Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10IUml ^-1), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10–20 IUml ^-1) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors'practice is now to start GH replacement at less than the usual recommended dose of 14IUm-² week^-1 in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilledema does not exclude the diagnosis.     

The glycosaminoglycans of the gubernaculum during testicular descent in the fetus

Tissues were obtained from 387 male pig fetuses ranging from 60 to 120 days of gestation. The relative wet mass and water content of the gubernaculum increased during and decreased after the period of testicular descent. The extracellular glycosaminoglycans (GAG) were assayed to determine whether these polyanionic macromolecules are responsible for the increased water content of the gubernaculum. The total GAG/wet tissue mass in the gubernaculum decreased during and increased after descent, while the total GAG/dry mass decreased during and after descent, indicating an accumulation of water during descent, with a loss of water and an increase in less hydrated tissue components after descent. The major GAG fraction in the gubernaculum was dermatan sulfate, but the percentage hyaluronate in the gubernaculum was two times higher than in striated muscle or umbilical cord, indicating that this GAG fraction may be responsible for the increased water content of the gubernaculum, which probably serves to dilate the inguinal canal and scrotum, thus facilitating descent.     

Blood pressure and excretion of sodium, potassium, calcium and magnesium in 8- and 9-year old boys from 19 European centres

We have measured systolic and diastolic blood pressure and excretions of sodium, potassium, calcium and magnesium in groups of about 50 8- and 9-year-old boys from 19 European centres using standardized methods for the measurement of blood pressure and collection of urine, and by carrying out all analyses in one laboratory. Weight, height, pulse rate and environmental temperature were also studied. Mean systolic blood pressure ranged from 91 to 105 mm Hg and diastolic blood pressure from 51 to 66 mm Hg. Mean 24-h excretion of sodium was between 91 and 146 mmol/d, that of potassium between 29 and 60 mmol/d, that of calcium between 1.5 and 2.6 mmol/d and that of magnesium between 2.7 and 4.2 mmol/d. Mean sodium excretion tended to be lower and potassium excretion tended to be higher in the boys from the north-western parts of Europe. Relations between either systolic or diastolic blood pressure and electrolyte excretions were generally weak or absent. Most remarkable is that only the association between mean diastolic blood pressure and 24-h magnesium excretion (partial regression coefficient (b +/- s.e., -5.04 +/- 2.08 mm Hg/mmol/d) was statistically significant after adjusting for differences in creatinine excretion and environmental temperature. Mean systolic blood pressure was not significantly related with any of the variables measured. The partial regression coefficient (b +/- s.e.) for diastolic blood pressure on weight was 0.186 +/- 0.062 mm Hg/kg, on height 0.165 +/- 0.056 mm Hg/cm, on pulse rate 0.364 +/- 0.100 mm Hg/beats per min and on outside temperature -0.25 +/- 0.07 mm Hg/degrees C.     

Marine biodiversity as a source of chemical diversity

Total global biodiversity is estimated at between 3 and 500 × 10⁶ species of prokaryote and eukaryote organisms spread across 70 or more phyla. The marine macrofauna alone are estimated between 0.5 and 30 × 10⁶ species and represents a broader range of taxonomic diversity than that found in the terrestrial environment, which has been the traditional source of natural products. With a typical eukaryote possessing 50,000 genes, the global marine macrofauna are the source of 2.5 × 10¹⁰ to 1.5 × 10¹² primary products and an associated extensive range of secondary products. However, only a few thousand novel compounds from marine organisms have been described. These compounds have proven unique in chemical and pharmacological terms but, as yet, no therapeutic agents have resulted. Given a broader drug discovery strategy, and facilitated by technological advances, it is predicted that the characterisation of marine chemical diversity will be accelerated. Strategies for drug discovery from the virtually untapped chemical diversity of marine organisms are discussed. © 1994 Wiley-Less, Inc.     

Low doses of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH DPAT) increase ethanol intake

Previous work has reported that the 5-hydroxytryptamine (5-HT)_1A agonist, 8-hydroxy 2-(di-n-propylamino)tetralin (8-OH DPAT), reduces ethanol intake by rats. However, as 8-OH DPAT reduces 5-HT neurotransmission, these findings are inconsistent with the proposed inhibitory role of central 5-HT neurons on ethanol intake. We examined the effect of 8-OH DPAT on ethanol, water and food intake in rats maintained on a limited access schedule using a lower dose range (6–250 µg/kg) and by assessing concomitant changes in behaviour. Low doses of 8-OH DPAT enhanced ethanol intake even when food and water were offered as alternatives. Suppression in ethanol intake was observed at higher doses where elements of the 5-HT syndrome were apparent. Similar observations were made in both fluid and non-fluid deprived water drinking rats, suggesting the latter effect is non-selective. Therefore 8-OH DPAT may both increase or decrease ethanol consumption in the rat depending on the dose used.     

TMB-8 (8-(N,N-diethylamino) octyl-3,4,5-trimethoxybenzoate) inhibits the ATP-sensitive K+ channel.

Whole-cell current clamp, single-channel recordings and 86Rb+ flux techniques have been used to show that 8-(N,N-diethyl-amino)octyl-3,4,5-trimethoxybenzoate (TMB-8) inhibits ATP-sensitive K+ channels in HIT-T15 beta-cells. TMB-8 inhibition is observed when KATP channels are activated by ATP depletion or by the K+ channel opener, diazoxide.     

Non-linear pharmacokinetics of high-dose intravenous verapamil

Aims In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic monitoring. We report the pharmacokinetics of escalating doses of verapamil. Methods We studied nine patients [ seven males, two females; median age 46 years (range, 31–57)] with advanced adenocarcinoma of the colon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg⁻¹ followed by 12 h continuous i.v. infusion at 0.20 mg kg⁻¹ h⁻¹ ), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg⁻¹ h⁻¹ ). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n=4) or 60 to 108 h (n=5). Blood samples and urine collections were taken every 12 h. Verapamil and nor-verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL=ko/C_ss ) and renal clearance (CLr) of verapamil and nor-verapamil. The C_ssvs rate relationship was fitted to a Michaelis-Menten equation: C_ss=ko(K_m+C_ss )/(V V_m ). Results CL was dose-dependent and in all nine patients a significant reduction in CL was observed over the dose range (mean CL±s.d. were 0.51±0.31, 0.38±0.16, 0.32±0.18, and 0.27±0.11 l h⁻¹ kg⁻¹, respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg⁻¹ h⁻¹; P=0.0001). C_ss increased more than proportionally to the dose rate and the C_ssvs rate relationship was best defined by a Michaelis-Menten equation (K_m=730 μg l⁻¹; V V_m=0.55 mg kg⁻¹ h⁻¹ ), (r=0.994; P=0.006). CLr of verapamil and nor-verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose. Conclusions These findings suggest a non-linear, capacity-limited metabolic clearance of high-dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500–2500 ng ml⁻¹ ) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses.     

Stimulation of phagocytic function in mouse macrophages by neurotensin and neuromedin N

The neuropeptides neurotensin and neuromedin N (from 10⁻¹² M to 10⁻⁹ M) have been showed in this study to stimulate significantly in vitro several steps of the phagocytic process: adherence to substrate, chemotaxis, ingestion of inert particles (latex beads) and production of superoxide anion measured by nitroblue tetrazolium reduction in resting peritoneal macrophages from BALB/c mice. A dose-response relationship was observed, with a maximal stimulation of the phagocytic process at 10⁻¹¹ M. The two neuropeptides induced no change of intracellular cyclic AMP in murine macrophages. Moreover, adherence and chemotaxis decreased significantly in the presence of EGTA (1 mM), a chelator of extracellular Ca²⁺, or ryanodine (0.5 mM), a blocker of a Ca²⁺-gated channel from the endoplasmic reticulum, in both controls and samples with the addition of neurotensin or neuromedin N. These results suggest that there is no relation between the cAMP messenger system and the phagocytic process stimulation in murine peritoneal macrophages by neurotensin or neuromedin N. In addition, the results observed with EGTA and ryanodine could indicate that these two neuropeptides produce their effects through an increase of intracellular Ca²⁺ concentration.     

R 75251, a new inhibitor of steroid biosynthesis

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11-deoxycorticosterone to corticosterone in human placenta microsomes, subcellular fraction of rat testis, bovine adrenocortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side-chain cleavage was found at concentrations up to 10 microM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed. In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17 alpha-hydroxyprogesterone and progesterone. As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco- and mineralocorticoids such as 11-deoxycortisol and 11-deoxycorticosterone accumulated more than after ketoconazole administration. The data show that the cytochrome P450-dependent aromatase, 17-hydroxylase/17,20-lyase, and 11-hydroxylase are the target enzymes for R 75251.