To assess the cause of nonspecific vaginitis, we performed a prospective case-control study of vaginal flora and a randomized unblinded trial of different therapies. Haemophilus vaginalis was isolated from 17 to 18 women with signs of vaginitis but only one of 18 normal matched controls (P less than 0.002). The concentration of anaerobic bacteria in vaginal washings also was increased in patients. Clinical improvement and eradication of H. vaginalis occurred in one of seven patients given sulfonamide vaginal cream, two of 15 given oral doxycycline, nine of 27 given oral ampicillin, and 80 of 81 given oral metronidazole. On the seventh day of therapy signs of nonspecific vaginitis persisted in 31 of 31 with, and in two of 92 without, persistent H. vaginalis infection (P less than 0.001). These data suggest the causal role of H. vaginalis in nonspecific vaginitis, possibly in concert with vaginal anaerobes. The widespread use of sulfonamide creams is inappropriate. Metronidazole is effective, but its efficacy must be weighed against its possible toxicity.

Periodontal disease is a common infection-induced inflammatory disease among individuals suffering from diabetes mellitus. The purpose of this study was to assess the effects of treatment of periodontal disease on the level of metabolic control of diabetes. A total of 113 Native Americans (81 females and 32 males) suffering from periodontal disease and non-insulin dependent diabetes mellitus (NIDDM) were randomized into 5 treatment groups. Periodontal treatment included ultrasonic scaling and curettage combined with one of the following antimicrobial regimens: 1) topical water and systemic doxycycline, 100 mg for 2 weeks; 2) topical 0.12% chlorhexidine (CHX) and systemic doxycycline, 100 mg for 2 weeks; 3) topical povidone-iodine and systemic doxycycline, 100 mg for 2 weeks; 4) topical 0.12% CHX and placebo; and 5) topical water and placebo (control group). Assessments were performed prior to and at 3 and 6 months after treatment and included probing depth (PD), clinical attachment level (CAL), detection of Porphyromonas gingivalis in subgingival plaque and determination of serum glucose and glycated hemoglobin (HbA1c). After treatment all study groups showed clinical and microbial improvement. The doxycycline-treated groups showed the greatest reduction in probing depth and subgingival Porphyromonas gingivalis compared to the control group. In addition, all 3 groups receiving systemic doxycycline showed, at 3 months, significant reductions (P < or = 0.04) in mean HbA1c reaching nearly 10% from the pretreatment value. Effective treatment of periodontal infection and reduction of periodontal inflammation is associated with a reduction in level of glycated hemoglobin. Control of periodontal infections should thus be an important part of the overall management of diabetes mellitus patients.

BACKGROUND: It is controversial whether prolonged antibiotic treatment is effective for patients in whom symptoms persist after the recommended antibiotic treatment for acute Lyme disease. METHODS: We conducted two randomized trials: one in 78 patients who were seropositive for IgG antibodies to Borrelia burgdorferi at the time of enrollment and the other in 51 patients who were seronegative. The patients received either intravenous ceftriaxone, 2 g daily for 30 days, followed by oral doxycycline, 200 mg daily for 60 days, or matching intravenous and oral placebos. Each patient had well-documented, previously treated Lyme disease but had persistent musculoskeletal pain, neurocognitive symptoms, or dysesthesia, often associated with fatigue. The primary outcome measures were improvement on the physical- and mental-health-component summary scales of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36)--a scale measuring the health-related quality of life--on day 180 of the study. RESULTS: After a planned interim analysis, the data and safety monitoring board recommended that the studies be discontinued because data from the first 107 patients indicated that it was highly unlikely that a significant difference in treatment efficacy between the groups would be observed with the planned full enrollment of 260 patients. Base-line assessments documented severe impairment in the patients' health-related quality of life. In intention-to-treat analyses, there were no significant differences in the outcomes with prolonged antibiotic treatment as compared with placebo. Among the seropositive patients who were treated with antibiotics, there was improvement in the score on the physical-component summary scale of the SF-36, the mental-component summary scale, or both in 37 percent, no change in 29 percent, and worsening in 34 percent; among seropositive patients receiving placebo, there was improvement in 40 percent, no change in 26 percent, and worsening in 34 percent (P=0.96 for the comparison between treatment groups). The results were similar for the seronegative patients. CONCLUSIONS: There is considerable impairment of health-related quality of life among patients with persistent symptoms despite previous antibiotic treatment for acute Lyme disease. However, in these two trials, treatment with intravenous and oral antibiotics for 90 days did not improve symptoms more than placebo.

We previously reported that low-dose doxycycline (DOXY) therapy reduces host-derived collagenase activity in gingival tissue of adult periodontitis (AP) patients. However, it was not clear whether this in vivo effect was direct or indirect. In the present study, inflamed human gingival tissue, obtained from AP patients during periodontal surgery, was extracted and the extracts partially purified by (NH4)2SO4 precipitation. The extracts were then analyzed for collagenase activity using SDS-PAGE/fluorography/laser densitometry, and for gelatinase activity using type I gelatin zymography as well as a new quantitative assay using biotinylated type I gelatin as substrate. DOXY was added to the incubation mixture at a final concentration of 0-1000 microM. The concentration of DOXY required to inhibit 50% of the gingival tissue collagenase (IC50) was found to be 16-18 microM in the presence or absence of 1.2 mM APMA (an optimal organomercurial activator of latent procollagenases); this IC50 for DOXY was similar to that exhibited for collagenase or matrix metalloproteinase (MMP)-8 from polymorphonuclear leukocytes (PMNs) and from gingival crevicular fluid (GCF) of AP patients. Of interest, Porphyromonas gingivalis collagenase was also inhibited by similar DOXY levels (IC50 = 15 microM), however the collagenase activity observed in the gingival tissue extracts was found to be of mammalian not bacterial origin based on the production of the specific alpha A (3/4) and alpha B (1/4) collagen degradation fragments. In contrast, the inhibition of collagenase purified from culture media of human gingival fibroblasts (MMP-1) required much greater DOXY levels (IC50 = 280 microM). The predominant molecular forms of gelatinolytic activity presented in the AP patients gingival tissue extracts were found to closely correspond to the 92 kD PMN-type gelatinase (MMP-9) although small quantities of 72 kD fibroblast-type gelatinase (MMP-2), and some other low molecular weight gelatinases, were also detected. The IC50 of DOXY versus gingival tissue gelatinolytic activity was estimated at 30-50 microM measure using either type I gelatin zymography or the biotinylated type I gelatin assay. We conclude that MMPS in inflamed gingival tissue of AP patients, like those in GCF, originate primarily from infiltrating PMNs rather than resident gingival cells (fibroblasts and epithelial cells) or monocyte/macrophages, and that their pathologically-elevated tissue-degrading activities can be directly inhibited by pharmacologic levels of doxycycline.

OBJECTIVE. In vitro studies have indicated that levels of neutral metalloproteinases in osteoarthritic (OA) cartilage are elevated and that doxycycline (doxy) inhibits collagenolytic and gelatinolytic activity in extracts of OA cartilage. The purpose of the present study was to test the effect of oral doxy administration on the severity of cartilage degeneration in OA. METHODS. OA was induced in 12 adult mongrel dogs by transection of the anterior cruciate ligament (ACL) 2 weeks after dorsal root ganglionectomy. Six dogs received doxy orally from the day after ACL transection until they were killed 8 weeks later; the other 6 served as untreated OA controls. RESULTS. The unstable knee of each untreated dog exhibited extensive full-thickness cartilage ulceration of the medial femoral condyle. In sharp contrast, cartilage on the distal aspect of the femoral condyle of the unstable knee was grossly normal in 2 doxy-treated dogs, and exhibited only thinning and/or surface irregularity in the others. Degenerative cartilage lesions on the medial trochlear ridge, superficial fibrillation of the medial tibial plateau, and osteophytosis were, however, unaffected by doxy treatment. Collagenolytic activity and gelatinolytic activity in cartilage extracts from OA knees of untreated dogs were 5-fold and 4-fold greater, respectively, than in extracts from dogs given doxy. CONCLUSION. Prophylactic administration of doxy markedly reduced the severity of OA in weight-bearing regions of the medial femoral condyle. It remains to be determined whether administration of doxy after OA changes have developed is also effective.

Ivermectin is the drug used for mass chemotherapy of onchocerciasis within the WHO African Programme for Onchocerciasis Control. This approach aims to eliminate the disease as a public health problem but using one dose per year may not completely interrupt transmission since it does not suppress microfilaridermia thoroughly enough. Here we show that additional treatment with doxycycline, previously shown to sterilise adult female worms for a few months by depletion of symbiotic wolbachia endobacteria, significantly enhances ivermectin-induced suppression of microfilaridermia, rendering anti-wolbachia treatment a promising basis for blocking transmission by a drug-based approach.

We reported previously that controlled expression of a foreign gene in response to tetracycline derivative can be accomplished in mice by the autologous transplantation of retrovirus-modified muscle cells. Although regulated systemic delivery of therapeutic proteins from engineered tissues has potential clinical application, the transplantation of muscle cells is not currently feasible in humans. Several studies have shown that a single injection of adeno-associated virus (AAV) vectors into mouse muscle results in long-term expression of reporter genes as well as sustained delivery of proteins into the serum. Because this method is potentially applicable clinically, we constructed an AAV vector in which the expression of the mouse erythropoietin (Epo) cDNA is modulated in response to doxycycline. The vector was injected intramuscularly in normal mice. We observed that hematocrit and serum Epo concentrations could be modulated over a 29-week period in response to the presence or absence of doxycycline in the drinking water of these animals. Thus, a regulated gene expression cassette can be incorporated into a single AAV vector, such that intramuscular injection of the vector allows sustained and regulated expression of a desired gene.

BACKGROUND: It is unclear whether antimicrobial treatment after an Ixodes scapularis tick bite will prevent Lyme disease. METHODS: In an area of New York where Lyme disease is hyperendemic we conducted a randomized, double-blind, placebo-controlled trial of treatment with a single 200-mg dose of doxycycline in 482 subjects who had removed attached I. scapularis ticks from their bodies within the previous 72 hours. At base line, three weeks, and six weeks, subjects were interviewed and examined, and serum antibody tests were performed, along with blood cultures for Borrelia burgdorferi. Entomologists confirmed the species of the ticks and classified them according to sex, stage, and degree of engorgement. RESULTS: Erythema migrans developed at the site of the tick bite in a significantly smaller proportion of the subjects in the doxycycline group than of those in the placebo group (1 of 235 subjects [0.4 percent] vs. 8 of 247 subjects [3.2 percent], P<0.04). The efficacy of treatment was 87 percent (95 percent confidence interval, 25 to 98 percent). Objective extracutaneous signs of Lyme disease did not develop in any subject, and there were no asymptomatic seroconversions. Treatment with doxycycline was associated with more frequent adverse effects (in 30.1 percent of subjects, as compared with 11.1 percent of those assigned to placebo; P<0.001), primarily nausea (15.4 percent vs. 2.6 percent) and vomiting (5.8 percent vs. 1.3 percent). Erythema migrans developed more frequently after untreated bites from nymphal ticks than after bites from adult female ticks (8 of 142 bites [5.6 percent] vs. 0 of 97 bites [0 percent], P=0.02) and particularly after bites from nymphal ticks that were at least partially engorged with blood (8 of 81 bites [9.9 percent], as compared with 0 of 59 bites from unfed, or flat, nymphal ticks [0 percent]; P=0.02). CONCLUSIONS: A single 200-mg dose of doxycycline given within 72 hours after an I. scapularis tick bite can prevent the development of Lyme disease.

Because leptospirosis has been an important cause of morbidity in U.S. soldiers training in the Republic of Panama, we conducted a randomized, double-blind, placebo-controlled field trial during the fall of 1982 to determine whether doxycycline was an effective chemoprophylactic agent against this infection. Doxycycline (200 mg) or placebo was administered orally on a weekly basis and at the completion of training to 940 volunteers from two U.S. Army units deployed in Panama for approximately three weeks of jungle training. Twenty cases of leptospirosis occurred in the placebo group (an attack rate of 4.2 per cent), as compared with only one case in the doxycycline group (attack rate, 0.2 per cent, P less than 0.001), yielding an efficacy of 95.0 per cent. This study demonstrated the value of doxycycline as a prophylactic drug against leptospirosis.

The targeted inactivation of oncogenes may be a specific and effective treatment for cancer. However, because human cancers are the consequence of multiple genetic changes, the inactivation of one oncogene may not be sufficient to cause sustained tumor regression. Moreover, cancers are genomically unstable and may readily compensate for the inactivation of a single oncogene. Here we confirm by spectral karyotypic analysis that MYC-induced hematopoietic tumors are highly genetically complex and genomically unstable. Nevertheless, the inactivation of MYC alone was found to be sufficient to induce sustained tumor regression. After prolonged MYC inactivation, some tumors exhibited a distinct propensity to relapse. When tumors relapsed, they no longer required the overexpression of MYC but instead acquired novel chromosomal translocations. We conclude that even highly genetically complex cancers are reversible on the inactivation of MYC, unless they acquire novel genetic alterations that can sustain a neoplastic phenotype.