis; antibiotic chemotherapy; isoniazid; persistence; drug resistance
7.  Activity of the Fluoroquinolone DC-159a in the Initial and Continuation Phases of Treatment of Murine Tuberculosis▿  
DC-159a is a new fluoroquinolone with more potent in vitro activity than available fluoroquinolones against both drug-susceptible and fluoroquinolone-resistant Mycobacterium tuberculosis. Here, we report that DC-159a displays pharmacokinetics similar to those of moxifloxacin yet is more active than moxifloxacin during both the initial and continuation phases of treatment in a murine model. These results warrant further preclinical evaluation of DC-159a in selected drug combinations against drug-susceptible and fluoroquinolone-resistant tuberculosis.
PMCID: PMC3067133  PMID: 21282421
8.  Dose-Dependent Activity of Pyrazinamide in Animal Models of Intracellular and Extracellular Tuberculosis Infections▿  
Recent in vitro pharmacokinetic data suggest that the currently recommended dose of pyrazinamide may be suboptimal for killing intracellular bacilli in humans. We evaluated a range of pyrazinamide doses against intracellular and extracellular Mycobacterium tuberculosis in chronically infected mice and guinea pigs, respectively. Antibiotics were given five times weekly for 4 weeks beginning 28 days after infection. Human-equivalent doses of isoniazid reduced lung bacterial counts 10-fold in each species. Pyrazinamide given at 1/4 and 1/2 the human-equivalent dose was minimally active, while human-equivalent doses reduced lung bacterial counts by ∼1.0 log10 in each species. Doubling the human-equivalent dose of pyrazinamide reduced the lung bacillary burden by 1.7 and 3.0 log10 in mice and guinea pigs, respectively. As in humans and mice, pyrazinamide showed significant synergy with rifampin in guinea pigs. Clinical studies are warranted to investigate the sterilizing activity and tolerability of higher doses of pyrazinamide in combination tuberculosis regimens.
PMCID: PMC3067197  PMID: 21282447
9.  Balloon sinuplasty 
Balloon sinuplasty is a technique in endoscopic sinus surgery that involves minimally invasive procedures to dilate the obstructed or stenosed anatomical sinus pathways. Procedure is derived from the well-recognized techinique of angioplasty. This article highlights the procedural methods with review of literature and my personal experience in balloon sinupalsty.
PMCID: PMC3450249  PMID: 23120718
Balloon sinuplasty; Sinostomy; Acclarent; Lumiview; ESS; Hybrid-ESS; Antrostomy
10.  PA-824 Exhibits Time-Dependent Activity in a Murine Model of Tuberculosis▿  
PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T>MIC (R2 = 0.87) and correlated with the free drug AUC/MIC (R2 = 0.60), but not with the free drug Cmax/MIC (R2 = 0.17), where T>MIC is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of ≤72 h, both the T>MIC and the AUC/MIC values fit the data well. Free drug T>MIC of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T>MIC values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T>MIC, in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.
PMCID: PMC3019674  PMID: 20937781
11.  Safety of day-stay tonsillectomy 
The appropriateness of tonsillectomy as a day case procedure is not universally accepted, however, the procedure has been performed in our institution since 1996. Our policy has been to continue this practice.
To assess the appropriateness of this practice in our institution, a retrospective study of 802 tonsillectomies performed over 16 months was conducted. A telephone based questionnaire was formed to assess safety of the procedure and to evaluate the experiences and attitude of the served community towards our practice.
Four hundred and thirty-three (61.3%) patients/parents were contactable to answer the questionnaire. Fifty-eight percent felt that a same day discharge was favorable with 6% considering that an overnight stay would have been preferable, others had no preference. Regarding the problems at home, 76% reported no problems on the first night, with 3% needing medical assistance that night, half of which were admitted in the hospital. We conclude that with the practices in place in this center, our policy of aiming for same day discharge is appropriate, being safe and agreeable to both patients and health care providers.
PMCID: PMC3450306  PMID: 23120704
Day case surgery; Tonsillectomy; Postoperative complications
12.  Activities of Rifampin, Rifapentine and Clarithromycin Alone and in Combination against Mycobacterium ulcerans Disease in Mice 
Treatment of Mycobacterium ulcerans disease, or Buruli ulcer (BU), has shifted from surgery to treatment with streptomycin(STR)+rifampin(RIF) since 2004 based on studies in a mouse model and clinical trials. We tested two entirely oral regimens for BU treatment, rifampin(RIF)+clarithromycin(CLR) and rifapentine(RPT)+clarithromycin(CLR) in the mouse model.
Methodology/Principal Findings
BALB/c mice were infected in the right hind footpad with M. ulcerans strain 1059 and treated daily (5 days/week) for 4 weeks, beginning 11 days after infection. Treatment groups included an untreated control, STR+RIF as a positive control, and test regimens of RIF, RPT, STR and CLR given alone and the RIF+CLR and RPT+CLR combinations. The relative efficacy of the drug treatments was compared on the basis of footpad CFU counts and median time to footpad swelling. Except for CLR, which was bacteriostatic, treatment with all other drugs reduced CFU counts by approximately 2 or 3 log10. Median time to footpad swelling after infection was 5.5, 16, 17, 23.5 and 36.5 weeks in mice receiving no treatment, CLR alone, RIF+CLR, RIF alone, and STR alone, respectively. At the end of follow-up, 39 weeks after infection, only 48%, 26.4% and 16.3% of mice treated with RPT+CLR, RPT alone and STR+RIF had developed swollen footpads. An in vitro checkerboard assay showed the interaction of CLR and RIF to be indifferent. However, in mice, co-administration with CLR resulted in a roughly 25% decrease in the maximal serum concentration (Cmax) and area under the serum concentration-time curve (AUC) of each rifamycin. Delaying the administration of CLR by one hour restored Cmax and AUC values of RIF to levels obtained with RIF alone.
These results suggest that an entirely oral daily regimen of RPT+CLR may be at least as effective as the currently recommended combination of injected STR+oral RIF.
Author Summary
Buruli ulcer (BU) is found throughout the world but is particularly prevalent in West Africa. Until 2004, treatment for this disfiguring disease was surgical excision followed by skin grafting, procedures often requiring months of hospitalization. More recently, an 8-week regimen of oral rifampin and streptomycin administered by injection has become the standard of care recommended by the World Health Organization. However, daily injections require sterile needles and syringes to prevent spread of blood borne pathogens and streptomycin has potentially serious side effects, most notably hearing loss. We tested an entirely oral regimen, substituting the long acting rifapentine for rifampin and clarithromycin for streptomycin. We also evaluated each drug separately. We found that rifapentine alone is as good as rifampin plus streptomycin, but the simultaneous addition of effective clarithromycin doses, at least in the mouse, reduces the activity of both rifampin and rifapentine, making it difficult to assess the efficacy of the oral regimens in the model. Studies of serum drug concentrations indicated that separating treatment times by one hour or reducing the clarithromycin dose to one active in humans should overcome this issue in experimental and clinical BU treatment, respectively.
PMCID: PMC3014976  PMID: 21245920
13.  Comparison of the ‘Denver regimen’ against acute tuberculosis in the mouse and guinea pig 
In this study, we sought to compare the sterilizing activity of human-equivalent doses of the ‘Denver regimen’ against acute tuberculosis (TB) infection in the standard mouse model and in the guinea pig.
Pharmacokinetic studies in guinea pigs were used to establish human-equivalent doses for rifampicin, isoniazid and pyrazinamide. Guinea pigs and mice were aerosol-infected with Mycobacterium tuberculosis CDC1551 and treatment was started 2 weeks later with rifampicin/isoniazid/pyrazinamide for up to 6 months. For the first 2 weeks of therapy, the dosing frequency was 5 days/week, and for the remaining period, twice weekly. Treatment was discontinued in groups of 30 mice and 10 guinea pigs at 5 months and at 6 months, and these animals were held for a further 3 months in order to assess relapse rates.
Guinea pig lungs became culture-negative after 3 months of predominantly twice-weekly treatment and relapse rates were 0% (0/10) both after 5 months and after 6 months of treatment. In contrast, all mice remained culture-positive despite 6 months of the same treatment, and 93% (28/30) and 69% (20/29) of mice relapsed after treatment for 5 and 6 months, respectively.
Treatment with rifampicin/isoniazid/pyrazinamide administered at human-equivalent doses is much more potent against acute TB infection in guinea pigs than in mice. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.
PMCID: PMC2837551  PMID: 20123722
Mycobacterium tuberculosis; isoniazid; rifampicin; pyrazinamide; chemotherapy; persistence
14.  An Evaluation of Use of Trans-Obturator Tape (TOT) Sling Procedure in the Current Surgical Management of Female Stress Urinary Incontinence 
To assess the role of TOT sling procedure in current surgical management of female Stress Urinary Incontinence (SUI) in terms of post-operative results, cost effectivenss, pt acceptance and complications.
From June 2006 to September 2008, 30 patients of SUI were treated surgically by TOT-sling procedure. Pre-operatively the patients were evaluated by thorough history taking, clinical examination and different diagnostic test depending upon the individual clinical scenario. Patients were explained in their own language the nature of procedure and the principle behind it. Any complication(s) (intra/postoperative) were noted. After discharging the patients they were followed up by atleast 3 visits (follow-up visits) at 1, 3 & 6 month interval. Any complications of the procedure and patient acceptance were evaluated at each follow-up.
The mean age of the total patients (n=30) was 39.5 yrs and 28 (93.33%) were multiparous. Involuntary loss of urine on straining was the most common complaint present in 25 (83.33%) patients and 22 (73.33) patients were having duration of symptoms less than 3 yrs. 9 (30%) patients were having mild cystocele pre-operatively which resolved after surgery. All the 30 (100%) patients were continent post-operatively while 7 (23.33%) were having lower urinary tract symptoms (LUTS). No major intra/post-operative complication was seen but, urgency, dysuria, fever and haematuria was seen post-operatively which resolved after few days. The operative time was 24 ± 3.8 months and catheter was removed on 2.7 ± 1.7 days post-operatively. Hospital stay was 6 ± 2.4 days (3 – 11) and app. Cost of the treatment was Rs3253 ± 360 (2700,3900).
TOT Sling procedure is currently the Gold Standard for management of female SUI. It is very important to diagnose SUI and rule out other causes of incontinence because only the former one (Genuine SUI) is improved by TOT sling and other types may be even worsened by this procedure.
PMCID: PMC3068739  PMID: 21475493
Assessment; TOT Sling; Efficacy; Post-op results; Cost effectiveness; Patient acceptance; Complications
15.  Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan 
BMC Medical Genetics  2004;5:24.
Mutant alleles of TMPRSS3 are associated with nonsyndromic recessive deafness (DFNB8/B10). TMPRSS3 encodes a predicted secreted serine protease, although the deduced amino acid sequence has no signal peptide. In this study, we searched for mutant alleles of TMPRSS3 in families from Pakistan and Newfoundland with recessive deafness co-segregating with DFNB8/B10 linked haplotypes and also more thoroughly characterized the genomic structure of TMPRSS3.
We enrolled families segregating recessive hearing loss from Pakistan and Newfoundland. Microsatellite markers flanking the TMPRSS3 locus were used for linkage analysis. DNA samples from participating individuals were sequenced for TMPRSS3. The structure of TMPRSS3 was characterized bioinformatically and experimentally by sequencing novel cDNA clones of TMPRSS3.
We identified mutations in TMPRSS3 in four Pakistani families with recessive, nonsyndromic congenital deafness. We also identified two recessive mutations, one of which is novel, of TMPRSS3 segregating in a six-generation extended family from Newfoundland. The spectrum of TMPRSS3 mutations is reviewed in the context of a genotype-phenotype correlation. Our study also revealed a longer isoform of TMPRSS3 with a hitherto unidentified exon encoding a signal peptide, which is expressed in several tissues.
Mutations of TMPRSS3 contribute to hearing loss in many communities worldwide and account for 1.8% (8 of 449) of Pakistani families segregating congenital deafness as an autosomal recessive trait. The newly identified TMPRSS3 isoform e will be helpful in the functional characterization of the full length protein.
PMCID: PMC523852  PMID: 15447792
16.  Acute respiratory tract obstruction in children 
35 cases of acute respiratory tract obstruction in paediatric age group who needed surgical intervention in the form of bronchoscopy, tracheostomy or both are reviewed here. All these patients were seen and managed at National Iranian Oil company Hospital Ummeidiya Khouzestan Iran, from April 1985 to April 1988. The results obtained with a review of use of instruments is described. Most of the patients presented with foreign body inhalations, some due to allergic oedema and one case had laryngeal cyst causing respiratory tract obstruction.
PMCID: PMC3451035  PMID: 23119541

Results 1-16 (16)