Combination Of Minocycline Research Articles

Longitudinal Clinical Evaluation of Adjunct Minocycline in the Treatment of Chronic Periodontitis

The clinical benefits of minocycline in combination with thorough scaling and root planing (SRP) have been examined in multicenter studies. The aim of this longitudinal investigation was to evaluate the clinical response to scaling and root planing combined with the use of locally delivered minocycline microspheres for 720 days in individuals with advanced chronic periodontitis. A total of 26 individuals aged 26 to 69 years (mean: 46.8+/-12.1 years) were included in this double-blind randomized clinical trial. After randomization, 13 individuals were selected for the test group (TG) and treated with SRP plus subgingival minocycline at baseline and 90, 180, and 270 days, and 13 individuals were selected for the control group (CG) and received SRP plus vehicle at the same timepoints. Two homologous sites with probing depth (PD)>or=6 mm were chosen in each subject. To evaluate the clinical response after treatment, PD, plaque index (PI), and gingival index (GI) were assessed at baseline and 90, 180, 270, 360, and 720 days. No statistical differences were found between test and control groups in relation to PD at the different timepoints. The mean values of PD demonstrated a higher reduction in the test group at 270 and 360 days. No statistical differences were observed at 90, 180, and 720 days between TG and CG (P<0.05; Wilcoxon test). There were no statistically significant differences between TG and CG concerning PI and GI (P<0.05; analysis of variance and t test) at all evaluated timepoints. Our findings demonstrated that both therapies reduced mean PD from 90 to 360 days; however, SRP combined with the use of subgingival minocycline showed a higher reduction at 270 and 360 days following therapy.

Successful management of acne fulminans with combination of minocycline and dapsone

Acne fulminans is a rare and unique variant of acne vulgaris and is characterized by a sudden, violent onset of tender, nodulo-cystic and ulcerocrusted lesions over the back and chest, with fever, arthralgia and weight loss, affecting predominantly adolescent males. The exact etiopathogenesis is unknown although a hypersensitivity reaction is the most accepted hypothesis. Systemic steroids alone or in combination with isotretinoin are the cornerstones of its treatment. The successful management of Acne fulminans in an Indian boy with a combination of minocycline (200 mg once a day) and dapsone (200 mg once a day) daily is reported. The efficacy of minocycline as an alternative to steroids in the management of acne fulminans is highlighted.

Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice

Huntington's disease (HD) is a fatal neurodegenerative disorder of genetic origin with no known therapeutic intervention that can slow or halt disease progression. Transgenic murine models of HD have significantly improved the ability to assess potential therapeutic strategies. The R6/2 murine model of HD, which recapitulates many aspects of human HD, has been used extensively in pre-clinical HD therapeutic treatment trials. Of several potential therapeutic candidates, both minocycline and coenzyme Q10 (CoQ10) have been demonstrated to provide significant improvement in the R6/2 mouse. Given the specific cellular targets of each compound, and the broad array of abnormalities thought to underlie HD, we sought to assess the effects of combined minocycline and CoQ10 treatment in the R6/2 mouse. Combined minocycline and CoQ10 therapy provided an enhanced beneficial effect, ameliorating behavioral and neuropathological alterations in the R6/2 mouse. Minocycline and CoQ10 treatment significantly extended survival and improved rotarod performance to a greater degree than either minocycline or CoQ10 alone. In addition, combined minocycline and CoQ10 treatment attenuated gross brain atrophy, striatal neuron atrophy, and huntingtin aggregation in the R6/2 mice relative to individual treatment. These data suggest that combined minocycline and CoQ10 treatment may offer therapeutic benefit to patients suffering from HD.

Effective combination of minocycline and interferon-β in a model of multiple sclerosis

The objective of the current study was to investigate whether minocycline improves the effect of an existing multiple sclerosis (MS) medication, interferon-β, on experimental autoimmune encephalomyelitis (EAE) in mice. When used at sub-optimal doses, neither medication affected EAE but their combination at these doses led to the significant alleviation of EAE disease severity scores and histological outcomes. In culture, the toxicity of T cells to neurons was alleviated by their prior exposure to minocycline or interferon-β and their combination further attenuated neuronal death. Collectively, these results suggest the utility of the combination of minocycline and interferon-β in MS.

Exciting, Radical, Suicidal

It is now widely accepted that not all brain cells die immediately after stroke. Surrounding a core of severe and rapid tissue injury, brain cell death evolves more slowly in a heterogeneous area that has been called the penumbra.1,2 In 1977, Astrup et al provided one of the first experimental demonstrations of the penumbra in a baboon model of cerebral artery occlusion.3 This region of brain in acute ischemic stroke was found to be electrically silent but sufficiently active metabolically to sustain membrane potentials. Neurons within the penumbra are functionally impaired but not yet dead. Without reperfusion, the penumbra collapses, brain cells die, and the lesion expands. Although the precise timing and cellular pathways involved are not fully understood, it is believed that mechanisms actively promoting cell death are triggered after stroke. Remarkable progress has been made in dissecting these mechanisms over the past 3 decades. Three major pathways have emerged: excitotoxicity, oxidative stress, and apoptosis, and they are inextricably linked. Here, we explore the notion that stroke is most fruitfully investigated by an integrative “systems biology” approach that encompasses cell death and survival signaling within all components of the neurovascular unit. How do brain cells die after stroke? A large body of data suggest that it may be exciting (glutamate and excitotoxicity), radical (oxidative stress and free radicals), and suicidal (apoptotic-like pathways).4–6 Simply put, when brain fails to generate sufficient ATP, such as after oxygen and glucose deprivation, energy failure occurs and ionic gradients are lost. Glutamate is released, reuptake processes are impaired, and this excitatory amino acid binds to its postsynaptic receptors and promotes excessive calcium entry and calcium release. Calcium-dependent synthases and proteases contribute to cell and tissue demise by degrading key cytoskeletal and enzymatic proteins, and generating nitric oxide and peroxynitrite. Mitochondrial functions …

Additive effect of the combination of glatiramer acetate and minocycline in a model of MS

There have been significant advances in the treatment of multiple sclerosis (MS) in recent years, but further improvement in therapy is required as not all patients have responded optimally. An approach to enhancing MS treatment is to combine drugs that impact on different aspects of the disease process. We have described that the tetracycline derivative, minocycline, attenuates the severity of experimental autoimmune encephalomyelitis (EAE), a model of MS. Here, we have evaluated the combination of minocycline and glatiramer acetate (GA), a current therapy in MS, on the course of EAE in mice. This combination resulted in a significant reduction of disease severity and disease burden with attenuation of the inflammation, axonal loss and demyelination.

Minocycline inhibits antigen processing for presentation to human T cells: additive inhibition with chloroquine at therapeutic concentrations

The ability of minocycline to inhibit processing of tetanus toxoid (TT) for presentation to human T cells was tested. Peripheral blood antigen presenting cells (APC) were incubated with TT before or after addition of test compounds for 4 h. APC were then fixed with paraformaldehyde, and added to autologous TT-responsive T cell lines for a proliferation assay. Minocycline (0.1–0.4 mM) gave significant inhibition of T cell response to TT and was equivalent to chloroquine. Inhibition was not observed when TT was incubated with APC before minocycline, indicating that presentation of preprocessed antigen was not inhibited. Minocycline, doxycycline, and tetracycline all inhibited the proliferation of PBMC to TT. The combination of minocycline and chloroquine resulted in additive inhibition at clinically relevant levels of both drugs (3.7 μM). This study suggests a novel immunosuppressive mechanism for minocycline, as well as possible additive anti-inflammatory effect when combined with chloroquine or hydroxychloroquine.

Types of urethral catheters for management of short-term voiding problems in hospitalised adults.

Types of urethral catheters for management of short-term voiding problems in hospitalised adults.

Antibiotic-Impregnated Catheters Associated With Significant Decrease in Nosocomial and Multidrug-Resistant Bacteremias in Critically Ill Patients

To evaluate the impact of using central venous catheters (CVCs) impregnated with the combination of minocycline and rifampin on nosocomial bloodstream infections (BSIs), morbidity, and mortality in cancer patients in the ICU. Prospective surveillance study consisting of the following two time periods: September 1997 through August 1998 (ie, fiscal year [FY] 1998); and from September 1998 through August 1999 (ie, FY 1999). ICUs of a tertiary care hospital in Houston, TX. Cancer patients in the medical ICU (MICU) and surgical ICU (SICU). ICUs started using CVCs impregnated with the minocycline-rifampin combination at the beginning of FY 1999. The rates of nosocomial BSIs and other patients' characteristics were compared for the two study periods to determine the impact of using the impregnated catheters in the ICU. Patients' characteristics, including antibiotic use, were comparable for the two study periods in both the MICU and the SICU. The rate of nosocomial BSIs in the MICU unit decreased from 8.3 to 3.5 per 1,000 patient-days (p < 0.01), and decreased in the SICU from 4.8 to 1.3 per 1,000 patient-days (p < 0.01) in FY 1999. Nosocomial vancomycin-resistant enterococcus (VRE) bacteremia also decreased significantly (p = 0.004). Length of stay in the MICU and SICU significantly decreased in FY 1999 (p < 0.01 and p = 0.03, respectively). The duration of hospitalization decreased for MICU and SICU patients (p = 0.06 and p < 0.01, respectively). The rate of catheter-related infections decreased from 3.1 to 0.7 per 1,000 patient-days in FY 1999 (p = 0.02). The decrease in infections resulted in net savings of at least $1,450,000 for FY 1999. The use of antibiotic-impregnated CVCs in the MICU and SICU was associated with a significant decrease in nosocomial BSIs, including VRE bacteremia, catheter-related infections, and lengths of hospital and ICU stays.

Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS.

The known neuroprotective effects of minocycline and creatine in animal models of amyotrophic lateral sclerosis (ALS) led us to examine whether the combination of these agents would result in increased neuroprotection. As previously reported, we confirmed in ALS mice that either minocycline or creatine treatment results in improvement in motor performance and extended survival. We report that combination of minocycline and creatine resulted in additive neuroprotection, suggesting this to be a novel potential strategy for the treatment of ALS. To our knowledge, this is the first report demonstrating additive neuroprotection of a combinatorial approach in a mouse model of ALS. Adding relevancy to our findings, minocycline and creatine, are relatively safe, cross the blood-brain barrier, and are currently available for human evaluation.

In vivo efficacy of antimicrobe-impregnated saline-filled silicone implants.

Bacterial colonization of mammary implants is a prelude to clinical infection and has been implicated in the etiology of capsular contracture. Antimicrobial impregnation of a variety of medical devices with the combination of minocycline and rifampin has recently emerged as a potentially effective method for preventing device colonization and device-related infection. The objective of this animal study was to examine in vivo the antimicrobial efficacy of minocycline/rifampin-impregnated, saline-filled silicone implants. A rabbit model of Staphylococcus aureus colonization and infection of subcutaneously placed implants was used. A total of 48 saline-filled silicone implants (24 antimicrobe-impregnated and 24 control unimpregnated implants) were suspended in a 106 colony-forming units/ml bacterial suspension of S. aureus for 30 minutes at room temperature, allowed to dry for 60 minutes, and then implanted subcutaneously in the back of 12 rabbits (two antimicrobe-impregnated and two control implants were placed in each rabbit). Rabbits were monitored daily, then killed either at 2 weeks (10 rabbits) or at 4 weeks (two rabbits) and cultured. The antimicrobe-impregnated implants were 12 times less likely to be colonized than control unimpregnated implants (two of 24 versus 23 of 24; p < 0.001), and they were a significantly less likely cause of implant-related infection (0 of 24 versus 22 of 24; p < 0.001) and implant-related abscess (0 of 24 versus 21 of 24; p < 0.001) than control implants. The minocycline/rifampin-impregnated implants routinely demonstrated zones of inhibition against S. aureus at the time of explantation. These results indicate that minocycline/rifampin-impregnated implants can significantly decrease the rate of bacterial colonization, implant-related infection, and implant-related abscess. Antimicrobe-impregnated implants also have the potential of reducing the likelihood of capsular contracture.

Increased Staphylococcus-killing activity of an antimicrobial peptide, lactoferricin B, with minocycline and monoacylglycerol.

This study aimed to find antibiotics or other compounds that could increase the antimicrobial activity of an antimicrobial peptide, lactoferricin B (LFcin B), against Staphylococcus aureus, including antibiotic-resistant strains. Among conventional antibiotics, minocycline increased the bactericidal activity of LFcin B against S. aureus, but methicillin, ceftizoxime, and sulfamethoxazole-trimethoprim did not have such an effect. The combination of minocycline and LFcin B had synergistic effects against three antibiotic-resistant strains of S. aureus, according to result of checkerboard analysis. Screening of 33 compounds, including acids and salts, alcohols, amino acids, proteins and peptides, sugar, and lipids, showed that medium-chain monoacylglycerols increased the bactericidal activity of LFcin B against three S. aureus strains. The short-term killing test in water and the killing curve test in growing cultures showed that a combination of LFcin B and monolaurin (a monoacylglycerol with a 12-carbon acyl chain) killed S. aureus more rapidly than either agent alone. These findings may be helpful in the application of antimicrobial peptides in medical or other situations.

In vitro evaluation of the risk of developing bacterial resistance to antiseptics and antibiotics used in medical devices.

The risk of development of resistance in Staphylococcus epidermidis to the antibiotics and antiseptics impregnated in central venous catheters was evaluated. The culture was passaged 10-20 times through subinhibitory concentrations of different antimicrobials, singly and in combination, and the MIC of each antimicrobial before and after passage was compared. There was a 10- to 16-fold increase in the MIC of the combination of minocycline and rifampicin, while no significant increase in the MIC of minocycline alone was seen. The MIC of rifampicin was 25,000-fold higher against strains passaged through rifampicin alone (as compared with that for the original strain), while the increase was only 80-fold when it was combined with minocycline for passage. There was no substantial change in susceptibility to the antiseptic chlorhexidine when used alone or in combination with either silver sulphadiazine or triclosan (the MIC of triclosan alone increased eight-fold). In time-kill studies, synergy was observed between chlorhexidine and both triclosan and silver sulphadiazine. Zone of inhibition tests of catheters impregnated with minocycline and rifampicin showed that their activity against rifampicin-resistant strains was lower than that against the susceptible strain. On the other hand, the activity of the antiseptic (chlorhexidine and silver sulphadiazine) catheters against the rifampicin-resistant and -susceptible strains was similar. Although this study indicates that antibiotic catheters may be at a higher risk of being colonized by antibiotic-resistant bacteria, the implications of these results in clinical settings need to be determined.

P201 ミノサイクリンのアルテメサとの併用によるネズミマラリア治療効果

P201 ミノサイクリンのアルテメサとの併用によるネズミマラリア治療効果

Comparison of a topical benzoyl peroxide gel, oral minocycline, oral doxycycline and a combination for suppression of P. acnes in acne patients

Four groups of ten acne patients each received one of the following treatments for 1 month: (1) minocycline-‘D’, 100mg twice daily; (2) doxycycline monohydrate, 100mg twice daily; (3) 6% benzoyl peroxidezinc gel twice daily; (4) minocycline-‘D’ 100mg twice daily and 6% benzoyl peroxide-zinc gel twice daily. Suppression of Propionibacterium acnes was assessed by the detergent scrub method after 2 and 4 weeks of treatment. Minocycline-‘D’ had a far greater ability to suppress P. acnes than doxycycline. Minocycline-‘D’ resulted in almost a 2-log decrease in P. acnes compared with less than 1-log decrease with doxycycline. Benzoyl peroxide-zinc gel was also more efficacious than doxy-cycline. As expected, the combination of minocycline-‘D’ and benzoyl peroxide-zinc gel was substantially more effective than the comparator treatments. The greater therapeutic efficacy of minocycline-‘D’ in acne cannot be fully explained by its antibacterial activity. Evidence is presented to show that minocycline has a wide spectrum of pharmacologic activities, including antiinflammatory effects, which explains its increasing therapeutic applications in a variety of unrelated disorders.

Efficacy of antibiotics alone for orthopaedic device related infections.

Treatment of orthopaedic device related infections with antibiotics alone generally has been thought to be inadequate. A rabbit model was used to compare the efficacy of 4 different antibiotic regimens for treating orthopaedic device related infection caused by slime producing Staphylococcus epidermidis. After bacterial inoculation of a hole drilled through the intercondylar notch, a stainless steel screw was placed into the femur. Two weeks later, rabbits were randomized to receive a 2-week course of antibiotics: (1) 9 rabbits received vancomycin alone; (2) 10 rabbits received minocycline alone; (3) 10 rabbits received vancomycin plus rifampin; and (4) 10 rabbits received minocycline plus rifampin. Quantitative bone cultures were performed, and antibiotic levels in serum, bone, and biofilm were determined. Despite high levels of vancomycin in biofilm, infection was never cured by vancomycin alone and was eradicated in only 20% of rabbits that received minocycline alone. The highest cure rate (90%) was achieved with the combination of vancomycin and rifampin, whereas the combination of minocycline and rifampin yielded a cure rate of 70%. These results encourage the clinical evaluation of the combination of vancomycin and rifampin in patients in whom infected orthopaedic device cannot be removed.

Antibiotic susceptibility of staphylococcal isolates from patients with vascular catheter-related bacteremia: potential role of the combination of minocycline and rifampin

The antimicrobial susceptibility to ten antibiotics of 197 staphylococcal isolates recovered over a 10-year period from patients with vascular catheter-related bacteremia was examined. Isolated organisms induced methicillin-sensitive Staphylococcus aureus (95 isolates), methicillin-resistant S. aureus (42 isolates) and methicillin-resistant S. epidermidis (60 isolates). A microtiter assay was used to determine the MIC and MBC of individual antibiotics and to conduct time-kill studies of certain drug combinations. The activity of clidamycin, cefamandole and oxacillin was generally restricted to methicillin-sensitive organisms, whereas daptomycin, novobiocin, teicoplanin and vancomycin exhibited bactericidal activity against all tested staphylococcal species. Bacterial resistance to ciprofloxacin was detected among the more recent isolates of methicillin-resistant staphylococci. Minocycline and rifampin demonstrated bacteriostatic and bactericidal activity, respectively, against all groups of organisms. The interaction of rifampin with minocycline, vancomycin, or novobiocin was generally indifferent. The results of this study support the ongoing efforts for evaluation of the antimicrobial efficacy of vascular catheters coated with the combination of minocycline and rifampin.

The role of minocycline in the treatment of intracranial 9L glioma.

This study was designed to explore the question of whether minocycline, a semisynthetic tetracycline shown to inhibit tumor-induced angiogenesis, could control the growth of the rat intracranial 9L gliosarcoma. Minocycline was tested alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in vivo. Treatment was started at the time of intracranial implantation of 9L gliosarcoma into male Fischer 344 rats, 5 days later, or after tumor resection. Minocycline was delivered locally with a controlled-release polymer or systemically by intraperitoneal injection. Systemic minocycline did not extend survival time. Local treatment with minocycline by a controlled-release polymer implanted at the time of tumor implantation extended median survival time by 530% (p < 0.001) compared to treatment with empty polymer. When treatment was begun 5 days after tumor implantation, minocycline delivered locally or systemically had no effect on survival. However, after tumor resection, treatment with locally delivered minocycline resulted in a 43% increase in median survival time (p < 0.002) compared to treatment with empty polymer. Treatment with a combination of minocycline delivered locally in a controlled-release polymer and systemic BCNU 5 days after tumor implantation resulted in a 93% extension of median survival time compared to BCNU alone (p < 0.002). In contrast, treatment with a combination of systemic minocycline and BCNU did not increase survival time compared to systemic BCNU alone. These results demonstrate that minocycline affects tumor growth when delivered locally and suggest that minocycline may be a clinically effective modulator of intracranial tumor growth when used in combination with a chemotherapeutic agent and surgical resection.

In vivo modulation of several anticancer agents by ?-carotene

The ability of the collagenase inhibitor minocycline and of beta-carotene to act as positive modulators of cytotoxic anticancer agents was assessed in vitro and in vivo. Cell-culture studies were conducted using the human SCC-25 squamous carcinoma cell line. Simultaneous exposure of the cells to minocycline and beta-carotene or 13-cis-retinoic acid along with cisplatin (CDDP) resulted in a small decrease in the cytotoxicity of the CDDP. The addition of each of the modulator combinations for 1 h or 24 h to treatment with melphalan (L-PAM) or carmustine (BCNU) resulted in greater-than-additive cytotoxicity with each of four regimens. The modulator combinations of minocycline and beta-carotene applied for 1 h or 24 h and the modulator combination of minocycline and 13-cis-retinoic acid produced greater-than-additive cytotoxicity at 50 microM 4-hydroperoxycyclophosphamide (4-HC), whereas minocycline and 13-cis-retinoic acid applied for 1 h was antagonistic with 4-HC and the other modulator treatments at low concentrations of 4-HC resulted in subadditive cytotoxicity. The effect of treatment with beta-carotene alone and in combination with several different anticancer agents was examined in two murine solid tumors, the FSaII fibrosarcoma and the SCC VII carcinoma. Administration of the modulators alone or in combination did not alter the growth of either tumor. Whereas increases in tumor growth delay occurred with the antitumor alkylating agents and beta-carotene and with minocycline and beta-carotene, a diminution in tumor growth delay was produced by 5-fluorouracil in the presence of these modulators. The modulator combination also resulted in increased tumor growth delay with adriamycin and etoposide. Tumor-cell survival assay showed increased killing of FSaII tumor cells with the modulator combination and melphalan or cyclophosphamide as compared with the drugs alone. These results indicate that further investigation of this modulator strategy is warranted.

Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo.

In the present study the potential of minocycline, a semisynthetic tetracycline that inhibits collagenase activity in vivo, as an adjuvant to standard anticancer therapies was explored in vitro and in vivo. In EMT-6 cells, minocycline proved to be only minimally cytotoxic, producing a 50% cell kill at concentrations of 132 and 220 microM in normally oxygenated and hypoxic cells, respectively, after 24 h exposure to the drug. In vitro, there appeared to be no interaction between minocycline and cisplatin (CDDP), melphalan, 4-hydroperoxycyclophosphamide, or radiation. In tumor-cell survival studies using the FSaIIC murine fibrosarcoma, short-term treatment with minocycline (5 x 5 mg/kg given over 24 h) was only minimally cytotoxic and did not alter the tumor response to a range of radiation doses. However, when minocycline (5 x 5 mg/kg given over 24 h) was added to treatment with cyclophosphamide, there was a 4-fold increase in FSaIIC tumor-cell killing across the dose range of cyclophosphamide doses tested, whereas the killing of bone marrow granulocyte macrophage colony-forming units (CFU-GM) remained unchanged. The Lewis lung carcinoma was used to assess the response of both the primary tumor and metastatic lung disease to treatment with minocycline (14 x 5 mg/kg) given alone or in combination with several cytotoxic anticancer drugs or with radiation delivered locally to the primary tumor. Of the various therapies tested, minocycline proved to be especially effective as an addition to treatment with cyclophosphamide both in increasing the response of the primary tumor and in reducing the number of lung metastases. The tumor growth delay produced by melphalan, radiation, Adriamycin, and bleomycin was also increased by the addition of minocycline to these therapies. These results indicate that minocycline given in clinically achievable doses may be an effective addition to some standard therapeutic regimens and that the mechanism of modulation by minocycline is likely to involve an effect of the drug on the host and not its direct interaction with other therapeutic modalities at the level of the tumor cell.