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Tissue distribution, bioavailability, and efficacy of alendronate in preventing progression of resorption of teeth were evaluated in cats. [Butyl-4-14C-]-alendronate accumulates on subgingival tooth and alveolar bone surfaces adjacent to vascularized tissue resulting in concentration of the drug around tooth roots. Three cats were treated with a 0.03 mg/kg IV bolus of [butyl-4-14C-]-alendronate followed by blood, urine, and feces collection and euthanasia 24-hours later. Drug tissue distribution was accessed by autoradiography and sample combustion. To assess bioavailability, 12 cats were administered alendronate orally (3.0 or 9.0 mg/kg in water or 9.0 mg/kg in tuna water) and urine was collected for 24-hours. In these formulations, alendronate oral bioavailability in cats was approximately 3 %. In addition, 10 cats with radiographic evidence of pre-existing tooth resorption (14 affected teeth) were treated with vehicle or 3.0 mg/kg alendronate per os once weekly for 22-weeks and, then, 9.0 mg/kg per os twice weekly for 27-weeks in a random, masked study. Radiographic area of resorption was measured and progression scored every 3 to 4-months.In placebo-treated cats, resorption progressed in five of six teeth (+ 97 % average increase in area of resorption), whereas progression of resorption was seen in only three of eight affected teeth in alendronate-treated cats with a – 22 % average change (decrease) in area (P < 0.01 difference in number of teeth showing progression; P < 0.001 difference in area of resorption).Alendronate accumulated preferentially on subgingival tooth surfaces and adjacent alveolar bone and, at a dose of 9 mg/kg twice weekly, effectively slowed or arrested the progression of resorption.

Twenty‐two beagles were divided into two equal groups, and the right hindlimb of each animal was immobilized at 105° of knee flexion by external fixation. After 10 weeks of fixation, the device was removed, allowing free mobility for the following 5 weeks. Each day throughout the 15 weeks, one group received a growth hormone secretagogue (treatment) at a dose of 5 mg/kg, and the other received a lactose placebo (control). At weeks 0, 10, and 15, strength as indicated by maximum isometric extension torque was measuredin the right hindlimb, biopsies of the vastus lateralis muscle were taken, and the dogs were weighed. Weekly blood samples were analyzed for insulin‐like growth factor‐I, blood urea nitrogen, and creatine phosphokaase. Between weeks 0 and 10, tetanic torque declined by about 60% (p < 0.001) in both groups, with no significant difference between the groups (p > 0.7). Between weeks 10 and 15, tetanic torque in the treated group increased by 0.81 Nm; this was significantly greater than the increase of 0.25 Nm in the placebo group (p < 0.05). The diameters of slow (type‐1) and fast (type‐2) fibers measured from the vastus lateralis muscle followed the same trend. At all time points, fiber diameter correlated strongly with torque; this argues against nonmuscular causes such as nerve injury for strength loss. The mean levels of insulin‐like growth factor‐1 increased 100% by week 4 in the treated group and remained elevated by about 60% throughout the experiment. Levels of insulin‐like growth factor‐1 in the placebo group decreased 30% within week 1 and remained depressed throughout the experiment. Our interpretation of these data suggests that the growth hormone secretagogue elevated levels of serum insulin‐like growth factor‐1, which in turn increased the size and strength of the quadriceos muscle during remobilization. These data may ultimately have therapeutic application to humans during rehabilitation after prolonged inactivity.

The low-molecular-weight, heat-stable type of Escherichia colienterotoxin (ST) was obtained from sterile syncase broth filtrates of human and animal enteropathogenic E. colistrains. ST was assayed in infant mice, and it was found that this assay was specific for ST in that the high-molecular-weight, heat-labile type of E. coliexterotoxin would not cause fluid accumulation in these animals. ST was first detected in the broth of a culture of human strain 334A(015:H11) 5 h after inoculation, immediately after the log phase of growth; the highest concentration of ST occurred at 24 h after inoculation. ST was purified 13-fold by ultrafiltration and gel filtration chromatography. The purest preparation contained 15% protein and 2% carbohydrate. The mean effective dose or 1 unit dose in infant mice was 5.0 μg/mouse. The ST molecular weight was between 1,000 and 10,000, and its activity was resistant to acid, trypsin, and Pronase.

Cephamycin C is a β-lactam antibiotic that has broad gram-negative activity and is resistant to degradation by β-lactamases and safe for use in animals. In colostrum-fed calves infected with Escherichia colistrain B44, cephamycin C administered by gavage at 31.3 to 1,000 mg per calf (0.75 to 24 mg/kg) twice a day for 6 days starting at 20 h post-inoculation eliminated the diarrhea and reduced the mortality from 90% in infected, nonmedicated calves to 14% in infected, medicated calves (P< 0.01). Comparable results were obtained with a shorter treatment regimen (30 mg of cephamycin C per calf [0.71 mg/kg] twice a day for 3 days). In colostrum-fed piglets infected with E. colistrain P155 and housed in cages, cephamycin C administered prophylactically by gavage at 12.5 mg per piglet (10.4 mg/kg) twice a day for 4 days completely prevented both diarrhea and mortality, whereas nonmedicated piglets had 100% diarrhea and all died. When eight doses of cephamycin C were given therapeutically starting at 6 h post-inoculation, mortality was reduced from 79 to 23% (P< 0.02), and diarrhea was eliminated in the surviving medicated piglets by 4 days post-inoculation. In infected suckling piglets, cephamycin C administered therapeutically by gavage at 12.5 mg per piglet twice a day for 3 days starting at 6 h post-inoculation, diarrhea and mortality were reduced (P< 0.05): infected, nonmedicated piglets had 87% diarrhea and 75% mortality, whereas infected, medicated piglets had 25% diarrhea and 31% mortality. All surviving medicated piglets had solid feces by 2 days post-inoculation. Thus, cephamycin C was highly effective in restoring the calves and piglets to good health by eliminating diarrhea and reducing mortality.

The treatment of periodontal disease has been largely directed at the microbiological etiology. The prevention of bone loss by modulating the host response to the bacteria may be a useful adjunctive method in the management of periodontitis. Alendronate, an amino bisphosphonate, may inhibit bone loss in osteolytic diseases by altering osteoclast activity. The objective of this double‐blind study was to evaluate alendronate inhibition of alveolar bone loss in the naturally occurring beagle dog model of periodontitis. Sixteen 7 to 9 year old beagles with moderate‐to‐severe periodontitis were studied for 6 months. The dogs were stratified into two groups based on initial periodontal severity. One group received 3.0 mg/kg alendronate weekly orally and the other group received a placebo. Silk ligatures were placed on the study teeth for the first 3 months of the study to exacerbate the periodontal destruction. Clinical data were collected for attachment level, gingival index, plaque index, and mobility at baseline and one‐month intervals. Intraoral radiographs were made at baseline and at 3 and 6 months. The mandibles were processed for histolology at month 6. The radiographs were analyzed by digital image analysis of the subtracted images. A statistically significant difference in bone mass (P<0.001) was observed between the alendronate and placebo groups. The bisphosphonate had no effect on the clinical parameters of gingival inflammation or plaque. A trend toward decreased attachment loss and mobility was observed in favor of the alendronate group. A significant difference in bone density (P<0.05) was found by histomorphometric analysis. Bisphosphonate treatment may be beneficial in the management of alveolar bone destruction associated with periodontal destruction. J Periodontol 1995; 66:211–217.

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substitutent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4and 1, respectively. The best of these compounds, 18(EC50= 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.

The synthesis and activities of a series of spiroindane growth hormone secretagogues is reported. Modification of the benzylic position of the spiroindane has resulted in a dramatic increase in potency resulting in subnanomolar peptidomimetic growth hormone secretagogues. In vivo data demonstrating the good oral activity of these analogs is reported.

A study was undertaken to determine whether virulence in mice could be used to assess the pathogenicity of a variety of Escherichia coliserotypes. Sixty-one E. colistrains isolated from animals, poultry, or humans were serotyped to determine their O, K, and H antigens, and were administered to mice via the intraperitoneal route with and without a mucin adjuvant. The ld50dose was then determined for each serotype. The results indicated that the source of the serotype may be associated with virulence for mice. Serotypes isolated from nonenteric, systemic sources showed a greater virulence for mice inoculated intraperitoneally than did the enteric and the nonenteric, nonsystemic (localized) isolates. It was observed that not all serotypes belonging to a specific serogroup were virulent for mice and that the presence or absence of a K antigen had no effect on the virulence of strains of one serotype.

The enterotoxic component in sterile syncase broth filtrates of Escherichia colistrains 340 (O9:K·:NM) and P307 (O8:K87,88a,b:H19) was studied. The enterotoxic activity in both strains was retained by an ultrafiltration membrane with a molecular weight retention of 100,000 (XM-100A) and eluted from a Sephadex G-200 column in the void volume. The enterotoxic activity in strain 340 was resistant to heating at 75 C for 30 min, but the activity in strain P307 was destroyed by heating at 60 C for 30 min. The P307 Sephadex G-200 column eluate possessing the enterotoxic activity, when desalted, contained 45.8% carbohydrate and 9.3% protein, and had an ED50of 2.2 mg/rabbit ileal loop. Immunodiffusion studies showed that this material contained both endotoxin and acid-polysaccharide capsular material. The enterotoxic activity was acidlabile and was destroyed by Pronase, but was resistant to trypsin and eluted as a single peak in the void volume of a 4% agarose column. The enterotoxic component could not be separated from the endotoxin; in fact, the data indicated that the two components are closely associated and that the enterotoxic activity resides in material of a protein nature.

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