Autoradiographic evidence for a calcitonin receptor on testicular Leydig cells.

Previous studies have indicated that there is a relation between testicular function and adequate concentrations of zinc in testicular cells, and that calcitonin alters cellular zinc transfer in the testis. The present studies provide autoradiographic evidence that calcitonin binds in vivo to the cell membrane of testicular Leydig cells. The data thus confirm the presence of the testicular cell membrane calcitonin receptors that were previously demonstrated indirectly by Scatchard analysis of data collected from binding studies.

Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade.

RATIONALE: Butorphanol exerts activity at mu, kappa, and delta opiate receptors in rats and monkeys but produces predominant mu-like effects in humans. OBJECTIVES: The aim of this study was to determine if the kappa receptor-mediated actions of butorphanol could be unmasked or enhanced by giving it in combination with naltrexone, an opioid antagonist with higher affinity for mu vs kappa receptors. MATERIALS AND METHODS: Ten healthy adult inpatient volunteers (eight men, two women), with opioid abuse histories, completed this double-blind, randomized, placebo-controlled study. Naltrexone (0, 1, 3, 10, or 30 mg, p.o.) was administered 1 h before butorphanol (0, 6, or 12 mg/70 kg, i.m.) during 15 test sessions. An array of physiological (e.g., vital signs, urine output, and subject- and observer-rated) measures was collected before and for 4 h after drug administration. RESULTS: Naltrexone alone produced no direct effects. Butorphanol alone produced typical mu-, but not kappa-, related physiological effects (e.g., miosis, respiratory depression) and produced mood and drug effects considered typical of both mu (e.g., "liking," "good drug effects") and kappa agonists (e.g., increases in perceptual disturbances). Naltrexone pretreatment led to significant butorphanol-induced diuresis (i.e., increased urine output and decreased urine osmolality). Naltrexone generally produced a dose-dependent blockade of subjective responses. CONCLUSION: These data suggest that naltrexone antagonism unveiled the kappaergic activity of butorphanol as measured by diuresis, while subjective responses generally attributed to mu vs kappa receptors were not dissociable. Moreover, these data demonstrate that butorphanol exerts physiologically relevant kappa agonist activity at these supraanalgesic doses in humans.

A multicenter trial of low dose gallium nitrate in patients with advanced Paget's disease of bone.

Gallium nitrate is a potent antiresorptive drug that has been extensively tested in patients with accelerated bone turnover. We have evaluated the effects of this new agent in a pilot multicenter trial of 49 patients with advanced Paget's disease of bone. Patients were randomized to receive 0.05, 0.25, or 0.5 mg/kg.day gallium nitrate administered by sc injection in two 14-day cycles. Serum alkaline phosphatase, fasting 2-h urinary hydroxyproline and N- telopeptide collagen cross-links excretion, and quality of life were assessed every 2 weeks for 12 weeks. The group mean alkaline phosphatase activity at baseline was 854 +/- 100 (+/- SEM) IU/L. The mean changes from baseline to week 12 in serum alkaline phosphatase were +0.5%, -24%, and -31%, respectively, for the three doses tested. The differences for each of the higher dose levels (0.25 and 0.5 mg/kg.day) was statistically significant (P < or = 0.05), and nearly half of the patients treated with the 0.5 mg/kg.day dose achieved a 50% or more reduction in enzyme activity. The nadir value in hydroxyproline excretion occurred at 10 weeks, with mean changes of +9%, -10%, and -17% for the 0.05, 0.25, and 0.5 mg/kg.day doses, respectively; the difference was significant only at the 0.5 mg/kg.day level (P < 0.01). Urinary collagen cross-link excretion showed a significant decrease at the 0.25 and 0.5 mg/kg.day doses. We also observed a definite, but nonsignificant, trend for improved quality of life in patients treated at the highest drug dose. Minor discomfort at the injection site was frequently reported, but did not lead to interruption of therapy. Our results in these patients who had received moderate to extensive prior therapies with other drugs show that cyclical, low dose, sc administration of gallium nitrate is safe and effective for treating patients with advanced Paget's disease of bone.

The role of D2-like dopamine receptors in the locomotor stimulant effects of cocaine in mice.

RATIONALE: Previous studies indicate antagonism of cocaine-stimulated locomotor activity by dopamine D2-like receptor antagonists, but only at doses of the antagonists, that by themselves attenuate locomotor activity, raising questions of the specificity of the interaction and whether it might be due solely to a summation of opposing effects. OBJECTIVES: The interactions of cocaine and several D2-like dopamine antagonists and non-dopamine "physiological antagonists" were compared across a full range of doses in order to fully characterize the interaction and assess the specificity of the effects of dopamine antagonists and cocaine. METHODS: Swiss-Webster mice were treated with either vehicle, a D2-like antagonist (haloperidol, spiperone, raclopride, spiperone, (+) or (-) eticlopride), or a "physiological" antagonist (chlordiazepoxide, clonidine, or R(-) N6-(2-phenylisopropyl)adenosine) and cocaine (5-80 mg/kg) prior to a 30-min locomotor activity test. RESULTS: All test drugs decreased locomotor activity when given alone. All test drugs attenuated cocaine-induced locomotion and decreased peak responding to cocaine. In general, the D2-like antagonists also decreased maximal responding to cocaine and decreased the slope of the ascending limb of the cocaine dose-effect curve, effects not obtained with physiological antagonists. CONCLUSIONS: Blockade of D2-like receptors resulted in an interaction with cocaine that was fundamentally different from that produced through non-dopaminergic mechanisms and appears to be more than a summation of opposing effects. The present data suggest that D2-like receptors are involved in the mechanisms underlying the induction of locomotor activity by cocaine.

Influence of parathyroid hormone and calcitonin on tissue zinc homeostasis in the rat.

Tissue zinc accumulation kinetics and compartmental analysis models were evaluated in thyroparathyroidectomized (TPTX) rats treated with parathyroid extract or calcitonin. The animals were injected with 65Zn and studied at multiple time intervals. SAAM-25 was utilized to generate models from the plasma specific activity decay curves. Calcitonin had a marked effect to decrease the fractional influx and efflux transfer coefficients in the model and inhibit tissue zinc accumulation in several, but not all, tissues. Parathyroid extract increased accumulation in all tissues studied, but had minimal effects on the model. It is concluded that parathyroid hormone acts nonspecifically and that calcitonin appears to have specific influences on zinc homeostasis.

Calcitonin, zinc, and testicular function.

Recent studies demonstrating decreases in transport kinetics of zinc (Zn) in testis in response to calcitonin (CT) and the presence of CT receptors on Leydig cells has suggested a physiological interrelationship between CT and cellular Zn metabolism in the testis. The present studies were undertaken to evaluate the acute effects of human synthetic calcitonin (hCT) on testosterone (T) synthesis and on transmembrane Zn transport as measured in a closed two-compartment model system in Leydig cells isolated from intact and thyroparathyroldectomized (TPTX) rats. Leydig cells acutely exposed to 1 ng/mL equine luteinizing hormone (LH) in vitro had a fivefold increase in medium T concentration. Calcitonin at 42 micrograms/mL had no effect on the basal T synthesis and did not affect the increase seen after LH administration. Lower doses of LH demonstrated a dose response for T production, but no alteration in the pattern of response. In TPTX rats pretreated with 167 micrograms/d (25 MRC U/d) hCT subcutaneously (sc) for three days before they were killed, a reduction to 73% of the control value was observed in the in vitro Leydig cell fractional influx coefficient for Zn transport (P less than .02). No difference was observed in the fractional efflux coefficient. Fractional flux coefficients from intact rats demonstrated qualitatively similar, but more variable, changes. These data demonstrate that there is no acute effect of CT on T synthesis in the isolated Leydig cell. There does appear, nevertheless, to be a role for CT in the modulation of transmembrane Zn transport. Clinically important Zn-dependent alterations of T synthesis may require long-term changes in Zn metabolism before they become manifest.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutaneous manifestations of tumoral calcinosis.

We have followed up a large family in which seven members have tumoral calcinosis. One girl had the skin lesions of localized calcinosis cutis apart from the typical subcutaneous deposits of calcium. Like most persons with tumoral calcinosis, our patient had normal serum calcium concentrations; however, the serum phosphorus levels were greatly elevated. The familial occurrence and elevated serum phosphorus levels suggest the possibility of some as yet undefined, heritable metabolic defect as the underlying cause. The occurrence of tumoral calcinosis with localized calcinosis cutis is a rare association, and there has been only one other reported case to our knowledge. This report describes our patient and offers a brief discussion of tumoral calcinosis. The therapeutic response to the phosphate depletion regimen and topical steroids was disappointing in our case.

Influence of cholecalciferol on tissue zinc homeostasis in the rat.

A role for calciferol in zinc homeostasis was investigated by radioisotope uptake and compartmental analysis techniques. cholecalciferol was injected into rats 4-5 days prior to radioisotopic study of rapidly exchangeable pools (< 4 h). Kidney, liver, and duodenum had significant increases in zinc uptake rates. Bone and skeletal muscle had significant decreases. No other tissues had significant differences. Compartmental analysis models generated by the SAAM-25 digital computer program suggested a decrease in the fractional tissue to plasma coefficient to be the mechanism for the observed changes in the serum zinc concentration and tissue zinc accumulation rates. It is not clear whether this is a specific effect of calciferol on zinc homeostasis or is a nonspecific response which may reflect some role for zinc in calciferol metabolism.

Intraaccumbens raclopride attenuates amphetamine-induced locomotion, but fails to prevent the response-reinstating properties of food reinforcement.

It has been well established that the presentation of a single reinforced trial in the midst of extinction results in a reinstatement of the previously reinforced operant response. In previous experiments, we have shown that systemically applied raclopride (a selective dopamine D2 receptor antagonist) dose dependently blocked the response-reinstating properties of food reinforcement, while SCH39166 (a selective dopamine D1 receptor antagonist) did not (11). The current experiments investigated the possible role of the nucleus accumbens in these actions of raclopride. In the first of two experiments, hungry rats were trained to traverse a straight runway for food reinforcement, a response that was then weakened through a series of extinction trials. On a single treatment trial, subjects were infused with one of three doses of intraaccumbens raclopride (0.0, 2.5, or 5.0 microg/0.5 microl/side) just prior to a reinforced trial. Twenty-four hours later, a single test trial was run in an unbaited runway. The results demonstrate that the prior day's reinforced trial produced a reinstatement of operant runway performance that was unaltered by intraaccumbens applications of raclopride. Two days later, the same animals were tested in a second experiment investigating the effects of intraaccumbens raclopride on amphetamine-induced locomotion. Subjects were pretreated with 1.0 mg/kg s.c. amphetamine prior to a 90-min locomotor activity session. The following day, subjects were again pretreated with amphetamine, but this time with a challenge dose of raclopride. Results demonstrate that the same raclopride doses that produced no effect in the response-reinstating experiment produced, in the same rats, a dose-dependent attenuation in amphetamine-induced locomotion. These data suggest that dopamine D2 receptors in the nucleus accumbens may not, in and of themselves, be necessary for the response-reinstating effects of food reinforcement.

A role for D2, but not D1, dopamine receptors in the response-reinstating effects of food reinforcement.

Although the reinforcing properties of food are reduced in the presence of dopamine antagonist drugs, controversy exists about the relative roles of D1 vs D2 receptor subtypes in the actions of these drugs. The current experiment compared the effects of raclopride (a selective D2 receptor antagonist) and SCH 39166 (a selective D1 receptor antagonist) in the response-reinstating effects of food reinforcement. Hungry rats were trained to run a straight-alley for food reinforcement during single daily trials. The operant was then extinguished during consecutive daily non-reinforced trials. Subjects were then injected with one of four doses of raclopride (0.0, 1.0, 0.5, and 0.25 mg/kg, i.p.) or SCH 39166 (0.0, 1.0, 0.5, and 0.1 mg/kg i.p.) 30 min prior to a single reinforced treatment trial. Twenty-four h later, a test trial was conducted in an unbaited runway. The single reinforced trial in the midst of extinction was observed to reinstate operant runway performance. Raclopride, but not SCH 39166, dose-dependently attenuated this reinstatement. Motor control groups ruled out the possibility that these results were due to differential residual motor effects of the drugs. Results suggest that D2, but not D1, dopamine receptors, are involved in the response-reinstating properties of food reinforcement.

Tumoral calcinosis: scintigraphic studies of an affected family.

Tumoral calcinosis is a rare, familial ectopic calcification syndrome associated with hyperphosphataemia. A family in which seven of 13 siblings had demonstrable, clinical, radiological and pathological findings of tumoral calcinosis was evaluated. The purposes were to compare the efficacy of bone scintiscans with serum phosphorus determination in detecting subclinical disease early in asymptomatic siblings and to assess therapeutic results in affected family members following initiation of phosphate depletion therapy. History, physical examination, serum calcium, serum phosphorus and bone scintiscans were performed in 12 of 13 siblings. All the affected siblings had markedly elevated serum phosphorus levels and abnormal bone scintiscans while the unaffected siblings had normal serum phosphorus levels and normal bone scintiscans. All the siblings, affected and unaffected, were normocalcaemic. After initiation of phosphate depletion therapy, gross changes in the appearance of lesions were detected on bone scintiscans. Serum phosphorus levels likewise showed a modest decline, although still remaining in the hyperphosphataemic range. In conclusion, bone scintiscans and serum phosphorus determinations are equally sensitive in detecting subclinical disease. However, the scintiscans are helpful in assessing not only the extent of the disease, but also whole-body and regional changes following any therapeutic interventions.

Prognostic evaluation in geriatric oncology: problems and perspectives.

The optimal management of older patients with malignant diseases may be prevented by two antithetic conditions: inadequate treatment and excessive treatment. A likely root of this problem appears to be paucity of prognostic information, which may hamper management-related decisions in the older person with cancer. The prognostic value of performance status and nutritional status may fade with aging, while the influence of mental, emotional and socioeconomic status on the outcome of neoplastic diseases may become more prominent. The Comprehensive Geriatric Evaluation (CGE), which encompasses emotional mental and social domains in addition to physical health and function, may prove a valuable clue for the selection of those older patients who are suitable candidates for antineoplastic treatment.

Caffeine as a model drug of dependence: recent developments in understanding caffeine withdrawal, the caffeine dependence syndrome, and caffeine negative reinforcement.

Caffeine is an excellent model compound for understanding drugs of abuse/dependence. The results of self-administration and choice studies in humans clearly demonstrate the reinforcing effects of low and moderate doses of caffeine. Caffeine reinforcement has been demonstrated in about 45% of normal subjects with histories of moderate and heavy caffeine use. Recent studies provide compelling evidence that caffeine physical dependence potentiates the reinforcing effects of caffeine through the mechanism of withdrawal symptom avoidance. Tolerance to the subjective and sleep-disrupting effects of caffeine in humans has been demonstrated. Physical dependence as reflected in a withdrawal syndrome in humans has been repeatedly demonstrated in adults and recently demonstrated in children. Withdrawal severity is an increasing function of caffeine maintenance dose, with withdrawal occurring at doses as low as 100 mg per day. Increased cerebral blood flow may be the physiological mechanism for caffeine withdrawal headache. Case studies in adults and adolescents clearly demonstrate that some individuals meet DSM-IV diagnostic criteria for a substance dependence syndrome on caffeine, including feeling compelled to continue caffeine use despite desires and recommendations to the contrary. Survey data suggest that 9% to 30% percent of caffeine consumers may be caffeine dependent according to DSM-IV criteria.

Zinc, insulin and diabetes.

The relationship between diabetes, insulin and zinc (Zn) is complex with no clear cause and effect relationships. In Type 1 diabetes there is a lack of insulin production, in Type 2 diabetes resistance to the effects of insulin are predominant. Both Type 1 and Type 2 have the same long-term complications. Diabetes effects zinc homeostasis in many ways, although it is most probably the hyperglycemia, rather than any primary lesion related to diabetes, which is responsible for the increased urinary loss and decreases in total body zinc. The role of Zn deficiency, which could, at least potentially, exacerbate the cytokine-induced damage in the autoimmune attack which destroys the islet cell in Type 1 diabetes, is unclear. Since Zn plays a clear role in the synthesis, storage and secretion of insulin as well as conformational integrity of insulin in the hexameric form, the decreased Zn, which affects the ability of the islet cell to produce and secrete insulin, might then compound the problem, particularly in Type 2 diabetes. Several of the complications of diabetes may be related to increased intracellular oxidants and free radicals associated with decreases in intracellular Zn and in Zn dependent antioxidant enzymes. There appears to be a complex interrelationship between Zn and both Type 1 and Type 2 diabetes. The role of Zn in the clinical management of diabetes, its complications, or in its prevention is, at best, unclear.