Comparison of the antinociceptive profiles of gabapentin and 3-methylgabapentin in rat models of acute and persistent pain: implications for mechanism of action.

The anticonvulsant gabapentin (GBP) has been shown effective for the treatment of neuropathic pain, although its mechanism of action remains unclear. A recent report has suggested that binding to the alpha(2)delta subunit of voltage-gated calcium channels contributes to its antinociceptive effect, based on the stereoselective efficacy of two analogs: (1S,3R)3-methylgabapentin (3-MeGBP) (IC(50) = 42 nM), which is effective in neuropathic pain models; and (1R,3R)3-MeGBP (IC(50) > 10,000 nM), which is ineffective (Field et al., 2000). The present study was designed to further examine the profiles of GBP and 3-MeGBP in rat models of acute and persistent pain. Systemic administration of GBP or (1S,3R)3-MeGBP inhibited tactile allodynia in the spinal nerve ligation model of neuropathic pain, whereas (1R,3R)3-MeGBP was ineffective. The antiallodynic effect of GBP, but not (1S,3R)3-MeGBP, was blocked by i.t. injection of the GABA(B) receptor antagonist [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl)phosphinic acid (CGP52432). Systemic GBP or (1S,3R)3-MeGBP also inhibited the second phase of formalin-evoked nociceptive behaviors, whereas (1R,3R)3-MeGBP was ineffective. However, both (1S,3R)3-MeGBP and (1R,3R)3-MeGBP, but not GBP, inhibited first phase behaviors. In the carrageenan model of inflammatory pain, systemic GBP or (1R,3R)3-MeGBP failed to inhibit thermal hyperalgesia, whereas (1S,3R)3-MeGBP had a significant, albeit transient, effect. Systemic (1S,3R)3-MeGBP, but not GBP or (1R,3R)3-MeGBP, also produced an antinociceptive effect in the warm water tail withdrawal test of acute pain. These data demonstrate that GBP and 3-MeGBP display different antinociceptive profiles, suggesting dissimilar mechanisms of antinociceptive action. Thus, the stereoselective efficacy of 3-MeGBP, presumably related to alpha(2)delta binding, likely does not completely account for the mechanism of action of GBP.

[2 cases of lymphangioleiomyomatosis treated by hormonal manipulation]. / To tilfaelde af lymfangioleiomyomatose behandlet med hormonal manipulation.

The course of disease in two women with bioptically verified lymphangioleiomyomatosis (LAM) is demonstrated. One was oestrogen- and progesterone-receptor negative, but responded promptly to hysterosalpingo-oophorectomy and has had no symptoms later. The other was receptor positive, but in spite of hysterosalpingo-oophorectomy and hormonal manipulation with tamoxifen and medroxyprogesterone, has had a complicated course of the disease with symptoms for ten years. LAM is a hormone dependent disease, but our knowledge is still incomplete. Hormonal manipulation should be tried in receptor positive as well as negative patients. Tamoxifen seems to have deleterious effects on the course of disease.

Anticonvulsive properties of pregnanolone emulsion compared with althesin and thiopentone in mice.

The anticonvulsive properties of pregnanolone (as an emulsion) were evaluated in mice and compared with similar properties of Althesin and thiopentone. Pregnanolone emulsion was found to antagonize convulsions induced by the GABA antagonists pentetrazole, bicuculline and picrotoxin and by the specific glycine receptor antagonist, strychnine. The drug was effective in all four convulsive tests at subanaesthetic doses with maximal activity appearing within less than 1 min. The anticonvulsive therapeutic indices of pregnanolone emulsion were superior when compared with the therapeutic indices of Althesin and thiopentone in all four tests. Pregnanolone emulsion might be a useful alternative drug in the management of convulsive states resistant to conventional therapy.

Long-term intravenous rifampicin treatment. Advantages and disadvantages.

A 28-year-old woman suffering from diabetes, malabsorption and pulmonary tuberculosis was treated successfully with ethambutol and rifampicin intravenously for 4 months. The drugs were given through a catheter placed in the upper caval vein. One month after the treatment was started the sputum cultures became negative. During oral therapy the patient suffered from characteristic "flu" syndrome which surprisingly disappeared during the intravenous treatment. The possible causes are discussed. Allergic reactions to rifampicin appeared among the staff. The results of the allergological examinations are mentioned and directions for handling rifampicin powder are suggested.

Carbonic anhydrase isoenzyme determination: An aid to the diagnosis of "small-for-date" infants.

A specific and quantitative immunological method for the determination of human erythrocyte carbonic anhydrase isoenzymes B and C has been used to determine these enzymes in erythrocytes of umbilical cord blood. The investigations have shown a content of both isoenzymes less than a tenth of that in adults. The isoenzyme content correlated significantly with the estimated gestational age. The ratio between isoenzyme B and C rose with gestational age, reaching adult level at term. A group of 19 "small-for-date" infants had isoenzyme levels in the same range as normal full-term infants, significantly higher than the levels in the same range as normal full-term infants, significantly higher than the levels in truly premature infants. It is concluded that the determination of carbonic anhydrase isoenzymes is an aid in distinguishing "small-for-date" infants from the truly premature.

Carbonic anhydrase isoenzyme B in erythrocytes of subjects with chronic acidosis.

A specific and quantitative immunological method for determination of human erythrocyte carbonic anhydrase isoenzyme B has been used to ascertain the contents of this enzyme in the erythrocytes of healthy persons and of subjects with chronic metabolic and respiratory acidosis. The investigations have shown significant increase of carbonic anhydrase type B in the erythrocytes of patients suffering from renal failure with chronic acidosis, and in patients with chronic obstructive lung disease and chronic respiratory acidosis. The erythrocytes of acidotic uremic patients have a significantly higher content of erythrocyte carbonic anhydrase isoenzyme B than do the erythrocytes of uremic subjects without chronic acidosis. In chronic obstructive lung disease, the content of this enzyme in erythrocytes was significantly higher in the hypercapnic patients than in the normocapnic ones. In renal failure, significant correlation was found between carbonic anhydrase isoenzyme B and standard bicarbonate. In chronic obstructive lung disease no significant correlation was found between carbonic anhydrase and pCO2.

Carbonic anhydrase isoenzyme B in erythrocytes of subjects with chronic obstructive lung disease.

A specific and quantitative immunological method for the determination of human erythrocyte carbonic anhydrase (HCA) isoenzyme B has been used to determine the contents of enzyme in the erythrocytes from healthy persons and from subjects with chronic obstructive lung disease. The investigations have shown a statistically significant increase of HCA type B in the erythrocytes of subjects suffering from chronic obstructive lung disease and hypercapnia. Subjects with chronic obstructive lung disease and normal PaCO2 showed no difference from normal subjects. No correlation was found between PaCO2 and human erythrocyte carbonic anhydrase.

Carbonic anhydrase isoenzyme B in erythrocytes of anemic and non-anemic uremic subjects.

A specific and quantitative immunological method for determination of human erythrocyte carbonic anhydrase isoenzyme B has been used to determine the contents of this enzyme in the erythrocytes from healthy persons and anemic and non-anemic subjects with renal insufficiency. The investigations have shown significant increase of carbonic anhydrase type B in the erythrocytes of patients with renal failure. The erythrocytes of anemic uremic patients have a significantly higher content of erythrocyte carbonic anhydrase isoenzyme B than the erythrocytes of non-anemic uremic subjects. Significant correlations were found between human erythrocyte carbonic anhydrase type B and hemoglobin and between it and plasma bicarbonate. No correlation was found between human erythrocyte carbonic anhydrase and plasma creatinine or creatinine clearance and serum zinc.

Carbonic andydrase isoenzyme B in erythrocytes of subjects with different types of anemia.

A specific and quantitative immunological method for determination of human erythrocyte carbonic anhydrase (HCA) isoenzyme B has been used to determine the contents of enzyme in the erythrocytes from healthy persons and from subjects with different types of anemia. The investigations have shown a statistically significant increase of HCA type B in the erythrocytes of subjects suffering from uremic anemia, cancer anemia, megaloblastic anemia while in sideropenic anemia the content was normal. In erythrocytes from patients with acute bleeding anemia the content of HCA type B was significantly decreased. An inverse relationship was found between B-hemoglobin and HCA type B in megaloblastic anemia but not in the other types of anemia.

Carbonic anhydrase isoenzymes in the erythrocytes of new-born premature and full-term infants.

A specific and quantitative immunological method for the determination of human erythrocyte carbonic anhydrase isoenzymes B and C has been used to determine these enzymes in erythrocytes of umbilical cord blood. The investigations have shown a content of both isoenzymes less than 1:10 of that in adults. Premature infants have significantly lower values than full-term infants. The influence of carbonic anhydrase in the respiratory distress syndrome is discussed. No conclusions are drawn. The content of carbonic anhydrase in erythrocytes has been suggested as a laboratory parameter of maturity. In our investigations it does not seem to be useful for the evaluation of muturity.