Anti-inflammatory activity of phosphodiesterase (PDE)-IV inhibitors in acute and chronic models of inflammation

Inhibitors of cyclic nucleotide phosphodiesterases are known to suppress lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-α) production in vitro in human monocytes. The most potent of these have selectivity for type IV PDEs, suggesting that this class of PDE is the major type involved in the regulation of human TNF-α production. Using compounds of two distinct chemical structural classes, a quinazolinedione (CP-77 059) and a 4 arylpyrrolidinone (rolipram). we show here that PDE-IV-specific inhibitors are also potent in suppressing LPS-induced TNF-α production in vitro in sodium periodate-elicited murine macrophages (IC₅₀s of 1 and 33, respectively). We then report the in vivo anti-inflammatory effect of PDE-IV inhibition in five murine models of inflammation: (i) elevation of serum TNF-α induced by a subtethal LPS injection; (ii) LPS-induced endotoxic shock; (iii) LPS/galactosamine-induced endotoxic shock; (iv) carrageenan-induced paw oedema; and (v) adjuvant arthritis. Following a sublethal (5 μg/mouse) injection of LPS, serum TNF-α levels in mice peaked sharply, reaching concentrations of 3–12 ng/ ml 90 min after injection. In this sublethal LPS assay, CP-77 059 was about 30 times more potent than rolipram, with a minimum effective dose of 0.1 mg/kg versus 3 mg/kg for rolipram. This rank order is in keeping with the relative in vitro IC₅₀S for CP-77059 and rolipram, as well as their relative Ki against the human PDE-IV enzyme (46 nM and 220 nM, respectively). In LPS-induced endotoxic shock, rolipram and CP-77 059 at relatively high doses of 30 and 10 mg/kg, respectively, significantly reduced serum TNF-α levels, and also inhibited mortality 66%. In the LPS/galactosamine shock model, in which mice are rendered exquisitely sensitive to LPS by co-injection with galactosamine, only 0.1 μg of LPS/mouse Is necessary for serum TNF-α elevation and death. Both rolipram and the CP-77059 caused dose-dependent reduction of serum TNF-α and lethality. In the carrageenan-induced paw oedema model, in which there is a pronounced local TNF-α response (without a serum TNF-α elevation), rolipram significantly inhibited paw swelling as well as localized TNF-α levels in the paw. In the adjuvant arthritis model, a chronic model of inflammation also possessing localized TNF-α elevation in the inflamed paw, rolipram and CP-77059 suppressed ankle swelling and radiological evidence of joint damage. These data are consistent with a major role for PDE-IV in regulation of TNF-α production and inflammatory responses in murine systems. It suggests a potential therapeutic use for PDE-IV-specific inhibitors in inflammatory disease such as rheumatoid arthritis, septic shock and other inflammatory diseases where TNF-α has been postulated to be a contributing factor in the pathology of the disease.     

Antisperm Antibodies Detected by ZER Enzyme-Linked Immunosorbent Assay Kit Are Not Those Detected by Tray Agglutination Test

ABSTRACT: Antisperm antibodies may play a role in the pathogenesis of infertility, particularly in the male. One of the standardized methods for detecting antisperm antibodies is the tray agglutination test (TAT). Unfortunately, this assay requires fresh motile spermatozoa. Tests for binding of antibody to fixed sperm or sperm extracts have been developed as enzyme-linked immunosorbent assays (ELISA), and we compared the results of using one such ELISA method with the TAT to detect antisperm antibodies in a panel of known positive and negative sera from infertile and control patients. With respect to the TAT assay, the ELISA gave a 75% false-positive test rate and a 63% false-negative rate. It is important to validate new assays such as the ELISA before widespread application to patient screening particularly since patients judged to have antisperm antibodies may be treated with high-dose corticosteroid drugs that are not without significant side effects.     

Evaluating the effectiveness of the coronary care nurses' role in smoking cessation

Summary

• ? The aim of this small-scale study was to assess the feasibility and impact of an individualized smoking cessation intervention among clients admitted to a coronary care unit with severe angina or a first time myocardial infarction.
• ? The intervention involved in-depth nursing assessment interviews related to client beliefs, motivation and experiences of smoking, culminating in an individualized cessation plan. Participants were offered follow up support during the first year post-intervention.
• ? The findings are highly encouraging with a 77% smoking cessation rate for surviving clients within the intervention group at the end of the first year, and with 75% continued successful smoking cessation amongst surviving clients 2 years post-intervention.

     

A Novel Tertiary Pyridostigmine Derivative [3-N,N-Dimethylcarbamyloxy)-1-Methyl-{Delta}3-Tetrahydropyridine]: Anticholinesterase Properties and Efficacy against Soman

In an effort to develop an effective centrally acting pretreatmentcompound against organophosphorus poisons, the tertiary pyridostigmine(Pyr) derivative 3-(N,N-dimethyI-carbamyloxy)-l-methyl-³-tetrahydropyridine(THP) was synthesized and studied for its anticholinesteraseproperties, as well as its efficacy against soman intoxicationin guinea pigs. Injection of THP (262 µg/kg, im) intoadult male guinea pigs caused inhibition of Wood (30%) and brain(25%) acetylcholinesterase (AChE), showing that THP penetratesthe blood-brain barrier. Pyr (131 µg/kg, im) caused AChEinhibition in the Hood (59%), but not in the brain. The inhibitorypotencies of THP and Pyr were compared by determining theirIC50 values for in vitroinhibition of both AChE (brain, erythrocyte)and pseudo-cholinesterase (plasma) in three mammalian species(guinea pig, rat, rabbit). THP, although effective in inhibitingboth types of cholinesterase, was in general less potent thanPyr. Pretreatment of guinea pigs with THP (262 µg/kg,im) plus Pyr (131 µg/kg, im). 30 min prior to subcutaneoussoman challenge, with no antimuscarink or oxime treatment, protected60% of the animals against 2 ? LD50 of soman. Neither THP norPyr alone was effective. The protective pretreatment regimendid not prevent convulsions, but shortened the recovery timein surviving animals (median recovery time 1.6 hr, comparedto 24 hr in control and other groups of animals pretreated withTHP or Pyr alone). A combination of THP and Pyr thus appearsto provide a means of evaluating the relative importance ofselective peripheral plus central vs peripheral AChE protectionagainst soman.     

FINDING MEANING IN A CHILD'S VIOLENT DEATH: A FIVE-YEAR PROSPECTIVE ANALYSIS OF PARENTS' PERSONAL NARRATIVES AND EMPIRICAL DATA

Finding meaning in the death of a loved one is thought to be extremely traumatic when the circumstances surrounding the death is perceived to be due to negligence, is intentional, and when the deceased suffered extreme pain and bodily harm immediately prior to death. We addressed this assumption by obtaining personal narratives and empirical data from 138 parents 4, 12, 24, and 60 months after an adolescent's or young adult child's death by accident, suicide, or homicide. Using the Janoff-Bulman and Frantz's(1997) framework ofmeaning-as-comprehensibility and meaning-as-significance, the purposes were to identify the time course to find meaning, present parents' personal narratives describing finding meaning in their experiences, identify predictors of finding meaning, and compare parents who found meaning versus those who did not on five health and adjustment outcomes. The results showed that by 12 months postdeath, only 12% of the study sample had found meaning in a child's death. By 60 months postdeath, 57% of the parents had found meaning but 43% had not. Significant predictors of finding meaning 5 years postdeath were the use of religious coping and support group attendance. Parents who attended abereavement support group were 4 times more likely to find meaning than parents who did not attend. Parents who found meaning in the deaths of their children reported significantly lower scores on mental distress, higher marital satisfaction, and better physical health than parents who were unable to find meaning. Recommendations for future research are made.     

THYROTROPHIN RESPONSE TO THYROTROPHIN-RELEASING HORMONE IN OPHTHALMIC GRAVES'' DISEASE: CORRELATION WITH OTHER ASPECTS OF THYROID FUNCTION, THYROID SUPPRESSIBILITY AND ACTIVITY OF EYE SIGNS

Thirty-four patients with ophthalmic Graves' disease were investigated by routine thyroid function tests, by measurement of the serum thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) and by measurement of the serum triiodothyronine (T₃) levels. The patients could be divided into four groups according to their response to TRH—normal, impaired, absent and exaggerated. Those with normal responses had routine thyroid function tests and serum T₃ levels which in general did not differ from normal control values. Those with impaired and with absent responses showed routine thyroid function tests which approached the hyperthyroid range together with significant elevation of serum T₃ levels. It is suggested that they might represent examples of ‘subclinical T₃ thyrotoxicosis’. Patients with exaggerated responses had routine thyroid function tests near the lower end of the normal range and could be regarded as suffering from ‘subclinical hypothyroidism’. There was a good correlation between a normal TRH response and normal thyroid suppressibility by T₃, and between impaired and absent responses and impaired thyroid suppressibility. It is evident that the TRH test which is safer, shorter and more convenient, can replace the T₃ suppression test in routine clinical practice. The response to TRH also provided information on the activity of the eye signs, a normal response was associated with improving eye signs whereas impaired, absent or exaggerated responses were associated with static signs or actual deterioration. The TRH test is of value in the diagnosis of unilateral exophthalmos since about three-quarters of the patients in this series showed some abnormality. The wide range of TRH response and of circulating thyroid hormone levels is to be expected since the thyroid is not subject to the normal finely-balanced negative feed-back mechanism via TSH.     

HYPERPROLACTINAEMIA AFTER EXTERNAL IRRADIATION FOR ACROMEGALY

The progress of twelve patients who received external irradiation of the pituitary as sole treatment for acromegaly was reviewed. In all cases a fall in serum GH was achieved and no patient developed hypopituitarism. Three had mild hyperprolactinaemia before therapy. In all twelve cases, PRL levels rose after treatment, in five entering the hyperprolactinaemic range. It is suggested that the most likely cause is interference with the supply of prolactin release inhibiting factor (PIF) by the effects of irradiation on the hypothalamus.     

Severe hypophosphataemia during stem cell harvesting in chronic myeloid leukaemia

Summary. Peripheral blood stem cell autografts for the treatment of chronic myeloid leukaemia (CML) are currently under evaluation. A patient with CML received intensive chemotherapy followed by granulocyte colony-stimulating factor prior to the collection of peripheral blood derived stem cells. He developed unusually severe, and fatal, hypophosphataemia and this coincided with the rapid rise of his peripheral blood white cell count. The hypophosphataemia was considered to be due to a combination of severe anorexia, sepsis and the rapid growth factor-stimulated myeloid regeneration in CML.     

Pharmacokinetics of recombinant factor VIII (Kogenate-FS®) in children and causes of inter-patient pharmacokinetic variability

Summary.  Understanding the pharmacokinetics (PK) of factor VIII (FVIII) is important in the management of patients with haemophilia A. We studied the PK of FVIII in order to determine aetiological factors contributing to PK variability of FVIII in children.
Twenty children with haemophilia A (mean age 12.8 years) were administered a single bolus of 50 U kg⁻¹ of recombinant FVIII (rFVIII; Kogenate-FS^®, Bayer).
The mean incremental FVIII recovery was 1.87 (U mL⁻¹)/(U kg⁻¹) (range: 1.25–2.76) and the mean FVIII half-life was 10.7 h (range: 7.8–15.3). FVIII recovery was positively correlated with body surface area (BSA; P  = 0.04). FVIII half-life was positively correlated with preinfusion levels of von Willebrand factor antigen (VWF:Ag) ( P  = 0.0001) and was reduced in patients ( n  = 6) with very low FVIII inhibitor titres (<0.5 BU) vs. those ( n  = 14) with negative inhibitor titres ( P  = 0.06).
These observations suggest that (i) young children with haemophilia in comparison with adults have a low recovery of FVIII and that this might be explained by differences in body composition (BSA, plasma volume), (ii) levels of VWF:Ag may explain some of the differences in the half-life and clearance of FVIII and (iii) very low inhibitor titres, previously regarded as clinically insignificant, may actually be significant and should be evaluated in the context of PK studies.