Therapeutic efficacy of anti-dandruff shampoos: a randomized clinical trial comparing products based on potentiated zinc pyrithione and zinc pyrithione/climbazole.

OBJECTIVES: Dandruff is a chronic, relapsing scalp condition that negatively impacts the quality of life of sufferers. Regular use of anti-fungal shampoos represents a proven therapeutic strategy to improve the most common symptoms of flakes and itch. Two recent approaches for enhancing the efficacy of anti-fungal shampoos are maximizing bio-availability of the active material or the addition of a second active material. Our aim is to compare the therapeutic efficacy of these two approaches - maximization of bio-availability of the zinc pyrithione (ZPT) active material or the combination of ZPT with a secondary active material. METHODS: The anti-fungal potency of shampoos representing each of these approaches was evaluated in vitro using a standard microbiology method. Spatial delivery of ZPT particles in the follicular infundibulum was assessed in vivo using a novel confocal microscopy methodology. Clinical efficacy was assessed in a randomized, double-blind trial involving 620 male and female subjects using scalp flaking and epidermal histamine level as endpoints. RESULTS: The shampoo formula with maximized ZPT bio-availability known as the Potentiated ZPT formula exhibited greater anti-fungal potency than the Dual Active shampoo containing both ZPT and climbazole. The Potentiated ZPT formula also delivered more ZPT to the lower infundibulum than the Dual Active shampoo. A 4-week treatment with the Potentiated ZPT formula resulted in superior clinical efficacy compared with the Dual Active product at all 4 weekly time points for both flaking and epidermal histamine endpoints. CONCLUSION: These results highlight the critical role that the shampoo vehicle plays in realizing full potency of active materials. By optimizing the delivery vehicle, the enhanced anti-fungal potency and the maximized spatial delivery of active materials result in greater symptomatic improvement than a product with two active materials. The therapeutic efficacy of a product based on a complex delivery vehicle such as a shampoo must be considered from a full-product perspective rather than just the active system as the non-active components of the composition will often play a significant role in the overall product pharmacology and resultant efficacy.

Rehabilitation of chronic low back pain using continuous epidural analgesia.

PURPOSE: Physical rehabilitation is one of the major forms of treatment of chronic low back pain. The ability of some patients to cooperate is limited by pain. Since 1992 continuous epidural analgesia has been combined with a physical rehabilitation programme for patients with chronic low back pain who have been unable to make progress with conventional physical rehabilitation due to severity of pain. METHOD: This study reports a series of 46 consecutive patients with chronic back pain admitted over a 6 month period to a 5-day inpatient rehabilitation programme. A lumbar epidural catheter was inserted and bupivacaine 0.125% was infused at a rate that produced analgesia without sensory or motor deficit over a period of 5 days. An intensive mobilizing physiotherapy programme was instituted. Physical and psychological parameters were measured on day 1, after 1 week, after 1 month and after 1 year. RESULTS: Time to complete a 50 m walk, time from sitting to standing, and spinal flexion were improved at 1 week and 1 month, but only time to complete the walk remained improved at 1 year. In Goldberg's General Health Questionnaire 28 scores were improved for social dysfunction, somatic symptoms, anxiety and insomnia, and depression, at 1 week and 1 month but only social dysfunction remained improved at 1 year. Using a Visual Analogue Scale pain ratings were unaltered after 1 year. CONCLUSION: Continuous 5 day epidural analgesia combined with intensive physiotherapy may offer a means of initial rehabilitation of chronic low back pain. The initial benefit was most marked at 1 week, with benefit still evident after 1 month. However, the benefit decreased with time. This technique may be of value as part of a more comprehensive programme of physical and psychological rehabilitation.

Dictyostelium discoideum mutants with temperature-sensitive defects in endocytosis.

We have isolated and characterized temperature-sensitive endocytosis mutants in Dictyostelium discoideum. Dictyostelium is an attractive model for genetic studies of endocytosis because of its high rates of endocytosis, its reliance on endocytosis for nutrient uptake, and tractable molecular genetics. Endocytosis-defective mutants were isolated by a fluorescence-activated cell sorting (FACS) as cells unable to take up a fluorescent marker. One temperature-sensitive mutant (indy1) was characterized in detail and found to exhibit a complete block in fluid phase endocytosis at the restrictive temperature, but normal rates of endocytosis at the permissive temperature. Likewise, a potential cell surface receptor that was rapidly internalized in wild-type cells and indy1 cells at the permissive temperature was poorly internalized in indy1 under restrictive conditions. Growth was also completely arrested at the restrictive temperature. The endocytosis block was rapidly induced upon shift to the restrictive temperature and reversed upon return to normal conditions. Inhibition of endocytosis was also specific, as other membrane-trafficking events such as phagocytosis, secretion of lysosomal enzymes, and contractile vacuole function were unaffected at the restrictive temperature. Because recycling and transport to late endocytic compartments were not affected, the site of the defect's action is probably at an early step in the endocytic pathway. Additionally, indy1 cells were unable to proceed through the normal development program at the restrictive temperature. Given the tight functional and growth phenotypes, the indy1 mutant provides an opportunity to isolate genes responsible for endocytosis in Dictyostelium by complementation cloning.

The GTP-binding protein Ypt1 is required for transport in vitro: the Golgi apparatus is defective in ypt1 mutants.

The YPT1 gene encodes a raslike, GTP-binding protein that is essential for growth of yeast cells. We show here that mutations in the ypt1 gene disrupt transport of carboxypeptidase Y to the vacuole in vivo and transport of pro-alpha-factor to a site of extensive glycosylation in the Golgi apparatus in vitro. Two different ypt1 mutations result in loss of function of the Golgi complex without affecting the activity of the endoplasmic reticulum or soluble components required for in vitro transport. The function of the mutant Golgi apparatus can be restored by preincubation with wild-type cytosol. The transport defect observed in vitro cannot be overcome by addition of Ca++ to the reaction mixture. We have also established genetic interactions between ypt1 and a subset of the other genes required for transport to and through the Golgi apparatus.

Nicotinamide as a rapid-acting inhibitor of renal brush-border phosphate transport.

Administration of nicotinamide to rats produces specific dose-dependent inhibition of Na+-dependent phosphate transport across the renal brush-border membrane (BBM) and an increase in urinary excretion of phosphate. The intracellular mechanism of action of nicotinamide is not well established. As a step in this direction, the present studies determined whether nicotinamide was a rapid- or slow-acting regulator of the BBM phosphate transport system. Nicotinamide (0.5 g/kg) inhibited Na+-dependent BBM phosphate transport under conditions when de novo protein synthesis was inhibited by cycloheximide (1.0 mg/kg). Furthermore, the degree of inhibition was not different from that achieved by nicotinamide alone, suggesting that the action of nicotinamide does not require de novo protein synthesis. Studies on the time course of the onset of nicotinamide action revealed inhibition of BBM phosphate transport within 1 h after injection of nicotinamide, even in rats pretreated with cycloheximide. The rapid response to nicotinamide and its independence of de novo protein synthesis characterize nicotinamide as a rapid-acting regulator of the Na+-dependent phosphate transport system in renal BBM.

Nicotinamide and the regulation of renal phosphate transport.

The specific inhibitory action of nicotinamide on renal Pi transport does not require de novo protein synthesis and can be detected within 1 hr, at least in low Pi diet rats. These properties characterize nicotinamide as a rapidly acting regulator of the Pi transport system in the renal BBM (Kempson and Dousa, 1986). The studies with LLC-PK 1 cells strongly suggest that the action of nicotinamide in rats is due to a direct effect on the cells of the proximal tubule. Further studies on the mechanism of action of nicotinamide may lead to an understanding of the intracellular mechanisms that mediate the action of rapidly acting physiological regulators of BBM transport of Pi.

Cycloheximide blocks nicotinamide action on phosphate excretion in thyroparathyroidectomized rats.

Nicotinamide causes marked inhibition of phosphate (Pi) reabsorption in the renal proximal tubule and this can be detected both as a specific decrease in Na+-dependent Pi uptake by isolated brush border membrane (BBM) vesicles and as a marked increase in urinary Pi excretion. In the present study, thyroparathyroidectomized (TPTX) rats were adapted to low-Pi diet and injected with cycloheximide (CHX), an inhibitor of protein synthesis, prior to nicotinamide treatment. Compared to rats that received nicotinamide alone, the pretreatment with CHX did not alter the inhibitory action of nicotinamide on BBM uptake of Pi. However, CHX completely blocked the phosphaturic response. We conclude that, at least in TPTX rats adapted to low-Pi diet, nicotinamide inhibits Pi reabsorption not only in the proximal convoluted tubule but also in other nephron segments such as the pars recta or distal sites. Nicotinamide action on these additional sites is dependent on protein synthesis, in contrast to its action in the proximal convoluted tubule.

Colchicine blocks the action of parathyroid hormone but not nicotinamide on renal phosphate transport.

Nicotinamide, like parathyroid hormone, is a rapidly acting specific inhibitor of Na+-dependent transport of phosphate (Pi) across the brush-border membrane of the proximal tubule of the mammalian kidney. Pretreatment of rats with colchicine (0.7 mg/kg body weight) for 1 h led to a significantly diminished phosphaturic response to parathyroid hormone (synthetic 1-34 fragment, 4 micrograms/kg). In contrast, the same dose of colchicine had no effect on the renal response to nicotinamide (1.0 g/kg), measured both as the change in urinary Pi excretion and as Na+-dependent Pi uptake by isolated brush-border membrane vesicles. These data suggest indirectly that the intracellular mechanism that mediates the inhibitory effects of nicotinamide on renal Pi transport does not require intact microtubules.