J. Mattila

Possible involvement of nigrostriatal dopamine system in the inhibition of thyrotropin secretion in the rat.

The dopaminergic inhibition of cold-stimulated thyrotropin (TSH) secretion was studied in male rats. Serum TSH levels were decreased by apomorphine (1 mg/kg i.p.) but not by dopamine (DA, 0.2--5 mg/kg s.c.). This effect of apomorphine was abolished by haloperidol (1 mg/kg i.p.), metoclopramide and sulpiride (10 mg/kg i.p.) but not by domperidone (0.1--5 mg/kg i.p.). Domperidone does not cross the blood-brain barrier while the other DA receptor antagonists do so. High doses of domperidone itself inhibited the cold-induced TSH secretion whereas the other DA antagonists did not. DA (1--10 micrograms/rat) into the medial basal hypothalamus (MBH) had no effect but 10--50 micrograms/rat into the 3rd ventricle inhibited the cold-stimulated TSH secretion. 6-Hydroxydopamine infusion after desipramine pretreatment (25 mg/kg i.p.) did not affect TSH secretion when given into the MBH (2 micrograms/rat), the 3rd ventricle (100 micrograms/rat) or unilaterally into the substantia nigra (SN, 6 micrograms/nucleus), but bilateral nigral infusions abolished the TSH cold response. The inhibitory effect of apomorphine (0.1 and 0.5 mg/kg i.p.) was amplified only in the rats whose SN was unilaterally destroyed. These results show that tuberoinfundibular DA neurons do not affect TSH secretion. Instead, the inhibition is mediated through the hypothalamic projections of the nigrostriatal DA system.

Dual action of morphine on cold-stimulated thyrotropin secretion in male rats

The effect of morphine infused into 4 hypothalamic locations and the periaqueductal gray (PAG) on cold-stimulated thyrotropin (TSH) secretion was studied in male rats. Morphine decreased TSH cold-response when infused into the 3rd ventricle (1-20 micrograms/rat) or the median eminence (5 and 10 micrograms/rat). Infusions bilaterally into the anterior hypothalamus (1-10 micrograms/side) or PAG (1 and 10 micrograms/rat) were ineffective, while those given into the posterior hypothalamus (1 and 5 micrograms/side, but not 10 micrograms/side) significantly enhanced TSH cold-response. Naloxone pretreatment (2 or 5 mg/kg, s.c.) reversed the decreasing effect of morphine in the 3rd ventricle (1 microgram/rat) and the increasing effect of morphine in the posterior hypothalamus (1 microgram/side). We conclude that morphine has a dual hypothalamic action on cold-stimulated TSH secretion: an inhibition periventricularly, and a stimulation in the posterior hypothalamus.

The Effect of Maneb, Zineb, and Ethylenethiourea on the Humoral Activity of the Pituitary-Thyroid Axis in Rat

Ethylenebisdithiocarbamates (EBDCs) maneb and zineb are widely used fungicides the final metabolite of which is ethylenethiourea (ETU). EBDCs distort the humoral activity of the thyroid gland, and ETU is especially active in this respect. Male Wistar rats were exposed either to exogenous (100 ng i.p.) or endogenous (+4 degrees C) TRH stimulation. ETU (100-500 mg/kg i.p.) caused no changes in serum TSH levels whereas zineb (70-500 mg/kg i.p.) significantly decreased the bursts induced by cold or exogenous TRH. Maneb (20-200 mg/kg i.p.) significantly decreased the cold-induced TSH response while it had no effect on the TRH-stimulated TSH secretion. None of the agents caused significant changes in serum T3 or T4 levels. It seems that maneb, and zineb, but not ETU, inhibit rat TSH secretion through an action on the endogenous TRH at the hypothalamic or pituitary level. The mechanism behind this action may be the inhibition of dopamine-beta-hydroxylase.

Complex Role of 5-HT in the Regulation of TSH Secretion in the Male Rat

The role of 5-hydroxytryptamine (5-HT) in the regulations of TSH secretion was studied in male rats using both peripheral and central administration of the drugs. Basal TSH levels were not modified by moderate doses of 5-HT (subcutaneously) or its precursors or antagonists (intraperitoneally) given 1 h before decapitation. The cold-stimulated TSH secretion was decreased by L-tryptophan (L-TRP, 400 mg/kg i.p.), quipazine (10 mg/kg i.p.) and 5-HT (1 or 5 mg/kg s.c. or i.v.) as well as by p-chlorophenylalanine (pCPA, 20 or more mg/kg i.p.) when the drugs were given 1 h before sampling. pCPA (100-400 mg/kg i.p.) was active 24-48 h after the injection but repetitive administration did not affect TSH levels. 5-HT (5 mg/kg s.c.) was effective also in pinealectomized animals. L-TRP and 5-hydroxytryptophan potentiated the TRH-stimulated TSH secretion when given 1 h before killing. 5-HT (10 microgram/rat) infused into the third ventricle enhanced the cold-stimulated TSH secretion when given 30-45 min before sampling. When injected into the medial basal hypothalamus, 50-HT (1-10 microgram/rat) had no effect on basal or stimulated TSH levels. The results suggest: (1) 5-HT does not play any role in the regulation of basal TSH secretion; (2) in the cold-stimulated TSH secretion 5-HT has a stimulatory action evidently inside the blood-brain barrier and also an inhibitory effect obviously outside this barrier.

Penetration of Metronidazole and Tinidazole into the Aqueous Humor in Man

500 mg of metronidazole or tinidazole were given as a 20-min infusion each to 10 patients who were hospitalized for elective cataract extraction. Metronidazole and tinidazole concentrations in aqueous humor were 5.2 +/- (SE) 0.5 and 5.3 +/- 0.7 micrograms/ml, respectively, 20-70 min after the end of the infusion. Aqueous humor/serum concentration ratios were 0.38 and 0.47 on the average for metronidazole and tinidazole, respectively.

Pharmacokinetics of sustained-release verapamil after a single administration and at steady state

SummaryPharmacokinetics of conventional 80 mg tablets and two types of sustained-release (SR) tablets containing 120 and 200 mg of verapamil were compared cross-over in 12 healthy volunteers. Serum concentrations of verapamil and norverapamil were analyzed both after a single oral dose and at steady state after t.i.d. administration of conventional tablets and b.i.d. administration of SR tablets. After 120 mg SR tablets serum concentrations of verapamil usually remained below 100 ng/ml for 5 days. This inadequate bioavailability was caused by very slow absorption. The relative bioavailability of verapamil in 200 mg SR tablets was 93–96% as compared to the conventional tablets. After 200 mg × 2 and 80 mg × 3 , the peak serum levels were about 300 and 190 ng/ml, respectively and the trough levels 123–153 and 52–56 ng/ml, respectively. The verapamil/norverapamil ratio varied from 0.69 to 0.84 after a single dose and from 0.8 to 0.93 at steady-state. By the 4th days of treatment, the accumulation ratios ranged between 1.75–2.07 and 1.30–1.75 for verapamil and norverapamil, respectively. For each preparation studied, the apparent Cl101 of verapamil was significantly reduced at steady-state. These results show that 200 mg SR verapamil tablets fulfill the basic requirements of retard preparations allowing for twice or even once daily administration.

Prophylaxis and Treatment of Anaerobic Infections following Caesarean Section with Tinidazole

The purpose of this prospective, double-blind, placebo-controlled study was to clarify the effect of a single intravenous infusion of 500 mg of tinidazole on infections that followed a caesarean section. 80 consecutive caesarean-section patients and thereafter 72 women undergoing non-elective caesarean section were randomly assigned to two groups, each receiving intravenous infusions at cord clamping. In the entire sample the incidence of endometritis/wound infection in the placebo group was 27.3% (21/77) versus 10.7% (8/75) in the tinidazole group (p less than 0.01). In the non-elective caesarean-section group the incidence of endometritis/wound infection was 39.6% (21/53) in the placebo group versus 14.3% (7/49) in the tinidazole group (p less than 0.01). 27 positive bacterial cultures yielded a pure anaerobic growth in 59% (16/27) of cases, of which 87.5% (14/16) were treated successfully with oral tinidazole.

Studies on the Role of the Pineal Gland in the Regulation of TSH Secretion in Postpuberal Male Rats

The role of the pineal gland in the regulation of thyroid-stimulating hormone (TSH) secretion was studied in postpuberal male rats using 12:12 h light:dark cycles. Pinealectomy, performed 3--4 days before decapitation, had no effect on the basal or thyrotropin-releasing hormone stimulated TSH secretion, but significantly decreased the cold-induced TSH response both at noon and at midnight. Neither hypothalamic thyrotropin-releasing hormone concentrations nor serum thyroid hormone levels were affected by pinealectomy. Melatonin injected intravenously (1 and 10 mg/kg) or intracerebroventricularly (5 and 50 microgram/rat) had no effect on the basal or cold-stimulated TSH levels, neither was the thyrotropin-releasing hormone induced (50 and 125 ng/rat i.p.) TSH response modified by melatonin (1 mg/kg i.v.). Arginine vasotocin (1 and 100 ng/rat) given intracerebroventricularly had no effect on the basal or cold-stimulated TSH secretion. These results suggest that the pineal has no influence on the basal activity of the hypothalamus-pituitary-thyroid system, but it seems that the cold-induced TSH response depends to a considerable degree on the intact pineal gland.

Trimethoprim and sulfadiazine penetration into bile and gallbladder in acute cholecystitis

The concentrations of trimethoprim (TMP) and sulfadiazine (SDZ) in serum, bile and gallbladder wall of 9 patients with acute cholecystitis were measured after b.i.d. treatment with 160 mg of TMP + 500 mg of SDZ. The samples were collected 2-4 h after the last dose. Mean TMP concentrations were 1.71 +/- (SE) 0.51 micrograms/ml, 4.53 +/- 5.26 micrograms/ml and 2.31 +/- micrograms/g in serum, bile and gallbladder, respectively. Mean SDZ concentrations were 22.2 +/- 14.9 micrograms/ml in serum, 9.37 +/- 8.99 micrograms/ml in bile and 16.1 +/- 10.1 micrograms/g in gallbladder. The average ratios of bile-serum and gallbladder-serum concentrations were 2.64 and 1.35 for TMP and 0.42 and 0.73 for SDZ. There was a significant correlation between serum and gallbladder concentrations of both TMP and SDZ. No correlation existed between serum and bile levels.

Effects of Some Putative Amino Acid Neurotransmitters on the Stimulated TSH Secretion in Male Rats

The importance of several amino acids (glycine, L-glutamic acid, L-serine, taurine and beta-alanine) in the regulation of the stimulated secretion of TSH was studied in male rats using both peripheral and central administration of the amino acids. Glycine (10-200 mg/kg i.p.), L-glutamic acid (10-500 mg/kg i.p.) and L-serine (500 mg/kg i.p.) decreased significantly the cold-induced TSH secretion whereas beta-alanine (1-500 mg/kg i.p.) and taurine (10-100 mg/kg i.p.) were not effective. The effect of L-glutamic acid (100 mg i.p.) was partially antagonized by bicuculline (1 mg/kg i.p.) but not by picrotoxin (1 or 2 mg/kg i.p.). Only glycine (50 and 100 mg/kg i.p.) inhibited the TRH-stimulated TSH secretion. When the intracerebroventricular route was used, L-serine (50 micrograms/rat) decreased the TSH could response whereas glycine and L-glutamic acid (1-50 micrograms/rat) had no clear effect. We conclude that glycine, glutamate and serine inhibit the cold-induced TSH secretion in the male rat. The action of serine and glycine is possibly mediated through the periventricular hypothalamus and the anterior pituitary, respectively. The inhibition caused by glutamate seems to be partially mediated through the bicuculline-sensitive GABA receptors in the hypothalamus. Taurine and beta-alanine play no role in the control of rat TSH secretion.