Double blind cross-over studies on phototoxicity to three tetracycline derivatives in human volunteers.

A double blind cross-over phototoxicity study using demethylchlortetracycline (DMCT) 0.3 g x 2, doxycycline 0.1 g x 2, lymecycline 0.6 g x 2 and placebo was performed on 8 healthy human volunteers. Drugs were given for 3 consecutive days, and on the third day the volunteers were tested with different modalities of artificial long-wave ultraviolet radiation (UVA) and assessed 24 h later for objective as well as subjective abnormal photoreactions. All 4 substances were tested in each individual at weekly intervals and serum concentrations of tetracycline were determined. It was found most convenient to irradiate relatively large skin areas using fluorescent tubes emitting mainly UVA but also a small proportion of UVB. Using this type of irradiation, weak erythemal reactions were obtained with all 3 derivatives. Taking only stronger reactions and stinging sensations into account, 0/8 reacted to lymecycline, 0/8 to DMCT and 4/8 to doxycycline. There was no significant difference in serum concentration among the 3 derivatives. It is concluded that doxycycline is the most potent photosensitizer at the dosage tested.

Demeclocycline-induced natriuresis and renal insufficiency: in vivo and in vitro studies.

We examined renal function and Na+ balance in a patient with congestive heart failure who was treated with demeclocycline (DMC) on three separate occasions under strict metabolic balance conditions. Natriuresis and reversible renal insufficiency, which could not be explained solely on the basis of negative Na+ balance, developed on each occasion. In contrast to reports of an association between elevated serum DMC levels and renal insufficiency in patients with cirrhotic edema, the renal insufficiency in this patient with cardiac edema occurred in the absence of high DMC levels. Consequently, markedly elevated serum DMC levels do not appear to be a prerequisite for the development of natriuresis or renal insufficiency in edematous patients receiving this drug. In an attempt to clarify the mechanism of the natriuresis, we also examined the effects of DMC on Na+ transport in an in-vitro model system, the toad urinary bladder. DMC inhibited aldosterone-stimulated Na+ transport, but had no effect on Na+ transport when the latter was jointly stimulated by ADH and theophylline. Despite this selective inhibition of the natriferic effect of aldosterone in vitro, it is unlikely that such a mechanism completely accounts for the natriuresis observed in-vivo since the natriuresis is generally of large magnitude and is usually accompanied by some degree of kaliuresis, and DMC had no consistent effect on urinary aldosterone excretion. Consequently, other mechanisms must be sought to explain the natriuretic effect of DMC in edematous patients. Likewise, mechanisms other than negative Na+ balance (perhaps primary alterations in renal hemodynamics) must underly the development of renal insufficiency in such individuals.

Effect of intrauterine administration of tetracyclines on cynomolgus monkeys.

Cynomolgus monkeys were used to screen for chemicals which potentially could be used as tubal occluding agents. Intrauterine administrations of solution or pellets of tetracycline and its analogues (100 mg doses) were tested for their effects on morphologic changes in the reproductive tract of monkeys. These effects were compared to monkeys receiving intrauterine administration of quinacrine pellets (36 mg) since quinacrine has been used successfully in the clinical setting. Blood levels of drugs, blood chemistry and hematology determinations and liver and kidney pathology data were also obtained as indices for toxicity. Morphologic damage to the uterine lining and intramural section of the tube (including necrosis, inflammation or scarring) was elicited by intrauterine tetracycline and doxycycline in the same frequency and severity as quinacrine. In contrast, saline or sham control monkeys showed no morphological damage of the tube or uterus. Although all drugs could be detected in the blood 4 hours after intrauterine administration, levels were near or below the limit of detection by one week. No evidence was found for toxicity of tetracycline or its analogues for the dosage given. Because of these results and the extensive literature on tetracycline toxicity, further studies should be directed toward the use of tetracycline as a sterilizing agent in women.

Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients.

In five hyponatremic, cirrhotic patients, demeclocycline hydrochloride was used to inhibit the hydroosmotic effect of vasopressin. In four, renal impairment developed during the 7 to 20 days of demeclocycline hydrochloride (900 to 1,200 mg/day) administration. In these four patients, creatinine clearance fell (72 to 20 mL/min, P less than .01) as BUN (12 to 47 mg/dl, P less than .02) and serum creatinine (0.9 to 4.2 mg/dl, P less than .01) levels rose. The azotemic effect of the drug could not be accounted for consistently by volume depletion secondary to its natriuretic effect. However, a close correlation between plasma demeclocycline levels and its azotemic effect was observed. We conclude that a nephrotoxic effect of demeclocycline severly limits its usefulness in treating hyponatremia in the cirrhotic patient.

Effects of repeated oral doses of demethylchlortetracycline on bones and dentin of young rhesus monkeys.

Seven oral doses of demethylchlortetracycline were administered to monkeys that received serial injections of lead acetate to intravitally stain calcification sites. Bone growth was greatly inhibited, whereas dentin apposition was spared from the cumulative toxicity of demethylchlortetracycline. Cessation of bone growth and its duration could be correlated with serum levels.